Systems-Based Emergency Medicine Course Objectives: Hematologic Emergencies PA 605 ER

Primary Immune Thrombocytopenia - Pediatric RAPID REVIEW

2-6 years old Antiplatelet autoantibodies H/o recent viral infection Non-blanching petechiae/purpura, gingival bleeding Labs: platelets < 100,000/µL, normal WBC, normal hematocrit Tx: activity restriction, observation, glucocorticoids and IVIG or IV anti-D if severe

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Acute leukemia

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) & LYMPHOBLASTIC LYMPHOMA (LBL) •Malignancy arising from immature lymphoid stem cells in the bone marrow. •B cell (most common), T cell, or null type (non-B or non-T cell). •Most common childhood malignancy (25%) - peak 2-5 years of age, boys > girls, Down syndrome. •PATHOPHYSIOLOGY: overpopulation of immature nonfunctioning WBCs (blasts) overtake normal hematopoiesis (bone marrow infiltration), resulting in pancytopenia. CLINICAL MANIFESTATIONS •Nonspecific symptoms associated with pancytopenia. •Pancytopenia: fever & infections (leukopenia), bleeding from thrombocytopenia (eg, petechiae, purpura), & anemia (eg, pallor, fatigue). Bone pain or musculoskeletal pain. •CNS symptoms: headache, stiff neck, visual changes, vomiting. METS most common to CNS & testes. •Physical examination: hepatomegaly or splenomegaly most common clinical findings - may manifest as anorexia, weight loss, abdominal distention or abdominal pain. Lymphadenopathy. DIAGNOSIS •CBC + peripheral smear: WBC 5,000 - 100,000, anemia, thrombocytopenia. •Bone marrow aspiration: hypercellular with >20% blasts (definitive diagnosis). •Flow cytometry test: most accurate test to distinguish subtypes of Leukemia. MANAGEMENT •Highly responsive to combination chemotherapy (remission >85%). Induction chemotherapy includes Anthracyclines, Vincristine, and Corticosteroids. Maintenance therapy includes 6-MP and Methotrexate. Imatinib used if Philadelphia chromosome positive. Relapsing: stem cell transplant. •CNS disease or CNS preventative: intrathecal Methotrexate. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL)] •Indolent malignancy characterized by clonal proliferation of morphologically mature but immunologically & functionally incompetent B cells (considered the dame disease as Small cell lymphoma) [SLL]. CLL = primarily in the blood; SLL = primarily in the lymph nodes. •Most common form of Leukemia in adults. Risk factors: increasing age (mean age 70y), men. CLINICAL MANIFESTATIONS •Usually asymptomatic, often an incidental finding of lymphocytosis on routine CBC testing. •Pancytopenia: anemia symptoms (eg, fatigue most common, dyspnea), increased infections (neutropenia), mucocutaneous bleeding (thrombocytopenia). •May have typical "B" symptoms of lymphoma (10%). •Physical examination: lymphadenopathy most common physical exam finding (cervical, supraclavicular axillary or generalized). The lymph nodes are usually firm, round, nontender and freely mobile. Splenomegaly second most common finding (25-55%) and is usually painless and nontender to palpation. Hepatomegaly. Skin lesions (leukemia cutis). DIAGNOSIS •CBC/peripheral smear: initial diagnostic test. Lymphocytosis hallmark: increased WBC (>20,000/mcL) with > 80% lymphocytes, absolute lymphocytosis ≥5,000/mcL small. well-differentiated, normal & mature-appearing lymphocytes with a darkly stained nucleus, partially condensed (clumped) chromatin, and indiscernible nucleoli. Scattered "smudge cells" (lab artifact when the fragile B cells become crushed by the cover slip during slide preparation). Neutropenia, •Hypogammaglobulinemia: decreased IgG, IgA, and IgM in ~25% of patients at the time of initial diagnosis. Increased incidence of Autoimmune hemolytic anemia. May have evidence of ITP. •Flow cytometry: most accurate test - immunophenotypic analysis: clone of mature B cells with expression of B cell-associated antigens CD19, CD20, CD 23 (CD5 marks B cell maturity). •Bone marrow aspirate and biopsy not required for CLL. Excisional or core biopsy used for SLL. MANAGEMENT No management (observation): •Indications: indolent, asymptomatic, early stages (I and II). During this observation period, the clinical examination of the patient and blood counts should occur every 3 months. Radiation in some. Chemotherapy: •Indications: symptomatic, progressive, stages III and IV for symptomatic relief, cytopenia reversal, prolonged remission, & prolonged survival in patients. Despite treatment, CLL remains an incurable disease. •High risk: 17p deletion and/or TP53 mutation - high risk of either not responding to initial chemoimmunotherapy or relapsing soon after achieving remission. Initial treatment with targeted therapy (eg, Ibrutinib-based therapy or Venetoclax-based therapy) rather than chemoimmunotherapy, regardless of patient age. •IGHV unmutated (without 17p deletion or TP53 mutation) - targeted therapy (eg, Ibrutinib-based therapy, Acalbrutinib, Venetoclax plus Obinutuzumab) often preferred or chemoimmunotherapy. •IGHV mutated (without 17p deletion or TP53 mutation) - chemoimmunotherapy or targeted therapy is used. If chemoimmunotherapy is chosen, the preferred regimen depends on clinical fitness - FCR: Fludarabine, Cyclophosphamide, and Rituximab for 6 cycles (younger patients); BR: Bendamustine plus Rituximab for 6 cycles (older patients); Ibrutinib as a single agent (all ages) or in combination with Rituximab or Obinutuzumab (younger patients); Chlorambucil plus Obinutuzumab. Curative therapy: •Allogeneic stem cell transplant. Acute blast crisis; •treat similar to Acute myelogenous leukemia. Poorer prognosis: ZAP-70+, del(17p), del(11q), TP53 mutation.

This patient is presenting with a history of sickle cell disease and exertional dyspnea in the setting of severe anemia without a reticulocytosis, suggesting a diagnosis of an aplastic crisis. Sickle cell disease typically presents with recurrent episodes of pain (termed pain crises). In a patient who presents with a pain crisis, the best initial step in management is to administer oxygen, IV fluids, and analgesics in addition to a workup for an underlying infectious etiology and broad-spectrum antibiotics if the patient has a fever (as sickle cell patients are particularly susceptible to infection secondary to splenic infarction). If a patient with sickle cell disease presents with severe anemia with a decreased reticulocyte count (keep in mind that the reticulocyte count should be elevated in anemia), then the most likely diagnosis is an aplastic crisis, most commonly secondary to infection (e.g. parvovirus B19 infection). These patients should immediately be transfused with packed red blood cells, in particular, if they are experiencing signs of decreased end-organ perfusion such as demand ischemia or exertional dyspnea.

Administer hydromorphone (A) would certainly be an important initial step in management in addition to administering IV fluids in the setting of an acute pain crisis, however, in the setting of this patient's aplastic crisis and severe anemia, transfusing red blood cells would be a more dire initial step in management. It is particularly concerning that this young patient is experiencing exertional dyspnea, which is likely secondary to his anemia. Discharge the patient with addiction medicine follow-up (B) is inappropriate. It can seem like many patients with sickle cell disease are malingering or only interested in pain medications secondary to their desire for specific and potent medications for their pain, however, this is typically based on their insight that they know which medications best control their pain crises rather than simply trying to obtain drugs. Perform an exchange transfusion (C) would be indicated in a sickle cell patient who presented with visual disturbances (secondary to retinal infarction), shortness of breath or pleuritic chest pain (secondary to pulmonary infarction), priapism, or stroke. This patient's intermittent dyspnea that is exacerbated by exertion is likely secondary to his anemia. Patients with acute chest syndrome may present with shortness of breath, but also typically have hypoxia and a new pulmonary consolidation on chest radiograph.

Question: Which class of medications is the most common cause of drug-induced immune hemolytic anemia?

Answer: Cephalosporins.

Question: What blood product may be used to reverse warfarin?

Answer: Fresh frozen plasma.

Question: What is the most common risk factor for new-onset childhood immune thrombocytopenia?

Answer: Viral infection.

Aplastic crisis (ROSH)

Aplastic crisis is an important complication of sickle cell disease in which the body is unable to make enough reticulocytes to compensate for hemolysis. The most common cause of aplastic crisis is infection, and human parvovirus B19 is the most frequently implicated. Aplastic crisis is seen more often in children than adults. Patients typically present with increasing fatigue and signs of infection, including fever and tachycardia. Labs will generally show anemia that is below the patient's baseline. The reticulocyte count is minimal, usually less than 0.5%. Other cell lines should be at normal levels or increased in response to infection. Aplastic crisis is usually self-limited and resolves in about 7-10 days. Care is supportive, with transfusions given as needed. All patients with sickle cell disease presenting with a fever should receive empiric antibiotics, even if a viral cause is found, and be worked up for acute chest crisis and sepsis, as they are at increased risk.

Autoimmune hemolytic anemia (ROSH)

Autoimmune hemolytic anemia is when autoantibodies are directed against a patient's own red blood cell membrane antigens. The exact mechanism of autoantibody creation is unclear, but at this time, they are thought to be formed by molecular mimicry after exposure to a medication or viral infection. The autoantibody usually reacts to an antigen common to all human red blood cells, not to the A, B, or O antigens. Most children with autoimmune hemolytic anemia are under 12 years of age and have an acute transient disease that lasts for 3-6 months. Older children are more likely to have a chronic course lasting for months or years. Most patients simply present with fatigue and pallor, but jaundice, fever, and hemoglobinuria are possible. Laboratory tests show profound anemia, usually some leukocytosis, and normal platelet levels. Reticulocytes may be low early in the disease but are markedly elevated later in the disease. The direct antiglobulin test detects the presence of antibodies or complement adhered to the red blood cell surface and establishes the diagnosis of autoimmune hemolytic anemia. Patients are treated with glucocorticoids (e.g., prednisone). If the response to glucocorticoids is poor, intravenous immunoglobulin or rituximab may be recommended by a hematologist. Most of these patients recover without significant sequelae, but nearly one-third go on to develop chronic hemolytic anemia.

Chronic myelogenous leukemia (CML) (ROSH)

Chronic myelogenous leukemia (CML), the least common of the major leukemias, is a myeloproliferative neoplasm in which the white blood cell count is elevated (often greater than 50,000 - 100,000 cells/mm3) but the differential is fairly normal. It primarily presents in adults over 40 years of age and follows a triphasic course. Most patients present in the chronic phase with symptoms of fatigue, weight loss, diaphoresis, abdominal fullness and hepatosplenomegaly. Patients may also be asymptomatic and identified only by routine laboratory assessment. In the accelerated phase, patients may develop bleeding and petechiae. Leukocyte counts become difficult to control in this phase. The blast phase is characterized by greater than 20% blasts and resembles acute leukemias. Diagnosis is suspected based on clinical symptoms and white blood cell counts. The hallmark of CML is the presence of the Philadelphia chromosome, a reciprocal translocation of chromosomal material between chromosomes 9 and 22, found on bone marrow analysis. It is found in nearly all patients with CML and is present throughout the entire course of disease.

Disseminated intravascular coagulation (DIC) (ROSH)

Disseminated intravascular coagulation (DIC) is characterized by inappropriate and widespread activation of the coagulation system, resulting in intravascular thrombin generation, small vessel thrombosis, and consumption of clotting factors and platelets. Concomitant activation of fibrinolysis also occurs, resulting in fibrin breakdown and bleeding. Some conditions associated with DIC include infection, cancer, trauma, liver disease, pancreatitis, pregnancy, envenomation, acute lung injuries, and transfusion reactions. Clinical features vary with the underlying precipitating illness, but classically, oozing from catheter or venipuncture sites is described, with petechiae and ecchymoses also present. There may be ischemia from thrombus formation that would present with stroke-like features, limb ischemia, cutaneous gangrene, or thrombotic purpura. Thrombocytopenia, prolonged PT and elevated international normalized ratio (INR), low fibrinogen, elevated fibrin-related markers, and anemia from intravascular hemolysis are classic laboratory markers. Management focuses on treating the underlying cause.

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Hypercoagulable states

FACTOR V LEIDEN MUTATION (ACTIVATED PROTEIN C RESISTANCE •Most common inherited cause of hypercoagulability (thrombophilia). •5% of the US population of European descent is heterozygous for this mutation (autosomal dominant). PATHOPHYSIOLOGY •Mutated factor V is resistant to breakdown by activated protein C, leading to increased hypercoagulability & increased conversion of prothrombin to thrombin. CLINICAL MANIFESTATIONS •Increased incidence of DVT, PE, hepatic vein or cerebral vein thrombosis. •Pregnancy complications: frisk of miscarriage, preeclampsia, placental abruption, & stillbirth. •Not associated with increased risk of Myocardial infarctions or CVA. DIAGNOSIS •Activated protein C resistance assay. If positive, confirm with DNA testing. Normal PT and PTT. •DNA testing mutation analysis. Used in patients with a family history of Factor V Leiden mutation or for members of a thrombophilic family. MANAGEMENT •Asymptomatic heterozygous: not treated routinely with anticoagulation. •High-risk: indefinite anticoagulation (Warfarin or direct oral anticoagulant). May need thrombophylaxis with low molecular weight heparin during pregnancy to prevent miscarriages. •Moderate-risk: (eg, 1 thrombotic event with a prothrombotic stimulus or asymptomatic) prophylaxis during high-risk procedures. PROTEIN C or S DEFICIENCY PATHOPHYSIOLOGY •Proteins C & S are vitamin K-dependent anticoagulant proteins produced by the liver that stimulate fibrinolysis and inactivate factors V and VIII. •Decreased protein C or S levels lead to hypercoagulability. ETIOLOGIES •Inherited: both are autosomal-dominant inherited hypercoagulable disorders (C more common). •Acquired: end-stage liver disease, severe liver disease with synthetic dysfunction, early Warfarin administration (vitamin K antagonist). CLINICAL MANIFESTATIONS •Increased incidence of venous thromboembolism - DVT & PE. •Warfarin-induced skin necrosis (any patient presenting with this should be tested for deficiency). •Purpura fulminans in newborns - red purpuric lesions at pressure points, progresses to painful black eschars. DIAGNOSIS •Protein C and S functional assay, plasma protein C and S antigen levels. •Genetic testing not routinely performed MANAGEMENT •Thrombosis: protein C concentrate. Indefinite anticoagulation (Warfarin or direct oral anticoagulant). •Warfarin-induced necrosis: immediately discontinue Warfarin, administer IV Vitamin K, therapeutic Heparin, protein C concentrate or fresh frozen plasma.

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Lymphomas

HODGKIN LYMPHOMA •Germinal or pregerminal B-cell malignancy originating in the lymphatic system. •Bimodal distribution: peaks at 20 years (15-34y) & then again >50 years (55 years and older). •Risk factors: Epstein-Barr virus (EBV), immunosuppression, smoking, Caucasians. 4 main types: •Nodular sclerosing: most common type overall (64%). Female predominance. •Mixed cellularity 25%. Associated with Epstein-Barr virus. Prevalent in both children and elderly patients and commonly presents with advanced disease stage. •Lymphocyte rich/predominant: most common in males <35y. Best prognosis. •Lymphocyte depleted: (4%). Most common in males >60y. Usually associated with other systemic diseases. Worst prognosis. CLINICAL MANIFESTATIONS •Asymptomatic painless lymphadenopathy: most common presentation (70%). Usually painless but ETOH ingestion may induce lymph node pain within minutes. •Upper body lymph nodes: neck most common site (eg, cervical and/or supraclavicular), axilla, shoulder, mediastinum, & abdomen. Usually rubbery in consistency, not fixed (does not adhere to the skin), & may fluctuate in size. Spreads in an orderly fashion to contiguous areas of lymph nodes. •Mediastinal lymphadenopathy or mass: second most common presentation - incidental finding on chest imaging. The mass may be large without producing local symptoms. If symptomatic - retrosternal chest pain, cough, or dyspnea may be experienced. Large mediastinal adenopathy is an adverse prognostic factor. •Fatigue, pruritus, intra-abdominal disease hepatomegaly, splenomegaly. Cholestatic liver disease. Nephrotic syndrome, hypercalcemia. •Systemic "B" symptoms: fever (> 100.4°F), night sweats, weight loss (> 10% of body weight over 6 months). Pel-Ebstein fever - cyclical fever that recurs at variable intervals of several days or weeks and lasts for 1-2 weeks before waning. B symptoms are due to cytokine release by Reed-Sternberg cells. B symptoms indicate advanced disease. DIAGNOSIS •Excisional whole lymph node biopsy: Reed-Sternberg cell pathognomonic - large cells with bi- or multilobed nuclei ("owl eye appearance") & inclusions in the nucleoli. Reed-Sternberg cells are derived from an abnormal germinal B cell in the early stage of differentiation with CD15 & CD30 positivity. MANAGEMENT •Early stage disease (stage I or II): combination of chemotherapy (eg, ABVD."gold standard" chemotherapy) followed by radiation therapy. "ABVD": Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine. The amount of chemotherapy and radiation dose varies in patients with favorable and unfavorable prognosis disease. Chemotherapy alone is an acceptable alternative in patients at increased risk of complication from radiation therapy. •Advanced stage (III to IV): combination chemotherapy is the main treatment (ABVD). Radiation therapy may be used for some as consolidation "MOPP" Mustine, Oncovorin/Vincristine, Procarbazine, Prednisolone. •Refractory: second-line High-dose chemotherapy not used in original treatment, followed by an Autologous stem cell transplant is the standard of care for the majority of patients who are refractory or relapse post-initial therapy. Prognosis: •Hodgkin lymphoma has an excellent overall prognosis (~80% cure rate) compared to Non-Hodgkin lymphoma. •Lymphocyte-predominant = best prognosis. Lymphocyte-deplete = worst prognosis. WORKUP: •Laboratory tests include CBC, complete metabolic panel, erythrocyte sedimentation rate, Hepatitis B virus, hepatitis C virus, and HIV. Testing for HIV is recommended as the treatment of the infection can improve outcomes in HIV positive individuals. •LDH levels correlate with the bulk of disease. Elevated levels of alkaline phosphatase may suggest liver or bone involvement. •Imaging for staging: chest radiographs and combined PET/CT scan of chest, thorax, abdomen, and pelvis. STAGING NOMENCLATURE (ANN ARBOR): •Stage I: involvement of single lymph node region (I) or one extranodal site (IE) •Stage II: >1 lymph node involvement all on the same side of the diaphragm or local extralymphatic extension plus one or more lymph node regions same side of the diaphragm (IIE). •Stage III: lymph nodes or structures on both sides of the diaphragm. •Stage IV: involvement of an extra lymphatic organ. •Disease staging is further categorized as "A" if patients lack constitutional symptoms or as "B" if patients have 10% weight loss > 6 months, fever, or drenching night sweats. Reed-Sternberg cell pathognomonic of Hodgkin lymphoma - large cells with bi- or multilobed nuclei ("owl eye appearance") & inclusions in the nucleoli comprising the minority (1-10%) of the cellular population, admixed with a cellular environment of lymphocytes, eosinophils, histiocytes, neutrophils, plasma cells, fibroblasts, and collagen fibers. Reed-Stemberg (RS) cells are derived from an abnormal germinal B cell in the early stage of differentiation with CD15 & CD30 positivity NON-HODGKIN LYMPHOMAS •Heterogenous group of lymphocyte neoplasms with proliferation in the lymph nodes & spleen. MAJOR TYPES •Diffuse large B-cell: most common type of NHL. Fast growing, aggressive form (rapidly enlarging lymph nodes of the neck, abdomen and groin). Most common in the middle aged & elderly (average age 70 years). Extranodal seen in 40%. Large size B cell proliferation. CD 20+. •Follicular: second most common. Small cell proliferation in follicles (circular pattern) CD20+. Most common in adults. Presents with painless lymphadenopathy (especially in the neck, groin, & axilla). Follicular is usually indolent (slow growing) but hard to cure. Sometimes not treated until symptomatic. Associated with t(14:18) mutation. Follicular may progress to large B cell lymphoma. •Mantle cell: small cell proliferation surrounding the follicular zone (mantle). 5-15%. CD 20+, CD5+ (poorer prognosis). Painless lymphadenopathy. T11;14) mutation. •Marginal zone: small B cell proliferation. 5-10% in the cells surrounding the mantle. CD 20+. Low grade [usually due to B-cell hyperplasia from chronic immune or inflammatory states: (eg, Hashimoto's thyroiditis, Sjogren syndrome)]. 3 subtypes: Extranodal (Mucosal-Associated Lymphoid Tissue) MALT: Gastric MALT lymphomas often associated with H-pylori infections. 8%. Nodal: originate in the lymph nodes. Splenic: originates in the spleen or bone marrow. •Burkitt Lymphoma: intermediate-sized B cell proliferation. CD 20+. Associated with Epstein-Barr virus infection (except sporadic). Usually presents as an extranodal mass. Most commonly seen in pediatric/adolescent & HIV pts. Endemic (Africa): usually involves the jaw & facial bones (especially with malaria). Sporadic type: GI & paraaortic involvement (may cause abdominal pain or fullness). Immunodeficient type: seen with HIV or immunosuppression (eg, post-transplant). Biopsy "starry sky" appearance. Burkitt's very aggressive (but highly curable). (8:14) mutation. •Small lymphocytic: spectrum of disease as Chronic lymphocytic leukemia. Small lymphocytic usually found in the lymph nodes & spleen (whereas CLL is found in the bone marrow and the blood). 7%. RISK FACTORS •Increased age, history of radiation therapy, family history. Chromosomal translocations. •Immunosuppression: HIV, HCV, viral infection, organ transplantation. Autoimmune disorders. •Infections: EBV, HHV-8, HIV. H. pylori associated with gastric lymphoma. CLINICAL MANIFESTATIONS •The clinical presentation varies tremendously depending on the type of NHL & areas of involvement. •Local: painless lymphadenopathy. Indolent lymphomas may present with slowly growing lymphadenopathy. Hepatosplenomegaly. •Extranodal involvement: common. Gl tract most common site of extranodal involvement (skin second most common). CNS also common. •Systemic B symptoms: (fever, night sweats, weight loss) rarer in NHL but may be seen if advanced. DIAGNOSIS •Lymph node &/or tissue biopsy: required for the diagnosis and classification of NHL. •Combined CT/PET scan of chest, abdomen and pelvis for staging. MANAGEMENT: •Standard management of indolent stage I and contiguous stage II NHL consists of radiation therapy alone. Careful observation an option of asymptomatic indolent NHL. •Limited stage (Stage I and II); chemotherapy mainstay for limited disease: R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Oncovorin, Prednisone) alone or with radiation. Chlorambucil, Fludarabine, 2-CdA (2-chloro-2'-deoxyadenosine). Rituximab (monoclonal antibody against CD20+). Stem cell transplant in refractory cases. BTK inhibitors for Mantle cell lymphoma. •Intermediate-grade: combination chemotherapy (R-CHOP) plus involved-field radiation therapy. •High Grade (Aggressive): R-CHOP.

Disseminated Intravascular Coagulation (DIC) RAPID REVIEW

History of sepsis, trauma, or obstetric complications Labs will show thrombocytopenia, decreased fibrinogen, increased fibrin split products, and increased BT, PT, and PTT Most commonly caused by inappropriate activation of the coagulation system by a massive release of tissue factor into the circulation Treat the underlying condition If bleeding complications: replete clotting factors and platelets with fresh frozen plasma and transfusing platelets

Hodgkin lymphoma (ROSH)

Hodgkin lymphoma is the most common childhood cancer in adolescents age 15-19 years. It has a very high survival rate. The malignant cells of Hodgkin lymphoma are germinal center B cells called Hodgkin and Reed-Sternberg cells. After becoming malignant, these cells proliferate in lymph nodes. The Epstein-Barr virus is associated with many of these cases and is thought to play a role in cell transformation. Patients typically complain of lymphadenopathy and systemic symptoms. Most adolescents present with painless lymphadenopathy in the cervical or supraclavicular region. They may also present with axillary or inguinal lymphadenopathy, but these are much less common presentations. Many adolescents will also have a mediastinal mass on a chest radiograph. Systemic symptoms include fatigue, anorexia, weight loss, low-grade fever, and night sweats. Patients with advanced disease may present with hepatomegaly and splenomegaly. Patients in the emergency department with suspected Hodgkin lymphoma should undergo further evaluation with CT imaging of the neck, chest, abdomen, and pelvis to determine the extent of the disease. They should also be referred for tissue biopsy. Treatment usually consists of combined chemotherapy and radiation therapy. As mentioned, most adolescents have an excellent prognosis, and the overall 5-year survival rate exceeds 90%.

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Easy bruising

Idiopathic thrombocytopenic purpura •Acquired, immune-mediated isolated thrombocytopenia (low platelet count) due to a combination of increased platelet destruction & impaired platelet production caused principally by antiplatelet autoantibodies PATHOPHYSIOLOGY •Autoantibodies against platelets, leading to splenic destruction of platelets. The autoantibodies develop against the GP IIb/IIIa receptor on platelets. TYPES •Primary ITP: idiopathic. ~60% of children with newly diagnosed ITP have a history of a preceding viral illness within the past month (self-limited). Most common type in adults. •Secondary ITP: immune-mediated but associated with underlying disorders (eg, SLE, HIV, HCV, antiphospholipid syndrome). More commonly seen in adults & is usually recurrent. CLINICAL MANIFESTATIONS •Often asymptomatic. •Mucocutaneous bleeding: eg, epistaxis, bleeding gums, petechiae, purpura, bruising, menorrhagia. •Severe bleeding: intracranial hemorrhage, Gl bleeding, hematuria. •Not associated with splenomegaly. DIAGNOSIS •Isolated thrombocytopenia with otherwise normal CBC (normal WBC count, normal hematocrit, & peripheral smear is usually normal). Normal coagulation studies (PT, PTT, INR), •Bleeding time may be elevated (as with other causes of thrombocytopenia). •Bone marrow: Megakaryocytes (large-sized platelets) may be seen. Marrow testing usually reserved for older patients or non-responsive patients. •Some patients with ITP have coincident warm Autoimmune hemolytic anemia (Evans syndrome). MANAGEMENT IN ADULTS Minor bleeding (platelet count usually <50,000): •Glucocorticoids first-line therapy & preferred (blunts the immune response) or IVIG or anti-D •Intravenous immunoglobulin (IVIG) second-line therapy or may be used if rapid rise in platelet count is required. •Refractory: Rituximab or TPO receptor agonist or Splenectomy. Severe (critical) bleeding (GI/CNS) + platelets < 30,000: •Platelet transfusion + IVIG + high-dose glucocorticoids. No bleeding + platelet ≥30,000: •Observation and monitor the platelet count. No bleeding + platelet <20,000 - 30,000: •Glucocorticoids (preferred) or IVIG or anti-D. MANAGEMENT IN CHILDREN •No bleeding or mild bleeding not at risk: observation. •When treatment is indicated, options include Intravenous immune globulin (IVIG), anti-D immune globulin (anti-D), or glucocorticoids. •Intravenous immunoglobulin (IVIG) if rapid rise in platelet counts required. •Glucocorticoids if increased risk of bleeding but rapid rise in platelets not needed. •Life-threatening bleeding: IV Glucocorticoids plus IVIG. Thrombotic thrombocytopenic purpura •Thrombotic microangiopathic hemolytic anemia resulting from deficiency of and/or inhibitory autoantibodies to ADAMTS13 (severely reduced ADAMTS13 activity). •More common in females. African-Americans. PATHOPHYSIOLOGY •Von Willebrand factor is normally secreted as ultra-large multimers, which are then cleaved by ADAMTS13 (ADAMTS13 is a von Willebrand factor-cleaving protease). •ADAMTS 13 deficiency leads to large vWF multimers that cause small vessel thrombosis via pathogenic platelet adhesion & aggregation (microangiopathic hemolytic anemia & thrombocytopenia). ETIOLOGIES •Primary: idiopathic (autoimmune) - autoantibodies against ADAMTS13. •Secondary: malignancy, bone marrow transplantation, estrogen, Systemic lupus erythematosus, pregnancy, HIV-1, medications (g, Quinidine, Ticlopidine, Clopidogrel, Cyclosporine). CLINICAL MANIFESTATIONS: pentad: •Only ~ 25% of patients with TMA manifest all components of the pentad. •(1) Thrombocytopenia: mucocutaneous bleeding - epistaxis, bleeding gums, petechiae, purpura, easy bruising, menorrhagia. •(2) Microangiopathic hemolytic anemia: anemia, jaundice, fragmented RBCs (schistocytes on peripheral smear). Splenomegaly. Gastrointestinal (abdominal pain, nausea, vomiting, diarrhea). •(3) Neurologic symptoms: headache, visual changes, confusion, somnolence, delirium, seizures, CVA. •(4) Fever (rare). Since Plasma exchange therapy, it is rare for patients to present with all 5 simultaneously. •(5) Kidney dysfunction: Acute kidney injury uncommon (less so than Hemolytic uremic syndrome). DIAGNOSIS •Labs: thrombocytopenia with normal coagulation studies (PT, aPTT, fibrinogen) are seen in both TTP & HUS. Normal coagulation studies (PT & aPTT) help to distinguish TTP & HUS from DIC. •Hemolysis: peripheral smear - schistocytes (helmet cells), bite or fragmented cells, reticulocytosis, increased lactate dehydrogenase [LDH], increased bilirubin, decreased haptoglobin. •Decreased ADAMTS13 levels. Coombs (antiglobulin) test negative. Increased bleeding time. MANAGEMENT •Plasmapheresis: Therapeutic plasma exchange is the mainstay of treatment of TTP. Plasmapheresis removes antibodies against ADAMTS13 & adds ADAMTS13 to serum. Monitor & continue plasma exchange until LDH & platelets normalize for at least 2 days. •Immunosuppression: glucocorticoids and/or Rituximab if no response to Plasmapheresis, Cyclophosphamide. Caplacizumab is an anti-VWF nanobody, decreases mortality when used in patients with ADAMTS13 <10%. •Platelet transfusions not usually indicated (may potentiate thrombi formation). •Splenectomy an option in patients refractory to Plasma exchange and immunosuppressants.

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Anemia

Iron deficiency anemia •Most common cause of anemia worldwide, especially in women of childbearing age, children, and individuals living in under-resourced & middle-income countries (~12% of the world population). ETIOLOGIES •Chronic blood loss: most common cause in the US - excessive menstruation, occult GI blood loss (eg, Colon cancer). In adults in the US, chronic blood loss is most likely until proven otherwise. Parasitic hookworms most common cause of blood loss-related IA in resource-poor countries. •Decreased absorption: diet (most common cause worldwide), Celiac, bariatric surgery, H. pylori. RISK FACTORS •Increased metabolic requirements: children, pregnant, and lactating women. •Cow milk ingestion in young children; infants fed cow's milk younger than 1 year of age, toddlers fed large volumes of cow's milk. PATHOPHYSIOLOGY •Decreased RBC production due to lack of iron & decreased iron stores (decreased ferritin). Normally, iron is stored in ferritin primarily in the bone marrow, liver, and spleen. •The first step is depletion of iron stores without anemia, followed by anemia with a normal red blood cell size (normal MCV), followed by anemia with reduced red blood cell size (low MCV). CLINICAL MANIFESTATIONS •Classic symptoms of anemia: easy fatigability, weakness, exercise intolerance, exertional dyspnea. •CNS: poor concentration, apathy, headache, irritability, poor school performance, cognitive disturbances. Restless legs syndrome. •Pagophagia: craving for ice (specific). Pica: appetite for non-food substances (eg, clay, starch). •Physical examination: koilonychia (spooning of the nails), angular cheilitis (inflammation of one or both corners of the mouth), tachycardia, glossitis (smooth tongue), signs of anemia (eg, pallor). DIAGNOSIS •CBC: microcytic hypochromic anemia classic (may be normocytic, normochromic early on). Increased RDW (red cell distribution width), anisocytosis. Decreased reticulocytes (decreased RBC production), decreased red blood cell count, target cells. May have thrombocytosis & poikilocytosis. •Iron studies: decreased ferritin <30 ng/mL if anemic (pathognomonic due to low iron stores) [some sources use a cutoff level of <12-15 ng/mL], increased TIBC (transferrin), decreased transferrin saturation <20-15% (due to increased transferrin), decreased serum iron. •Bone marrow iron stain: absent iron stores is the criterion standard (rarely performed). MANAGEMENT •Iron replacement results in symptom resolution, increased reticulocytes (peaks within 5-10 days), correction of anemia (6-8 weeks), & repletion of iron stores (1-3 months). Lack of response may be due to nonadherence to oral iron (most common), continuing blood loss, misdiagnosis, or the presence of additional diagnoses. •Preparations: oral (eg, Ferrous sulfate, 325 mg once daily or every other day on an empty stomach), iron-containing formulas in bottle-fed infants. Iron-enriched food, and red meats. Parenteral iron. •Increased absorption: take iron replacement with vitamin C (ascorbic acid), with water or orange juice & on an empty stomach. Iron should be given 2 hours before or 4 hours after ingestion of antacids (reduced acidity impairs absorption). •Adverse effects: GI most common (eg, nausea, vomiting, constipation, flatulence, diarrhea, dark stool). Strategies to reduce these effects include reducing the dose, reducing the frequency to every other day if not done already, dietary modifications, and switching to a liquid formulation. •Severe life-threatening anemia: red blood cell transfusion (eg, myocardial ischemia).

von Willebrand Disease RAPID REVIEW

Most common inherited bleeding disorder due to reduced, dysfunctional, or absent von Willebrand factor Sx: increased mucocutaneous bleeding, heavy menses, excessive postpartum bleeding Labs: aPTT may be prolonged, VWF antigen, platelet-dependent VWF activity (ristocetin cofactor assay), factor VIII activity Tx options: desmopressin (DDAVP), von Willebrand factor concentrate Most cases autosomal dominant, consider genetic counseling and testing of 1st degree relatives

Chronic Myelogenous Leukemia (CML) RAPID REVIEW

Most commonly diagnosed at 30-60 years old Sx: many patients asymptomatic, fatigue, weight loss, abdominal pain or early satiety PE: hepatosplenomegaly Labs: ↑WBC, and low leukocyte alkaline phosphatase (LAP), platelets ↑ or normal Clinical course: chronic phase, accelerated phase, blast crisis. Phase determined by various criteria, include blast percentage, thrombocytopenia, etc. Dx: bone marrow biopsy, Philadelphia chromosome t(9;22), BCR-ABL gene Tx: allogeneic HSCT (curative), tyrosine kinase inhibitors (imatinib)

This patient is presenting with asymptomatic supratherapeutic international normalized ratio (INR) due to warfarin toxicity. Warfarin is a commonly used anticoagulant in atrial fibrillation, mechanical heart valves, and prothrombotic states. By interfering with the vitamin K cycle, warfarin prevents the activation of clotting factors II, VII, IX, and X. However, warfarin requires close dose titration and monitoring, as its efficacy is affected by genetic variability and dietary changes. The effect of warfarin is monitored with prothrombin time and INR, with a goal INR commonly between 2-3.5, depending on the condition being treated. Patients will commonly present to the emergency department with supratherapeutic INR, requiring appropriate management to prevent negative outcomes. As INR increases, risk for spontaneous hemorrhage or traumatic bleeding is significantly increased. Patients on warfarin who present with elevated INR and no significant bleeding should be treated based on the INR level. Patients with an INR greater than 10 should receive oral vitamin K, hold the next warfarin dose, and repeat labs in 24-48 hours. Patients without bleeding and an INR less than 10 should lower or omit their upcoming warfarin doses and have the INR rechecked to ensure it is therapeutic.

No treatment and repeat labs in 24-48 hours (A) would be appropriate for minimally elevated INRs (less than 4) without signs of bleeding. Reversal with four-factor prothrombin complex concentrate (C) is appropriate for any patient on warfarin with serious or life-threatening bleeding, such as intracranial bleeding, gastrointestinal bleeding, or bleeding causing patients to become unstable. In addition to reversal of the anticoagulation, these patients may require massive transfusion of blood products to provide hemodynamic support and will also receive vitamin K intravenously for longer-term warfarin reversal. Protamine sulfate (D) is the reversal agent for heparin.

Polycythemia Vera RAPID REVIEW

Patient presents with headache, dizziness, pruritus after showering PE will show hypertension, splenomegaly Labs will show increased RBC mass, overproduction of all cell lines, increased Hgb Most commonly caused by mutation of the Janus kinase 2 gene (JAK2) Treatment is phlebotomy, hydroxyurea, aspirin

Polycythemia Vera (ROSH)

Polycythemia, also known as erythrocytosis, is defined as an increase in relative or absolute hemoglobin or hematocrit levels. Relative polycythemia is due to a decrease in plasma volume, commonly caused by dehydration or excessive diuresis. Absolute polycythemia is an increase in red blood cell (RBC) mass. Absolute polycythemia can be further classified as primary, due to mutations in erythroid cell lines or erythropoietin (EPO) receptors, or secondary, due to increased levels of circulating EPO, which directly stimulates RBC production. Polycythemia vera is an absolute primary polycythemia associated with a JAK2 gene mutation and is considered to be one of the chronic myeloproliferative disorders. The classic symptoms of polycythemia vera include pruritus, particularly when exposed to hot water, and early satiety due to splenomegaly from increased RBC production as a result of the JAK2 gene mutation. Other symptoms vary and are vague, including fatigue, generalized weakness, headache, chest pain, abdominal pain, or muscle pain. Some patients may be asymptomatic and are diagnosed incidentally after routine blood work. A rare but classic symptom of polycythemia vera is erythromelalgia, which occurs due to episodic occlusion of peripheral blood vessels that become hyperemic and inflamed when unoccluded. Patients with erythromelalgia present with intense, burning pain and a red-blue discoloration of the affected extremities. A feared and life-threatening complication of polycythemia vera is hyperviscosity syndrome that presents with the triad of vision changes, bleeding, and focal neurologic deficits due to microhemorrhage and thrombosis. On physical exam, patients with polycythemia vera may have splenomegaly, plethoric facies, flushed skin, nail clubbing, and distal cyanosis. Definitive diagnosis of polycythemia vera is made via biopsy or genetic testing for the JAK2 gene mutation. In the acute workup, patients will have hemoglobin levels > 18.5 g/dL in male patients and 16.5 g/dL in female patients, or hematocrit > 52% in male patients and 48% in female patients. Patients may also have a leukocytosis, thrombocytosis, and elevated lactate dehydrogenase. A useful blood test in distinguishing causes of polycythemia prior to the availability of genetic testing or biopsy is an EPO level. Patients with polycythemia vera will have low EPO levels due to negative feedback repressing kidney EPO production, whereas patients with absolute secondary polycythemia due to chronic lung disease or high altitude will have increased EPO levels. Treatment for polycythemia vera is low-dose aspirin and correction of decreased plasma volume with phlebotomy to a hematocrit of 45%. After confirmation of diagnosis and discussion with a hematologist, other treatment options include hydroxyurea, interferon-alpha, and ruxolitinib, a JAK1 and JAK2 inhibitor. Patients with hyperviscosity syndrome require intravenous fluid hydration and hematology consultation.

Transient Aplastic Crisis RAPID REVIEW

Risk factors: sickle cell anemia, iron deficiency anemia, or hereditary spherocytosis Sx: pallor, fatigue, lethargy, and shortness of breath Labs will show low or undetectable reticulocyte count and a drop in hemoglobin concentration of > 30% Most commonly caused by recent parvovirus B19 infection Tx: self-limited, transfusion support

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Sickle cell anemia/crisis

SICKLE CELL DISEASE •Group of inherited disorders affecting the beta-globin gene, leading to the production of RBCs that sickle, causing hemolysis (hemolytic anemia) & vaso-occlusive disease. •Disorders include Sickle cell disease (homozygous sickle mutation), sickle beta thalassemia, Hemoglobin SC disease, etc. PATHOPHYSIOLOGY •Point mutation where valine substitutes for glutamic acid on the beta chain. Sickle hemoglobin (HbS) has decreased solubility under hypoxic conditions, leading to conformational change of the RBC shape (sickling) with subsequent vaso-occlusion (microthrombosis) & hypoxia. Sickled cells are destroyed by the spleen (hemolytic anemia). SICKLE CELL TRAIT: •Heterozygous (AS). 8% of African-Americans. Patients with Sickle cell trait are usually asymptomatic and are not anemic unless exposed to severe hypoxia, extreme physical stress, high altitudes, or dehydration. May develop episodic hematuria or isosthenuria (due to papillary necrosis). SICKLE CELL DISEASE: •Homozygous sickle mutation (SS). 0.2% of African-Americans. The main clinical manifestations are due to hemolytic anemia and vaso-occlusion (eg, acute or chronic pain, tissue ischemia or infarction).

SICKLE CELL TRAIT

Sickle cell trait: heterozygous (AS). •Epidemiology: 8% of African-Americans. Increased in populations where Malaria is endemic. •Pathophysiology: In Sickle cell trait, about 35-45% of their hemoglobin is HbS. CLINICAL MANIFESTATIONS •Patients with Sickle cell trait are usually asymptomatic and are not anemic unless exposed to severe hypoxia, extreme physical stress, low temperatures, high altitudes, or dehydration. •May develop episodic hematuria or isosthenuria (concentrating defects) due to infarction & necrosis of the papillae of the renal medulla. •May develop splenic infarction at high altitude and sudden death with prolonged exercise or physical training. DIAGNOSIS Hemoglobin electrophoresis: •Sickle cell trait: HbS, decreased HbA - presence of both hemoglobin A (HbA) and Hemoglobin S (HbS) [~35-45% HbS] with the amount of HbA greater than HbS. (FAS pattern in neonates). The presence of <35% Hb S suggests the presence of Alpha thalassemia. Peripheral smear: •Usually normal hemoglobin, hematocrit, reticulocyte count, and peripheral smear. MANAGEMENT •Sickle cell trait usually does not require treatment. Painful crisis is not a component of the trait. •Papillary necrosis: conservative (eg, IV fluids, bed rest, and pain management).

Isolated thrombocytopenia due to autoantibodies occurs in immune thrombocytopenia (ITP)

This patient presents with a bleeding disorder, as evidenced by prolonged and difficult-to-control epistaxis and cutaneous findings. Other possible findings include easy bruising, menorrhagia, hematuria, gingival bleeding, and GI bleeding. The etiologies of dysfunctional bleeding in children are broad. Hereditary causes such as von Willebrand factor deficiency, hemophilia, and connective tissue disorders are less likely in this child with no family history and no personal history of easy bleeding, bruising, or hemarthrosis. Acquired bleeding disorders such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation can be excluded in this patient due to the benign clinical history and presentation. In this patient, the presence of mucocutaneous bleeding and petechiae is most likely attributed to thrombocytopenia, among the answer choices provided. Isolated thrombocytopenia due to autoantibodies occurs in immune thrombocytopenia (ITP) of childhood in more than half of cases, in the absence of other causes (such as drugs, malignancy, or infection). Cutaneous findings are present in the majority of children diagnosed with ITP. Other than mucocutaneous bleeding, children with ITP generally appear well and lack systemic symptoms. Thrombocytopenia is generally defined as a platelet count < 100,000/µL. Most cases of ITP are self-limited and resolve within 6 months. Management is guided by hematology consultation, but it generally involves steroids or intravenous immune globulin, along with admission in the case of spontaneous bleeding or platelet count < 20,000/µL.

Autoimmune Hemolytic Anemia (AIHA)

•Acquired hemolytic anemia due to autoantibody production against RBCs. PATHOPHYSIOLOGY •Warm: IgG antibodies activated by protein antigens on self RBC surface at body temperatures, leading to RBC destruction by splenic macrophages, & / or complement 3 (C3) activation-mediated RBC destruction by hepatic Kupffer cells. •Cold agglutinin disease (CAD): IgM antibodies against polysaccharides bind to the RBC surface especially at colder temperatures (<39F). When the RBCs return to a warmer temperature, the IgM dissociates, leaving complement (C3b) on the cell, causing hepatic RBC destruction by hepatic Kupffer cells (extravascular hemolysis). Intravascular complement-mediated BC hemolysis. ETIOLOGIES •Warm agglutinin: idiopathic (most common - 50%), medications (Penicillin, Cephalosporins, Methyldopa, Rifampin, Phenytoin), autoimmune (eg, Systemic lupus erythematosus, RA), malignancy (eg, CLL, non-Hodgkin lymphoma), viral infections (especially in children), HIV. •Cold agglutinin disease (CAD): idiopathic (most common), infection (eg, Mycoplasma pneumoniae, Epstein-Barr virus, HIV), malignancy (eg, CLL, lymphoma), Waldenström macroglobulinemia. CLINICAL MANIFESTATIONS •Anemia (eg, pallor fatigue, weakness, dyspnea), hemolysis (eg, hemoglobinuria, jaundice, splenomegaly). Warm AIHA has a rapid onset (may be life-threatening); slower onset if CAD. •Cold-induced vascular phenomenon in CAD: acrocyanosis (numbness or mottling of the fingers, toes, nose, ears) when exposed to cold temperatures that resolves with warming up of the body parts. Raynaud phenomenon, livedo reticularis (mottling). •~ 10% of patients with warm AlHA have coincident immune thrombocytopenia (Evans syndrome). DIAGNOSIS •CBC + peripheral smear: decreased hemoglobin, hemolysis (reticulocytosis), microspherocytes (especially warm), may have increased MCHC. Polychromasia. RBC agglutination only in CAD. •Labs: hemolysis: increased indirect bilirubin, increased LDH, decreased haptoglobin, reticulocytes. •+Direct Coombs (anticlobulin) test: - IgG &/or C3 positivity most accurate test in Warm. AIHA. Only positive for complement 3 (C3b, C3d) in Cold agglutinin disease (CAD). •Cold agglutinin tier most accurate for CAD (> 1:64). MANAGEMENT Warm agglutinin AlHA •First line: Glucocorticoids first-line if symptomatic (‡Rituximab). Folic acid supplementation. •Second-line: Rituximab (anti CD20) can be added if no response & it wasn't given previously &/ or Mycophenolate. IV Cyclophosphamide may be used if severe intravascular hemolysis. Azathioprine, Cyclophosphamide, Cyclosporine, or Mycophenolate. Children and young adults with coexisting autoimmune lymphoproliferative syndrome may be given Sirolimus. •Splenectomy is an option if 1 or 2 other immunosuppressive agents have been tried. •Transfusion if severe (eg, Hb <7 g/dL). Cold agglutinin disease: •Avoidance of cold temperatures & exposure mainstay of treatment; warm fluids if hospitalized. •Rituximab first-line medication when medications are needed. •B-cell receptor inhibitors Venetoclax and Ibrutinib; Bortezomib (proteasome inhibitor). •Severe or symptomatic anemia: transfusions. Plasmapheresis or IVIG are rarely used.

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Polycythemia

•Acquired myeloproliferative disorder with autonomous bone marrow overproduction of all 3 hematopoietic myeloid stem cell lines (primarily increased RBCs, but associated with increased granulocytic WBCs and platelets). •Pathophysiology: JAK2 mutation leads to Primary erythrocytosis (increased hematocrit in the absence of hypoxia). Risk factors: peaks 50-60 years of age. Most common in men (60%). CLINICAL MANIFESTATIONS •Symptoms due to increased RBC mass (hyperviscosity &/or thrombosis). •Hyperviscosity; headache, dizziness, tinnitus, blurred vision, weakness, fatigue, pruritus, especially after a hot bath or shower (due to histamine release from basophils), epistaxis, bleeding. •Thrombosis: Thrombotic complications (eg, hepatic vein thrombosis, DVT, TIA). Erythromelalgia (episodic burning or throbbing of hands & feet with edema, cyanosis or pallor) is rare but classic. •Physical examination: hepatosplenomegaly, facial plethora (flushing), & engorged retinal veins. LABS: •CBC/peripheral smear: in pre-polycythemia & overt polycythemia, excess of normochromic & normocytic red blood cells are seen - increased hemoglobin & hematocrit (a hypochromic and microcytic pattern can accompany concomitant iron deficiency). Thrombocytosis is common. Granulated white blood cell leukocytosis (predominantly with neutrophils) can be seen in the absence of fever or infection (lymphocytes and monocytes are not usually significantly increased in PV and blasts are not a characteristic feature). In contrast, the post-polycythemic stage (spent phase), myelofibrosis - teardrop red blood cells, poikilocytosis, & nucleated red cells. •Normal 02 saturation: arterial oxygen saturation usually ≥92%. •Increased LAP leukocyte alkaline phosphatase often > 100 U/L due to increased functioning WBCs. Helps to distinguish PV (high LAP) from Chronic myelogenous leukemia (low LAP). •Increased serum B-12 levels >900 pg/mL in ~30% of because of increased transcobalamin-Ill, a binding protein found in WBCs (due to total WBC counts in the peripheral blood & bone marrow). •Iron deficiency despite polycythemia due to disordered iron metabolism, defects in iron absorption, aberrant hypoxia sensing and signaling, and increased frequency of bleeding. DIAGNOSIS: All 3 major OR first 2 major + 1 minor Major criteria: •(1) Increased RBC mass: increased hemoglobin & hematocrit - Hg ≥16.5 g/dL or Hct ≥49% in men; Hg ≥16.0 g/dL or Hct ≥48% in women; or red blood cell mass >25% above mean normal predicted. •(2) Bone marrow biopsy: hypercellularity with trilineage growth (panmyelosis with erythroid, granulocytic, & megakaryocytic proliferation) with pleomorphic, mature megakaryocytes. •(3) JAK2 mutation presence (most accurate) - JAK2 V617F exon 14 mutation or JAK2 exon 12 mutation. Minor criterion: •Low or subnormal serum erythropoietin level increased RBCs despite low EPO level due to negative feedback. Increased EP levels usually suggest Secondary erythrocytosis. MANAGEMENT •Low-risk (< 60 years & no thrombosis): Phlebotomy first-line until hematocrit <45%. Low-dose Aspirin to prevent thrombosis. •High-risk (60 years or older &/or thrombosis): all the above + Hydroxyurea (decreases cell count). Pegylated Interferon-alfa second-line. Ruxolitinib (JAK inhibitor) if no response to Hydroxyurea. •Symptomatic: Antihistamines for pruritus. Allopurinol if hyperuricemia. •Avoid iron supplementation. Avoid alkylating agents (increased risk of myelofibrosis & progression to AML). SECONDARY ERYTHROCYTOSIS •Major cause of 1RBC mass. Most common in obese, history of cigarette smoking. •Secondary erythrocytosis = 1hematocrit as a response to another process. ETIOLOGIES 3 major causes: • (1) Reactive (physiologic); due to hypoxia - eg, pulmonary disease (COPD), high altitude, tobacco smokers, cyanotic heart disease. Reactive most common type. Increased erythropoietin. • (2) Pathologic: no underlying tissue hypoxia. Renal disease (eg, renal cell CA), fibroids, hepatoma. • (3) Relative polycythemia: normal RBC mass in the setting of I plasma volume or dehydration. CLINICAL MANIFESTATIONS • Symptoms related to the underlying precipitating cause (eg, COPD, renal disease, cyanosis etc). • Physical Exam: cyanosis, clubbing, hypertension, hepatosplenomegaly, ‡heart murmur. DIAGNOSIS: • increased RBCs/hematocrit with normal WBC & platelets. Increased erythropoietin levels & RBC mass if reactive or pathologic. Relative polycythemia: Normal erythropoietin levels & normal BC mass because the polycythemia is relative (due to ) plasma volume). MANAGEMENT: treat underlying disorder. Smoking cessation.

Heparin-induced thrombocytopenia (HIT)

•Acquired thrombocytopenia especially within the first 5-10 days of the initiation of Heparin. •In HIT, (1) the thrombocytopenia is not usually severe, with nadir counts rarely <20,000/uL. (2) Heparin-induced thrombocytopenia (HIT) is not associated with bleeding and, in actuality, markedly increases the risk of thrombosis. RISK FACTORS •Unfractionated Heparin > Low molecular weight Heparin; surgical > medical; female > male. PATHOPHYSIOLOGY •Autoantibody formation to the hapten complex of Heparin + platelet factor 4 causes platelet activation & consumption, leading to simultaneous thrombocytopenia & thrombosis. CLINICAL MANIFESTATIONS •Thrombocytopenia most common but bleeding is uncommon (due to prothrombotic nature of HIT). •Thrombosis: venous thrombosis, gangrene, organ infarction and skin necrosis. DIAGNOSIS •4 Ts: Thrombocytopenia, Timing of platelet drop, Thrombosis, absence of other causes. •HIT antibody testing: Enzyme-linked immunoassay (ELISA) with PF4/polyanion complex as the antigen (screening). If positive, confirm with functional assays (eg, 14-C-serotonin release assay). •Patients with overt HIT should be screened with lower extremity US to assess for asymptomatic DVT. MANAGEMENT •Immediate discontinuation of all Heparin + initiation of non-Heparin anticoagulants. •Non-Heparin anticoagulants: direct thrombin inhibitors (eg, Argatroban, Lepirudin, Bivalirudin), Fondaparinux, direct oral anticoagulants (eg, Apixaban, Edoxaban, Rivaroxaban or Dabigatran). •Long-term anticoagulation with Warfarin can only be started (1) after other non-Heparin anticoagulation has been started & (2) the thrombosis has decreased because of the initial prothrombotic state normally associated with the first 5 days of the initiation of Warfarin therapy.

VON WILLEBRAND DISEASE

•Autosomal dominant disorder associated with ineffective platelet adhesion due to deficient or defective von Willebrand Factor. •Most common hereditary bleeding disorder (1% of population). May also be acquired. FUNCTION OF VWE: •Von Willebrand factor (VWF) promotes platelet adhesion by crosslinking the GP1b receptor on platelets with exposed collagen on damaged epithelium. VWF also prevents Factor VIII degradation. CLINICAL MANIFESTATIONS •Mucocutaneous bleeding: eg, prolonged bleeding from mucosal surfaces (oral, uterine, gastrointestinal) & skin - epistaxis, bleeding from gums & oral cavity, easy bruising, petechiae, purpura, prolonged bleeding after minor cuts, dental extractions or procedures, trauma, or other forms of surgery, heavy menstrual bleeding, postpartum hemorrhage, gastrointestinal. •Incisional bleeding less common in VWD than in Hemophilia. INITIAL LABS •Coagulation studies: normal or prolonged PTT that corrects with mixing study. PT is not affected by VWD. PTT & bleeding time prolongation worse with Aspirin. •Platelet count is usually normal (except in 2B, which is associated with mild thrombocytopenia). SCREENING TESTS •Plasma VWF antigen - decreased VWF antigen or VWF activity ≤30 IU is diagnostic. •Plasma VWF activity (Ristocetin cofactor activity and VWF collagen binding). No platelet aggregation with Ristocetin in VWD. Factor VIII activity: may be decreased SPECIALIZED ASSAYS; helps to determine the type of VWD. •VWF multimer distribution using gel electrophoresis. •Ristocetin-induced platelet aggregation (gold standard). Management (Type 1): Quantitative deficiency (most common type 75%) •Mild to moderate bleeding: DDAVP (Desmopressin) first-line. VWF concentrates. •Severe: VWF-containing product - eg, factor VIII concentrates, purified VWF concentrates, recombinant VWF. •Minor procedures: Desmopressin used in type 1 and 2A for minor trauma, dental and minor surgical procedures. •Major procedures: VWF containing products - eg, human derived Factor VIII concentrates. Management of Type 2 (qualitative deficiency): •Desmopressin (DDAVP) for most. VWF-containing product or DDAVP prior to procedures. •Patients with Type 2B may also require platelet transfusion prior to the procedure. Management of Type 3 (severe, absent VWF): •VWF-containing product eg, human-derived factor VIII concentrates, purified VWF concentrates, recombinant VWF. Desmopressin not used because Type 3 is associated with undetectable VWF. Desmopressin (DDAVP) •Mechanism of action: transiently increases plasma concentration of VWF & Factor VIII (8) levels by releasing from endogenous VWF storage pools in platelet granules and vascular endothelial cells. Synthetic analog of vasopressin (antidiuretic hormone - ADH). •Indications: used in Type 1 and some Type 2 VWD. Desmopressin increases plasma von Willebrand factor and factor VIII (8) levels from twofold to more than fivefold over baseline levels. •Administration: Desmopressin is generally administered for short periods (48 to 72 hours), and no more often than at 24- to 48-hour intervals because of tachyphylaxis and adverse effects. •Monitoring: if a longer duration or shorter intervals are required, the patient should be monitored for fluid and electrolyte problems because Desmopressin may lead to ADH-induced symptomatic hyponatremia (eg, neurological symptoms & seizure).

Hereditary spherocytosis

•Chronic hemolytic anemia due to a genetic red cell membrane defect. HS is a result of heterogeneous alterations in 1 of 5 genes that encode red blood cell (BC) membrane proteins and cytoskeleton, most commonly spectrin (SPTA1 & SPTB genes) & ankyrin (ANK1 gene). Often autosomal dominant. •Most common in Northern Europeans, with a 1 in 5,000 incidence in this population. PATHOPHYSIOLOGY •Normally, spectrin & ankyrin are proteins that strengthen the linkage between the BC & underlying cytoskeleton, allowing for the elastic deformability of the BC and the biconcave disc shape. •In HS, deficiency in red cell membrane & cytoskeleton proteins (eg, spectrin, ankyrin, & actin), leads to increased RBC fragility, & sphere-shaped RBCs due to decreased BC surface. •These abnormal spherocytic red cells are detected, destroyed, & removed by the spleen (splenic macrophages) as they pass through the splenic microcirculation (extravascular hemolysis). CLINICAL MANIFESTATIONS •Broad spectrum of clinical presentations. Mild cases may not present until adulthood or incidentally. •Severe cases may present in infancy (eg, neonatal jaundice, hyperbilirubinemia, normal hemoglobin at birth with severe anemia particularly in the first 3 weeks). May have a family history of anemia. •Anemia: fatigue, pallor, and delayed capillary refill time. Medial malleolar ulcers (chronic hemolysis). •Hemolysis: recurrent episodes of Coombs-negative (eg, non-immune) hemolytic anemia (anemia, dark-colored urine, & splenomegaly) hallmark often associated with infections (eg, viral such as Parvovirus B19), stress, fatigue, pregnancy; Pigmented gallstones (calcium bilirubinate). Aplastic crisis with Parvovirus B19 infection is a possible complication. •Nutrient deficiencies: due to high BC turnover, patients may develop folate, iron, or B12 deficiency. DIAGNOSIS •Peripheral smear: -HypERchromic microcytosis, 80% spherocytes (round RBCs that lack central pallor). -Increased MCHC most reliable (mean corpuscular hemoglobin concentration MCHC >34). Increased RDW (>14%). Suspect HS in patients with microcytosis + increased MCHC. -May have a hemolytic smear (schistocytes, increased reticulocytes). •Hemolysis: increased indirect bilirubin, increased reticulocyte count, decreased haptoglobin. •Negative Coombs testing: Coombs negativity distinguishes Hereditary spherocytosis from Autoimmune hemolytic anemia (which also has spherocytes but is Coombs positive). Confirmatory tests: •EMA binding: preferred confirmatory test (most accurate; high sensitivity & specificity). Flow cytometric analysis of eosin-5'-maleimide-labeled intact red blood cells & acidified glycerol lysis test (decreased fluorescence in patients with HS). •Osmotic fragility test: RBCs placed in a relatively hypotonic solution rupture easily due to the increased permeability of the BC membrane (can be used if EMA is not available or is equivocal). •Osmotic gradient ektacytometry, Glycerol lysis (regular or acidified). Cryohemolysis. •Definitive diagnosis: Genetic testing may also be used for confirmation of HS. MANAGEMENT •Mild to moderate: Folic acid not curative but helpful to sustain BC production & DNA synthesis. •Splenectomy curative in severe or refractory disease to stop splenic BC destruction by eliminating the site of destruction. When possible & if needed, it should be delayed in children until at least 4-6 years of age (after the risk of severe sepsis from asplenia has peaked). Anti-pneumococcal vaccine should be given prior to splenectomy.

Alpha Thalassemia

•Decreased a-globin chain production. 4 genes determine it. •Most common in Southeast Asians (68%), Africans (30%), Mediterranean (5-10%). Silent Carrier State (minima) Abnormal Alleles: 1/4 CLINICAL MANIFESTATIONS: Clinically normal (usually asymptomatic & no anemia). Alpha Thalassemia minor (trait) Abnormal Alleles: 2/4 CLINICAL MANIFESTATIONS: Mild microcytic anemia - no treatment needed. Alpha Thalassemia Intermedia (Hemoglobin H disease) Abnormal Alleles: 3/4 CLINICAL MANIFESTATIONS: Presents similar to B-Thalassemia major Hydrops Fetalis (Hb Barts) Abnormal Alleles: 4/4 CLINICAL MANIFESTATIONS: Associated with stillbirth or death shortly after birth Thalassemia should be suspected in any patient with: •Microcytic hypochromic anemia (microcytosis disproportionate to the degree of anemia) •Normal or increased serum iron •Normal or increased ferritin Hemoglobin electrophoresis in Beta thalassemia: increases in HbA2 &/or HbF. Hemoglobin electrophoresis in Alpha Thalassemia: •1 & 2 gene deletion: normal Hb ratios in adults (distinguishes alpha from beta). •3 gene deletion: presence of HbH (beta chain tetramers) 10-40% - Heinz bodies. •4 gene deletion: presence of Hb Bart [gamma tetramers (yyyy)]. DNA analysis provides definitive diagnosis. HEMOGLOBIN H DISEASE (ALPHA THALASSEMIA INTERMEDIA) PATHOPHYSIOLOGY •3/4 gene deletions (--/a-) cause decreased alpha chain production. Excess beta chains pair together to form insoluble beta chain tetramers (Heinz bodies) with no oxygen-carrying capacity in the RBCs. The presence of Heinz bodies in RBCs lead to their destruction by the spleen (hemolytic anemia). Associated with moderate to severe anemia (hemoglobin levels of 7-11 g/dL). CLINICAL MANIFESTATIONS •Patients usually symptomatic at birth (neonatal jaundice & anemia) but do not require transfusions. •Symptoms of anemia, hepatosplenomegaly (due to chronic hemolysis), pigmented gallstones. •Increased bone marrow hematopoiesis: frontal bossing, maxilla overgrowth, Osteopenia. DIAGNOSIS •CBC: Microcytosis, hypochromia, hemolytic anemia (schistocytes, tear drop cells, increased reticulocytes), target cells, normal or increased RBC count, decreased hemoglobin (7-10 g/dL). Acanthocytes (cells with irregularly spaced spiked projections). + Heinz bodies (HbH). •Hemolysis: increased indirect bilirubin, increased lactate dehydrogenase LDH, decreased haptoglobin. •Iron overload: normal or increased serum iron. Causes include ineffective erythropoiesis, which promotes increased intestinal iron uptake, and transfusional iron overload. •Hemoglobin electrophoresis: presence of HbH (beta chain tetramers) comprising 10-40% of hemoglobin. MANAGEMENT •Vitamin C & folate supplementation (substrates for RBC production). •Episodic blood transfusions during periods of increased hemolysis or severe anemia (eg, infection, pregnancy). Some individuals may be transfusion-dependent. •Iron chelating agents (eg, Deferoxamine, Deferasirox) prevent iron overload & remove excess iron from chronic transfusions. Avoid iron supplementation (patients are iron-overloaded). •Splenectomy in some cases (stops RBC destruction) may be needed by the second or third decade. •Bone marrow transplantation definitive treatment in major.

Antithrombin III deficiency

•Decreased levels of antithrombin Ill, leading to hypercoagulability. PATHOPHYSIOLOGY •Normally, antithrombin III inhibits coagulation by neutralizing the activity of thrombin (factors 2a), 9a, and 10a. Decreased levels or dysfunction lead to increased risk of clotting. ETIOLOGIES •Inherited: autosomal-dominant. •Acquired: liver disease, nephrotic syndrome, DIC, chemotherapy CLINICAL MANIFESTATIONS •Increased incidence of venous thromboembolism - DVT & PE. DIAGNOSIS •Antithrombin III assays MANAGEMENT •Asymptomatic; anticoagulation only before surgical procedures. •Thrombosis: high-dose IV heparin followed by oral anticoagulation therapy indefinitely.

FOLATE DEFICIENCY

•Functions of Folate: folate required for DNA synthesis. Folate deficiency causes abnormal synthesis of DNA, nucleic acids, & metabolism of erythroid precursors. Folate stores only last for 2 - 4 months. EPIDEMIOLOGY: •Most common vitamin deficiency in the US. •If occurs during pregnancy, there is an increased risk of neural tube defects in neonates. ETIOLOGIES •Inadequate dietary intake: most common cause (eg, alcoholics, unbalanced diet, anorexia). •Increased requirements: pregnancy, infancy, hemolytic anemias, malignancy, Psoriasis (increased skin turnover). •Impaired absorption: Celiac disease, Inflammatory bowel disease, chronic diarrhea, anticonvulsants (eg, Phenytoin, Phenobarbital, Carbamazepine). •Impaired metabolism: Methotrexate, Trimethoprim, Pentamidine, antiseizure agents (eg, Phenytoin, Valproate, Carbamazepine), ethanol. •Loss: dialysis. CLINICAL MANIFESTATIONS •Anemia symptoms similar to B12 deficiency but without neurologic abnormalities [eg, subacute combined degeneration of the cord (progressive weakness, ataxia, paresthesias, paraplegia)]. •Hematologic: fatigue, exercise intolerance, pallor, chlorosis (pale, faintly green complexion extremely rare). •Epithelial: glossitis, aphthous ulcer, diarrhea, malabsorption. DIAGNOSIS •CBC with peripheral smear: Increased MCV (macrocytic anemia) >100 + megaloblastic anemia (hypersegmented neutrophils, macro-ovalocytes), low reticulocytes. May develop pancytopenia. •Decreased serum folate levels < 2 ng/mL. Decreased BC folate levels (< 150 ng/mL). • Increased LDH, increased homocysteine, normal methylmalonic acid (distinguishes folate from B12 deficiency). Patients should also be evaluated for B12 deficiency as both can coexist. MANAGEMENT •Oral folic acid first-line treatment (eg, 1 - 5 mg/day). Diet rich in fruits and vegetables. Overconsumption of folate may be associated with increased risk of malignancy. •Parenteral folic acid in severe folic acid deficiency. •Replacing folic acid in patients with B12 deficiency may correct the anemia but neurologic symptoms will worsen and may cause permanent neurological damage. •In patients on chronic folic antagonist therapy, Folic acid or folinic acid supplementation may prevent Folate deficiency. EXAM TIP •B12 & folate (in common): anemia, macrocytosis, macro-ovalocytes, decreased reticulocytes, hypersegmented neutrophils, and increased homocysteine. •B12 only: neurologic symptoms, increased methylmalonic acid. •Folate only: no neurologic symptoms, normal methylmalonic acid. CAUSES OF MACROCYTIC ANEMIA •B12 (Cobalamin) deficiency. Folate deficiency •Chronic liver disease, Alcoholism, Hypothyroidism •Myelodysplastic syndrome and acute leukemia

Beta Thalassemia

•Genetic hemoglobinopathy characterized by decreased production of beta-globin chains, leading to excess alpha chains. •Risk factors; most common in Mediterranean (eg, Greek, Italian), Africans, & Indians. B-Thalassemia trait (minor) Abnormal alleles: ½ B-Thalassemia Major (Cooley's Anemia) Abnormal Alleles: 2/2 B-Thalassemia Intermedia Milder homozygous form CLINICAL MANIFESTATIONS •Beta thalassemia minor (trait): most common type. Only one gene is defective. Usually asymptomatic but may have mild to moderate anemia. •Beta thalassemia intermedia: milder homozygous form (anemia, hepatosplenomegaly, bony disease). •Beta thalassemia major (Cooley's anemia): both beta genes are mutated. Deficient beta-chain production leads to excess alpha chains that are not able to form tetramers. This leads to ineffective erythropoiesis & shortened RBC life span. CLINICAL MANIFESTATIONS OF BETA-THAL MAJOR: •Symptoms often occur after 6-9 months of life when the switch from fetal hemoglobin (HbF), containing gamma globin, to adult hemoglobin (HbA), containing beta globin normally occurs. •Anemia: severe, chronic anemia: Pallor, irritability, dyspnea, mental delays. •Hemolytic anemia: jaundice, pigmented gallstones (calcium bilirubinate), hepatosplenomegaly. •Extramedullary hematopoiesis; marked overgrowth of the sinuses, abnormal, delayed skeletal development, increased prominence of the malar eminences, producing the characteristic "chipmunk facies" & dental malocclusion. Extramedullary expansion (frontal bossing, "hair on end" appearance of the skull, Osteoporosis, abnormal ribs). •Osteoporosis: by age 10, the haematopoietically-active red marrow is replaced by inactive yellow marrow, leading to Osteoporosis, compression fractures, cord compression, scoliosis, & disc degeneration. •Endocrine abnormalities: (due to iron overload) hypogonadism, diabetes, growth failure, hypothyroidism. Enlarged kidneys (due to increased hematopoiesis in the kidney) •Cardiac dysfunction: heart failure (high output), arrhythmias. •CBC in Beta thalassemia major: hypochromic, microcytic anemia (IMCV), normal or TRBC count, normal or serum iron. Hgb usually about 6g/dL. -Peripheral smear: microcytosis, target cells, teardrop cells, basophilic stippling, nucleated RBCs. Skull radiographs: bossing with "hair on end appearance" (due to extramedullary hematopoiesis). MANAGEMENT •Beta thalassemia minor (trait): no treatment needed. Genetic counseling •Moderate disease; folate (if increased reticulocyte count), avoid oxidative stress (eg, Sulfa drugs). Management of Beta thalassemia major (Cooley's anemia): •Often require frequent transfusions during periods of increased hemolysis or severe anemia. •Iron chelating agents (eg, Deferoxamine, Deferasirox) prevent iron overload & remove excess iron from chronic transfusions. Patients may develop endocrine deficiencies as a result of iron overload (eg, hypothyroidism, hypoparathyroidism, gonadal failure, diabetes mellitus) or CHF. •Vitamin C & folate supplementation (substrates for RBC production). •Splenectomy in some cases (stops RBC destruction). Allogeneic stem cell transplantation (curative). •Luspatercept promotes erythroid maturation, reducing transfusion needs in Beta-thalassemia.

Acute Myeloid Leukemia (AML)

•Group of hematopoietic neoplasms characterized by clonal proliferation of myeloid precursors with decreased ability to differentiate into more mature cells & blood, bone marrow, & tissue infiltration. •Most common acute leukemia in adults (80% of cases). Median onset 65 years of age. •PATHOPHYSIOLOGY: accumulation of leukemic blasts (immature WBCs) in the bone marrow, peripheral blood or occasionally other tissues. Increased production leads to pancytopenia. 3 MAJOR SUBTYPES: •Acute promyelocytic leukemia (APL or M3): t(15;17). Associated with DIC, presence of Auer rods (peroxidase-positive cytoplasmic inclusions), & myeloperoxidase positivity. •Acute megakaryoblastic leukemia: most common in children < 5 years of age with Down syndrome. •Acute monocytic leukemia: associated with infiltration of the gums (gingival hyperplasia). CLINICAL MANIFESTATIONS •Pancytopenia: anemia (eg, general fatigue most common presenting symptom, dyspnea, weakness), thrombocytopenia (mucocutaneous bleeding), and neutropenia (increased infections & fever). Leukostasis. Uncommon symptoms include lymphadenopathy and hepatosplenomegaly. DIAGNOSIS •CBC with peripheral smear: best initial test - normocytic normochromic anemia with normal or decreased reticulocyte count. Thrombocytopenia. May have circulating myeloblasts. The median presenting leukocyte count is ~15,000/uL (but they are dysfunctional) •Bone marrow biopsy: gold standard: >20% myeloblasts (immature cells with prominent nucleoli). Auer rods (pink/red rod-like granular structures in the cytoplasm) with APL. •Immunophenotyping: flow cytometry helps to characterize the types with FISH analysis - most accurate test. May have myeloperoxidase positivity with APL. MANAGEMENT •Combination chemotherapy: The most commonly used induction regimen includes Cytarabine PLUS an anthracycline (Doxorubicin, Daunorubicin, Idarubicin) alone or with other agents. •All-trans-retinoic acid can be added to M3 (Promyelocytic leukemia) because it induces the differentiation of leukemic cells bearing the t(15;17). •Hematopoietic stem cell transplant curative in some after remission.

Sickle cell disease

•Group of inherited disorders affecting the beta globin gene, leading to production of RBs that sickle, causing hemolysis & vaso-occlusive disease. CLINICAL MANIFESTATIONS Symptoms begin as early as 6-9 months (when HbSS replaces fetal hemoglobin). •Dactylitis most common initial presentation. Delayed growth & development, fever, infections. Bone infarction •Infections: -Functional asplenia & autosplenectomy (from repeated splenic infarctions) often by 1.5 - 3 years of age lead to increased risk of infection with encapsulated organisms (eg, S. pneumoniae, H. influenzae, N. meningitidis, Group B Streptococcus, Klebsiella, Salmonella). -Osteomyelitis: Salmonella spp. common organism in patients with Sickle cell disease. -Aplastic crisis associated with Parvovirus B19 infections. •Splenic sequestration crisis: vaso-occlusion in the spleen & RBC pooling in the spleen leads to acute splenomegaly and rapid decrease in hemoglobin. Often occurs in children. •Hemolytic anemia: jaundice, pigmented gallstones (calcium bilirubinate). •Painful vaso-occlusive "crisis": triggered by hypoxia, cold weather, infection, dehydration, ETOH, & pregnancy. Associated with abrupt onset of pain (acute chest syndrome, back, abdominal, bone pain). Renal or hepatic dysfunction. Priapism common. •Acute chest syndrome; fever, cough, tachypnea, oxygen desaturation, acute chest pain, and pulmonary infiltrates on chest radiographs and must be distinguished from an infectious pneumonia. •Bony vaso-occlusion: avascular (ischemic) necrosis of bones (eg, femoral or humeral head), "H" - shaped vertebrae (central endplate depression with normal anterior & posterior margins). •Skin Ulcers: especially on the tibia. •Chronic hypoxia: pulmonary hypertension, congestive heart failure, symptoms of fatigue, dyspnea. •Stroke (25% have one by age 45y, 25% children have silent episodes). Myocardial infarction. •Renal infarction or medication toxicity DIAGNOSIS Peripheral smear; best initial test •Target cells, sickled erythrocytes, decreased hemoglobin (baseline 8-10 g/dL but decreased in crisis), decreased hematocrit, reticulocytosis. •Howell-jolly bodies indicates functional asplenia. Hemoglobin electrophoresis: •Sickle cell disease: HbS (85-98%), no HbA, increased HbF, normal amounts of HbA2. •Sickle cell trait: HbS, decreased HbA - presence of both hemoglobin A (HbA) and Hemoglobin S (HbS) [~35-45% HbS] with the amount of HbA greater than HbS. DNA analysis definitive. MANAGEMENT Acute crises: •pain control: IV hydration & oxygen first step in the management of pain crisis (reverses & prevents sickling). Fast-acting oral or intravenous opiate as initial therapy. Meperidine is not recommended in patients with SCD (may lead to seizures & renal failure at high doses). •RBC transfusion therapy may be needed in some crises (eg, acute chest syndrome, splenic sequestration, preoperative transfusion). •Exchange transfusion therapy is used if there is severe or intractable vasoocclusive crisis (eg, acute chest syndrome, stroke, priapism, retinal infarction leading to visual changes). Reduction of episodes: •Hydroxyurea is first-line. Options for individuals who cannot tolerate Hydroxyurea or who have continued pain despite Hydroxyurea include L-glutamine, Crizanlizumab-tmca, & Voxelotor. Long-term: •Folic acid supplementation needed for RBC production & DNA synthesis without iron supplements. •Stroke prevention: Children with SS who are aged 2-16 years should have annual transcranial ultrasounds and, if the Doppler velocity is abnormal (200 cm/s or greater), beginning transfusions to prevent stroke should be considered. •Allogeneic stem cell transplant: is the only potentially curative treatment for Sickle cell disease but has significant adverse effects. Ideally performed in childhood before end-organ damage. INFECTION PREVENTION IN CHILDREN •In patients with Sickle cell disease, functional asplenia & autosplenectomy (from repeated splenic infarctions) often by 1.5 - 3 years of age lead to increased risk of infection with encapsulated organisms (eg, S. pneumoniae, H. influenzae, N. meningitidis, Group B Streptococcus, Klebsiella, Salmonella). Salmonella Osteomyelitis is usually associated with Sickle cell disease. •Prophylactic Penicillin (Erythromycin if Penicillin-allergic) is given as early as 2-3 months of age until at least 5 years of age to prevent infectious complications. •Pneumococcal and Influenza vaccines also help to reduce mortality. HYDROXYUREA Mechanism of action: •Increases production of HbF (which does not sickle and has a higher affinity for oxygen), increases RBC water, reduces RBC sickling, alters RBC adhesion to the endothelium. Inhibits ribonucleotide reductase. Indications: •Mainstay of treatment in SCD - reduces the frequency and severity of pain episodes, decreases hospitalization rates, and prolongs survival. •Because it takes weeks to months to take full effect, it is not used for acute episodes. Uses: •Sickle cell disease, Polycythemia vera, Essential thrombocythemia. •The combination of Hydroxyurea and L-glutamine can have additive benefits. Adverse effects: •Myelosuppression, GI (anorexia, nausea)

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Hemolytic anemia

•Hemolytic anemia: anemia caused by high RBC destruction when the rate of destruction exceeds the bone marrow's ability to replace the destroyed cells. There are two types: (1) intrinsic & (2) extrinsic. Intrinsic (inherited disorders): Sickle cell anemia, Thalassemia, G6PD deficiency, Hereditary spherocytosis. Extrinsic (acquired disorders): autoimmune hemolytic anemia, DIC, TTP, HUS, Paroxysmal nocturnal hemoglobinuria, Hypersplenism. DIAGNOSIS •Peripheral smear: increased reticulocytes (immature RBCs). Schistocytes (bite cells) if intravascular hemolysis. •Haptoglobin is decreased because it becomes depleted when Haptoglobin binds the free hemoglobin in the setting of continued RBC destruction. •Indirect bilirubin is increased due to increased BC destruction, which overwhelms the liver's ability to convert indirect bilirubin to direct bilirubin. •Reticulocyte count increases in response to increased BC destruction.The immature RBCs (reticulocytes) attempt to replace the mature RBCs that are being destroyed. •LDH increases because it is an enzyme that is released from destroyed RBCs. LOOK FOR THE FOLLOWING TO HELP DISTINGUISH BETWEEN THE HEMOLYTIC ANEMIAS: •Sickle cell anemia: sickled cells on peripheral smear, Hgb S on hemoglobin electrophoresis •Thalassemia: microcytic anemia with normal/high serum Fe or no response to Fe tx. Thalassemias are also associated with severe anemia & abnormal peripheral smear for a given hematocrit level. Alpha Thalassemia: hemoglobin electrophoresis with normal Hgb ratios of HgbA, A2, & F (Alpha thalassemia minima & minor; the presence of Hemoglobin H in Alpha thalassemia intermedia (Hemoglobin H disease). Hb Bart (gamma tetramers). Alpha thalassemia is a diagnosis of exclusion (since the peripheral smear is normal). Beta Thalassemia: hemoglobin electrophoresis: high HgbA2 &/or high HgbF; low HgbA. •G6PD deficiency: EPISODIC hemolytic anemia associated with sulfa drugs, fava beans, infections. •Hereditary spherocytosis: microspherocytes, Coombs NEGATIVE, + osmotic fragility test. •Autoimmune hemolytic anemia: microspherocytes, Coombs POSITIVE, RBC agglutination. •TTP & HUS: normal coags (PT & aPTT; unable to distinguish between TTP & HUS via labs). TTP: Pentad: Thrombocytopenia, hemolytic anemia, kidney damage, neurologic symptoms, fever. HUS: Triad: thrombocytopenia, hemolytic anemia, & kidney damage. HUS MC seen in children (especially with diarrhea prodrome). HUS has a higher association with kidney involvement than TTP & does not classically have fever or neurologic symptoms. •Disseminated intravascular coagulation: abnormal cogs (prolonged PT & PTT), decreased fibrinogen. •Paroxysmal nocturnal hemoglobinuria: dark urine (worse in the morning).

Myelodysplastic Syndrome (MDS)

•Heterogenous group of preleukemic disorders characterized by (1) clonal hematopoiesis, (2) abnormal maturation of cells of the myeloid cell line, resulting in ineffective hematopoiesis in the bone marrow and (3) one or more cytopenias (eg, anemia, neutropenia, &/or thrombocytopenia). RISK FACTORS •>65 years, radiation or chemotherapy, Benzene exposure, tobacco smoke, mercury or lead exposure. CLINICAL MANIFESTATIONS •May present as asymptomatic pancytopenia on routine CBC due to bone marrow failure. •Symptoms of pancytopenia - easy bruising, bleeding, frequent infections, & fatigue. DIAGNOSIS •CBC with peripheral smear: -Decreased number of one or more myeloid cell lines - platelets, neutrophils, or RBCs (may be nucleated). Normocytic or macrocytic anemia. Macro-ovalocytes may be seen. -Granulocytes commonly display reduced segmentation (hyposegmentation) often accompanied by decreased or absent granulation (known as pseudo Pelger-Huet cells). DIAGNOSTIC CRITERIA: •Cytopenia: - at least one of the following: hemoglobin <10 g/dL (100 g/L); absolute neutrophil count <1.8 x 10^9/L (<1800/microL); &/or platelets <100 x 10^9/L (<100,000/microL). •Dysplasia - Morphologic or immunophenotypic evidence of significant dysplasia in at least 10% of erythroid precursors, granulocytes, or megakaryocytes on the blood smear or bone marrow examination, in the absence of other causes of dysplasia. Increased myeloblasts in the blood and/or bone marrow (but <20%). •Cytogenetic abnormalities chromosomal abnormalities characteristic of MDS and not a component of Acute myelogenous leukemia [AML abnormalities include (8;21) (q22;q22); inv(16)(p13.1q22) or t(16;16) (p13.1;q22); and t(15;17) (q22;q21.1)] MANAGEMENT •Goals are symptomatic improvement, to improve survival, and to decrease progression to Acute myelogenous leukemia (AML). Lower-risk MDS management: •Asymptomatic patients: monitoring rather than immediate treatment is often used because early treatment of asymptomatic patients does not improve long-term survival and deferral management prevents potential treatment-related adverse events. •Symptomatic patients are treated according to the severity of cytopenias and symptoms (eg, ongoing transfusion requirements, progressive cytopenias, or a declining quality of life). Most patients are treated with a lower-intensity therapy eg, intermittent transfusions, Erythropoietin alfa, Luspatercept (hematopoietic growth factor), Hypomethylating agent (eg, Azacytidine, Decitabine), or Lenalidomide (if 5q deletion present). Higher-risk MS management: •Medically-fit - the choice of therapy is influenced by adverse pathologic features (eg, TP53 mutation, adverse cytogenetic abnormalities), targetable mutations, availability of a stem cell donor, and individual values and preferences. Treatment may include intensive (eg, intensive remission induction chemotherapy, with or without Allogeneic hematopoietic stem cell transplant) or lower-intensity therapies. •Medically-unfit, but not frail - lower-intensity therapy for most patients, with the choice of therapy based on pathologic features, drug availability, and patient preference. •Frail - patients are unlikely to tolerate treatment other than supportive care.

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Aplastic anemia

•Immune-mediated suppression of, or injury to, the hematopoietic stem cell characterized by bone marrow failure leading to varying degrees of (1) peripheral blood pancytopenia and (2) bone marrow hypocellularity (decreased or absent hematopoietic precursors in bone marrow). PATHOPHYSIOLOGY: •Loss of hematopoietic stem cells (HSCs): bone marrow hypoplasia or aplasia, most often due to autoimmune injury to multipotent hematopoietic stem cells (T cells attack hematopoietic stem cells) or direct stem cell damage leads to bone marrow failure, including replacement of marrow with fat. Other causes include direct stem cell injury & viral suppression. •Loss of HSCs result in a decrease in peripheral mature blood cells and pancytopenia. ETIOLOGIES •Idiopathic most common cause (65%) - T-cell mediated autoimmune response. •Ionizing radiation exposure (predictable, dose-related response). Chemicals (g, Benzene). •Viral infections: seronegative viral hepatitis (non-A through G) seen in 5-10% and most often affecting boys and young men, HIV. Parvovirus B19 in patients with baseline hemolytic anemias (eg, Sickle cell disease, G6PD deficiency). Other viruses. •Medications: antibiotics (eg, Chloramphenicol, Sulfa drugs), cytotoxic chemotherapy (anticipated dose-related effect), anti-epileptics (Carbamazepine, Phenytoin, Valproic acid), Quinine, NSAIDs, anti-thyroid medications, immunosuppressive agents (eg, Azathioprine, Methotrexate). •B12 & Folate deficiency can cause pancytopenia. •Acquired clonal abnormalities - Paroxysmal nocturnal hemoglobinuria (PNH), Myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML). •Fanconi anemia: most common hereditary cause. Pancytopenia, organ hypoplasia, and bone defects. CLINICAL MANIFESTATIONS Symptoms of pancytopenia - bleeding, easy bruising, frequent infections, & fatigue. •Thrombocytopenia: mucocutaneous bleeding - eg, epistaxis, bleeding gums, petechiae, purpura, bruising, menorrhagia. •Anemia: weakness, fatigue, dyspnea, pallor. Leukopenia: recurrent or frequent infections, fever. DIAGNOSIS •CBC/peripheral smear: at least 2 cytopenias reticulocytopenia <1% or < 40,000/ microL, neutropenia <500/microL, thrombocytopenia < 20,000/ microL, and/or anemia. •Bone marrow biopsy: hypocellular/aplastic bone marrow - marked hypocellularity with normal cell morphology, fatty bone marrow (replacement of normal marrow elements with fat cells & fibrotic stroma). No infiltration of the bone marrow with fibrosis or malignant cells. •Often a diagnosis of exclusion in the setting of bone marrow failure (PNH & myelodysplastic syndrome may present similar). MANAGEMENT •Supportive management initial treatment of choice - eg, infection prophylaxis with broad-spectrum antibiotics, PRBC transfusion for hemoglobin < 7 mg/dL, platelet transfusion for counts <10,000 or active bleeding. •Moderate AA: - For most medically-fit or less-fit patients with moderate AA, initial treatment with either lower-intensity Immunosuppressive therapy (IST) or single-agent Eltrombopag, rather than intensive IT or allogeneic HCT may be used. •Severe AA in otherwise healthy patients <40 years: Allogeneic hematopoietic stem cell transplantation treatment of choice with HLA-matched donor rather than immunosuppressants •Immunosuppressive therapy: severe or very severe AA in patients > 40 years of age (some experts advise >50 years) or in younger patients without a matched donor. Triple therapy used if medically fit (eg, horse anti-thymocyte globulin + Cyclosporine + Eltrombopag).

For each of the following hematologic conditions, students should describe the underlying pathophysiology, presenting signs and symptoms, basic epidemiology, modifiable (when applicable) and non-modifiable risk factors, differential diagnosis, appropriate diagnostic studies, clinical intervention, treatment guidelines, pharmaceutical therapies, and health maintenance concerns: Deep venous thrombosis (DVT)

•Most important consequence is pulmonary embolism (50%): both are manifestations of a single entity. RISK FACTORS (Virchow's triad) •Intimal damage: trauma, infection, inflammation Endothelial damage triggers the clotting cascade. •Stasis eg, Immobilization or prolonged sitting >4hours, surgery (typically within 12 weeks of surgery or trauma), Stroke with hemiplegia or immobility. •Hypercoagulability: eg, Protein C or S Deficiency, Factor V Leiden mutation, antithrombin III deficiency, oral contraceptive use, malignancy, pregnancy, smoking. CLINICAL MANIFESTATIONS •DVT should be suspected in patients who present with leg swelling, pain, warmth, and erythema. Physical examination: •Unilateral calf swelling (edema) 3 cm or greater than the other leg, measured 10 cm below the tibial tuberosity most specific sign. Calf pain & tenderness. May be warm to palpation. •Homan sign: deep calf pain with foot dorsiflexion while squeezing the calf (not reliable). DIAGNOSIS •Venous Duplex Ultrasound: usually first-line imaging. Most DVTs originate in the calf. •Compression ultrasonography (CUS) with Doppler is the diagnostic test of choice in patients with suspected DVT. Non-compressibility of the affected vein = DVT. •D-dimer: highly sensitive but not specific. There are 2 main uses of D-dimer: negative D-dimer with a low-risk for DVT can exclude DVT as the diagnosis. In a patient with moderate risk, a positive D-dimer and a negative initial ultrasound, serial ultrasounds are recommended. In general, any positive VT should be followed by ultrasonography. •Contrast venography: definitive diagnosis (gold standard). It is invasive, difficult to perform, and rarely used. CT venography and MR venography rarely used. MANAGEMENT •Anticoagulation: first-line treatment for most patients with DVT (eg, popliteal, femoral, iliac veins). Options include (1) Low molecular weight heparin + Warfarin, (2) LMWH + either Dabigatran or Edoxaban or (3) monotherapy with either Rivaroxaban or Apixaban. A minimum of 3 months of oral therapy has been suggested after a first episode of DVT or PE. •IVC filter: 3 main reasons for IVC filter placement: recurrent DVT/PE despite adequate anticoagulation OR stable patients in whom anticoagulation is contraindicated OR right ventricular dysfunction with an enlarged RV on echocardiogram. •In general, subcutaneous LMWH (eg, Enoxaparin) is preferred over IV Unfractionated Heparin (UFH) or subcutaneous UFH in most pregnant patients with DVT/PE because it is easier to use, appears to be more efficacious, and has a better safety profile. •Thrombolysis or Thrombectomy: generally not performed (reserved for massive DVT or if severe) RISK FACTORS VENOUS THROMBOEMBOLISM (VTE) RECOMMENDED DURATION OF THERAPY 1st event with reversible or time-limiting RF for VTE at least 3 months (Risk factors: trauma, surgery, OCPs etc). 1st episode of IDIOPATHIC VT (no malignancy) Proximal DVT or PE Distal DVT Long-term anticoagulation 3 months if severely symptomatic distal DVT No tx & surveillance (ultrasound) if asymptomatic distal DVT LMWH preferred as initial & long-term therapy. Pregnancy LMWH as initial & long-term therapy. Warfarin or direct oral Malignancy anticoagulants are alternatives to LMWH in these patients. 2016 ACCP guidelines: novel oral anticoagulants (Apixaban, Dabigatran, Edoxaban, Rivaroxaban) are preferred over Warfarin therapy in the management of DVT/PE (if no cancer is present).

Chronic Myelogenous Leukemia (CML)

•Myeloproliferative disorder of uncontrolled production of mature and maturing granulocytes with fairly normal differentiation (predominately neutrophils but also basophils & eosinophils). PATHOPHYSIOLOGY •Fusion of 2 genes: BCR (on chromosome 22) & ABL1 (on chromosome 9), result in BCR-ABL1 fusion gene. Translocation between chromosomes 9 & 22 = Philadelphia chromosome (abnormal chromosome 22 which harbors the BCR-ABL1 gene) causes hyperactive tyrosine kinase activity. CLINICAL MANIFESTATIONS •Chronic phase: 70% asymptomatic - usually detected incidentally on CBC (well-differentiated WBCs - granulocyte proliferation). Pruritus after hot baths/showers (histamine release from Basophils). Fatigue, night sweats, malaise, weight loss, fever, early satiety. Splenomegaly most common finding. Tenderness over the lower sternum. •Accelerated phase: neutrophil differentiation becomes progressively impaired and leukocyte counts are more difficult to control with chemotherapy. Fatigue, weight loss, excessive sweating, bleeding from thrombocytopenia, abdominal pain. •Blastic crisis: presents as acute leukemia and extramedullary tissue involvement (eg, lymph nodes, skin, and soft tissues). May be associated with rapidly enlarging spleen. DIAGNOSIS •CBC with peripheral smear: leukocytosis (may be strikingly elevated) with granulocytic cells (eg, basophilia, neutrophilia, & eosinophilia). The cells look morphologically normal but are cytochemically abnormal on immunochemistry. Anemia in 1 /3 of patients. •Leukocyte alkaline phosphatase score: decreased LAP score due to dysfunctional WBCs (LAP only found in functioning WBCs not leukemic cells). •Bone marrow biopsy: granulocytic hyperplasia (hypercellular with elevated basophils & eosinophils). Chronic: < 5% blasts, Accelerated: 10-19% blasts; Acute blast crisis: > 20% blasts. Genetic testing: •Cytogenic analysis and fluorescence in situ hybridization (FISH) most accurate - genetic testing for the Philadelphia chromosome (BCR-ABL1 fusion gene) or the fusion BCR-ABL1 fusion mRNA via conventional cytogenetic analysis (karyotyping) or via reverse transcription polymerase chain reaction (RT-PCR) can be performed on peripheral blood or bone marrow aspirate. 90-95% have the t(9;22)(q34;911.2) reciprocal translocation that results in the Philadelphia chromosome. MANAGEMENT: •Tyrosine kinase inhibitors: first-line therapy for almost all newly diagnosed CML (eg, First-generation Imatinib & second-generation Dasatinib, Nilotinib, or Bosutinib). TKIs inhibit Philadelphia chromosome tyrosine kinase activity and myeloid leukemic cell proliferation implicated in the pathogenesis of CML. They often achieve long-term control in a majority of patients (especially in the chronic phase). CML in the accelerated phase or blastic crisis is much more difficult to control & initial response to TKI therapy in these patients is often of short duration. For chronic phase, CML with intermediate- or high-risk score, second-generation tyrosine kinase inhibitors (Bosutinib, Dasatinib, Nilotinib) as first-line therapy may have an additional benefit over Imatinib. •Omacetaxine is a selective inhibitor of the synthesis of the BCR-ABL1 oncoprotein used as a treatment option in cases refractory to tyrosine kinase inhibitor therapy that advanced from chronic phase CML. •Allogeneic hematopoietic stem cell transplant is a curative treatment option but not often used as first-line therapy because it is associated with potential increase in toxicity and early mortality. Indications include treatment of advanced CML (accelerated phase & blast crisis), and chronic phase in patients with a suitable donor who are resistant to TKI therapy. •Palliative therapy with cytotoxic agents - Hydroxyurea, Interferon alfa with or without Cytarabine, and Busulfan.

Tumor Lysis Syndrome

•Oncologic emergency occurring with the treatment of neoplastic disorders due to rapid tumor cell lysis after initiation of chemotherapy, releasing massive amounts of potassium, phosphate, and nucleic acids into the circulation. Calcium & uric acid deposition can lead to Acute kidney injury. RISK FACTORS •High tumor burden (eg, initial WBC count > 20,000/microL), dehydration, & volume depletion. •Large proliferation rate (eg, Acute lymphoblastic leukemia) and high-grade Lymphomas (eg, Burkitt). CLINICAL MANIFESTATIONS •Related to the metabolic derangements muscle cramps, tetany, nausea, vomiting, diarrhea, anorexia, lethargy, syncope, hematuria, heart failure, kidney injury, & cardiac dysrhythmias. LABORATORY FINDINGS: •Hyperphosphatemia, hypocalcemia, hyperuricemia, hyperkalemia, and acute kidney injury (including uric acid nephropathy). MANAGEMENT •Treatment of electrolyte abnormalities, IV fluids (may add loop diuretic) to promote excretion & wash out of the obstructing uric acid crystals, & a hypouricemic agent (Rasburicase preferred). • Hemodialysis (renal replacement therapy) if severe. PROPHYLAXIS •Rasburicase (or Allopurinol) PLUS aggressive IV fluid hydration. •Rasburicase: recombinant uricase that catalyzes oxidation of uric acid to a stable compound. Maybe more effective than Allopurinol. Contraindicated if G6PD deficiency. •Allopurinol: xanthine oxidase inhibitor, leading to decrease uric acid production.

Disseminated Intravascular Coagulation (DIC)

•Pathological intravascular activation of the coagulation system PATHOPHYSIOLOGY: •Uncontrolled fibrin production due to tissue factor activation leads to widespread microthrombi, which consumes coagulation proteins (V, VIlI, fibrinogen) & platelets. Consumption then leads to severe thrombocytopenia, manifested by diffuse bleeding & organ ischemia from microthrombi. ETIOLOGIES •Usually occurs as an acute complication of underlying life-threatening illnesses. •Infections (eg, bacterial sepsis most common), Rocky Mountain spotted fever, viral •Malignancies: Acute myelogenous leukemia; Lung, Gl, or prostate malignancies. •Obstetric: Pre-eclampsia; ~50% of patients with Abruptio placenta or amniotic fluid embolism have evidence of DIC, septic abortion; Hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). •Massive tissue injury & trauma, complications after surgery, burns, liver disease, Aortic aneurysm, Acute respiratory distress syndrome (ARDS). CLINICAL MANIFESTATIONS •Bleeding: oozing from venipuncture sites, catheters, drains, extensive bruising, bleeding from multiple sites (eg, gingiva, areas of trauma or surgery, the rectum, the vagina, etc.), ecchymoses. •Thrombosis; arterial and/or venous - gangrene or multi-organ dysfunction (eg, renal, hepatic). Physical examination: •Bleeding: ecchymosis, purpura, petechiae, hematomas, obvious bleeding, frank hemorrhage in various areas of the body may be noted. Clotting: mottling, cyanosis, gangrene. DIAGNOSIS •Increased thrombin formation: decreased fibrinogen (widespread activation of the clotting cascade). Reduced levels of coagulation inhibitors (eg, antithrombin, protein C, and protein S). •Coagulation factor consumption: prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), increased International normalized ratio (INR). Decreased levels of procoagulant factors [eg, factors 7, 10, 5, and 2 (prothrombin)]. Increased bleeding time. •Increased fibrinolysis: elevated fibrin degradation products and D-dimer. D-dimer is a fibrin degradation product that has a high sensitivity but low specificity for the presence of DIC. •CBC with peripheral smear: thrombocytopenia, fragmented RBCs, & schistocytes. MANAGEMENT •Treating the underlying cause is the mainstay of treatment. •Platelet transfusion if platelet count <20,000/microL if not actively bleeding. •Fresh frozen plasma if severe bleeding (replaces coagulation factors) •Cryoprecipitate (replaces fibrinogen in patients with severely low levels). •Heparin for thrombosis in some patients.

B12 deficiency

•Sources of B12: natural sources mainly animal in origin (eg, fish, meats, eggs, dairy products). •Absorption: B12 is released by the acidity of the stomach and combines with intrinsic factor (produced by the parietal cells) in an acidic environment, later absorbed mainly via distal ileum. •Function of B12: Vitamin B12 is essential for neurologic function, red blood cell production. and DNA synthesis; it is a cofactor for 3 major reactions: conversion of methylmalonic acid to succinyi Coenzyme A; conversion of homocysteine to methionine; & conversion of 5-MTH to tetrahydrofolate. •Substantial hepatic B12 stores may delay manifestations for 5-10 years after the onset of deficiency. ETIOLOGIES Decreased B12 absorption: •Decreased intrinsic factor: Pernicious anemia most common cause of B12 deficiency (lack of intrinsic factor due to parietal cell antibodies, leading to gastric atrophy), gastric bypass, post gastrectomy, gastritis, achlorhydria, tropical sprue, Gastrinoma (Zollinger-Ellison syndrome). •Ileal disease: Crohn disease (affects the terminal ileum), Ileal resection, Fish tapeworm. •Medications: H2 blockers & Proton pump inhibitors (decrease acid), decreased nucleic acid synthesis (Metformin, Zidovudine, Hydroxyurea), anticonvulsants. Chronic alcohol use. Decreased intake; Vegans (due to lack of consumption of meat and meat products). CLINICAL MANIFESTATIONS •Anemia symptoms similar to Folate deficiency but associated with spinal cord involvement. •Hematologic: fatigue, exercise intolerance, pallor. Epithelial: glossitis, diarrhea, malabsorption. •Neuropsychiatric symptoms: symmetric paresthesias & numbness most common initial symptom (especially involving the legs). Later, lateral and posterior spinal cord demyelination & degeneration: gait ataxia, weakness, vibratory, sensory, & proprioception deficits, including difficulty with balance. May develop dementia, psychosis, or seizures. On examination, decreased deep tendon reflexes (hypotonia) or + Babinski, may be seen. DIAGNOSIS •CBC with peripheral smear: increased MCV (macrocytic anemia) + megaloblastic anemia (macro-ovalocytes & hypersegmented neutrophils with >5 lobes). May be accompanied by a mild leukopenia and/or thrombocytopenia (B12 deficiency affects all cell lines). Low reticulocytes. •Increased serum LDH & indirect bilirubin due to intramedullary destruction of developing abnormal erythroid cells. •Decreased serum B12 levels: <200 pg/mL; symptomatic patients are often <100 pg/mL. •Increased homocysteine. Increased methylmalonic acid [MMA] distinguishes B12 from Folate deficiency, (FD is associated with increased homocysteine & normal MMA). 1MMA in B12 deficiency occurs because B12 is a cofactor in the conversion of methylmalonyl-CoA to succinyl-CoA. MANAGEMENT B12 replacement •Routes of administration: oral, sublingual, nasal and intramuscular/deep subcutaneous injection. Symptomatic anemia or neurological findings: •Start with IM B12. In adults, IM Cyanocobalamin injection weekly until the deficiency is corrected and then once monthly. Patients can be switched to oral therapy after resolution of symptoms. Patients with Pernicious anemia need lifelong monthly IM therapy (or high-dose oral therapy). •With adequate treatment, a brisk reticulocytosis occurs in 5-7 days, and the hematologic picture normalizes in 2 months. •Hypokalemia may complicate the first several days of therapy, particularly if the anemia is severe (due to placement of potassium into the newly formed cells). Dietary deficiency: Oral B12 replacement.

Leukostasis reaction

•Symptomatic hyperleukocytosis most commonly seen in Acute myeloid leukemia or Chronic myeloid leukemia in blast crisis. Medical emergency due to decreased tissue perfusion from leukostasis. •Pathophysiology: leukostasis leads to increased blood viscosity and white cell plugs in the microvasculature, impeding blood flow in addition to causing local hypoxemia due to high metabolic activity of the rapidly dividing blasts. CLINICAL MANIFESTATIONS •Pulmonary: dyspnea, hypoxemia with or without diffuse alveolar or interstitial infiltrate formation. •Neurologic: headache, dizziness, visual changes, tinnitus, gait instability, confusion, somnolence, coma. Other: priapism, bowel infarction, myocardial ischemia. DIAGNOSIS •Hyperleukocytosis (WBC > 50 - 100 x 109/L 100,000/microL) + symptoms due to tissue hypoxia (eg, lung, CNS). MANAGEMENT •Cytoreduction: leukapheresis (associated with rapid improvement), cytoreduction therapy (eg, Hydroxyurea), or induction chemotherapy. Prophylaxis for tumor lysis syndrome initiated.

Hemolytic Uremic Syndrome (HUS)

•Thrombotic microangiopathy due to platelet activation by exotoxins leads to microvascular thrombosis. •Triad of (1) thrombocytopenia, (2) microangiopathic hemolytic anemia. & (3) renal dysfunction (uremia). Fever and neurologic symptoms (seen in TP) are often absent in HUS. RISK FACTORS •Predominantly seen in children (especially <5y) with a recent history of gastroenteritis. •In adults, it is associated with HIV, SLE, antiphospholipid syndrome or chemotherapy (eg, Mitomycin, Bleomycin, Cisplatin Gemcitabine). PATHOPHYSIOLOGY •D+ HUS (classic): associated with diarrhea prodrome (>90% in children). Exotoxins (eg, Shigella toxin & Shiga-like toxin of Enterohemorrhagic E. coli 0157:H7) enter the blood, where they damage the vascular endothelium, activating platelets (microthrombi formation), eventually depleting platelets. The toxins preferentially damage the kidney, leading to uremia. •P-HUS: Streptococcus pneumonia releases neuraminidase, which initiates an inflammatory reaction. Occurs mainly in young children and infants who usually present with Pneumonia. •Complement-mediated [D- HUS (atypical)]: not associated with diarrhea (not related to Shiga toxin). Not common. Genetic defects in proteins that regulate complement activity. CLINICAL MANIFESTATIONS •In children, may have a prodromal diarrheal illness (abdominal pain, diarrhea which is usually bloody, nausea, vomiting) 5-10 days prior to renal manifestations (eg, oliguria & hematuria). •Physical examination: pallor (anemia), jaundice (hemolysis), hepatosplenomegaly. Petechiae & purpura are uncommon. DIAGNOSIS Labs are the same in TTP and HUS •Labs: thrombocytopenia with normal coagulation studies (PT, aPTT, fibrinogen) are seen in both TTP & HUS. Normal coagulation studies (PT & aPTT) help to distinguish TTP & HUS from DIC. •Hemolysis: peripheral smear - schistocytes (helmet cells), bite or fragmented cells, reticulocytosis, increased lactate dehydrogenase [LDH], increased bilirubin, decreased haptoglobin. •Increased BUN and creatinine. Coombs negative. Increased bleeding time. •Positive stool culture for E coli 0157:H7 or detectable antibody to Shiga toxin MANAGEMENT •Supportive therapy mainstay of treatment - eg, fluid & electrolyte replacement, dialysis discontinuing any nephrotoxic medications, & RBC transfusion if severe anemia. •Plasma exchange therapy [Plasmapheresis] (with or without fresh frozen plasma) if severe, neurologic complications (eg, stroke), & non-renal complications. •Antibiotics and anti-motility agents are usually avoided because they may worsen the condition.

Hemophilia B

•X-linked recessive disorder occurring almost exclusively in males (rarely in homozygous females). •Also known as Christmas disease. Clinically indistinguishable from Hemophilia A. •Lack of Factor IX (9) affects the clotting cascade, leading to failure of hematoma formation. CLINICAL MANIFESTATIONS •Hemarthrosis: delayed bleeding after trauma or spontaneously, or swelling in weight-bearing joints (eg, ankles, knees, elbows), soft tissues, & muscles (eg, forehead hematoma). May lead to arthropathy (may be preventable by long-term prophylaxis with factor concentrates). •Excessive hemorrhage due to trauma, surgery, or incisional bleeding (eg, tooth extraction). •Epistaxis, bruising. Gl or urinary tract hemorrhage. •Hemophilias less commonly present with purpura, petechiae (because platelet function is normal), or spontaneous hemorrhage (except in the severe form). DIAGNOSIS •Low Factor IX (9) - most sensitive. •CBC & coagulation studies: Prolonged aPTT. Normal PT, fibrinogen, & platelets (bleeding time). •Mixing studies: prolonged PTT corrects with mixing studies (indicating a factor deficiency). MANAGEMENT •Factor IX (9) infusion first-line therapy to increase levels 25-100% (depending on severity). Can be given in response to an acute bleeding episode or prophylaxis (eg, prior to surgery). •Unlike Hemophilia A, Desmopressin is not useful.

Hemophilia A

•X-linked recessive disorder occurring predominantly in males (rarely in homozygous females). Can also be caused by spontaneous mutation. •Most common type of Hemophilia. First episode usually <18 years of age. •Lack of Factor VIII (8) affects the clotting cascade, leading to failure of hematoma formation. CLINICAL MANIFESTATIONS •Hemarthrosis (80%): delayed bleeding after trauma or spontaneously, or swelling in weight-bearing joints (eg, ankles, knees, elbows), soft tissues, & muscles (eg, forehead hematoma). May lead to arthropathy (may be preventable by long-term prophylaxis with factor concentrates). •Excessive hemorrhage due to trauma, surgery, or incisional bleeding (eg, tooth extraction). •Epistaxis, bruising. Gl or urinary tract hemorrhage. •Hemophilias less commonly present with purpura, petechiae (because platelet function is normal), or spontaneous hemorrhage (except in the severe form). DIAGNOSIS •Low Factor VIII (8) - most sensitive. •CBC & coagulation studies: Prolonged aPTT. Normal PT, fibrinogen, platelet levels (bleeding time). •Mixing studies: PTT corrects with mixing studies (factor deficiency). MANAGEMENT •Factor VIII infusion first-line therapy to increase levels 25-100% (depending on severity). Can be given in response to an acute bleeding episode or prophylaxis (eg, prior to surgery, after trauma). •Desmopressin (DDAVP): transiently increases Factor VIII & vWF release from endothelial stores. May be used prior to procedures to prevent bleeding in mild disease. •Emicizumab is a humanized bispecific monoclonal antibody that binds to both factor IXa and factor X, substituting for the role of factor VIII in hemostasis.

G6PD deficiency anemia

•X-linked recessive enzymatic disorder of RBCs that may cause (1) neonatal hyperbilirubinemia, (2) episodic acute hemolytic anemia, or (3) chronic hemolysis. EPIDEMIOLOGY •Primarily males (X-linked recessive). Black males most commonly affected in the US - 10-15%. •Common in areas where Malaria is endemic: most commonly affects persons of African, Southeast Asian, Mediterranean, Middle-Eastern descent (G6PDD thought to decrease risk of severe Malaria). PATHOPHYSIOLOGY •Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that normally catalyzes NADP to generate nicotinamide dinucleotide phosphate (NADPH), which protects erythrocytes from oxidative injury. •In G6PD deficiency, decreased G6PD activity during oxidative stress results in rapid depletion of reduced glutathione, resulting in an oxidative denatured form of hemoglobin (methemoglobin) that precipitates as Heinz bodies. •Hemolysis; BC membrane damage and fragility causes both extravascular & intravascular hemolysis. Extravascular RBC destruction by reticuloendothelial macrophages in the spleen, marrow & liver. EXACERBATING FACTORS •Infection most common cause (eg, DKA). Fava beans (broad beans) ingestion. •Oxidative medications: Dapsone, Primaquine, Methylene blue, Nitrofurantoin, Phenazopyridine, Rasburicase. Naphthalene mothball, henna. "Sulfa" drugs at high doses. CLINICAL MANIFESTATIONS •Most are asymptomatic, with no anemia or hemolysis until times of oxidative stress. •Episodic hemolytic anemia: symptoms begin 2-4 days after exposure of precipitants - sudden onset of symptoms of anemia (eg, fatigue, pallor), jaundice & dark urine (indirect bilirubinemia), back or abdominal pain. Acute kidney injury may occur in severe cases. •Neonatal jaundice - G6PD deficiency should be considered in neonates who develop hyperbilirubinemia within the first 24 hours of life or 2-3 days after birth. •Physical examination: during hemolytic episodes +jaundice, scleral icterus, & transient splenomegaly. DIAGNOSIS •Peripheral smear: Normocytic hemolytic anemia only during crises - schistocytes ("bite" or fragmented cells). + Heinz bodies hallmark. Smear is usually normal when not in acute stage. •Hemolytic anemia: increased reticulocytes, increased indirect bilirubin, increased lactate dehydrogenase (LDH), and decreased haptoglobin. Screening tests: •G6PD activity enzyme assays: Rapid fluorescent spot test most sensitive in detecting the generation of NADPH from NADP. The test is positive if the blood spot fails to fluoresce under ultraviolet light. Timing of testing: Performed after episodes because in acute hemolysis, testing for G6PD deficiency may be falsely negative (older erythrocytes with higher enzyme deficiency have been hemolyzed). If initial testing is negative + suspicion remains, repeat testing ~3 months. •Confirmatory tests: Quantitative G6PD assays. Molecular, genetic, or DNA testing not used routinely MANAGEMENT •Conservative: avoidance of oxidative stressors is the mainstay of treatment, such as avoiding offending food & medications, treating underlying infection. Acute hemolysis usually self-limited •Severe anemia: iron and folic acid supplementation. Rarely, blood transfusions are indicated if severe (eg, hemoglobin < 7 g/dL without hemolysis if hemoglobin < 9 g/dL with hemolysis), •Neonatal jaundice: phototherapy first-line. Exchange transfusion if refractory to phototherapy.