Bleeding Disorders

How is a the bleeding time affected by a disorder or primary hemostasis?

Bleeding time is increased

What is the main histological finding in Thrombotic Thrombocytopenic Purpura (TTP)?

Hyaline thrombi in small blood vessels (arterioles and capillaries) throughout the body

What is the best clotting test to measure patient responsiveness to warfarin therapy?

PT/INR

Prothrombin Time (PT) measures the integrity of the _________ (intrinsic/extrinsic) system as well as factors common to both systems and Partial Thromboplastin Time (PTT), measures the integrity of the ___________ (intrinsic/extrinsic) system and the common components.

PT: extrinsic PTT: intrinsic

Disorders of primary hemostasis are usually due to abnormalities in _______ They can be divided into _________ or ___________ disorders

usually due to abnormalities in *platelets* divided into *quantitative* or *qualitative*

What activates Factor 7?

Tissue Thromboplastin/ Tissue Factor

Bleeding Time Test

Normal bleeding time is between 2-7 minutes

What is the mechanism by which Prostacyclin (PGI2) inhibits platelet aggregation?

PGI2 is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn, activates adenylyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade *Summary: PGI2 activates Gs receptors => Increased cAMP => decreased Ca2+ => inhibition of platelet degranulation

What is the first step in primary hemostasis?

Vasoconstriction is the initial response to vessel injury. It is mediated primarily by endothelin (ET-1), an extremely potent vasoconstrictor peptide synthesized by injured endothelium. Also mediated by reflex neural stimulation

Both Von Willebrand Disease and Bernard Soulier Syndrome are characterized by an abnormal ristocetin test (no aggregation). How can these two disorders be distinguished?

Von Willebrand disease can be corrected with the addition of normal plasma Bernard Soulier will not be corrected with the addition of normal plasma Von Willebrand disease will not be corrected with the addition of platelet transfusions Bernard Soulier will not be corrected with the addition of platelet transfusions (The reason for these findings is that the defect in VWD is in the plasma and not intrinsic to the platelets and therefore addition of plasma will correct but addition of platelets will not correct)

Schistocytes

* * * * * *often called *Helmet Cell*

A 35-year-old man presents to the clinic with bruising and several episodes of epistaxis that occurred a week ago. He states that in the past month he has not been feeling well. It started with severe headaches and a cold with fever of 102 F. He hasn't completely recovered, remaining weak and tired. In addition, now he "started bleeding for no apparent reason." The patient uses no medications. He has no history of transfusions in the past or any bleeding disorders in the family. His medical history is significant for a hepatitis C infection diagnosed 5 years ago and a recent episode of bacterial gastroenteritis. On physical examination, the patient is slim with pale conjunctiva. Petechiae are present on his legs. Pulse is 85/min, blood pressure is 115/70 mm Hg, and temperature is 100 F. Abdominal examination reveals a slightly enlarged liver with mild tenderness in the right upper quadrant, but no splenomegaly. Neurologic examination reveals no focal deficits. Laboratory studies show the following: WBC 5,000/mm3; hematocrit 35%; platelets 30,000/mm3; MCV 90 µm3; BUN 19 mg/dL; creatinine 1.0 mg/dL; LDH 190 U/L; AST 45 U/L; ALT 50 U/L; direct bilirubin 0.2 mg/dL; indirect bilirubin 0.9 mg/dL; PT 13 seconds; PTT 30 seconds. Peripheral blood smear shows no white or red cell abnormalities, but occasional megathrombocytes are seen. Head CT without contrast shows no cerebrovascular disease or lesions. What is the best initial management of this patient? (A) Intravenous immunoglobulins (B) Prednisone (C) Plasmapheresis (D) Fresh frozen plasma (E) Platelet transfusion

(B) Prednisone This patient presents with symptoms of mucosal bleeding (epistaxis, gum bleeding, and petechiae). Petechiae are seen almost exclusively in conditions of thrombocytopenia, as confirmed in this patient by the low platelet count of 30,000/mm3. Thrombocytopenia may stem from failure of platelet production, as seen in leukemia, aplastic anemia, or myelodysplastic syndrome. Increased platelet destruction occurs with ITP, TTP, hemolytic uremic syndrome (HUS), or disseminated intravascular coagulation. Increased platelet sequestration happens with an enlarged spleen. Dilution of platelets, lowering the count, occurs with massive blood transfusions. The normal smear, except for large platelets, points in the direction of increased platelet destruction. Like reticulocytes, newly formed platelets are larger than older platelets. TTP and HUS would show red-blood-cell fragmentation, whereas myelodysplastic syndrome would exhibit white cell abnormalities. This patient has no history of transfusion. Aspirin by itself rarely causes significant bleeding, but it may unmask bleeding disorders, such as mild von Willebrand's disease or mild thrombocytopenia. The patient's presentation is consistent with ITP, the hallmark of which is isolated thrombocytopenia with a normal-sized spleen and megathrombocytes on peripheral smear. PT and PTT are normal in ITP. Prednisone is the initial treatment for ITP. Plasmapheresis and fresh frozen plasma infusion are the treatments for TTP. TTP is unlikely in this patient because there is no evidence of microangiopathic hemolytic anemia. Fresh frozen plasma is also a treatment of choice for the coagulopathy of liver disease. Hepatic causes are unlikely in this patient because the PT and PTT are normal. Platelet infusion is given in life-threatening bleeding secondary to low platelet counts most often from production problems. Platelet transfusions are rarely used in the treatment of idiopathic thrombocytopenic purpura because exogenous platelets will survive no better than the patient's own and last for less than a few hours. It should be reserved for cases of life-threatening bleeding in which intravenous immunoglobulins and steroids are ineffective.

Clinical Presentation of Hemophilia A and B

**Hemophilia A and B are clinically indistinguishable* *Presentation varies in severity based on degree of Factor VIII/IX deficiency *<1%: severe; (spontaneous hemorrhages) *2-5%: moderately severe *6-50%: mild *If bleeding in joints is severe, patients may feel an "abnormal sensation within the joints" *Excessive bleeding may occur in male newborns after circumcision or umbilical cord separation

What diseases are associated with Idiopathic Thrombocytopenic Purpura

**SLE* *HIV **Lymphoproliferative disorders*

Bernard Soulier Syndrome

*AR * * * *

Glanzmann Thrombasthenia

*AR *Impaired platelet aggregation from genetic deficiency of GpIIb/IIIa *Defect in platelet plug formation *normal PT/PTT *Normal Platelet count, morphology, and absence of clumping *Only laboratory abnormality is prolonged bleeding time *Tx:

Maternal Idiopathic Thrombocytopenic Purpura and Neonatal thrombocytopenia

*Autoantibodies, especialy IgG, are able to cross the placenta and attack fetal platelets *The mother has a normal platelet count, while the fetus can be severely thrombocytopenic. * * * ************

TTP vs ITP vs DIC vs HUS

*Can't find the fever distinction anywhere on google

What is the normal platelet count?

150,000-400,000/µL mean platelet counts in pregnant women generally are lower

Where does von willebrand factor come from?

*Weibel-Palade Bodies of endothelial cells *Alpha granules of Platelets

Describe the laboratory findings seen in Idiopathic Thrombocytopenic Purpura

*Decreased platelet count < 50000/microL **Normal PT/PTT* **Increased megakaryocytes on bone marrow biopsy (many may be immature; nonlobulated, single nuclei* *Large platelets on peripheral blood smear (sign of accelerated thrombopoiesis)

Hemolytic Uremic Syndrome (HUS)

*E Coli verotoxin damages endothelial cells resulting in platelet microthrombi *Occurs most often in children *Typically follows a gastroenteritis (typically due to verotoxin producing E Coli 0157:H7) *Results from exposure to undercooked beef *Preceding bloody diarrhea may or may not be present *Both TTP and HUS will present with both renal problems and CNS abnormalities but renal problems are the predominant ones in HUS, while CNS abnormalities are predominant in TTP **HUS in adults does not present with diarrhea* *Increased megakaryocytes in bone marrow biopsy *

Hemophilia A and B

*Genetic Factor 8/9 Deficiency respectively *Both are XLR *Predominantly affects males; females are asymptomatic carriers **Females may be affected due to unequal inactivation of X chromosome (lyonization)* *About 30% have no family history; represent new mutation *Hemophilia A is more common than Hemophilia B ***Clinical severity correlates with the level of factor VIII/IX* Tx: Recombinant factor VIII/IX

Idiopathic (Autoimmune) Thrombocytopenic Purpura

*Most common cause of thrombocytopenia *Autoantibody-mediated platelet destruction; directed against GpIIb/IIIa and GPIb-IX (most often IgG; Type 2 HSR) *Antibodies act as opsonins; leading to destruction of platelets in the spleen by splenic macrophages (which have Fc receptors that bind IgG coated platelets) *Often follows a viral infection or immunization *Acute and self limiting in children after upper respiratory infection *Typically chronic in adults *Females are affected twice as often as males (often during pregnancy) **ITP can be distinguished from other hematologic causes of thrombocytopenia by lack of fever, splenomegaly, schistocytes on blood smear, and a normal PT/PTT* *Tx:

Microangiopathic Hemolytic Anemia

*Pathologic formation of platelet microthrombi in small vessels *Platelets are consumed in the formation of microthrombi *RBCs are sheared as they cross the microthrombi, resulting in hemolytic anemia with schistocytes *Seen in TTP and HUS* *A form of Intravascular Hemolysis* * *

How do the manifestations of disorders of secondary hemostasis differ from disorders of primary hemostasis?

*Primary: Superficial Bleeding *Secondary: Deep tissue bleeding into muscles and joints; rebleeding after surgical procedures *Manifestations of Seondary Hemostasis include bleeding from larger vessels,resulting in hemarthroses (blood in joint spaces), large hematomas, large ecchymoses, and extensive bleeding with trauma. *Bleeding time or platelet count is not affected (thus distinguishing secondary hemostatic disorders from primary hemostatic disorders)*

Thrombotic Thrombocytopenic Purpura (TTP)

*Severe bleeding disorder due to a decrease in ADAMTS13 function *Can be acquired (autoantibody against ADAMTS13) or inherited (deficiency of ADAMTS13) **Large uncleaved multimers adhere platelets and form microthrombi* *results in diffuse emboli and thrombi that damage brain and kidneys *Similar to Hemolytic Uremic Syndrome (HUS) *Most commonly seen in adult female *Increased megakaryocytes in bone marrow biopsy *Histology: hyaline thrombi in small blood vessels (arterioles and capillaries) throughout the body *Tx: * * *

How does uremia impair platelet function?

*Uremia disrupts both platelet adhesion and aggregation* Seen primarily in dialysis patients Platelet count will be normal as this is a qualitative and not quantitative disorder Primarily manifests as GI bleeding Dialysis may improve symptoms

Hemostasis

*a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel *It is the instinctive response for the body to stop bleeding and loss of blood. *Occurs in two stages; Primary and Secondary * * * *

What are the characteristic features of disorders of primary hemostasis?

*symptoms of mucosal bleeding* *epistaxis *hemoptysis *GI bleeding *hematuria *menorrhagia *Intracranial bleeding occurs with severe thrombocytopenia *symptoms of skin bleeding* *petechiae *purpura *ecchymoses *easy bruising *Petechiae are a sign of thrombocytopenia and are not usually seen with qualitative disorders*

Steps in primary hemostasis

1) Transient vasoconstriction - mediated by neural reflex & endothelin release by damaged endothelial cells 2) Vessel injury exposes subendothelial collagen 3) Platelet Adhesion: vWF binds exposed subendothelial collagen. Platelets bind vWF using GP1b receptor 4) Adhesion induces shape change in platelets; 5) Degranulation => Release of multiple mediators from both Alpha and Dense Granules; ADP (promotes GP2b/3a receptor expression on platelets) and TXA2 (promotes platelet aggregation) 6) Activation of the membrane enzyme phospholipase A2. This leads to the formation of thromboxane A2 (TXA2) 7) Platelet aggregation - GP2b/3a aggregates platelets using circulating fibrinogen as a linker

Steps in Secondary hemostasis

1. Coagulation cascade generates thrombin 2. Thrombin converts fibrinogen in the platelet plug to fibrin 3. Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus

Dr. Sattar's way of organizing the Coagulation Cascade

12,11,skip 10, 9, 8 Intrinsic is on the left left has more letters so it is useful to measure PTT Factor 12 is activated by subendothelial collagen or SEC Heparin is commonly referred to as HEP and is therefore on the left *PTT,SEC,HEP all have three letters Common Pathway: 10,5,2,1 1*2*5=10 Extrinsic is on the right 7 Extrinsic is just like my ex, all by herself (7) How do we remember that intrinsic is on the left? INtrinsic is on the same side as heparIN HEP is on the LEPt; go to WAR with my ex

A 27-year-old male presents to the emergency department with a one day history of progressive confusion and oliguria. The patient has had several episodes of epistaxis and bleeding gums since the onset of his illness. Past medical history is unremarkable and the patient does not take medications. Temperature is 39C, blood pressure is 100/62 mm Hg, pulse is 95/min, and respiratory rate is 18/min. Physical exam is notable for a purpuric rash in the lower extremities bilaterally. Peripheral blood smear is shown in Figure A. Which of the following is the most likely mechanism behind the patient's illness? FIGURES: A 1. Defect in platelet aggregation 2. Deficiency in degradation of von Willenbrand Factor (vWF) multimers 3. Peripheral platelet destruction 4. Defect in platelet-to-collagen adhesion 5. Decreased levels of von Willenbrand Factor (vWF)

2. Deficiency in degradation of von Willenbrand Factor (vWF) multimers The patient presents with signs and symptoms of thrombotic thrombocytopenic purpura (TTP). The vWF metalloprotease ADAMTS13 is deficient in TTP, leading to decreased degradation of vWF multimers and subsequent clotting disorders due to a deficiency of available vWF. Patients presenting with thrombocytopenia and microangiopathic hemolytic anemia should be admitted to the hospital with a presumptive diagnosis of TTP. Signs and symptoms include fever, neurological symptoms and mental status changes, renal impairment, and thrombocytopenia. Labs may also show prolonged bleeding time and evidence of hemolytic anemia such as elevated bilirubin and LDH.

A 15-month-old boy is brought to his pediatrician by his mother with a swollen and painful right elbow. She reports that he stumbled and fell on the carpeted floor of their living room, hitting his right elbow on the ground. The mother reports that he did not appear to be in a great deal of pain after the fall, and that she noted the swelling of the joint a few hours after the fall. He recently started walking approximately 2 weeks ago. He does not have any known medical issues, and he is not currently on medication. The mother's pregnancy was without complications and the boy was delivered vaginally without complications at 40 weeks. Aspiration of the right elbow joint reveals frank blood. Which of the following should be included in the work-up of this patient? 1. Peripheral blood smear 2. Creatinine level and percutaneous kidney biopsy 3. Prothrombin time/partial thromboplastin time 4. 24 hour urine collection for porphyrin levels 5. Rheumatoid factor

3. Prothrombin time/partial thromboplastin time This pediatric patient is presenting with hemarthrosis following relatively minor trauma. Platelet count and coagulation studies, including CBC (for platelet count), PT/INR, and PTT, should be obtained to rule out an underlying coagulopathy. There are numerous causes of hemarthrosis, including: trauma, bleeding disorders (hemophilia), neurologic deficits, arthritis, neoplasms, vascular damage, and recent joint arthroplasty. Pharmacologic anticoagulation may also predispose a patient to develop hemarthrosis; this is most commonly seen in patients with supratherapeutic levels of warfarin.

A 45-year-old man is brought to the emergency room by his wife because he has been acting confused for the past day. He is febrile, with an oral temperature of 103.6 deg F; vital signs are otherwise stable. His physical exam is significant for scattered petechiae and ecchymoses. He has never noticed lesions like these before. He also has subtle right-sided weakness affecting upper and lower extremities. Labs reveal: hemoglobin 7.0 g/dL, hematocrit 21%, white blood count of 10.2 x 10^3 µL, and platelet count of 20 x 10^3 per µL. PT/INR and PTT are normal. A peripheral blood smear is shown. What is the most likely diagnosis? 1. Idiopathic thrombocytopenic purpura 2. Disseminated intravascular coagulation 3. Thrombotic thrombocytopenic purpura 4. Hemolytic uremic syndrome 5. Evan's syndrome

3. Thrombotic thrombocytopenic purpura This clinical presentation is consistent with thrombotic thrombocytopenic purpura (TTP), which is associated with a pentad of signs and symptoms including fever, microangiopathic hemolytic anemia, thrombocytopenia (with associated petechiae), renal dysfunction, and neurological or mental status changes. TTP is a rare and severe bleeding disorder caused by strands of fibrin being deposited in multiple small vessels and the presence of hyaline thrombi affecting multiple organs, including the kidneys and brain. It presents with the pentad of symptoms described above. Pertinent laboratory findings include: anemia, thrombocytopenia (with prolonged bleeding time), elevated indirect bilirubin and LDH, negative Coombs' test, and normal PT/INR and PTT. In TTP there is reduced ADAMTS13 activity. This metalloprotease is involved in the cleaving of von Willebrand factor (vWF); when its activity is reduced, unusually large vWF multimers accumulate and cause aggregation and activation of platelets and subsequent thrombi.

What is the function of ADAMTS13? Why does ADAMTS13 dysfunction cause TTP?

ADAMSTS13 is a metalloprotease that normally cleaves vWF multimers into small monomers for eventual degradation When its activity is reduced, unusually large vWF multimers accumulate and cause aggregation and activation of platelets and subsequent thrombi

A 65-year-old woman on hemodialysis for chronic renal failure requires an urgent dental extraction for an abscessed tooth. Of the following, the most appropriate agent to administer to reduce the risk of significant bleeding would be A) desmopressin B) conjugated estrogen C) erythropoietin D) fresh-frozen plasma E) aminocaproic acid

A is correct Chronic uremia produces a complex abnormality of hemostasis, but patients generally have a prolonged bleeding time due to abnormal platelet function. Desmopressin given before the planned dental extraction is a reasonably safe and rapid way to decrease the risk of bleeding. Both conjugated estrogens and erythropoietin can also reduce the risk of bleeding in patients with uremia undergoing surgical procedures. However, since the effect is delayed, they would not be appropriate in an acute setting. The use of fresh-frozen plasma will not ameliorate prolongation of the bleeding time. The use of the fibrinolysis inhibitor -aminocaproic acid may have some utility in primary mennorhagia, genitourinary tract bleeding after prostate surgery, mild hemophilia, or profound thrombocytopenia or to reduce blood loss after cardiac or joint surgery.

A 12-year-old girl with chronic renal failure has had persistent epistaxis for 15 days. Laboratory studies show: Hemoglobin 7.2 g/dL Platelet count 175,000/mm3 Bleeding time 12 min Prothrombin time 12 sec Partial thromboplastin time (activated) 30 sec Serum urea nitrogen (BUN) 125 mg/dL Which of the following is the most likely cause of the epistaxis? A) Acquired platelet dysfunction B) Circulating immune complexes C) Erythropoietin deficiency D) Factor III deficiency E) Hypocalcemia

A) Acquired platelet dysfunction

A 13 year-old male presents to the emergency room with a deep skin abrasion on his knee. He states that it had not stopped leeding since it happened during recess approximately 20-30 min ago. physical examination reveals a well developed well nourished adolescent. There are multiple purpura over his legs and arms, and a few scattered petechiae on his chest and gums. His bleeding time is 22 minutes, platelets = 300,000/mm3, hemoglobin = 11 g/dL. A trial of cyroprecipitate transfusion does not improve his bleeding time. A normal platelet transfusion does improve bleeding time. Which of the following is the correct diagnosis? A. Bernard-Soulier syndrome B. Henoch-Schonlein purpura C. Idiopathic thrombocytopenic purpura D. Thrombotic thrombocytopenic purpura E. Von Willebrand's disease

A) Bernard-Soulier Disease Bernard-Soulier syndrome is an autosomal recessive disease of platelet adhesion which causes prolonged bleeding times in the presence of normal (or decreased) platelet counts. These patients' platelets cannot bind to subendothelial collagen properly because of a deficiency or dysfunction of the glycoprotein Ib-IX complex. Clinically the patients have impaired hemostasis and recurrent severe mucosal hemorrhage. The only treatment for an acute episode is a transfusion of normal platelets. This patient has a slightly decreased hemoglobin due to blood loss. HSP would have a normal bleeding time Both ITP and TTP are associated with decreased platelet counts . Von Willebrand's disease (choice E) causes increased bleeding times with normal platelet counts. It is the most common inherited bleeding disorder, caused by a defect in von Willebrand factor, which aids the binding of platelets to collagen. Even though the platelets themselves are normal, binding is impaired, thus a platelet transfusion would not correct the problem. Cryoprecipitate, a plasma fraction rich in von Willebrand factor, would help in the case of von Willebrand's disease, but would not help with Bernard-Soulier syndrome.

A 68-year old man comes to the emergency department because of chest pain for 30 minutes. An ECG shows a regular rate and rhythm and inverted T waves. While Laberatory studies are being done he gies oxygen and aspirin. Aspirin is most appropriate in the treatment of this patient because of inhibition of which of the following enzymes? A) Cyclooxygenase B) Lipoxygenase C) Phospholipase A2 D) Prostacyclin (PGI2) synthase E) Thromboxane A2 synthase

A) Cyclooxygenase

A 5-year-old boy is being evaluated for recurrent epistaxis and other abnormal bleeding episodes, including excessive bleeding from the umbilical cord at birth. Laboratory studies reveal the following: decreased hemoglobin (with microcytic hypochromic red cell indices), normal platelet count, markedly prolonged prothrombin time (PT) and partial thromboplastin time (PTT), and unmeasurable thrombin time (TT). Platelet aggregation studies reveal a normal platelet response to ristocetin, but with other substances (including collagen, ADP, and epinephrine), this patient’s platelets exhibit a primary wave defect. Based on these findings, which of the following is the most likely diagnosis? A. Afibrinogenemia B. Bernard-Soulier syndrome C. Glanzmann's thrombasthenia D. Gray platelet syndrome E. Wiskott-Aldrich syndrome

A. Afibrinogenemia Platelet aggregation refers to platelets binding to other platelets. One mechanism for this involves fibrinogen, which can act as a molecular bridge between adjacent platelets by binding to GpIIb and GpIIIa receptors on the surface of platelets. Abnormalities of platelet aggregation (aggregation defects or primary wave defects) include Glanzmann;s thrombasthenia and afibrinogenemia. Patients with Glanzmann's thrombasthenia have a deficiency of GpIIb-IIIa and defective platelet aggregation. Patients with low or no fi-brinogen levels characteristically have prolonged PT, PTT, and TT values: in fact, they are so prolonged they are unmeasurable. In contrast to platelet aggregation, platelet secretion refers to the secretion of the contents of two types of granules within the platelet cytoplasm. granules contain fibrinogen, fibronectin, and platelet-derived growth factor, while dense bodies contain ADP, ionized calcium, histamine, epinephrine, and serotonin. Decreased platelet secretion (activation defects) is seen with deficiencies of these granules; these diseases are called storage pool defects. They can involve either granules (gray platelet syndrome) or dense bodies (Chadiak-Higashi syndrome, Wiskott-Aldrich syndrome, or TAR). Wiskott-Aldrich syndrome is an X-linked disorder that is characterized by eczema, thrombocytopenia (small platelets), and immunodeficiency consisting of decreased levels of IgM and progressive loss of T cell function. These patients have recurrent infections with bacteria, viruses, and fungi. TAR refers to the combination of thrombocytopenia and absent radii.

Platelet activation is characterized by ______________(increased/decreased) intracellular cAMP and ______________(increased/decreased) intracellular calcium

Activation: decreased cAMP and increased calcium (promotes degranulation of platelets) Vice versa for inactivated platelet

ITP is seen most commonly in what adult patient population?

Adult females under 40 years of age

After which step does Platelet shape change occur? Describe the shape change

After Platelet aggregation, Platelets change shape from Smooth Discs to Spiky Sea-Urchins with greatly increased surface area

Compare the components of Platelet Alpha vs Dense granules

Alpha **vWF* *Fibrinogen *PDGF and TGF-a **P-selectin is located on the membrane* Dense **ADP, ATP* *Calcium *Serotonin, Histamine, and Epinephrine

Name 2 Anti-aggregation factors Name 1 Pro-aggregation factor Are Anti-aggregation or Pro-aggregation factors associated with increased blood flow?

Anti: PGI2 and NO Pro: TXA2 Pro-aggregation factors are associated with increased blood flow

Aspirin inhibits platelet activation and aggregation through what mechanism?

Aspirin inhibits TXA2 synthesis by acetylation of a serine residue on COX-1; resulting in irreversible inhibition of the enzyme COX-1 converts Arachidonic acid to prostaglandin H2 , the precursor to TXA2

A 2-year-old boy with normal size, weight, and development is brought to the physician because of a painful, swollen left knee for the past week. He has had two episodes of asymptomatic hematuria during the past 6 months. Both parents are healthy. He has achieved developmental milestones at appropriate ages. His height and weight are at the 70th percentile. Examination shows bruises and resolving hematomas on both elbows and signs of cutaneous hemorrhages at the site of a deep splinter. Laboratory studies show: Hemoglobin 12 g/dL Erythrocyte count normal Leukocyte count normal Bleeding time normal Partial thromboplastin time increased The most likely diagnosis can be proven by the therapeutic response to a single injection of which of the following materials? A. Factor I (fibrinogen) B. Factor VIII (antihemophilic factor) C. Factor IX (plasma thromboplastin component) D. Folic acid E. Vitamin K

B. Factor VIII (antihemophilic factor) Diagnosis = Hemophilia Hemophilia A is more common than B so most likely deficiency in Factor VIII

Chronic ITP is most commonly seen in ___________ (children/adults) and has a (insidious/acute) onset and requires (treatment/no treatment) Acute ITP is most commonly seen in ___________ (children/adults) and has a (insidious/abrupt) onset and requires (treatment/no treatment)

Chronic ITP; adults; insidious; treat with Acute ITP; children; abrupt; no treatment (self limiting)

Two teenage siblings in the same family are noted to have frequent nosebleeds and easy bruising from even minor trauma. The girl has had menorrhagia since menarche. The girl's CBC shows Hgb 14 g/dL, Hct 42.3%, MCV 90 fL, platelet count 242,000/microliter, and WBC count 7720/microliter. Her prothrombin time is 12 seconds and partial thromboplastin time 25 seconds. Platelet function studies show decreased aggregation in response to ADP, collagen, epinephrine, and thrombin. Which of the following disorders are these siblings most likely to have? A Hemophilia A B Antithrombin III deficiency C Glanzmann thrombasthenia D Systemic lupus erythematosus E Von Willebrand disease

C Glanzmann thrombasthenia There is a clue in the question stem; "fails to aggregate with ADP". Therefore they are an aggregating disorder Furthermore Glanzmann Thrombasthenia is characterized by normal platelet number, morphology, and absence of clumping

A 40-year-old woman has had a week long course of fever and mental confusion. Physical examination shows T 38.2 C, P 100/minute, RR 20/minute, and BP 100/60 mm Hg. She has widespread petechiae of skin and mucosal surfaces. Laboratory studies show her serum urea nitrogen is 52 mg/dL with creatinine 5.3 mg/dL. She has a hemoglobin of 12.2 g/dL, hematocrit 36.8%, MCV 93 fL, platelet count 19,000/microliter, and WBC count 8180/microliter. Schistocytes are seen on her peripheral blood smear. Her condition deteriorates rapidly following platelet transfusion. At autopsy, pink hyaline thrombi are found in small myocardial arteries. Which of the following is the most likely diagnosis? A Disseminated intravascular coagulopathy B Idiopathic thrombocytopenic purpura C Thrombotic thrombocytopenic purpura D Trousseau syndrome E Warm autoimmune hemolytic anemia

C Thrombotic thrombocytopenic purpura The hyaline thrombi are typical for TTP, as is the pentad of fever, mental changes, renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. Therapy of choice for TTP is plasmapheresis ( Patients with TTP have unusually large multimers of von Willebrand factor (vWF) in their plasma. Patients with TTP lack a plasma protease that is responsible for the breakdown of these ultralarge vWF multimers) Platelet transfusion is contraindicated because it is associated with rapid deterioration. The platelet aggregation worsens with platelet transfusions. Anecdotal reports have documented myocardial infarction and stroke following platelet transfusion in patients with TTP.

A 30-year-old woman has unusually heavy menstrual bleeding and intermittent gingival hemorrhages. She has multiple bruises. Laboratory studies show: Hemoglobin 13.3 g/dL Hematocrit 40% Leukocyte count 5000/mm3 Platelet count 25,000/mm3 PT 12 sec (INR= 1.0) Activated PTT 34 sec A peripheral blood smear shows normochormic normocytic erythrocytes without anisopoikilocytosis. A photomicrograph of bone marrow aspirate is shown. Which of the following is the most likely diagnosis? A) Acquired aplastic anemia B) Acute leukemia C) Disseminated intravascular coagulation D) Immune thrombocytopenic purpura

D) Immune thrombocytopenic purpura

A previously healthy 40 year old woman is brought to the emergency department by her husband because of a 2-day history of fever, lethargy, and confusion. Her temperature is 38*C (100.4*F), pulse is 80/min, respirations are 18/min, and blood pressure is 140/90 mm Hg. Physical examination shows scattered petechiae and ecchymoses over the lower extremities. Neurologic examination shows moderate generalized weakness. She is oriented to person but not to place or time. Laboratory studies show: Hemoglobin 9g/dL Hematocrit 27% Leukocyte count 8000/mm3 with normal differential Platelet count 15,000/mm3 PT 12 sec (INR = 1.1) PTT 30 sec Serum Urea nitrogen 25 mg/dL Haptoglobin <10 mg/dl (N = 40-180) Lactate dehydrogenase 1000 U/L A direct antiglobulin (coombs) test result is negative. A chest x-ray shows no abnormalities. The patient is admitted to the hospital and intravenous plasma exchange twice daily is started. Three days later, the patient is fully oriented. Her hemoglobin concentration is 11 g/dL, hematocrit is 33%, and platelet count is 85,000/mm3. A peripheral blood smear at the time of administration most likely showed which of the following erythrocyte abnormalities? A) Cabot rings B) Hypochromic microcytes C) Pappenheimer bodies D) Schistocytes E) Teardrop forms

D) Schistocytes Thrombocytopenia + Normal PT/PTT + neurologic symptoms + fever + decreased haptoglobin/increased LDH (signs of hemolytic anemia) = TTP

A 17-year-old girl has Hemophilia A. Her older brother also has Hemophilia A, but neither of their parents is affected. Which of the following is the most likely explanation for the development of Hemophilia in this girl? A. Aneuploidy B. Balanced autosomal translocation C. Inheritance of defective factor VIII alleles from both parents D. Skewed X-chromosome inactivation E. Unequal recombination

D. Skewed X-chromosome inactivation

A 1 1/2 -year-old girl is sent to a children's hospital for evaluation following a nosebleed which was so severe as to require nasal packing and transfusion of platelet concentrates. When a blood sample had been drawn in the emergency room for serum chemistry studies, the local hospital laboratory had noted that the clot that formed was unusual in that it failed to retract. Peripheral blood smear obtained by finger puncture showed an appropriate number of normal-sized platelets, all of which were individual, without clumping. At the children's hospital, it was noted that the child's parents were cousins. Special platelet studies showed that the child's platelet's failed to aggregate with any physiologic aggregating agent, including a high concentration of exogenous ADP. Which of the following is the most likely diagnosis? A. Bernard-Soulier syndrome B. Chediak-Higashi syndrome C. May-Hegglin anomaly D. Thrombasthenia E. Von Willebrand disease F. hemophilia A

D. Thrombasthenia There is a clue in the question stem; "fails to aggregate with ADP". Therefore they are an aggregating disorder Furthermore Glanzmann Thrombasthenia is characterized by normal platelet number, morphology, and absence of clumping

Name 9 triggers of Thrombotic Thrombocytopenic Purpura (TTP)

Drugs: ticlopidine, clopidogrel, and cyclosporine) Infection Pregnancy SLE Leukemias/Lymphomas Radiation Bone Marrow Transplantation

An 8-year-old girl is brought to the emergency department after experiencing sudden severe dyspnea. On examination, she has upper airway obstruction from soft tissue swelling in her neck. A radiograph shows a hematoma compressing the trachea. Laboratory studies show her prothrombin time is normal, but her partial thromboplastin time is increased. Further testing reveals less than 1% of normal factor VIII level. Both parents and two female siblings are unaffected by this problem, but a male sibling has experienced a similar episode. Which of the following genetic abnormalities is most likely to account for the findings in this girl ? A Autosomal dominant mutation B Autosomal recessive mutation C Genomic imprinting D Germline mosaicism E Random X inactivation F Spontaneous new mutation

E Random X inactivation This girl has features of hemophilia A. This X-linked recessive condition is expected to occur in males, however, who inherit the one maternal X chromosome with the genetic mutation, and they do not have another X chromosome with a normal functional allele, as is the case in her brother. Hemophilia in a female can be explained by the Lyon hypothesis, which states that only one X chromosome in a female is active (the "turned off" X chromosome is the Barr body) for most genes, but this inactivation is a random event. Some individuals are out on the tail end of the Poisson distribution of random events and have few active X chromosomes with the normal allele, leading to markedly diminished factor VIII levels.

A 68 y/o caucasian man is admitted with Dx of left lower lobe pneumonia and is started on gatifloxacin. He has a long hx of diabetes, hypothyroidism, hypercholesterolemia and hypertension.He also has diabetic retinopathy, peripheral neuropathy and nephropathy. He has an AV-fistula placed for a possible dialysis. His medications are insulin, furosemide, atorvastatin, metoprolol and levothyroxine. After having his blood drawn for some lab studies today, he bleeds persistently. Lab: Hb---------------- 11.5 Platelets--------- 160,000 Blood glucose-- 178 BUN------------- 56 Cr--------------- 3.5 Which of the following is the most likely cause of his bleeding? A-DIC B-Factor VIII deficiency C-Consumptive coagulopathy E-Platelet dysfunction F-Thrombocytopenia

E. Platelet Dysfunction (associated with uremia)

A 47-year-old woman is brought to the hospital by her husband because of fever, headache, confusion, and jaundice for 1 week. She underwent a hysterectomy 2 months ago and began estrogen replacement therapy recently. On admission, her temperature is 38.7 C (102 F), blood pressure is 140/90 mm Hg, pulse is 98/min, and respirations are 20/min. She appears disoriented to time and place. Physical examination reveals jaundiced sclerae and skin, purpura on the trunk, and bleeding gums. Her platelet count is 25,000/mm3, hematocrit is 24%, and creatinine is 4.9 mg/dL. Lactate dehydrogenase (LDH) and indirect bilirubin are elevated. Coagulation tests are within normal limits, but the bleeding time is increased; fibrin-split products and Coombs test are negative. A peripheral blood smear shows schistocytes, helmet-shaped cells, and cells with a triangular shape. Which of the following is the most likely diagnosis? A. Autoimmune hemolytic anemia B. Disseminated intravascular coagulation (DIC) C. Hemolytic-uremic syndrome (HUS) D. Idiopathic thrombocytopenic purpura (ITP) E. Thrombotic thrombocytopenic purpura (TTP)

E. Thrombotic thrombocytopenic purpura (TTP) Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of unknown etiology. It is characterized by an increased bleeding time but a decreased platelet count,. It causes purpura, fever, renal failure, microangiopathic hemolytic anemia, and microthrombi, frequently in young women. Elevated indirect bilirubin and high LDH are characteristic, as are schistocytes in the blood smear, renal dysfunction, and neurologic and systemic symptoms. Negative findings important to rule out similar conditions include a negative Coombs test and absence of fibrin split products. TTP is thought to be initiated by endothelial injury, which releases certain procoagulant materials into the circulation, causing platelet aggregation. This condition may be precipitated by pregnancy or use of estrogens. Autoimmune hemolytic anemia (choice A) can cause anemia and an elevated indirect bilirubin, but generally produces only mild symptoms, is not associated with thrombocytopenia, and does not cause fragmentation of red blood cells on the peripheral smear. The negative Coombs test argues against autoimmune hemolytic anemia. Disseminated intravascular coagulation (DIC; choice B) can be differentiated from TTP because of abnormal coagulation tests. In DIC, microangiopathic hemolysis is also present, but the prothrombin time (PT) and partial thromboplastin time (PTT) are prolonged, fibrinogen levels are reduced, and fibrin split products are elevated. Hemolytic-uremic syndrome (HUS; choice C) is not significantly different from TTP. The two conditions, in fact, are considered manifestations of the same pathogenetic spectrum. However, the vascular bed of the CNS is not involved in HUS. Thus, mental status changes are not part of the clinical picture of HUS. Idiopathic (autoimmune) thrombocytopenic purpura (ITP; choice D) is an immune disorder caused by autoantibodies to platelet antigens. Systemic illness is not present in ITP, which is characterized by isolated thrombocytopenia without other hematologic abnormalities. Ten percent of cases will manifest in association with autoimmune hemolytic anemia (Evans syndrome).

During injury to a blood vessel, which protein binds to platelet glycoprotein Ib? A. Glycoprotein Ia B. GpIIb/IIIa C. Keratan sulfate D. Hyaluronic acid E. von Willebrand factor

E. von Willebrand factor

What 2 molecules secreted by endothelial cells can inhibit platelet aggregation?

Endothelial cells synthesize prostaglandin I2 (PGI2 or prostacyclin) and nitric oxide (NO), which are potent inhibitors of aggregation.

What mnemonic can be used to remember the symptoms classically present in Thrombotic Thrombocytopenic Purpura (TTP)?

FAT RN *Fever *Microangiopathic hemolytic Anemia *Thrombocytopenia (bleeding, bruising) *Renal dysfunction (more pronounced in HUS) *Neurologic abnormalities and mental status changes

Platelets bind vWF using _________ receptor

GP1b

Platelets aggregate to each other using __________ receptor

Gp2b/3a

Fill in the blanks

GpIIb/IIIa: Glanzmann's thrombasthenia Von Willebrand Factor: Von Willebrand disease GpIb: Bernard-Soulier Disease

What is another name for Factor 12?

Hagemann Factor

Why may someone with von Willebrand's disease be mistakenly diagnosed with hemophilia A?

Hemophilia A is caused by low levels of factor VIII. vWF acts as a carrier protein for factor VIII, so patients with von Willebrand's disease commonly have low levels of factor VIII Both may have and increased PTT, normal PT, and normal platelet count *however the bleeding time is increased in VWD but normal in hemophilia*

What is the most common cause of thrombocytopenia in children and adults?

ITP (Idiopathic Thrombocytopenic Purpura)

How can you differentiate ITP from TTP

ITP can be distinguished from other hematologic causes of thrombocytopenia via the absence of fever, splenomegaly, schistocytes on blood smear, and by a normal PT/PTT.

What is the mechanism of IVIG use in the treatment of Immune Thrombocytopenic purpura.

IVIG is used acutely to increase platelet count and stop serious bleeding It is thought to achieve this by inhibition of Fc-receptor mediated platelet phagocytosis

What are important endogenous inhibitors of the coagulation cascade?

Inhibition of the clotting cascade occurs via *activated protein C* (which requires protein S as a co-factor) and *antithrombin III*.

Treatment of Idiopathic Thrombocytopenic Purpura

Initial treatment is corticosteroids (prednisone) Children respond well Adults may show early response but often relapse IVIG used acutely to increase platelet count Splenectomy in refractory cases TPO mimetics may be promising

Why are antibiotics contraindicated in kids with HUS caused by Shiga-like toxin producing E Coli 0157:H7?

Killing the bacteria increases release of Shiga-like toxin, which in turn increases the risk of HUS

Lab Findings in Hemophilia A vs Hemophilia B

Labs show elevated PTT normal PT platelet count bleeding time reduced factor 8 (Hemophilia A) factor 9 (Hemophilia B)

Describe the pathophysiology of MAHA

Mechanism of MAHA is due to a formation of a fibrin mesh due to increased activation of the coagulation system The red blood cells are physically cut by these protein networks,

What is the treatment of TTP and HUS?

Plasmaphareresis and Corticosteroids (particularly in TTP) Corticosteroids may decrease the production of autoantibodies

Why is platelet transfusion contraindicated in the treatment of Thrombotic Thrombocytopenic Purpura (TTP)?

Platelet transfusion is contraindicated because it is associated with rapid deterioration. The platelet aggregation worsens with platelet transfusions. Anecdotal reports have documented myocardial infarction and stroke following platelet transfusion in patients with TTP. *Platelet transfusions are also contraindicated in ITP and HUS

While disorders of primary hemostasis are usually due to abnormalities in ________, disorders of secondary hemostasis are usually due to abnormalities in ________

Primary: Platelets Secondary: Factors of the Coagulation Cascade

Factors of the coagulation cascade are produced by the _______ in an inactive state. What are the requirements of activation?

Produced by the liver Requires exposure to an activating substance Phospholipid surface (surface of the platelets) Calcium

Are petechiae a sign of quantitative or qualitative plate disorders?

Quantitative Petechiae are a sign of thrombocytopenia and are not usually seen with qualitative disorders

What activates Factor 12?

Subendothelial Collagen/damaged blood vessel walls (according to Pathoma) Factor 12 is activated by negatively charged substances according to wiki

What is the role of TXA2? What is the role of ADP? What is the role of fibrinogen? (in primary hemostasis)

TXA2: Promotes platelet aggregation ADP: Promotes GP2b/3a receptor expression on platelets; also helps platelets adhere to the endothelium Fibrinogen: Binds GpIIb/IIIa receptors and links platelets

Muscle Hematomas characteristic of Hemophilia occur most commonly in which muscles?

The Calf and Psoas Muscle

What is the goal of secondary hemostasis?

The goal of secondary hemostasis is to convert fibrinogen into fibrin to stabilize the loose platelet plug formed in primary hemostasis.

What is the purpose of primary hemostasis? What is the purpose of secondary hemostasis?

The purpose of primary hemostasis is *formation of a weak platelet plug* that serves to prevent or lessen the extent of hemorrhage. The goal of secondary hemostasis is to convert *fibrinogen into fibrin to stabilize the loose platelet plug* formed in primary hemostasis.

What is the mechanism of Splenectomy in Immune Thrombocytopenic purpura.

The spleen is both the site of synthesis of the antiplatelet antibodies seen in ITP as well as the site of destruction of antibody-coated platelets Two birds killed with one stone Splenectomy is used in refractory cases

What is the end product of the coagulation cascasde?

Thrombin

__________ converts Fibrinogen to Fibrin

Thrombin

Which factors comprise the extrinsic pathway of the coagulation cascade?

Tissue Factor and factor VII

What is the mechanism of corticosteroid use in the treatment of Immune Thrombocytopenic purpura

decreases antibody production

Which factors comprise the common pathway of the coagulation cascade?

factors X, V, II (prothrombin) and I (fibrinogen)

Which factors comprise the intrinsic pathway of the coagulation cascade?

factors XII, XI, IX and VIII