EOR - Family Med - Hematology

Hemolytic Uremic Syndrome

Thrombotic microangiopathy due to *platelet activaion by exotoxins* *Triad of:* 1) *thrombocytopenia* 2) *hemolytic anemia* 3) *renal dysfunction* (uremia) - Fever and neuro symptoms (seen in TTP) are often ABSENT in HUS RF: - *Predominantly seen in kids with hx of gastroenteritis* - In adults, it is associated with HIV, SLE< antiphospholipid syndrome, or chemotherapy (i.e. Mitomycin, Bleomycin, Cisplatin Gemcitabine Patho: - *D(+) HUS (classic): associated with diarrhea prodrome*. Exotoxins (i.e. Shigella toxin and Shiga-like toxin in *Enterohemorrhagic E coli 0157:H7)* enters the blood where it *damages vascular endothelium, activating platelets (microthrombi formation)*, eventually depleting platelets. The toxins preferentially damage the kidney, --> *UREMIA*. - D(-) HUS: not associated with diarrhea. Not common - P- HUS: Streptococcus pneumonia releases neuraminidase, which initiates an inflammatory reaction ----------------------------------------------- CF: - May have a prodromal illness 5-10 days prior (*Abdominal pain, bloody diarrhea, nausea, vomiting). Renal involvement (i.e. *oliguria and hematuria*) PE: - pallor (anemia), jaundice (hemolysis), hepatosplenomegaly. Petechiae and purpura are uncommon DX: - Labs are the same in TTP and HUS: - *thrombocytopenia with normal coagulation studies* (seen in both TTP and HUS). - Normal coagulation studies (PT and PTT) helps to distinguish TTP/HUS from DIC - *Hemolysis* - peripheral smear - schistocytes (helmet cells), bite or fragmented cells, reticulocytes, increased LDH and bilirubin, decreased haptoglobin - *Increased BUN and Creatinine*. Coombs (-). Increased bleeding time TX: - *INITIAL TOC = Supportive* - i.e. fluid/electrolyte replacement, dialysis, D/C any nephrotoxic medications, RBC transfusion if severe anemia - *plasmapheresis* (with or without FFP). *If severe*, neuro complications and non-renal complications - *Antibiotics and anti-motility agents are usually avoided bc they may worsen the condition*

Hemophilia B

"CHRISTMAS DISEASE" FACTOR IX DEFICIENCY" *B-9" *X0linked recessive disorder occurring aALMOST EXCLUSIVELY IN MALES* (rarely in homozygous females). - Clinically indistinguishable from hemophilia A - *lack of Factor IX* affects the clotting cascade --> failure of *hematoma formation* CF: - *Hemarthrosis* (80%) --> *delayed bleeding or swelling in weight-bearing joints* (i.e. *ankles*, knees, elbows), soft tissues, and muscles (i.e. forehead hematoma) - *Excessive hemorrhage due to trauma and surgery or incisional bleeding* (i.e. tooth extraction) - Epistaxis, bruising, GI or urinary tract hemorrhage - Hemophilias less commonly present with purpura, petechiae (because platelet function is normal), or spontaneous hemorrhage (except in the severe form) ----------------------------------------------- DX: - CBC and coag studies --> *Prolonged aPTT*. Normal PT, fibrinogen, *platelet levels* (bleeding time). - Mixing studies: *PTT corrects with mixing studies* (factor deficiency). *low Factor IX* - most sensitive TX: - *Factor IX infusion = 1st line* --- to increase levels 25-100% (depending on severity). -Can be given in response to an *acute bleeding episode or prophylaxis* (i.e. prior to sx, after trauma) - *UNLIKE HEMOPHILIA A, Desmopressin is NOT useful*

Chemo Drugs: Platinum Agents MOA: Indications: ADR:

Cisplatin Carboplatin ----------------------------------------------- MOA: - Inhibits DNA synthesis similar to *alkylating agents* - The platinum ion binds to DNA and crosslinks DNA. This interferes with DNA synthesis and cellular metabolism, triggering cell death! ----------------------------------------------- Indications: - Cisplatin: advanced metastatic testicular, ovarian, and bladder cancers - Carboplatin: advanced ovarian cancer ----------------------------------------------- ADR: - *Neurotoxicity - ototoxicity* (acoustic nerve damage causes hearing loss usually bilateral and irreversible, tinnitus, vertigo), peripheral neuropathy - *Nephrotoxicity* - AKI may be reduced with hydration and Amifostine, a free radical scavenger - *Highly emetogenic* - Electrolyte disorders: i.e. Hypomagnesemia, Hypocalcemia

Chemo Drugs: Alkylating Agents MOA: Indications: ADR:

Cyclophosphamide Ifosfamide ----------------------------------------------- MOA: - inhibits DNA replication by *alkylating DNA* (requires bioactivation by the liver) ----------------------------------------------- Indications: - leukemia, lymphoma, multiple myeloma, ovarian and breast cancer, RA, rapidly-progressive GN ----------------------------------------------- ADR: - *hemorrhagic cystitis* (reduced by increased hydration, Mesna or N-acetylcystein) - GI mucosal damage (i.e. NV, *Stomatitis, Diarrhea*), emesis, myelosuppression - SIADH - *bladder cancer*

Chemo Drugs: Antimetabolites: CYTARABINE AND GEMCITABINE MOA: Indications: ADR:

Cytarabine MOA: - inhibits DNA and RNA synthesis ----------------------------------------------- Indications: - hematologic cancers (AML, ALL, blastic phase of CML), NHL - poor activity vs solid tumors ----------------------------------------------- ADR: - *CNS neurotoxicity* (cerebellar syndrome), myelosuppression, stomatitis, emetogenic, sloughing off of the skin on the palms and soles, *ocular toxicity, ototoxicity* ----------------------------------------------- ----------------------------------------------- Gemcitabine MOA: - inhibits DNA synthesis ----------------------------------------------- Indications: - advanced breast, ovarian, pancreatic, and non-small cell lung cancers ----------------------------------------------- ADR: - emetogenic, hepatitis, myelosuppression

Hodgkin Lymphoma (HL): DX and TX

DX: - *Excisional whole lymph node biopsy*: *REED-STERNERG CELL PATHOGNOMONIC* - large cells with bi- or multilobed nuclei (*owl eye appearance*) and inclusions in the nucleoli. Reed-Sternberg cells are derived from an abnormal germinal B cell in the early stage of differentiation with CD15 and CD30 positivity - Imaging for staging: combined PET/CT scan of chest, thorax, and abdomen ----------------------------------------------- TX: - Early stage disease (stage I or II): *Combination of chemo+radiation therapy*. Chemo alone is an acceptable alt - Advanced stage (III to IV): *combination chemo = MAINSTAY. - Radiation therapy may be used for select patients as consolidation. - *"ABVD"*: Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine - "MOPP": Mustine, Oncovorin/Vicristine, Procarbazine, Prednisolone - Refractory/Resistant: 2nd line high dose chemotherapy and autologous hematopoietic cell transplant are options

Factor V Leiden

Most common inherited cause of hypercoagulability (thrombophilia) - 5% of the US population Patho: - *mutated Factor V is resistant to breakdown by activated protein C* --> increased hypercoagulability CF: - Increased incidence of DVT, PE, hepatic vein, or cerebral vein thrombosis*. Increased risk of miscarriages during pregnancy - Not associated with increased risk of myocardial infarctions or CVA. DX: - Activated protein C resistance assay. (if (+), confirm with DNA testing) - DNA testing mutation analysis. Used in patients with a FHx or Factor V Leiden mutation or for members of a thrombophilic family - Normal PT and pTT TX: - High-risk: *indefinite anticoagulation* - may need thromboprophylaxis with low molecular weight Heparin during pregnancy to prevent miscarriages. - Moderate-risk: (i.e. 1 thrombotic event with a prothrombotic stimulus or asymptomatic) prophylaxis during high-risk procedures

Chronic Myelogenous Leukemia (CML)

Myeloproliferative disorder of *uncontrolled production of mature and maturing granulocytes* with fairly normal differentiation (*predominantly neutrophils* but also basophils and eosinophils) Patho: - Fusion of 2 genes: BCR (chromosome 22) and ABL1 (chromosome 9), resulting in the *BCR-ABLE1 fusion gene. Translocation between chromosomes 9 and 22 = Philadelphia chromosome* (abnormal chromosome 22 which harbors the BCR-ABL1 gene) CF: - Fatigue, night sweats, malaise, weight loss, fever - *MC finding = Splenomegaly* - *Pruritus after hot baths/showers* (histamine release from basophils) - Chronic phase: 70% asymptomatic - usually detected on CBC (well-differeniated WBCs - granulocyte proliferation) - 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 intramedullary tissue involvement (i.e. lymph nodes, skin, and soft tissues) ----------------------------------------------- DX: - CBC with peripheral smear: *leukocytosis* (may be strikingly elevated) with *granulocytic cells* (i.e. *neutrophilia, basophilia*, and eosinophilia). These cells look normal but are abnormal on immunochemistry - *Leukocyte ALP score: decreased* (LAP only found in functioning WBC's not leukemic cells) - Bone marrow biopsy: granulocytic hyperplasia - Chronic: <5% blasts. - Accelerated: 5-30% blasts. -Acute blast crisis: >20% blasts - Cytogenetic analysis and fluorescence in situ hybridization (FISH) - genetic testing for the Philadelphia Chromosome ----------------------------------------------- TX: - *Philadelphia (+): Tyrosine kinase inhibitors = 1st line!!* (i.e. *Imatinib*, Nilotinib, Dasatinib). - They inhibit the Philadelphia chromosome tyrosine kinase activity and myeloid leukemic cell proliferation - Hematopoietic stem cell transplant = most effective cure

Hereditary Hemochromatosis

Autosomal recessive disorder characterized by *excess iron deposition* in the parenchymal cells of the *heart, liver, pancreas, and endocrine organs* - Associated with *C282Y HFE genotype* (increased in N. Europeans) Patho: - Mutation in the HFE protein --> decreased hepcidin, the iron regulatory hormone - *Decreased hepcidin --> increased intestinal iron absorption* --> organ dysfunction from iron deposition in the parenchymal cells CF: - May be asymptomatic in the early stages. Symptoms usually begin after 40 yo - Liver: abd pain, *cirrhosis*, fatigue, weakness, hepatomegaly - Endocrine: *Diabetes* from pancreatic beta cell damage. hypothyroidism - Heart: *restrictive or dilated cardiomyopathy, arrhythmias*, HF, heart blocks - Reproductive: *hypogonadism, ED*, testicular atrophy - Joints: arthralgias, arthritis, synovitis - Skin: *metallic or bronze skin* (from iron deposition). "Bronze diabetes" - Increased susceptibility to bacteria that feed on iron (i.e. *Yersinia enterocoliticia, Vibrio vulnificus*) ----------------------------------------------- DX: - Iron studies: initial DOC - *increased serum iron, ferritin, and transferrin saturation*. Normal or decreased TIBC. May have abnormal LFTs - Genetic testing for the HFE gene (C282Y and H63D) + abdominal MRI - Performed if iron studies are abnormal - Liver biopsy: *most accurate test - increased hemosiderin* in the liver parenchyma with Prussian blue staining. May be performed if genetic testing + MRI are negative ----------------------------------------------- TX: - *MAINSTAY = PHLEBOTOMY* - may be performed weekly until ferritin decreases <50 mcg/dL, decrease in transferrin saturation or until a mild anemia occurs. May need maintenance phlebotomy therapy (i.e. 3-4 times a year for life) - Iron-chelating agents: in patients who are unable to undergo phlebotomy. More effective in patients with erythropoietic hemochromatosis. Deferoxamine, Deferasirox, Deferiprone. - Treat underlying cause. Avoid Fe supplements, Vitamin C, and alcohol intake

Chemo Drugs: Chemo combo regimens 1) R-CHOP 2) ABVD 3) MOPP

1) R-CHOP - Rituximab (ab vs CD20) - Cyclophosphamide - Hydroxydaunorubicin - Oncovin/Vincristine - Prednisone *USED IN NON-HODGKIN LYMPHOMA* ----------------------------------------------- 2) ABVD - Adriamycin (Doxorubicin) - Bleomycin - Vinblastine - Dacarbazine *USED IN HODGKIN LYMPHOMA* ----------------------------------------------- 3) MOPP - Mustargen - Oncovin (Vincristine) - Procarbazine - Prednisone *OLDER REGIMEN FOR HODGKIN LYMPHOMA*

Monoclonal Gammopathy of Undetermined Significance (MGUS)

*Clinically asymptomatic* premalignant clonal lymphoplasmacytic or plasma cell proliferative disease --> *increased immunoglobulins* - 1% of adults, 3% of adults >70yo. 1% yearly risk of developing multiple myeloma or lymphoma - *IgG MC* (69%), IgM (17%), IgA (11%), IgD, kappa light chains (62%), labda light chains (38%) - May be associated with other diseases, infection, autoimmune disorders (i.e SLP, ITP) CF: - *asymptomatic by definition* - often incidental finding DX: - Serum protein electrophoresis: IgG monoclonal spike (elevated but usually <3g/dL). Monoclonal spike is usually stable over time (usually does not progress) - Bone marrow: *<10 % plasmacytoid or plasma cells* - Urine protein electrophoresis: none (or stable) amounts of Bence-Jones Proteins -Absence of the symptoms or multiple myeloma (i.e. hypercalcemia, anemia, renal failure, lytic bone lesions ----------------------------------------------- TX: - Conservative or observation: low malignant potential risk

Hemophilia A

*Factor VIII DEFICIENCY* "A-ight" *X-linked recessive disorder occurring ALMOST EXCLUSIVELY in males* (rarely seen in homozygous females). Can also be caused by spontaneous mutation. - *MC type of Hemophilia*. - First episode usually <18 yo - *lack of Factor VIII* affects the clotting cascade --> *failure of hematoma formation* CF: - *Hemarthrosis* (80%) --> *delayed bleeding or swelling in weight-bearing joints* (i.e. *ankles*, knees, elbows), soft tissues, and muscles (i.e. forehead hematoma) - *Excessive hemorrhage due to trauma and surgery or incisional bleeding* (i.e. tooth extraction) - Epistaxis, bruising, GI or urinary tract hemorrhage - Hemophilias less commonly present with purpura, petechiae (because platelet function is normal), or spontaneous hemorrhage (except in the severe form) ----------------------------------------------- DX: - CBC and coag studies --> *Prolonged aPTT*. Normal PT, fibrinogen, *platelet levels* (bleeding time). - Mixing studies: *PTT corrects with mixing studies* (factor deficiency). *low Factor VIII* - most sensitive TX: - *Factor VIII infusion = 1st line* --- to increase levels 25-100% (depending on severity). -Can be given in response to an *acute bleeding episode or prophylaxis* (i.e. prior to sx, after trauma) - *Desmopressin (DDAVP)*: transiently *increases Factor VIII and vWF* release from endothelial stores. may be used prior to procedures to *prevent bleeding in mild disease*

Sickle Cell Trait

*Heterozygous (AS)* - 8% of AA, populations where malaria is endemic Patho: - in sickle cell trait, about 25-45% of their hemoglobin is HbS CF: - *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* (due to papillary necrosis) - May develop splenic infarction at high altitude and sudden death with prolonged exercise or physical training ----------------------------------------------- DX: - *Hemoglobin electrophoresis:* presence of *both hemoglobin A (HbA) and Hemoglobin S (HbS) with the amount of HbA > HbS*. (FAS pattern in neonates) - Peripheral smear: usually associated with normal hemoglobin,m hematocrit, reticulocyte count and peripheral smear TX: - *Sickle cell trait usually does not require treatment*. Painful crisis is not a component of the trait - Papillary necrosis: conservative (i.e. IV fluids, bed rest, and pain management)

Waldenstrom Macroglobulinemia

*Lymphoplasmacytic B-cell lymphoma that produces excess IgM* - Considered an indolent (little to no pain) type of non-Hodgkin lymphoma (incurable but treatable) Patho: - *clonal B cell IgM production* (postgerminal center IdM memory B cell that has failed to switch isotype class) CF: - Often asymptomatic (aka smoldering) - If symptomatic, associated with "OVA" - *Organomegaly, Viscosity, Anemia* - *Hyperviscosity syndrome*: large IgM molecules increase serum viscosity --> slows passage of blood through capillaries --> blurred vision, *engorged retinal veins*, papilledema, HA, vertigo, nystagmus, dizziness, tinnitus, diplopia, ataxia, stupor, or coma - *Anemia:* due to bone marrow failure - weakness, fatigue, weight loss, pallor - *Chronic, oozing blood from nose and gums*: IgM interaction with platelets and inhibition of fibrin. - *peripheral neuropathy* (10%) especially due to IgM acting as an autoab vs myelin-associated glycoprotein in nerves and other nerve components - *Organomegaly*: lymphadenopathy, seplnomegaly, hepatomegaly (30-40%) - *Cryoglobulinemia*: IgM precipates out of the serum in cold temperatures --> results in symptoms - *Raynaud phenomenon*, urticaria, acral cyanosis, and/or tissue necrosis ----------------------------------------------- DX: - Serum protein electrophoresis: *IgM monoclonal spike* (macroglobulinemia) - Bone marrow biopsy: *>10% lymphoplasmacytic infiltrate* (must excluse CLL). *Dutcher bodies* - Anemia,, thrombocytopenia, neutropenia, elevated beta-2 microglobulin level TX: - Observation can be done in asymptomatic cases. Highly responsive to chemotherapy (rarely curative) - *Rituximab + Bendamustine* = 1st line medical management - Failure or relapse: Bortezomib. Cyclophosphamide or Ibrutinib - *PLASMAPHERESIS used to treat severe hyperviscosity* syndrome with complications

Microcytic Anemias: Iron Deficiency Anemia

*MC cause of anemia worldwide* Etio: - *Chronic blood loss: MC cause in US* - excessive menstruation, occult GI blood loss (i.e. *Colon cancer*). Parasitic hookworms MC cause of blood-loss related IDA in resource- poor countries - Decreased absorption: *Diet (MC cause worldwide)*, Celiac, bariatric surgery, H pylori RF: - Increased metabolic requirements: children, pregnant and lactating women - Cow milk ingestion in young children: infants fed cow's milk's milk younger than 1 yo, toddlers fed large volumes of cow's milk Patho: - Decreased RBC production due to lack of iron and decreased iron stores (decreased ferritin). Normally, iron is stored in ferritin primarily in the bone marrow, liver, and spleen CF: - Classic symptoms of anemia: fatigue, weakness, exercise intolerance, dyspnea - CNS: poor concentration, apathy, irritability, poor school performance, cognitive disturbances. Restless leg syndrome - *Pagophagia* --> craving for ice (specific); *PICA* - appettite for non-food substances (i.e. clay, starch) PE: - *koilonychia* = spooning of the nails - angular cheilitis = inflammation of one or both corners of the mouth - tachycardia, glossitis (smooth tongue), signs of anemia (i.e. pallor) ----------------------------------------------- DX: - CBC --> *microcytic hypochromic anemia is CLASSIC (may be normocytic, normochromic early on) - *Increased RDW* (red cell distribution width), anicystosis. Decreased reticulocytes. May have thrombocytosis and poikilocytosis - Iron studies --> *decreased ferritin (PATHOGNOMONIC), increased TIBC* (transferrin), *decreased transferrin saturation* <20-15%, decreased serum iron - Bone marrow --> absent iron stores = definitive dx (rarely performed) ----------------------------------------------- TX: - *Iron replacement* --> increased reticulocytes (within 5-10 days), correction of anemia (6-8 weeks), and repletion of iron stores (1-3 mos) - Preparations: oral (i.e. ferrous sulfate), iron-containing formulas in bottle-fed infants. iron-enriched food and red meats. Parenteral - Increased absorption: *take iron replacement with Vitamin C (ascorbic acid)*, with *water or orange juice and on an emtpy stomach* - iron should be given 2 hours before or 4 hours after ingestion of antacids (reduced acidity impairs absorption) - ADR --> GI (NV, constipation, flatulence, diarrhea, dark stool). gradually increase the dose to reduce GI effects - Severe life-threatening anemia --> red blood cell transfusion (i.e myocardial ischemia)

Multiple Myeloma

*Plasmacytoma* Cancer associated with proliferation of a single clone of *plasma cells* --> increased production of ineffective monoclonal ab (esp IgG and IgA). IgM - *MC primary bone malignancy in adults* RF: - *elderly >65yo, AA, men*, benzene exposure Patho: - plasma cells accumulate in the bone marrow, interrupting bone marrow's normal cel production. Protein accumulation causes kidney injury ----------------------------------------------- CF: *"BREAK" your bones in Multiple Myeloma* - B - *Bone pain = MC symptom. Vertebral involvement = MC, ribs*. Due to *osteocytic lesions*, pathogenic osteopenic fx's, spinal cord compression, radiculopathy (plasma cells can form soft tissue tumor). Neuro involvement - R - Recurrent infections: due to leukopenia and ineffective Ig production. Hyperviscosity (esp with IgM) - *E = Elevated Calcium*: due to osteoclast activating factor from plasma cells --> leading to bone destruction - A = Anemia: fatigue, pallor, weakness, weight loss, hepatosplenomegaly - K = *Kidney Injury*: due to light-chain protein ab deposition in kidneys. Increased BUN and Creatinine ----------------------------------------------- DX: - Serum protein electrophoresis: *monoclonal protein spike - IgG = MC* (60%) - Urine protein electrophoresis: *Bence-Jones proteins* (composed of *kappa or lambda light chains*). 15% have light chains only - CBC: *Rouleaux formation* - RBCs with a "stack of coins" appearance due to increased plasma protein (*increased ESR*) - Skull Xrs: *"punched out lytic lesions*". Bone scans NOT helpful - Bone marrow aspiration: *plasmacytosis >10% = DEFINITIVE DX* ----------------------------------------------- TX: - *Autologous stem cell transplant = MOST EFFECTIVE TX* - may be preceded by induction chemotherapy (i.e Dexamethasone with Lenalidomide, Bortezomib) - Chemotherapy usually controls symptoms temporarily - Radiation therapy, local treatment, Biphosphanates

Paroxysmal Nocturnal Hemoglobinuria: DX and TX

- Hemolysis: (i.e. increased indirect bilirubin and LDH, decreased haptoglobin) - hemoglobinuria - Increased reticulocytes - Hemosiderinuria - *Flow cytometry test:* *best test to look for PNH* - CD55/CD59 - deficient RBCs - RBC fragility: sucrose test (cells lyse in hypotonic sucrose solution) and osmotic fragility test. Increased RDW and Coombs (-) ----------------------------------------------- TX: - *Complement inhibitors* --> *Eculizumab* - anti-complement ab targeting the C5 complement component - Ravulizumab (longer 1/2 life) -Folic acid supplementation - Allogeneic hematopoietic cell transplantation is only potential for cure

Hemoglobin H Disease (Alpha Thalassemia Intermedia)

A type of Alpha thalassemia characterized by decreased alpha-globin chain production Patho: - *3/4 gene deletions cause --> decreased alpha chain production. Excess beta chains form *insoluble beta chain tetramers (Heinz bodies)* with no I2-carrying capacity in the RBCs. - The presence of Heinz bodies in RBCs --> destruction by the spleen (hemolytic anemia). It is characterized by *moderate to severe anemia* (Hgb levels of 7-10 g/dL) CF: - Patients usually *symptomatic at birth* (neonatal jaundice and anemia) - Symptoms of anemia. hepatosplenomegaly, pigmented gallstones - Increased bone marrow hematopoiesis: *frontal bossing*, maxilla overgrowth ----------------------------------------------- DX: - *Microcytosis, hemolytic anemia (schistocytes*, tear drop cells, *increased reticulocytes*)_, *target cells*, basophilic stippling, *increased RBC count*, decreased hemoglobin (7-10 g/dL) - *(+) Heinz bodies* (HbH) - Iron overload: *normal or increased serum iron* - *hemoglobin electrophoresis:* presence of HbH (beta chain tetramer) TX: - *episodic blood transfusions* during periods of increased hemolysis or severe anemia (i.e. infection, pregnancy) - Vitamin C and folate supplementation (substrates for RBC production) - *iron-chelating agents* (i.e. *Deferoxamine,*, Deferasirox) to prevent iron overload and remove *excess iron* from chronic transfusions. Avoid iron supplementation (patients are iron-overloaded) - Splenectomy in some cases (stops BC destruction) may be needed by the 2nd or 3rd decade - Bone marrow transplantation = definitive treatment in major

Autoimmune Hemolytic Anemia (AIHA)

Acquired hemolytic anemia due to autoab production against RBCs Patho: - *Warm: IgG ab* activated by protein antigens on the RBC surface at BODY temperatures --> RBC destruction by splenic macrophages or complement 3 activation (i.e. Idiopathic, SLE, RA, CLL) - *Cold: IgM ab* against polysaccharides on the RBC surface induce --> intravascular *complement-mediated RBC lysis*, especially at *COLDER temperatures* (<39 F). IgM molecule binding can lead to agglutination Etio: - *Warm agglutinin*: Idiopathic = MC, medications (i.e. *PCN, CPH*, Methyldopa, Rifampin, Phenytoin), autoimmune (i.e *SLE*), malignancy (i.e. CLL, non-Hodgkin lymphoma), viral infections (esp in kids), HIV. - *Cold agglutinin disease (CAD)*: infection (i.e. *Mycoplasma pneumoniae, Epstein-Barr virus*, HIV), malignancy (i.e. CLL, lymphoma), Waldenstrom macroglobulinemia ----------------------------------------------- CF: - Anemia (i.e. pallor, fatigue, weakness, dyspnea), hemolysis (i.e. hemoglobinuria, jaundice). - Splenomegaly - Cold-induced vascular phenomena in CAD: *acryocyanosis* (numbing or mottling of the fingers, toes, nose, ears) that resolves with warming up of the body parts. Raynaud phenomenon, livedo reticularis (mottling). DX: - CBC + peripheral smear: decreased Hgb, hemolysis (reticulocytosis), *microspherocytes (especially warm)*, may have increased MCHC. Polychromasia, RBC agglutination only in CAD. - Labs: *hemolysis* (increased indirect bilirubin, increased LDH, decreased haptoglobin) - *(+) Direct Coombs (antiglobulin) test:* *positive - IgG* and C3 positivity = MOST ACCURATE test in WARM. - only (+) for complement 3 in cold - Cold agglutinin titer most accurate for CAD (>1:64) ----------------------------------------------- TX: - Warm agglutinin AIHA: - *1st line = Glucocorticoids* if symptomatic. Transfusion if severe. - 2nd line = *splenectomy or Rituximab* (antiCD20) if no response to glucocorticoids. - 3rd line = steroid-sparing agents (i.e Azathioprine, Cyclophosphamide, Cyclosporine) _ Cold agglutinin AIHA: - *AVOID cold temperatures = mainstay*, warm fluids if hospitalized. - Severe or symptomatic anemia: transfusions, plasmapharesis, IVIG. - Rituximab-containing regimens or Bortezomib in some patients

Immune Thrombocytopenic Purpura (ITP)

Acquired immune-mediated *isolated thrombocytopenia* (low platelet count) Patho: - *Autoantibodies against platelets --> splenic destruction of platelets*. The autoantibodies develop against the GP IIb/IIa receptor on platelets Types: - Primary ITP: idiopathic. *MC after viral infection (self-limited)* - Secondary ITP: immune-mediated but *associated with underlying disorders* (i.e. SLE, *HIV, HCV*, antiphospholipid syndrome). MC in adults and is usually recurrent CF: - Often asymptomatic - *Mucocutaneous bleeding:* i.e. epistaxis, bleeding gums, petechiae, purpura, bruising, menorrhagia. - Severe bleeding: not common - intracranial hemorrhage, GI bleeding, hematuria - *NOT ASSOCIATED WITH SPLENOMEGALY* ----------------------------------------------- DX: - *Isolated thrombocytopenia* with *normal coagulation studies (PT, PTT, INR)*, normal WBC count, normal hematocrit. Peripheral smear usually normal - 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 TX in Adults: - Mild bleeding +platelets <30,000: *Glucocorticoids - 1st line!!!!* (blunts the immune response_ - *IVIG = 2nd line*; or if rapid rise in platelet counts required - Refractory: *Rituximab or Splenectomy* - Severe bleeding (GI/CNS) + platelets <30,000: Platelet transfusion + IVIG + high dose glucocorticoids - No bleeding + platelets >30,000: Observation TX in KIDS: - No bleeding or mild bleeding not at risk: *observation* - *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

Polycythemia Vera (Primary Erythrocytosis)

Acquired myeloproliferative disorder with autonomous bone marrow *overproduction of all 3 myeloid stem cell lines (primarily increased RBCs*, but associated with increased granulocytic WBCs and platelets). Patho: - *JAK2 mutation* --> primary erythrocytosis (increased hematocrit in the absence of hypoxia) CF: - Symptoms due to *increased RBC mass (hyperviscosity or thrombosis)* - Hyperviscosity: HA, dizziness, tinnitus, blurred vision, weakness, fatigue, *pruritus, especially after a hot bath or shower* (due to histamine release from basophils), epistaxis - Thrombosis: erythromelalgia (episodic burning or throbbing of hands and feet with edema, cyanosis, or pallor). TIA PE: - *hepatosplenomegaly, facial plethora (flushed face*), engorged retinal vein DX: - ALl 3 major or first 2 major + 1 minor: Major: - *increased RBC mass (increased hemoglobin, increased hematocrit* >54% in men or 51% in women) - bone marrow biopsy: hypercellularity (i.e. erythroid, granulocytic and megakaryoctye proliferation) - JAK 2 mutation presence Minor: - *decreased serum EPO levels* - normal O2 sat - *increased leukocyte ALP* - increased granulocytic WBCs - platelets - B12 - iron deficiency despite polycythemia ----------------------------------------------- TX: - Low risk (<60 yo and no thrombosis): *1st line = PHLEBOTOMY* - *until hematocrit <45%. Low dose ASA* (to prevent thrombosis) - High risk (60 yo or greater and/or thrombosis): *all of the above + Hydroxyurea* (decreased cell count). Interferon-alfa = 2nd line. *Ruxolitinib (JAK inhibitor)* if no response to Hydroxyurea - Symptomatic: Antihistamines for pruritus. Allopurinol if hyperuricemia - Avoid Fe supplementation. Avoid alkylating agnets (increasing risk of myelofibrosis and progression to AML) ----------------------------------------------- EXAM TIP: Primary vs Secondary Erythrocytosis Primary erythrocytosis (PV): - normal 02 sat - decreased EPO - increased WBCs and platelets Secondary erythrocytosis (i.e. hypoxemia): - decreased O2 sat - increased EPI - normal WBCs and platelets

Heparin-Induced Thrombocytopenia

Acquired thrombocytopenia especially *within the first 5-10 days of the initiation of Heparin.* RF: - Unfractioned > low molecular weight, surgical > medical, female > male Patho: - *Autoantibody formation to the hapten of Heparin + platelet factor 4* --> causes platelet activation and consumption, leading to --> simultaneous *thrombocytopenia and thrombosis* CF: - Thrombocytopenia --> bleeding - Thrombosis: venous thrombosis, gangrene, organ infarction, and skin necrosis DX: "4 T's" 1) thrombocytopenia 2) timing of platelet drop 3) thrombosis 4) absence of other sequelae - HIT ab testing: 14-C serotonin release assay = GOLD STANDARD - ELISA, functional assays TX: - *Immediate D/C of all Heparin + initiation of non-heparin anticoagulants* - Non-Heparin anticoagulants: *direct thrombin inhibitors (I.e. Argatroban and Lepirudin*). Fondaparinux, direct oral anticoagulants (i.e. Apixaban, Edoxaban, Rivaroxaban, or Dabigatran) - Long-term anticoagulation with Warfarin can only be started after other non-Heparin anticoagulation has been started and the thrombosis has decreased bc of the initial prothrombotic state normally associated with the 1st 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* - *MC hereditary bleeding disorder* (1% of population). may also be acquired Function of VWF: - Von Illebrand Factor promotes platelet adhesion by crosslinking the GP1b receptor platelets with exposed collagen on damaged epithelium. VWF also prevents Factor VIII degradation CF: - *Mucocutaneous bleeding*: i.e. epistaxis, bleeding gums, petechiae, purpura, bruising, menorrhagia, prolonged bleeding after minor cuts. - Incisional bleeding less common in VWD than in Hemophilia ----------------------------------------------- Initial Labs: - Coag studies --> *prolonged PTT* (corrects with mixing studies) - *PTT and bleeding time prolongation WORSE WITH ASA* - Platelet count is usually normal (except in 2B, which is associated with mild thrombocytopenia Screening Tests: - Plasma CVW antigen - *Decreased VWF antigen or VWF activity* - 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 ----------------------------------------------- TX: *Type I: quantitate deficiency. MC type* (75%) - Mild to moderate bleeding: **DDAVP* (Desmopressin) - Severe: *VWF-containing product* (i.e. Factor VIII concentrates, purified VWF concentrates, recombinant VWF) - *Minor procedures* --> *Desmopressin used in Type I and IIA* for minor trauma, dental, and minor surgical procedures. Desmopressin stimulates the release of vWF and Factor VIII from endothelial cells - *Major procedures: VWF-containing products* (i.e. human-derived Factor VIII concentrates) *Type II (qualitative defects:*: *DDAVP* for most. VWF or DDAVP prior to procedures Type III (severe, absent VWF): VWF-containing product (i.e. human-derived Factor VIII concentrates, purified VWF concentrates, recombinant VWF)

Hereditary Spherocytosis (HS)

Autosomal dominant hereditary intrinsic hemolytic anemia (some recessive forms as well). - MC in Northern Europeans, 1 in 5k incidence Patho: - *Deficiency in RBC membrane and cytoskeleton (spectrin)*, --> *increased RBC fragility and sphere-shaped RBCs*. These abnormal RBCs are detected and destroyed by the spleen (hemolysis) CF: -Broad spectrum of clinical presentations. Severe cases may present in infancy (i.e. neonatal jaundice). Mild cases may present in adulthood - *Recurrent episodes of hemolysis: anemia, jaundice, and splenomegaly = HALLMARK*. Pigmented gallstones (calcium bilirubinate) ----------------------------------------------- DX: - *Peripheral smear*: *hyperchromic microcytosis*, 80% *spherocytes* (rounded RBCs that lack central pallor) - may have hemolytic smear (schistocytes, increased reticulocytes) - *Increased MCHC most reliable* (mean corpuscular hemoglobin concentration). Increased RDW - Hemolysis: increased indirect bilirubin, decreased haptoglobin - *FMA binding*: *preferred test/most accurate*. Flow cytometric analysis of eosin-5'-maleimide-labeled intact RBCs and acidified glycerol lysis test - Osmotic fragility test: RBCs placed in a relatively hypotonic solution rupture easily due to the increased permeability of the RBC membrane. - *Negative Coombs testing*: Coombs negativity distinguishes Hereditary spherocytosis from Autoimmune Hemolytic anemia (which also has spherocytes but is Coombs (+)) ----------------------------------------------- TX: - *Folic acid* = not curative but helpful to sustain RBC production and DNA synthesis - *Splenectomy* = *curative in severe or refractory disease* (stops splenic RBC destruction). It should be delayed in kids until at least 4 yo (after the risk of severe sepsis has peaked). Anti-pneumococcal vaccine should be given prior to splenectomy

Beta Thalassemia: Electrophoresis Results and Management

B-Thal trait (minor): - HgB F: increased - HgBA2: increased - HgbA: decreased (due to decreased beta chain production) ----------------------------------------------- B-Thal Major (Cooley's): - HgB F: increased *up to 90%* - HgBA2: increased - HgbA: *little to no HgbA* - *CBC in Beta-thal major:* hypochromic, microcytic anemia (decreased MCV), normal or increased RBC count, normal or increased serum iron. Hgb usually about 6g/dL - Peripheral Smear: *target cells*, teardrop cells, basophilic stippling, nucleated RBCs - *Skull XRs --> bossing with "hair on end appearance" (due to extramedullary hematopoiesis) ----------------------------------------------- TX: - Beta-thalassemia minor (trait) --> none needed. Genetic counseling - Moderate disease --> folate (if increased retic count). Avoid oxidative stress (i.e. sulfa drugs) -love me - Beta- Thalassemia major: - *often require frequent transfusions* during periods of increased hemolysis or severe anemia - *iron-chelating agents (I.e. Deferoxamine*, Deferasirox) to prevent Fe overload and remove *excess iron* from chronic transfusions. Patients may develop endocrine deficiencies as a result of iron overload (i.e. hypothyroidism, hyperparathyroidism, gonadal failure, DM) or CHF - *Vitamin C and folate supplementation* (substrates for RBC production) - Splenectomy in some cases (stops RBC destruction). ALlogenic hematopoietic cell transplantation

Chemo Drugs: Other Agents (Bleomycin and Hydroxyurea) MOA: Indications: ADR:

Bleomycin MOA: - Glycopeptide antibiotic that affects the G2 phase of cell division, generates free radicals, and inhibits DNA synthesis with lesser inhibition of protein and RNA synthesis ----------------------------------------------- Indications: - *Hodgkin lymphoma* (the B in ABVD), no-Hodgkin lymphoma, squamous cell and testicular cancer - Sclerosing agent for *pleurodesis in patients with malignant pleural effusions* ----------------------------------------------- ADR: - *Pulmonary toxicity: pulmonary fibrosis and pneumonitis* due to free radical production - Dermatologic: alopecia, hyperpigmentation - Raynaud phenomenon - Myelosuppression not a significant S/E ----------------------------------------------- ----------------------------------------------- Hydroxyurea MOA: - *increases production of HbF* (which does not sickle and has a higher affinity for O2) - increases RBC water - *reduces RBC sickling* - Alters RBC adhesion to the endothelium - inhibits ribonucleotide reductase ----------------------------------------------- Indications: - *MAINSTAY in SCD - reduces the frequency and severity of pain episodes, decreases hospitalization rates and prolonged surivival* - Because it takes weeks to mo's to take full effect, it is not used for acute episodes - Uses: Sickle Cell Disease, Polycythemia Vera, Esesntial thrombocythemia - the combination of Hydroxyurea and L-glutamine can have additive benefits ----------------------------------------------- ADR: - Myelosuppression, GI (anorexia, nausea)

Exam Tip: B12 and Folate Compare and Contrast

Both: - anemia, macrocytosis, macro-ovalocytes, decreased reticulocytes, hypersegmented neutrophils, and increased homocysteine B12 only: - *Neuro symptoms, increased Methylmalonic acid* Folate only: - NO neuro symptoms, normal methylmalonic acid ----------------------------------------------- Causes of Macrocytic Anemia: - B12 (Cobalamin) Deficiency - Folate Deficiency - Chronic liver disease - Alcoholism - Hypothyroidism - Myelodysplastic syndrome and acute leukemia

Aplastic crisis vs Splenic Sequestration

Both: - rapid drop in hemoglobin, thrombocytopenia, Both may have caused by Parvovirus B19 infections Aplastic crises: - drop in reticulocytes, mild neutropenia Splenic sequestration: - reticulocytosis, rapidly enlarging spleen, hypovolemia, thrombocytopenia

Alpha Thalassemia

Decreased a-globin chain production. 4 genes determine it - *MC in SE Asians* (68%), Africans (30%) and Mediterranean (5-10%) ----------------------------------------------- Disease state: - Silent Carrier State - 1/4 Abnormal Alleles - CF are clinically normal (usually asymptomatic) - Alpha Thalassemia minor (trait) - 2/4 - Mild microcytic anemia - no tx needed - Alpha Thalassemia Intermedia - 3/4 - *presents similar to B- Thalassemia major* - Hydrops fetalis - 4/4 - Associated with stillbirth or death shortly after birth. *Hgb Barts: gamma tetramers (yy/yy)* ----------------------------------------------- Thalassemia should be suspected in any patient with: - *microcytic hypochromic anemia* - *normal or increased serum iron* - *Normal or increased ferritin* *Hgb electrophoresis in Alpha Thalassemia*: - 1 and 2 gene deletion: *normal Hb ratios in adults* (distinguishes alpha from beta) - 3 gene deletion: presence of *HbH (beta chain tetramer) - Heinz bodies* - 4 gene deletion: presence of Hb Bart (gamma tetramer) - DNA analysis --> shows definitive dx TX: look at Hemoglobin H Disease card

Antithrombin III Deficiency

Decreased levels of antithrombin III --> hypercoagulability Patho: - Normally, AT3 inhibits coagulation by neutralizing the activity of thrombin (factors IIa, IXa, and Xa). Decreased levels --> increased risk of clotting Etio: - Inherited: autosomal dominant - Acquired: liver disease, nephrotic syndrome, DIC, chemotherapy CF: - *increased incidence of DVT and PE* DX: - AT3 assays TX: - Asymptomatic: anticoagulation only before surgical procedures - Thrombosis: high-dose IV heparin followed by oral anticoagulation therapy indefinitely

Chemo Drugs: Anthracyclines MOA: Indications: ADR:

Doxorubicin Daunorubicin ----------------------------------------------- MOA: - *Intercalating agents* - inhibit nucleic acid and protein synthesis by intercalating and binding with DNA. Generate free radicals and inhibit topoisomerase (antibiotics derived from Streptomyces fungus) ----------------------------------------------- Indications: - Hematologic malignancies: AML, ALL, Hodkin Lymphoma (the A in ABVD) - Solid tumors: endometrial, lung, breast and ovarian cancer ----------------------------------------------- ADR: - *Cardiotoxicity: dilated cardiomyopathy*, myopericarditis - GI S/E: NV, stomatitis - Bone marrow suppression and alopecia ----------------------------------------------- Monitoring: - *Echocardiogram or MUGA scan should be performed prior to initiation of therapy* to document the ejection fraction ----------------------------------------------- Prevention of cardiotoxicity: - Dexrazoxane is a cardioprotective agent against the toxic effects of anthracyclines used in select patients (prevents free radical formation)

Normocytic Anemias: Anemia of Chronic Disease

Etio of normocytic anemias: - Anemia of Chronic disease = MC - renal, mixed disorders (i.e. iron + B12 deficiency), endocrine, early Fe deficiency, asplenia, dilutional, sickle cell, G6PD ----------------------------------------------- Anemia of Chronic Disease Etio: - Chronic inflammatory conditions: infection, inflammation, autoimmune disorders, malignancy Patho: - 3main factors decrease serum iron: 1) *Increased hepcidin:* hepcidin is an acute phase reactant that blocks the release of Fe from macrophages and reduces GI absorption of Fe 2) *Increased ferritin* ferritin is an acute phase reactant that sequesters Fe into storage 3) Erythropoietin inhibition: via cytokines ----------------------------------------------- DX: - *CBC: mild normocytic normochromic anemia (may present with microcytic hypochromic anemia early on)* Hgb usually not <9-10 mg/dL. Decreased reticulocytes, normal to increased RDW - Iron studies: *normal to increased ferritin + decreased TIBC + decreased serum iron* (serum freritin and TIBC may be within normal limits). Normal or low transferrin saturation TX: - Treating underling disease will help to correct anemia - *Erythropoietin-alpha if renal disease* or low EPO levels ----------------------------------------------- Exam Tip (Fe deficiency vs Anemia of chronic disease vs Thalassemia) - Fe deficiency --> microcytic hypochromic, *decreased feritin* (depleted Fe stores), increased TIBC, decreased serum iron - Anemia of chronic disease: normocytic, normochromic anemia (may be microcytic early on), *normal or increased ferritin, decreased TIBC*, decreased serum iron - Thalassemia: microcytic hypochromic anemia, normal or increased ferritin, *normal or increased serum iron*

Macrocytic Anemias: Folate Deficiency

Functions of folate: - folate required for DNA synthesis. Folate deficiency causes *abnormal synthesis of DNA*, nucleic acids, and metabolism of erythroid precursos. - Folate stores only last for 2-4 mos Etios: - *inadequate intake: MC cause* (i.e. alcoholics, unbalanced diet) - Increased requirements: pregnancy, infancy, hemolytic anemias, malignancy, Psoriasis (increased skin turnover) - Impaired absorption: celiac disease, IBD, chornic diarrhea, anticonvulsants (i.e. Phenytoin, Phenobarbital, Carbamazepine) - Impaired metabolism: *Methotrexate, Trimethoprim*, Pentamidine, antiseizure agents (i.e. Phenytoin, Valproate, Carbamazepine), ethanol - Loss: dialysis CF: - Anemia symptoms *similar to B12 deficiency but WITHOUT NEURO SYMPTOMS* - Hematologic: fatigue, exercise intolerance, pallor, chlorosis (pale, faintly green complexion - extremely rare) - Epithelial --> glossitis, aphthous ulcer, diarrhea, malabsorption ----------------------------------------------- DX: - CBC w/ peripheral smear --> *Increased MCV (macrocytic)* + megaloblastic anemia (*hypersegmented neutrophils, macro-ovalocytes)*, low reticulocytes. May develop pancytopenia - Decreased serum folate levels, increased LDH, *Increased Homocysteine, NORMAL methylmalonic acid* (distinguishes folate from B12 deficiency) TX: - Oral folic acid. parenteral in severe folic acid deficiency - Replacing folic acid in patients with B12 deficiency may correct anemia but neuro symptoms will worsen

Beta Thalassemia: patho and CF

Genetic hemoglobinopathy characterized b y *decreased production of beta-globin chains* --> excess alpha chains RF: - *MC in the Mediterranean* (i.e. Greek, Italian), Africans, and Indians Disease States: - B-Thalassemia trait (minor) --> 1/2 abnormal alleles - B-Thalassemia Major (Cooley's Anemia) --> 2/2 abnormal alleles - B-Thalassemia Intermedia --> mild homozygous form CF: - Beta-thalassemia minor (trait) = *MC type*. Only one gene is defective, usually asymptomatic but may have mild-moderate anemia - Beta-thalassemia intermedia = mild homozygous form (anemia, hepatosplenomegaly, bony disease) - Beta-thalassemia major (*Cooley's anemia*) = both beta genes are mutated. Deficient beta-chain production --> excess alpha chains that are not able to form tetramers. This leads to ineffective erythropoiesis and shortened RBC life span ----------------------------------------------- CF of Beta-Thal Major: - *Symptoms often occur after 6mos of life* (when fetal Hgb begins to diminish - Anemia: *severe, chronic anemia*: pallor, irritability, dyspnea, mental delays. *hemolytic anemia:* jaundice, *hepatosplenomegaly* - Extramedullary hematopoiesis: bony abnormalities, delayed skeletal development, intramedullary expansion (frontal bossing, "hair on end" appearance of the skill, osteoporosis, abnormal ribs) - Osteoporosis: by age 10, the haematopoietically-active red marrow is replaced by inactive yellow marrow --> leading to osteoporosis, compression fx's, scoliosis, and disc degeneration - Endocrine abnormalities: (due to iron overload) - hypogonadism, diabetes, growth failure, hypothyroidism - Enlarged kidneys (due to increased hematopoiesis in the kidney) - *Cardiac dysfx* - heart failure (high output), arrhythmias

Hodgkin Lymphoma (HL): Types and CF

Germinal or pregerminal *B-cell malignancy* originating in the lymphatic system *Bimodal: peaks at 20yo then again >50yo* RF: - *Epstein-Barr virus*, immunosuppression, smoking 4 main types: 1) *Nodular sclerosing = MC overall* (64%). *Female predominance* 2) Mixed cellularity (25%) Associated with EBV 3) Lymphocyte rich/predominant: MC in males >60 yo. Usually associated with other systemic diseases. Worst prognosis ----------------------------------------------- CF: - *Asymptomatic painless lymphadenopathy: MC presentation* (70%). Usually painless but *ETOH ingestion may induce lymph node pain* within minutes - *Upper body lymph nodes: NECK = MC SITE!!* (i.e. *cervical and/or supraclavicular)*, axilla, shoulder, mediastinum, and abdomen. Usually rubbery in consistency, not fixed (does not adhere to the skin) and may fluctuate in size - *Mediastinal lymphadenopathy or mass: 2nd MC presentation!!!* - incidental finding on CXR. 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 - *hepatosplenomegaly, 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 1-2 weeks before waning. Symptoms due to cytokine release by Reed-Sternberg cells. *B symptoms indicate advanced disease*

Acute Myeloid Leukemia (AML)

Group of hematopoietic neoplasms characterized by clonal proliferation of myeloid precursors with decreased ability to differentiate into more mature cells **MOST COMMON ACUTE LEUKEMIA IN ADULTS**(80% of cases) - Median onset 65 yo Patho: - *Accumulation of leukemic blasts (immature WBCs)* in the bone marrow, peripheral blood or occasionally other tissues. Increased production --> pancytopenia ----------------------------------------------- 3 Major Subtypes: 1) *Acute promyelocytic leukemia (APL or M3)*: - (15;17) associated with *DIC, presence of Auer rods, and myeloperoxidase positivity* 2) Acute megakaryoblastic leukemia: - MC in kids <5 yo with Down Syndrome 3) Acute monocytic leukemia: - associated with *infiltration of the gums (gingival hyperplasia*) ----------------------------------------------- CF: - *Pancytopenia*: anemia (i.e. *general fatigue = MC*, dyspnea, weakness) - thrombocytopenia (mucocutaneous bleeding) - Neutropenia (increased inf and fever) - Leukostasis. Uncommon symptoms include lymphadenopathy and hepatosplenomegaly DX: - CBC with peripheral smear: *BEST INITIAL* - normocytic normochromic anemia with normal or decreased reticulocyte count. Thrombocytopenia. May have circulating *myeloblasts* - Bone marrow biopsy: *GOLD STANDARD* *>20% myeloblasts* (immature white cells with prominent nucleoli) - *Auer rods* (pink/red rod-like granular structures in the cytoplasm) with APL - Immunophenotyping: flow cytrometry helps to characterize the types with FISH analyasis - most accurate test. May have *meyloperoxidase positivity* with APL ----------------------------------------------- TX: - *Combination chemotherapy* (i.e. Cytarabine, Doxorubicin) - *All-trans-retinoic acid can be added to M3 (promyelocytic leukemia)* - Hematopoietic stem cell transplant = CURATIVE

Sickle Cell Disease: Overview - Trait vs Disease

Group of inherited disorders affecting the beta-globin gene --> production of RBCs that sickle --> hemolysis and vaso-occlusive disease - Disorders include Sickle Cell Disease (homozygous sickle mutation), sickle beta thalassemia, Hemoglobin SC disease. etc Patho: - Point mutation where *valine substitutes for glutamic acid on the beta chain*. *Sickle hemoglobin (HbS) has decreased solubility under hypoxic conditions* --> conformational change of the RBC shape (sickling) with subsequent *vaso-occlusion* (microthrombosis) and hypoxia. Sickled cells are destroyed by the spleen (*hemolytic anemia*) ----------------------------------------------- Sickle Cell Trait: - *Heterozygous (AS)*. 8% of AA, patients with sickle cell trait are usually asymptomatic and are not anemic unless exposed to severe hypoxia, extreme physical stress, high altitude, or dehydration. *may develop episodic hematuria or isosthenuria* (due to papillary necrosis) Sickle Cell Disease: - *Homozygous sickle cell mutation (SS)* - 0.2% of AA. Main clinical manifestations are due to *hemolytic anemia and vaso-occlusion* (i.e. acute or chronic pain, tissue ischemia or infarction)

Myelodysplastic Syndrome

Heterogenous *preleukemic disorders* characterized by *abnormal differentiation of cells of the myeloid cell line* (hypercellular bone marrow), resulting in ineffective hematopoiesis in the bone marrow (*pancytopenia*) RF: - *>65 yo*, radiation therapy, chemotherapy, Benzene exposure, tobacco smoke, mercury, or lead exposure CF: - May present as asymptomatic pancytopenia on routine CBC - *Symptoms of pancytopenia - easy bruising, bleeding, frequent infections, fatigue* ----------------------------------------------- DX: - CBC with peripheral smear: - *decreased number of one or more myeloid cell lines* (platelets, neutrophils, or RBCs (may be nucleated)). - Hyposegmented neutrophils, normocytic or macrocytic anemia - Bone marrow biopsy: - normal or hypercellular - 20% associated with hypocellularity - *Dysplastic bone marrow = HALLMARK - increased myeloblasts but <20%*, ringed sideroblasts, *pseudo-Pelger,Huet cells* (hyposegmented and hypogranulated neutrophils_ TX: - Goals are symptomatic improvement, to improve survival and to decrease progression to Acute myelogenous leukemia (AML) - Supp management: not all patients require management but some may need intermittent blood or platelet transfusions. EPO - Systemic: Pyrimidine analogs (i.e. 5-Azacitidine, Dectiabine), Lenalidomide (if 5q deletion present) - Allogeneic stem cell transplantation only effective cure but difficult in patients >50 yo

Non-Hodgkin Lymphoma (NHL): Types (6)

Heterogenous group of lymphocyte neoplasms with proliferation in the lymph nodes and spleen Major Types (6): *Diffuse large B-cell: MC type of NHL: - Fast growing, aggressive form (rapidly enlarging lymph nodes* of the neck, abdomen, and groin). - MC in the middle-aged and elderly (avg age = 70 years) - Extranodal seen in 40% - Large size B cell proliferation - CD20+ ----------------------------------------------- *Follicular: 2nd MC*: - Small cell proliferation in follicles (circular pattern), CD20+ - MC in adults - Presents with painless lymphadenopathy (esp in neck, groins, 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% - CD20+, CD5+ (poorer prognosis). - MC seen in older adult population - Painless lymphadenopathy - GI, bone marrow, and liver involvement common - T(11;14) mutation ----------------------------------------------- *Marginal zone*: - Small B-cell proliferation. 5-10% in the cells surrounding the mantle. Cd20+ - Low grade (usually due to B-cell hyperplasia from chronic immune or inflammatory states: (i.e. Hashimoto's thyroiditis, Sjogren's syndrome)) - 3 subtypes: 1) *Extranodal (mucosal-associated Lymphoid Tissue- MALT) --> Gastric MALT lymphomas often associated with H-pylori infections* 2) Nodal -->oringinate in the lymph node 3) Splenic --> originate in the spleen or bone marrow ----------------------------------------------- *Burkitt's Lymphoma*: - Intermediate-sized B cell proliferation. Cd20+ - *Associated with Epstein-Barr virus infection* (except sporadic) - usually presents as an extranodal mass. - *MC seen in pediatric/adolescent and HIV patients* -Subtypes: 1) *Endemic (Africa)* --> usually involves the jaw and facial bones (es with malaria) 2) *Sporadic type* --> GI and paraaortic involvement 3) *Immunodeficient type* --> seen with HIV or immunosuppression (i.e. post-transplant). - Biopsy will show --> *"starry-sky appearance". Highly aggressive (but highly curable)* - T(8;14) mutation ----------------------------------------------- *Small lymphocytic*: - spectrum of disease as Chronic lymphocytic leukemia. - Small lymphocytic usually found in the lymph nodes and spleen (whereas CLL is found in the bone marrow and the blood)

Chemo Drugs: Antimetabolites: FLUOROURACIL (5-FU) MOA: Indications: ADR:

MOA: - antimetabolite - *pyrimidine analog* that inhibits RNA synthesis in cancer cells by uracil antagonism (uracil is essential for RNA synthesis). Inhibits thymididylate synthase --> decreased DNA and protein synthesis. Low emetogenic potential ----------------------------------------------- Indications: - Topical: superficial basal cell cancer, actinic keratosis - Metastatic colon and breast cancers, ovarian cancer, head or neck cancer ----------------------------------------------- ADR: - *GI (i.e. NVD*, anorexia, stomatitis) - Teratogenicity, *alopecia*, cardiotoxicity (i.e. bradycardia, hypotension), ocular toxicity. - *myelosuppression ("rescue" with Thymidine)* - Dermatitis and photosensitivity with topical

Chemo Drugs: Antimetabolites: METHOTREXATE MOA: Indications: ADR:

MOA: - inhibits dihydrofolate reductase (*Folic acid antagonist*) --> decreased DNA and protein synthesis; inhibits lymphocyte proliferation ----------------------------------------------- Indications: - Chemotherapy: non-Hodgkin lymphoma, trophoblastic tumors (i.e. choriocarcinoma, hyatidiform mole), lung, breast, CNS, neck cancers, osteosarcoma - Inflammatory arthritis: RA, Psoriatic arthritis - Reproductive: ectopic pregnancy and termination of pregnancy ----------------------------------------------- ADR: - GI effects: MC - *Stomatitis*, NVD - 3 cardinal side effects of MTX involve the *liver, lung, and marrow: hepatitis, interstitial pneumonitis,a nd marrow suppression*. - *Leukopenia (prevented by administration of Leucovorin/Folinic acid)* - Neurotoxicity, thrombocytopenia, nephrotoxicity ----------------------------------------------- DDR: - *PCN's may increase toxicity of MTX* by decreasing elimination - AMGs reduce GI absorption of MTX - Retinoids increase hepatotoxicity - *Bactrim and sulfonamides increase Hemotoxicity* (synergistic folate antagonism) - *AVOID NSAIDs with high-dose MTX* (anti-neoplastic doses) due to increased toxicity from decreased renal excretion of MTX ----------------------------------------------- CI: - *Pregnancy* (folic acid inhibition), severe liver disease, renal disease

Secondary Eryrthocyosis

Major cause of increased RBC mass. MC in obsee, hx of smoking cigarettes - *Secondary erythrocytosis = increased hematocrit as a response to another process* Etio: 3 major 1) Reactive (physiologic): *due to hypoxia - i.e. pulmonary disease (COPD)*, high altitude, tobacco smokers, cyanotic heart disease. - *Reactive = MC type* 2) Pathologic: no underlying tissue hypoxia, renal disease (i.e. renal cell CA), fibroids, dehydration 3) Relative polycythemia: normal RBC mass in the setting of decreased plasma volume, dehydration CF: - Symptoms related to the underlying precipitating cause (i.e. COPD, renal disease, cyanosis, etc) - PE: cyanosis, clubbing, HTN, hepatosplenomegaly, +/- heart murmur DX: - *Increased RBCs/hematocrit with normal WBC and platelets*, normal EPO levels (RBC mass normal in reactive polycythemia due to decreased plasma volume) TX: - Treat underlying - Smoking cessation ----------------------------------------------- EXAM TIP: Primary vs Secondary Erythrocytosis Primary erythrocytosis (PV): - normal 02 sat - decreased EPO - increased WBCs and platelets Secondary erythrocytosis (i.e. hypoxemia): - decreased O2 sat - increased EPI - normal WBCs and platelets

Acute Lymphocytic Leukemia (ALL)

Malignancy arising from immature lymphoid stem cells in the bone marrow - B cell (MC), T cell, or null type (non B or T cell) **MC CHILDHOOD MALIGNANCY** (25%) - *peak 2-5 yo*, boys>girls, Down Syndrome Patho: - overpopulation of immature WBCs (blasts) overtake normal hematopoiesis resulting in pancytopenia CF: - Nonspecific symptoms associated with pancytopenia - *Pancytopenia: fever and infections (leukopenia), bleeding* from thrombocytopenia (i.e. petechiae, purpura), and *anemia* (i.e. pallor, fatigue) - CNS symptoms: HA, stiff neck, VA changes, vomiting. - METS MC to CNS and testes PE: - *hepatomegaly or splenomegaly = MC* - may manifest as anorexia, weight loss, abdominal distention, or abdominal pain. - *Lymphadenopathy* ----------------------------------------------- DX: - CBC + peripheral msears: WBC 5,000-100,000, anemia, thrombocytopenia - Bone marrow aspiration: *hypercellular with >20% blasts* = DEFINITIVE - Flow cytometry test: most accurate test to distinguish subtypes of Leukemia TX: - *highly responsive to combination chemotherapy* (remission >85%). - Induction chemotherapy includes Anthracyclines, Vincristine, and Corticosteroids - Maintenance therapy includes 6-MP, and MTX. - Imatinib used if Philadelphia chromosome (+). - Relapsing: stem cell transplant - *CNS disease or CNS preventative: intrathecal MTX*

Chronic Lymphocytic Leukemia (CLL) (B Cell)

Mature B cell clonal malignancy (considered same disease as Small cell lymphocytic lymphoma) **MOST COMMON FORM OF LEUKEMIA IN ADULTS** RF: - *increasing age* (70 yo median age), men CF: - *Usually asymptomatic* (incidental finding of lymphocytosis) - *Pancytopenia*: anemia symptoms (i.e. *Fatigue = MC*, dyspnea), increased infections (neutropenia), and mucocutaneous bleeding (thrombocytopenia) - May have typical "B" symptoms ff lymphoma (10%) PE: - *MC = lymphadenopathy* (cervical, supraclavicular, axillary, or generalized). The lymph nodes are usually firm, round, non-tender, and freely mobile. - *splenomegaly = 2nd MC finding* (25-55%) and is usually painless and NTTP. - Hepatomegaly - Skin lesions (leukemia cutis) DX: - CBC with peripheral smear: *absolute lymphocytosis* >5,000/microL - *small, well-differentiated, normal-appearing lymphocytes* with scattered *SMUDGE CELLS* (lab artifact when the fragile B cells become crushed by the coverslip during slide preparation) - Neutropenia - *Hypogammaglobulinemia*. Increased incidence of autoimmune hemolytic anemia. May have evidence of ITP - Immunophenotypic analysis (flow cytometry) - expression of B cell- associated antigens CD19, CD20, and CD23. CD5 (B cell maturity) - Bone marrow aspirate not required ----------------------------------------------- TX: - Indolent, asymptomatic, stage I and II: observation. Radiation - Symptomatic, progressive III and IV: chemotherapy (i.e. *Fludarabine*, Rituximab, Cyclophosphamide, Chlorambucil) - Acute blast crisis: treat similar to AML - Allogeneic stem cell transplant = CURATIVE - Poorer prognosis: ZAP-70 (+), del(17p), del (11q)

Tumor Lysis Syndrome

Oncologic emergency due 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 RF: - High tumor burden (i.e. initial WBC count >20k/microL), dehydration, and volume depletion - Large proliferation rate (i.e. ALL) and high-grade Lymphomas (i.e. Burkitt) CF: - Related to the metabolic derangements, including, muscle cramps, tetany, NV, lethargy, HF, kidney injury, and arrhythmias Lab Findings: - *Hyperphosphatemia* - *Hypocalcemia* - *Hyperuricemia* - *Hyperkalemia* - *Acute Kidney injury* (including uric acid nephropathy) ----------------------------------------------- TX: - *Tx of electrolyte abnormalities, IV fluids* (may add loop diuretic to promote excretion) - Rasburicase Prophylaxis: - *Rasburicase (or Allopuriniol) PLUS aggresive IV fluid hydration* - Hemodialysis if severe. - Rasburicase = recombinant uricase that catalyzes oxidation of uric acid to a stable compound. May be more effective than Allopurinol. CI'd if G6PD deficiency - Allopurinol: xanthine oxidase inhibitor --> decrease uric acid production

Leukostasis Reaction

Symptomatic hyperleukocytosis MC seen in Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML) in blast crisis. - *Medical emergency* - due to decreased tissue perfusion from leukostasis Patho: - Leukostasis --> 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 CF: - Pulmonary: dyspnea, hypoxemia with or without diffuse alveolar or interstitial infiltrate formation - Neuro: HA, diziness, VA changes, tinnitus, gait instability, confusion, somnolence, coma - other: priapism, bowel infarction, AMI DX: - *hyperleukocytosis (WBC >1000,000/microL) + symptoms due to tissue hypoxia* (i.e. lungs, CNS) TX: - Cytoreduction: *leukapharesis = 1st line* -associated with rapid improvement. Chemotherapy (i.e. Hydroxyurea) or induction chemotherapy - Prophylaxis for tumor lysis syndrome should also be initiated

Chemo Drugs: Mitosis Inhibitors (Taxanes) MOA: Indications: ADR:

Paclitaxel Docetaxel ----------------------------------------------- MOA: - *stabilizes mcirotubules, preventing mitosis and cell division* ----------------------------------------------- Indications: - *Paclitaxel: advanced ovarian cancer (with Cisplatin)*, advanced breast and non-small cell lung cancers. 2nd line for Kaposi Sarcoma - Docetaxel: advanced and metastatic breast, prostate, gastric, squamous cell, head, neck, and non-small cell lung cancers ----------------------------------------------- ADR: - *Black-box warning for hypersensitivity reactions and bone marrow suppression* - Hypersensitivity reaction* (may need to be treated with Dexamethasone, Diphenhydramine and H2 blockers, such as Ranitidine, prior to infusion to reduce the incidence) - Alopecia, NV, mucositis, anorexia, brittle nails, change in taste, leukopenia, neutropenia, myalgia, weakness, and peripheral neuropathy - Hyaluronidase via the same IV line = antidote for Paclitaxel toxicity due to extravasation

Sickle Cell Disease: TX

Pain control: *IV hydration and O2 = 1st step in TX* - reverses and prevents sickling - Meperidine is not rec in patients with SCD (may lead to --> seizures and renal failure at high doses -Folic acid supplementation needed for RBC production and DNA synthesis - RBC transfusion therapy: may be needed in some crises (i.e. acute chest syndrome, splenic sequestration, preoperative transfusion) - Exchange transfusion therapy is used if there is severe vasoocclusive crisis (i.e. acute chest syndrome, stroke, priapism, retinal infarction leading to visual changes) - Allogeneic stem cell transplant: only potentially curative tx for Sickle cell disease but has significant S/E ----------------------------------------------- Reduction of Episodes: - *Hydroxyurea* - MOA: (increases production of HbF* (which does not sickle and has a higher affinity for O2) increases RBC water, *reduces RBC sickling*, alters RBC adhesion to the endothelium. Inhibits ribonucleotide reductase - Indications: *MAINSTAY of tx* in SCD - *reduces the frequency and severity of pain episodes, decreases hospitalization rates, 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 combo of Hydroxyurea and L-glutamine can have additive benefits - ADR: Myelosuppression, GI (anorexia, nausea) ----------------------------------------------- Infection Prevention in Kids: - In patients with sickle cell disease, functional asplenia and autosplenectomy (from repeated splenic infarctions) often by 1.5-3 yo lead to increased risk of infection with encapsulated organisms (S pneumonia, H influenza, N meningitidis, Group B Streptococcus, Klebsiella, Salmonella) - Salmonella Osteomyelitis is usually associated with Sickle cell disease - *Prophylactic PCN is given as early as 2-3 mos of age until at least 5 yo to prevent infectious complications* - Pneumococcal and Influenza vaccine also help to reduce mortality

Aplastic Anemia

Pancytopenia with bone marrow hypocellularity Patho: - T cells attack hematopoietic stem cells (autoimmunity) or direct stem cell damage --> bone marrow fialure, including replacement of marrow with fat Etio: - Idiopathic=MC cause - Radiation exposure - Infections: seronegative viral hepatitis (non A through G). *Parvovirus B19* in patients with baseline hemolytic anemias (i.e. Sickle Cell disease, G6PD deficiency), other viruses - Medications: antibiotics (i.e. *Chloramphenicol, Sulfa drugs*), chemotherapy (anticipated effect), Benzene, *anti-epileptics* (i..e *Carbamazepine*, Phenytoin), Quinine, NSAIDs, anti-thyroid medications - B12 and folate deficiency can cause pancytopenia ----------------------------------------------- CF: - *Symptoms of pancytopenia:* *easy bruising, bleeding, frequent infections, and fatigue* - Thrombocytopenia --> *mucocutaneous bleeding* (i.e. epistaxis, bleeding gums, petechiae, purpura, bruising, menorrhagia) - Anemia: weakness, fatigue, dyspnea - Leukopenia: recurrent or frequent infections, fever DX: -CBC with peripheral smear --> *at least 2 cytopenias* - few or absent reticulocytes, thrombocytopenia, neutropenia, anemia (nucleated RBCs if marrow fibrosis is present) - Bone marrow biopsy --> *most accurate test - hypocellular, fatty bone marrow* (fat cells and fibrotic stroma replace normal marrow) - Often a dx of exclusion in the setting of bone marrow failure (PNH and myelodysplastic syndrome may present similar) ----------------------------------------------- TX: - Supportive management = *INITIAL TOC*: infection prophylaxis with broad-spectrum abx, PRBC transfusion for hemoglobin <7 mg/dL, or platelets for counts <10,000 or active bleeding - Severe AA in otherwise healthy patients <50 years: *Allogenic hematopoietic stem cell transplantation = TOC* - *Immunosuppression therapy: patients >50 yo* or in younger patients without matched donor: Eltrombopag, anti-thymocyte globulin (ATG), Cyclosporine, Prednisone

Microcytic Anemias: Lead Poisoning Anemia (Plumbism)

Patho: - Lead poisons enzymes --> cell death: it shortens the life span of RBCs; it inhibits multiple enzymes needed for heme synthesis causing an *acquired sideroblastic anemia* RF: - *MC in. kids* (esp in kids <6yo) due to increased permeability of the BBB as well as iron deficiency (may increase lead absorption) Sources: - *Ingestion or inhalation of environmental lead (i.e. paint chips or lead dust)* = lead primary source of childhood lead poisoning in the US (lead was used in household paints prior to the 1970s). Lead in gasoline and industrialized use of lead ----------------------------------------------- CF: - May be asymptomatic or nonspecific symptoms - *Neuro symptoms* --> *ataxia, fatigue, learning disabilities, difficulty concentrating*, developmental delays, hearing loss. - peripheral neuropathy (i.e. *wrist or foot drop* - encephalopathy: mental status changes, vomiting, seizures, cerebral edema, SIADH - *GI symptoms: lead colic - intermittent abd pain, vomiting, loss of appetite, and constipation* - Anemia: pallor, shock, coma -Renal: glycosuria, proteinuria, chronic interstitial nephritis - Burton's line: thin, blue-black line at the base of the gums near the teeth (seen primarily in adults) ----------------------------------------------- DX: - *Serum lead levels* --> >10mcg/dL on venous sampling most accurate. Capillary fingerstick sample often the initial test performed - Peripheral smear --> *microcytic hypochromic anemia with basophilic stippling* (dots of denatured RNA seen in RBCs). *Ringed sideroblasts in the bone marrow* - Normal or increased serum iron, decreased TIBC - Increased erythrocyte protoporphyrin: elevations can be seen in both iron deficiency and lead poisoning but tend to be worse in lead poisoning - Radiographs --> *lead lines* - linear hyperdensities at the metaphyseal plates in kids ----------------------------------------------- TX: - *removal of the source of lead = most important component of treatment*!! - Mild (44mc/dL or lower --> outpatient FU and lifestyle modifications - Moderate (45-69 mcg/dL) --> *1st line = Succimer* as inpatient (oral chelation). Calcium disodium edetate if oral therapy (CaNa2EDTA) not tolerated. 3rd line --> D-penicilliamine - Severe (70 or higher) --> without encephalopathy (succimer + CaNa2EDTA). With encephalopathy --> Dimercaprol (IM) followed by XaNa2EDTA (IMor IV)

Protein C or S deficiency

Patho: - Proteins C and S are vitamin-K dependent anticoagulant proteins produced by the liver that stimulates fibrinolysis and inactivates factors V and VIII. Etio: - Inherited: both are autosomal-dominant inherited hypercoagulable disorders ( C is more common) - Acquired: end-stage liver disease, severe liver disease with synthetic dysfunction, early Warfarin administration (Vit K antagonist) CF: - *increased incidence of DVT and pE* - *Warfarin-induced skin necrosis* - Purpura fulminans in newborns - red purpuric lesions at pressure points, progress to --> painful black eschars DX: - Protein C and S functional assay, plasma protein C and S antigen levels - Genetic testing not routinely performed TX: - Thrombosis: protein C concentrate. Indefinite anticoagulation - Warfarin-induced necrosis: Immediate D/C of Warfarin, administer IV Vit K, heparin, protein C concentrate, or FFP

Disseminated Intravascular Coagulation (DIC)

Pathological activation of the coagulation system Patho: - Uncontrolled fibrin production due to tissue factor activation --> *widespread microthrombi*, which consumes coagulation proteins (V, VII, fibrinogen) and platelets. Consumption then --> *severe thrombocytopenia*, manifested by *diffuse bleeding* from the skin, respiratory tract, and GI tract. Microthrombi --> organ ischemia Etio: - *infections (i.e. G(-) sepsis MC)*, Rocky Mountain spotted fever, viral - *Malignancies* - acute myelogenous leukemia: lung, GI, or prostate malignancies - *Obstetric*: pre-eclampsia; ~50% of patients with abruptio placentae or amniotic fluid embolism have evidence of DIC; septic abortion - Massive tissue injury and trauma: burns, liver disease, aortic aneurysms, ARDS ----------------------------------------------- CF: - *bleeding: oozing from venipuncture sites, catheters, drains*, extensive bruising - *Thrombosis:* arterial and/or venous - *gangrene* or multi-organ failure (i.e. renal or hepatic) DX: - Increasing thrombin formation: *decreased fibrinogen* (from consumption) - Bleeding: *increased PT, PTT, and INR. Thrombocytopenia* - Increased fibrinolysis: *increased D-dimer* (D-dimer is a fibrin degradation product) - Peripheral smear: fragmented RBCs, schistocytes TX: - *Treat the underlying cause = MAINSTAY* - Platelet transfusion if platelet count is <20,000/microL if not actively bleeding - FFP if severe bleeding (replaces coag factors) - Cryoprecipitate (replaces fibrinogen in patients with severely low levels) - Heparin for thrombosis in some patients

Non-Hodgkin Lymphoma (NHL): RF, CF, DX, TX

RF: - *Increased age*, history of radiation therapy, FHx - Chromosomal translocations - *immunosuppression: HIV*, HCV, viral infection, organ transplantation - *Infections: EBV, HHV-8, HIV. H-pylori associated with gastric lymphoma* - *Autoimmune disorders* (i.e. SLE, Dermatomyositis, RA, Sjogren syndrome, Hashimoto thyroiditis) CF: - The clinical presentation varies tremendously depending on the type of NHL and areas of involvement - Local: *painless lymphadenopathy* Indolent lymphomas may present with slowly growing lymphadenopathy. Hepatosplenomegaly - Extranodal involvement: common, *GI tract MC site of extranodal involvement* (skin = 2nd MC). CNS also common - Systemic B symptoms: (fever, night sweats, weight loss) = rarer in NHL but may be seen if advanced ----------------------------------------------- DX: - Lymph node and/or tissue biopsy: required for the dx and classification of NHL - Combined CT/PET scan of chest, abdomen, and pelvis for staging TX Low grade: - asymptomatic --> no treatment - Localized disease (stage I) --> radiation therapy - Chemotherapy: Chlorambucil, Fludarabine, 2-CdA (2-chloro-2'deoxyadenosine) - Rituximab (monoclonal ab against CD20+) - Stem cell transplant in refractory cases Intermediate, High grade (Aggressive): - chemotherapy; i.e. *R-CHOP* = 1) Rituximab 2) Cyclophosphamide 3) Doxorubicin 4) Hydrochloride 5) Oncovorin (Vincristine) 6) Prenisolone

Paroxysmal Nocturnal Hemoglobinuria: Patho and CF

Rare, acquired stem cell mutation - *RBCs become deficient in GPI anchor surface proteins* (CD55 and CD59) Patho: - CD55 AND CD59 normally protect RBCs from complement destruction. Deficiency in these proteins --> *increased complement activation and intravascular RBC destruction* - This hemolysis can be dramatically increased during a viral or bacterial infection due to antigen-antibody reactions CF: - Triad of: 1) hemolytic anemia (hemoglobinuria) 2) pancytopenia and 3) unexplained thrombosis in atypical veins - Hemolytic anemia: *dark, cola-colored urine during the night or early in the morning* with partial clearing during the day - Venous thrombosis of large vessels: due to haptoglobin and nitric oxide depletion. *Thrombosis in unusual veins* (i.e. hepatic, cerebral, abd, subdermal veins). Abdominal or back pain, ED, chest pain. Thrombosis usually the cause of death - Pancytopenia: protein deficiency seen in RBCs, WBCs, and platelets derived from stem cells, causing bone marrow failure. Often occur after bone marrow injury. *Hyeprcoaguability despite pancytopenia = HALLMARK*!!

Macrocytic Anemias: B12 Deficiency (Cobalamin)

Sources of B12: natural sources *mainly animal in origin (i.e. meats, eggs, dairy products)* Absorption: B12 is released by the acidity of the stomach and *combines with intrinsic factor, where it is absorbed mainly in the distal ileum* Patho: - B12 deficiency causes *abnormal synthesis of DNA*, nucleic acids, and metabolism of erythroid precursors. B12 needed to convert homocysteine to methionine for DNA synthesis Etio: - *Decreased absorption: Pernicious anemia MC cause* (lack of intrinsic factor due to parietal cell ab --> gastric atrophy). Pancreatic insufficiency, *Crohn disease* (affects the terminal ileum); Ileal resection, gastric bypass, post gastrectomy, gastritis, achlorhydria, tropical sprue, Zollinger-Ellison syndrome, Celiac disease. - *Chronic alcohol use* - Meds: *H2 blockers and PPIs* (decreased acidity leads to decreased absorption), decreased nucleic acid synthesis (*Metformin*, Zidovudine, Hydroxyurea), anticonvulsants. Fish tapeworm - Decreased intake: *vegans* (lack of consumption of meat and meat products) ----------------------------------------------- CF: - Anemia symptoms *similar to folate but associated with NEUROLOGIC ABNORMALITIES* - hematologic: fatigue, exercise intolerance, pallor - Epithelial: glossitis, diarrhea, malabsorption - *Neurologic symptoms: symmetric paresthesias = MC initial symptoms* (esp involving the legs). *lateral and posterior spinal cord demyelination and degeneration* --> ataxia, weakness, *vibratory, sensory and proprioception deficits, decreased DTR* (hypotonia, (+) Babinski, seizures, and psychosis ----------------------------------------------- DX: - CBC with peripheral smear --> *increased MCV (macrocytic anemia)* + megaloblastic anemia (*hypersegmented neutrophils, macro-ovalocytes*, mild leukopenia and/or thrombocytopenia) - Decreased serum B12 levels, increased LDH, *increased homocysteine* - *INCREASED METHYLMALONIC ACID* distinguishes B12 from folate deficiency TX: - ROA: oral, sublingual, nasal, and IM/deep SQ inj - *Symptomatic anemia or neuro 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 an oral therapy after resoluion of symptoms - *patients with Pernicious anemia need lifelong monthly IM therapy* (or high-dose oral therapy) - Dietary deficiency - oral B12 replacement

Microcytic Anemias:Thalassemia Overview

Thalassemia= *decreased production of globin chains*. Distribution of Thalassemia follows Plasmodium falciparum --> thought to be *genetic benefit vs Malaria*. Most adults are heterozygotes ----------------------------------------------- *Normally after 6 mos of age, adult Hgb is the predominant Hgb produced:* - HgbA (Adult): 2 alphas, 2 betas (*aa/BB*) - 95% - HgbA2: 2 alphas, 2 deltas (aa/dd) - 1.5-3% - HgbF (Fetal): 2 alphas, 2 gammas (aa/yy) - trace amounts *Think Thalassemia if microcytic anemia with normal/increased serum Fe or no response to Fe treatment!!!*

Disorders and their Effect on--> PT, PTT, Bleeding Time, Platelet Count 1) Thrombocytopenia 2) Hemophilia 3) Von Willebrand Disease 4) Vit K Deficiency (i.e. Warfarin) 5) DIC

Thrombocytopenia - PT: Unaffected - PTT: Unaffected - Bleeding Time: *Prolonged* - Platelet Count: Decreased ----------------------------------------------- Hemophilia - PT: Unaffected - PTT: *Prolonged* - Bleeding Time: Unaffected (normal platelets) - Platelet Count: Unaffected ----------------------------------------------- Von Willebrand Disease - PT: Unaffected - PTT: *Prolonged* - Bleeding Time: *Prolonged (especially with ASA challenge)* - Platelet Count: Unaffected ----------------------------------------------- Vit K Deficiency (i.e. Warfarin) - PT: *Proonged* - PTT: Normal or minor prolongation - Bleeding Time: Unaffected - Platelet Count: Unaffected ----------------------------------------------- DIC - PT: *Prolonged* - PTT: *Prolonged* - Bleeding Time: Prolonged* - Platelet Count:*Decreased*

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic microangiopathy from ADAMTS13 deficiency Patho: - ADAMST13 is a von Willebrand factor-cleaving protease - *ADMAST13 deficiency --> large vWF multimers that cause small vessel thrombosis* Etio: - Primary: idiopathic (autoimmune) - ab against ADAMST13 - Secondary: malignancy, bone marrow transplantation, estrogen, *SLE*, pregnancy, HIV1, medications (i.e. Quinidine, Ticlopidine, Clopidogrel, Cyclosporine) CF: PENTAD 1) *Thrombocytopenia* - *mucocutaneous bleeding* - epistaxis, bleeding gums, petechiae, purpura, bruising, menorrhagia 2) *Microangiopathic hemolytic anemia:* - anemia, jaundice, fragmented RBCs (schistocytes on peripheral smear). *Splenomegaly* 3) *Neurologic symptoms:* HA, VA changes, confusion, seizures, CVA 4) *Fever:* (rare) Since plasma exchange therapy, it is rare for patients to present with all 5 simultaneously 5) *Kidney failure or uremia*: not as common ----------------------------------------------- DX: - Labs: *thrombocytopenia with normal coagulation studies* (seen in both TTP and HUS). - Normal coagulation studies (PT and PTT) helps to distinguish TTP/HUS from DIC - *Hemolysis* - peripheral smear - schistocytes (helmet cells), bite or fragmented cells, reticulocytes, increased LDH and bilirubin, decreased haptoglobin - Decreased ADAMST13 levels. Coombs (-), increased bleeding time TX: - *INITIAL TOC* - *Plasmapheresis* - removes ab vs ADAMST13 and adds ADAMST13 to serum - Monitor LDH/platelets until normal x 2 days - Immunosuppression: *Glucocorticoids and/or Rituximab if no response to plasmapheresis*, cyclophosphamide, etc - Platelet transfusions not usually indicated may potentiate thrombi formation) - Splenectomy an option in patients refractory to plasma exchange and immunosuppressants

Chemo Drugs: Mitosis Inhibitors MOA: Indications: ADR:

Vincristine Vinblastine ----------------------------------------------- MOA: - destabilizes microtubules, *preventing mitosis and cell division* ----------------------------------------------- Indications: - Vincristine: used for leukemia, Hodgkin lymphoma, non-Hodkin lymphoma - Vinblistine: used for lymphoma and testicular cancer ----------------------------------------------- ADR: - *neurotoxicity: MC S/E especially with Vincristine (i.e. neuropathy such as foot drop*, CN palsies, demyelination, pain), myelosuppression, dermatologic (alopecia, rashes). - GI (*constipation*, NV, abd pain) - GU (i.e. urinary retention, bladder dysfunction) - Oculotoxicity and hyperuricemia

Sickle Cell Disease: CF, DX

group of inherited disorders affecting the beta-globin gene --> production of RBCs that sickle, causing hemolysis and vaso-occlusive disease CF: - symptoms begin as *early as 6 mo* (when HbSS replace fetal hemoglobin) - *Dactylitis = MC initial presentation*. Delayed growth and development, fever, infections - Infections: - *Functional asplenia* and autosplenectomy (from repeated splenic infarctions) often by 1.5-3 years of large lead to *increased risk of infection with encapsulated organisms* (i.e. S. pneumoniae, H influenza, N meningitidis, Group B Strep, 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 and RBC pooling in the spleen leads to *acute splenomegaly and rapid decrease in Hgb* Often occurs in kids - Hemolytic anemia: jaundice, gallstones (pigmented) - Painful "vaso-occlusive crisis": triggered by hypoxia, cold weather, infection, dehydration, ETOH, and pregnancy. Associated with abrupt onset of pain (*acute chest syndrome, back, abdominal, bone pain)*. Renal or hepatic dysfunction. *Priapism is common* - Acute chest syndrome: fever, cough, tachypnea, O2 desaturation, chest pain - Bony vaso-occlusion: *avascular (ischemic) necrosis of bones (i.e. femoral or humeral head), "H-shaped vertebrae"* (central endplate depression with normal anterior and posterior margins) - Skin Ulcers: especially on the tibia - Chronic hypoxia: pulmonary HTN, CHF, symptoms of fatigue, dyspnea - *Stroke* (25% have one by age 45yo, 25% kids have silent episode) ----------------------------------------------- DX: - *Peripheral smear* - best initial test - Target cells, *sickled erythrocytes*, decreased hemoglobin (baseline 8-10 g/dL but decreased in crisis), decreased hematocrit - *Howell-Jolly bodies* --> indicated functional asplenia - Hemoglobin electrophoresis: - *Sickle cell disease: HbS, little to no HbA, increased HbF* - Sickle cell trait: Hbs, decreased HbA - DNA analysis = DEFINITIVE