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165 Cards in this Set
- Front
- Back
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What are the components necessary for normal clotting?
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- Vessel wall
- Platelets - Clotting factors |
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What tests are used to investigate suspected coagulopathies?
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- Prothrombin Time (PT)
- Partial Thromboplastin Time (PTT) - Platelet Count - Tests of Platelet Function |
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What is done to measure the Prothrombin Time (PT)? What is it assessing?
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- Measures time (seconds) for plasma to clot after adding tissue thromboplastin and Ca2+ ions
- Assesses the EXTRINSIC and common coagulation pathways |
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What can cause a prolonged Prothrombin Time (PT)?
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- Deficiency of Factor V, VII, or X
- Deficiency of Prothrombin or Fibrinogen - Acquired inhibitor (eg, antibody) that interferes w/ EXTRINSIC pathway |
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What is done to measure the Partial Thromboplastin Time (PPT)? What is it assessing?
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- Measures time (seconds) for plasma to clot after adding kaolin, cephalin, and Ca2+
- Kaolin activates Factor XII - Cephalin substitutes for platelet phospholipids - Assesses the INTRINSIC and common coagulation pathways |
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What can cause a prolonged Partial Thromboplastin Time (PPT)?
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- Deficiency of Factor V, VIII, IX, X, XI, or XII
- Deficiency of Prothrombin or Fibrinogen - Acquired inhibitor (eg, antibody) that interferes w/ INTRINSIC pathway |
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What is done to measure the Platelet Count? What is a normal range?
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- Use electronic particle counter on anti-coagulated blood
- Normal: 150,000 to 450,000 / µL |
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What do you need to do if the electronic particle counter counts <150,000/µL or >450,000/µL platelets?
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Must do a visual inspection of a peripheral blood smear
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What are some of the tests for platelet function?
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- Platelet Aggregation Tests - measures response of platelets to certain agonists
- Tests of von Willebrand Factor - required for platelet adherence to subvascular collagen |
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What is the function of von Willebrand Factor?
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Required for platelet adhesion to sub-vascular collagen
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Abnormalities of what can cause bleeding disorders?
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- Vessel wall
- Platelets - Clotting factors |
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What are some causes of bleeding disorders due to vascular fragility?
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- Vitamin C deficiency (scurvy)
- Systemic amyloidosis - Chronic glucocorticoid use - Rare inherited conditions affecting CT - Infectious and hypersensitivity vasculitides |
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What infectious and hypersensitivity vasculitides can cause vascular fragility, leading to a bleeding disorder?
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- Meningococcemia
- Infective endocarditis - Rickettsial diseases - Typhoid - Henoch-Schönlein purpura |
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What are the signs/symptoms of bleeding due to vascular fragility?
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- "Spontaneous" appearance of petechiae and ecchymoses in skin and mucous membranes (probably from minor trauma)
- Normal coagulation tests most of the time |
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What are the types of abnormalities that can cause damage to vessel walls leading to bleeding disorders?
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- Vascular fragility
- Systemic conditions that inflame or damage endothelial cells |
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What can result from severe inflammation or damage to endothelial cells by systemic conditions?
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Disseminated Intravascular Coagulation:
- Can convert vascular lining to a prothrombotic surface - This activates coagulation throughout circulatory system - Platelets and coagulation factors are used up faster than they can be replaced - Leads to deficiencies that may lead to severe bleeding (= consumptive coagulopathy) |
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What does the term Consumptive Coagulopathy mean?
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There are deficiencies of platelets and coagulation factors that lead to severe bleeding because there was previously TOO MUCH clotting occurring
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What are some causes of bleeding disorders caused by abnormalities of platelets?
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Quantitative:
- Thrombocytopenia - deficiency of platelets Qualitative: - Acquired: uremia, certain myeloproliferative disorders, and aspirin ingestion - Inherited: von Willebrand disease and other rare congenital disorders |
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What are the clinical signs of inadequate platelet function?
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- Easy bruising
- Nosebleeds - Excessive bleeding from minor trauma - Menorrhagia |
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How do you diagnose a bleeding disorders stemming from defects in one or more coagulation factors?
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Prolongation of Prothrombin Time (PT) and/or Partial Thromboplastin Time (PTT)
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What kind of test is done by adding Tissue Thromboplastin and Ca2+ ions to plasma?
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Prothrombin Time (PT) measured in seconds
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What kind of test is done by adding Kaolin, Cephalin, and Ca2+ ions to plasma?
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Partial Thromboplastin Time (PTT) measured in seconds
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What are the signs of bleeding disorders stemming from defects in one or more coagulation factors?
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- NO petechiae or mucosal bleeding
*Hemorrhages in areas subject to trauma like the joints of the lower extremities - Massive hemorrhage may occur after surgery, dental procedures, or severe trauma - Hemophilias (inherited coagulation disorders) |
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What are some examples of bleeding disorders d/t multiple effects?
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- Disseminated Intravascular Coagulation (DIC) - both thrombocytopenia and coagulation factor deficiencies
- von Willebrand Disease - both platelet function and coagulation factor function are abnormal |
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What is DIC? What causes it?
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Disseminated Intravascular Coagulation
- Systemic activation of coagulation - Both thrombocytopenia and coagulation factor deficiencies |
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What happens during systemic activation of coagulation in Disseminated Intravascular Coagulation (DIC)?
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- Platelets and coagulation factors are consumed
- Fibrinolysis is activated |
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What can Disseminated Intravascular Coagulation (DIC) give rise to?
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- Tissue hypoxia and microinfarcts caused by myriad microthrombi
- Bleeding disorder d/t pathologic activation of fibrinolysis and depletion of elements required for hemostasis |
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How can clotting be initiated?
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- Extrinsic Pathway: release of tissue factor (tissue thromboplastin)
- Intrinsic Pathway: activation of factor XII by surface contact, collagen, or other negatively charged substances |
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What do both the Extrinsic and Intrinsic Pathway lead to?
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Generation of thrombin
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What limits clotting?
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- Rapid clearance of activated clotting factors by macrophages and liver
- Endogenous anticoagulants (eg, protein C) - Concomitant activation of fibrinolysis |
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What are the two triggers of Disseminated Intravascular Coagulation (DIC)?
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- Release of tissue factor or thromboplastic substances
- Widespread endothelial damage |
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What stimulates the release of tissue factor?
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- Massive tissue destruction
- Sepsis - Endothelial injury |
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What are some sources of thromboplastic substances, which when released into circulation can trigger Disseminated Intravascular Coagulation (DIC)?
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- Placenta (in obstetric complications)
- Cancer cells (acute promyelocytic leukemia and adenocarcinoma) |
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How can cancer cells provoke Disseminated Intravascular Coagulation (DIC)?
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- Release thromboplastic substances into circulation
- Release proteolytic enzymes - Express tissue factor |
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How does sepsis trigger Disseminated Intravascular Coagulation (DIC)?
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- G- and G+ septic infections can release endotoxins or exotoxins
- These can stimulate release of tissue factor from monocytes |
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What do activated monocytes release which can trigger Disseminated Intravascular Coagulation (DIC) during sepsis?
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- Release IL-1 and TNF
- This stimulates expression of Tissue Factor on endothelial cells - Simultaneously decreases expression of Thrombomodulin which activates Protein C (an anti-coagulant) |
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How does severe endothelial injury initiate Disseminated Intravascular Coagulation (DIC)?
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- Release of tissue factor
- Exposes subendothelial collagen and von Willebrand Factor (vWF) |
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What can provoke widespread endothelial injury that can initiate Disseminated Intravascular Coagulation (DIC)?
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- Deposition of Ag-Ab complexes (eg, SLE)
- Temperature extremes (eg, after heat stroke or burn injury) - Infections (eg, meningococci or rickettsiae) - Endotoxemia from G- sepsis |
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What is Disseminated Intravascular Coagulation (DIC) most associated with?
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- Sepsis
- Obstetric complications - Malignancy - Major trauma (especially to brain) |
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What initiates Disseminated Intravascular Coagulation (DIC) in obstetric conditions?
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- Tissue factor derived from placenta, retained fetus, or amniotic fluid enter circulation
- Shock, hypoxia, and acidosis often coexist and can lead to widespread endothelial injury |
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How can trauma to the brain initiate Disseminated Intravascular Coagulation (DIC)?
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- Trauma to brain releases fat and phospholipids
- These act as contact factors that activate the intrinsic pathway |
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What are the two consequences of Disseminated Intravascular Coagulation (DIC)?
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1) Widespread fibrin deposition within microcirculation
- Leads to ischemia - Hemolysis (micro-angiopathic hemolytic anemia) 2) Bleeding diathesis / disposition - D/t depletion of platelets and clotting factors - D/t secondary release of plasminogen activators |
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What is the action of plasmin?
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- Cleaves Fibrin (fibrinolysis)
- Cleaves Factors V and VIII |
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What are the results of fibrinolysis?
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- Fibrinolysis creates fibrin degradation products
- These inhibit platelet aggregation, have anti-thrombin activity, and impair fibrin polymerization - All contribute to hemostatic failure (bleeding) |
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What are the obstetric complications associated with Disseminated Intravascular Coagulation (DIC)?
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- Abruptio placentae
- Retained dead fetus - Septic abortion - Amniotic fluid embolism - Toxemia |
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What are the infections associated with Disseminated Intravascular Coagulation (DIC)?
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- Sepsis (G- and G+)
- Meningococcemia - Rocky Mountain spotted fever - Histoplasmosis - Aspergillosis - Malaria |
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What are the neoplasms associated with Disseminated Intravascular Coagulation (DIC)?
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- Carcinomas of pancreas, prostate, lung, and stomach
- Acute Promyelocytic Leukemia |
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What are the massive tissue injuries associated with Disseminated Intravascular Coagulation (DIC)?
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- Trauma
- Burns - Extensive surgery |
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What are the miscellaneous associations with Disseminated Intravascular Coagulation (DIC)?
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- Acute intravascular hemolysis
- Snakebite - Giant hemangioma - Shock - Heat stroke - Vasculitis - Aortic aneurysm - Liver disease |
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Where are microthrombi most often found in Disseminated Intravascular Coagulation (DIC)?
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Arterioles and capillaries of kidneys, adrenals, brain, and heart (but no organ is spared)
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How does the bleeding tendency of Disseminated Intravascular Coagulation (DIC) manifest?
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- Larger than expected hemorrhages near foci of infarction
- Diffuse petechiae and ecchymoses on skin, serosal linings of body cavities, epicardium, endocardium, lungs, and mucosal lining of urinary tract |
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How does acute vs chronic DIC change the clinical course? What kind of situations are associated with each?
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- Acute (eg, obstetric complications) - bleeding predisposition; can be life-threatening; treat aggressively w/ anti-coagulants like heparin or coagulants from fresh frozen plasma
- Chronic (eg, cancer) - thrombosis predisposition; may be identified w/ lab testing unexpectedly |
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What type of vessels are affected by Disseminated Intravascular Coagulation (DIC)?
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Usually in microcirculation, but large vessels may be involved on occasion
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What will lab studies show in Disseminated Intravascular Coagulation (DIC)?
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- Thrombocytopenia
- Prolongation of PT and PTT (d/t depletion of platelets, clotting factors, and fibrinogen) - Fibrin split products are increased in plasma |
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Isolated thrombocytopenia is associated with what finding?
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- Bleeding tendency
- Normal coagulation tests |
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What do the different levels of thrombocytopenia (platelets/µL) tell you?
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- Diagnosis of thrombocytopenia: <250,000/µL
- Increased risk of post-traumatic bleeding: 20,000-50,000/µL - Spontaneous bleeding: <20,000/µL |
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Where does bleeding in thrombocytopenia usually occur? Results?
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- Small, superficial blood vessels → petechiae or large ecchymoses in skin, mucous membranes of GI and urinary tracts, and other sites
- Larger hemorrhages in CNS are a major hazard in those w/ markedly depressed platelet counts |
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What are the major causes of thrombocytopenia?
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- Decreased production of platelets
- Decreased platelet survival - Sequestration - Dilutional |
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What are the clinically important thrombocytopenia causes? How can you distinguish these?
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- Reduced production of platelets
- Increased destruction of platelets - leads to compensatory increase in number of megakaryocytes, which can be observed in BM |
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What happens in the BM in accelerated destruction of platelets?
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BM usually reveals compensatory increase in number of megakaryocytes
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What is one of the most common hematologic manifestations of AIDS? Why?
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Thrombocytopenia
- Immune complex-mediated platelet destruction - Anti-platelet auto-antibodies - HIV-mediated suppression of megakaryocyte development and survival |
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What are the types of Immune Thrombocytopenic Purpura (ITP)? Who is affected by each most commonly?
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- Chronic ITP: woman between 20-40 years
- Acute ITP: child after viral infections (self-limited) |
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What is detected in chronic Immune Thrombocytopenic Purpura (ITP)?
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80% have antibodies directed against platelet membrane glycoproteins IIb/IIIa or Ib/IX complexes
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Where are the antibodies produced that cause chronic Immune Thrombocytopenic Purpura (ITP)? What kind of antibodies?
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- Spleen
- Produces Abs against platelet membrane glycoproteins IIb/IIIa or Ib/IX complexes |
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What happens in the spleen in Chronic Immune Thrombocytopenic Purpura (ITP)?
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- Abs produced against platelet membrane glycoproteins IIb/IIIa or Ib/IX complexes
- Major site of destruction of the IgG-coated platelets |
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How do you treat Chronic Immune Thrombocytopenic Purpura (ITP)? Effects?
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Splenectomy - normalizes platelet count and induces complete remission in more than 2/3 of patients
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What does the BM show in Chronic Immune Thrombocytopenic Purpura (ITP)?
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Increased megakaryocytes d/t accelerated platelet destruction (finding in all thrombocytopenias)
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What are the signs/symptoms of Chronic Immune Thrombocytopenic Purpura (ITP)?
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- Onset is insidious
- Petechiae, easy bruising, epistaxis (nose bleeds), gum bleeding, and hemorrhages from minor trauma - Serious intracerebral or subarachnoid hemorrhages are uncommon |
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How do you diagnose Chronic Immune Thrombocytopenic Purpura (ITP)?
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- Clinical features
- Thrombocytopenia - Examination of marrow (↑megakaryocytes) - Exclusion of secondary Immune Thrombocytopenic Purpura (ITP) |
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How common is Heparin Induced Thrombocytopenia? How long does it take?
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3-5% of patients on unfractionated heparin will present with moderate to severe thrombocytopenia after 1-2 weeks of treatment
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What is the mechanism responsible for Heparin Induced Thrombocytopenia?
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- IgG antibodies bind to platelet factor 4 on platelet membranes in heparin-dependent fashion
- Leads to activation of platelets and induces aggregation (exact opposite of what heparin is designed for) |
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What are the complications of Heparin Induced Thrombocytopenia?
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- Both venous and arterial thromboses occur
- Severe morbidity (loss of limbs) and mortality |
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How do you treat / prevent Heparin Induced Thrombocytopenia?
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- Cessation of heparin therapy
- Lower this risk of complication by using low-molecular-weight heparin preps |
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What are the types of Thrombotic Microangiopathies?
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- Thrombotic Thrombocytopenic Purpura (TTP)
- Hemolytic Uremic Syndrome (HUS) |
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What are the defining features of Thrombotic Thrombocytopenic Purpura (TTP)?
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PARTNER:
- Platelet count low (thrombocytopenia) - Anemia (microangiopathic, hemolytic) - Renal failure - Temperature rise (fever) - Neurological deficits - ER admission (as it is an emergency) |
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What are the defining features of Hemolytic Uremic Syndrome (HUS)?
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CRAP:
- Children - Renal failure* - Anemia (microangiopathic, hemolytic) - Platelet count low (thrombocytopenia) |
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What are the similarities / distinctions between Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)?
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Similar:
* Widespread formation of platelet-rich thrombi in microcirculation - Renal failure - Anemia (microangiopathic, hemolytic) - Platelet count low (thrombocytopenia) Distinctions (some exceptions to these): - HUS: usually children - TTP: usually fever and neurological deficits |
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What causes thrombocytopenia in the Thrombotic Microangitopathies (TTP and HUS)?
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Consumption of platelets
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What causes microangiopathic hemolytic anemia in the Thrombotic Microangitopathies (TTP and HUS)?
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Narrowing of blood vessels by platelet-rich thrombi
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How do you treat Thrombotic Thrombocytopenic Purpura (TTP)? Efficacy?
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Plasma exchange - successfully treats >80% of patients
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What is the cause of most cases of Thrombotic Thrombocytopenic Purpura (TTP)?
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- Symptomatic patients are deficient in Metalloprotease ADAMTS 13
- This enzyme degrades very high molecular weight multimers of von Willebrand factor (vWF) - Deficiency allows abnormally large vWF multimers to accumulate in plasma - They promote formation of platelet microaggregates |
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What does a deficiency of Metalloprotease ADAMTS 13 cause? How do you get this deficiency?
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- Causes Thrombotic Thrombocytopenic Purpura (TTP)
- Inherited or acquired (auto-antibodies that bind and inhibit metalloprotease) |
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When should you consider a diagnosis of Thrombotic Thrombocytopenic Purpura (TTP)?
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Any patient w/ unexplained thrombocytopenia and microangiopathic, hemolytic anemia
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What is the most common cause of Hemolytic Uremic Syndrome (HUS)?
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- In children and elderly, triggered by infectious gastroenteritis caused by E. coli strain O157:H7
- Releases a Shiga-like toxin that damages endothelial cells - This initiates platelet activation and aggregation |
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How do patients with Hemolytic Uremic Syndrome (HUS) caused by E. coli strain O157:H7 present? Treatment?
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- Bloody diarrhea
- Followed a few days later by acute renal failure and microangipathic anemia - Treat with supportive care and plasma exchange - Irreversible renal damage and death occur in severe cases |
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What are some less common causes of Hemolytic Uremic Syndrome (HUS)?
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- 10% caused by inherited mutations or auto-antibodies
- Leads to deficiency of factor H, factor I, or CD46 - each of which is a negative regulator of alternative complement cascade - Leads to uncontrolled complement activation after minor endothelial injury, resulting in thrombosis - Also can be seen after other exposures to certain drugs or radiation that cause damage to endothelial cells - More chronic and life-threatening |
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What are the similarities / distinctions of DIC and thrombotic microangiopathies?
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Similarities:
- Microvascular occlusion - Microangiopathic hemolytic anemia Differences: - DIC: prolonged PT and PTT - TTP and HUS: normal PT and PTT (activation of coagulation cascade is not of primary importance) |
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What causes coagulation disorders?
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Deficiencies of clotting factors
- Acquired (more common - often several factors simultaneously) - Congenital |
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What are some acquired causes of coagulation disorders?
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- Vitamin K deficiency
- Hepatic parenchymal disease - Disseminated Intravascular Coagulation - Auto-antibodies |
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What are the implications of a Vitamin K deficiency?
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- Vitamin K is required for synthesis of prothrombin and clotting factors VII, IX, and X
- Deficiency causes a severe coagulation defect |
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What are the implications of Hepatic Parenchymal disease?
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- Liver synthesizes several coagulation factors and also removes many activated coagulation factors from circulation
- Hepatic parenchymal disease is a common cause of complex hemorrhagic tendencies |
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What are some hereditary causes of coagulation disorders?
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X-linked:
- Hemophila A - deficiency of factor VIII - Hemophila B - deficiency of factor IX (aka Christmas disease) Autosomal Dominant: - von Willebrand disease - deficiency of vWF |
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What do Hemophilia A and von Willebrand disease have in common?
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They both involve defects in the Factor VIII-vWF complex
- Hemophilia A - Factor VIII - von Willebrand disease - vWF |
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What is the function of Factor VIII?
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- Factor VIII is an essential cofactor for Factor IX
- Factor IX activates Factor X in intrinsic coagulation pathway - Circulating Factor VIII binds non-covalently to vWF |
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What is the source of Factor VIII?
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Synthesized in liver
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What is the source of von Willebrand Factor? Where is it found?
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- Made in endothelial cells
- Found in plasma (attached to Factor VIII), platelet granules, endothelial cells w/in cytoplasmic vesicles called Weibel-Palade bodies, and in subendothelium where it binds to collagen |
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What is the function of von Willebrand Factor?
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- When endothelial cells are stripped away by trauma or injury, subendothelial vWF is exposed
- It binds to platelets mainly through glycoprotein Ib and a lesser degree through glycoprotein IIb/IIIa * Most importantly it facilitates the adhesion of platelets to damaged blood vessel walls - It also stabilized Factor VIII, thus vWF deficiency leads to a secondary deficiency of Factor VIII |
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How do you diagnose the various forms of von Willebrand disease?
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- Measure the quantity, size, and function of vWF
- vWF function is assessed using Ristocetin Platelet Agglutination Test - Ristocetin somehow activates the bivalent binding of vWF and platelet membrane glycoprotein Ib, creating inter-platelet "bridges" - This causes platelets to clump / agglutinate - which is measured to ***** vWF function |
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How does von Willebrand disease present?
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- Spontaneous bleeding from mucous membranes
- Excessive bleeding from wounds - Menorrhagia - Usually quite mild |
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How common is von Willebrand disease?
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Approximately 1% of people in US have it, making it the most common inheritable bleeding disorder
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How is von Willebrand disease inherited?
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Autosomal Dominant
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What kind of defects cause von Willebrand disease?
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- Both defects in platelet function and coagulation
- In most cases the platelet defect causes the clinical findings - Exception: rare patients with homozygous von Willebrand disease, in which there is a concomitant deficiency of factor VIII severe enough to produce features resembling hemophilia |
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What is the classic and most common variant of von Willebrand disease? Features?
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Type I von Willebrand disease
- Autosomal dominant - Decreased circulating vWF - Insignificant decrease in Factor VIII |
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What are the less common variants of von Willebrand disease? Features?
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Type IIA
- High-MW multimers of vWF are not synthesized - True deficiency Type IIB - Abnormal hyperfunctional high-MW multimers of vWF are synthesized and then rapidly removed - Cause spontaneous platelet aggregation - Some have mild chronic thrombocytopenia d/t platelet consumption |
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What is the most common hereditary cause of serious bleeding? How is it inherited?
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Hemophilia A
- X-linked recessive disorder caused by reduced Factor VIII activity - 30% arise from spontaneous mutations |
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Who is affected by Hemophilia A?
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- Mostly males
- Less commonly in heterozygous females w/ preferential inactivation of the X chromosome w/ normal Factor VIII gene ("unfavorable lyonization") |
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What are the degrees of Hemophilia A? Features?
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- Severe: observed in people with marked deficiencies of Factor VIII (<1% normal activity)
- Milder: becomes apparent when other predisposing condition (eg, trauma) is present |
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What explains the varying degrees of Factor VIII deficiency / severity of Hemophilia A?
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Many different causative mutations have been identified
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How common is normal Factor VIII concentration in patients with Hemophilia A? Why is there disease then?
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10% have normal Factor VIII concentration, but the coagulant activity is low because of a mutation causing a loss of function
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What are the signs/symptoms in symptomatic Hemophilia A?
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- Easy bruising
- Massive hemorrhage after trauma or operative procedures - Spontaneous hemorrhages in areas that are subject to mechanical stress (eg, joints - hemarthoses), can lead to cripping deformities - NO petechiae |
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How do you confirm a diagnosis of Hemophilia A?
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* Specific assays for Factor VIII
- Also prolonged PTT (not specific for Hemophilia A) |
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How can you treat Hemophilia A? Effects?
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** Factor VIII Infusions: recombinant forms and highly purified forms prepared from human plasma **
- Mix patient's plasma with normal plasma = replacement therapy - In 15%, complicated by neutralizing antibodies against Factor VIII (PTT fails to be corrected in these mixing studies) |
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What causes Hemophilia B?
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Severe factor IX deficiency - X-linked
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How does Hemophilia B compare to Hemophilia A?
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- Indistinguishable from Hemophilia A, but much less common
- PTT is prolonged in both - Diagnosis made by specific assays for Factor VIII (A) and Factor IX (B) - Treated by infusion of respective recombinant factor |
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What are the the three primary abnormalities that lead to thrombus formation?
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Virchow's Triad:
- Endothelial injury - Stasis or turbulent blood flow - Hypercoagulability of the blood |
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What are some examples of thrombosis related to endothelial injury?
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- Formation in cardiac chambers after MI
- Over ulcerated plaques in atherosclerotic arteries - Sites of traumatic or inflammatory vascular injury (vasculitis) |
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What happens when the endothelium is damaged that leads to thrombosis?
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- Loss of endothelium exposes the subendothelial ECM
- Leads to platelet adhesion, release of tissue factor, and reduces local production of PGI2 and plasminogen activators |
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Besides being physically disrupted, how can changes to the endothelium affect thrombosis?
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- Any perturbation in the dynamic balance of the prothrombotic and antithrombotic effects of endotheliuum can influence clotting locally
- Dysfunctional endothelium synthesizes ↑ procoagulant factors and ↓ anticoagulant molecules |
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What procoagulant factors can the endothelium release? How are these affected by a dysfunctional endothelium?
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- Platelet adhesion molecules
- Tissue Factor - OAI |
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What anticoagulant factors can the endothelium release? How are these affected by a dysfunctional endothelium?
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- Thrombomodulin
- PGI2 - t-PA |
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What can induce endothelial dysfunction?
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- Hypertension
- Turbulent blood flow - Bacterial products - Radiation injury - Metabolic abnormalities (eg, hypocystinuria and hypercholesterolemia) - Toxins from cigarette smoke |
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How does abnormal blood flow lead to thrombosis?
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Stasis and turbulent (chaotic) blood flow lead to:
- Endothelial cell activation and procoagulant activity (via changes in endothelial gene expression) - Platelets and leukocytes come into contact w/ endothelium when flow is sluggish (stasis) - Slows washout of activated clotting factors and impedes inflow of inhibitors (stasis) |
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How does normal (laminar) blood flow differ from turbulent (chaotic) blood flow?
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- Normal laminar blood flow - platelets and other cells are mainly in the center of the vessel lumen, separated from endothelium by slower-moving layer of plasma
- Turbulent chaotic blood flow - platelets and other cells are adjacent to endothelium |
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What clinical settings cause turbulent and static blood flow that can lead to thrombosis?
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Turbulence
- Ulcerated atherosclerotic plaques Stasis - Aneurysms - Acute MI that results in non-contractile mycoardium - Acute MI that results in ventricular remodeling can lead to aneurysm formation - Mitral valve stenosis → LA dilation w/ A fib - Hyperviscosity syndromes (eg, polycythemia) increase resistance to flow - Sickle Cell Anemia |
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What clinical settings cause turbulent flow that can lead to thrombosis?
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Ulcerated atherosclerotic plaques
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What clinical settings cause static blood flow that can lead to thrombosis?
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- Aneurysms
- Acute MI that results in non-contractile mycoardium - Acute MI that results in ventricular remodeling can lead to aneurysm formation - Mitral valve stenosis → LA dilation w/ A fib - Hyperviscosity syndromes (eg, polycythemia) increase resistance to flow - Sickle Cell Anemia |
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How do you define a state of "hypercoagulability" that can predispose someone to thrombosis?
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Any alteration of the coagulation pathways that predisposes affected persons to thrombosis
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What are the two types of hypercoagulability?
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- Primary (genetic) disorders
- Secondary (acquired) disorders |
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Hypercoagulability contributes to what kinds of thrombosis? And less commonly to what other thrombosis?
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More commonly a risk factor for:
- Venous Thrombosis Less commonly a risk factor for: - Arterial Thrombosis - Intracardiac Thrombosis |
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What are the primary (genetic) disorders that contribute to hypercoagulability?
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- Leiden mutation (Factor V mutation)
- Prothrombin mutation - Deficiencies of anticoagulants (anti-thrombin III, protein C, or protein S) |
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How common is the Leiden mutation? What is affected?
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- 2-15% of whites carry a Factor V mutation
- Mutation makes Factor V resistant to Protein C (anti-coagulant) |
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If you have a Leiden mutation (Factor V mutation), how is your risk for venous thrombosis changed?
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- Heterozygotes: 5-fold increase
- Homozygotes: 50-fold increase |
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How common is the Prothrombin mutation? What is affected?
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- Found in 1-2% of general population
- Single nucleotide substitution (G to A) in 3' untranslated region of prothrombin gene |
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If you have a Prothrombin gene mutation, how is your risk for venous thrombosis changed?
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- Increased prothrombin transcription
- Nearly 3-fold increased risk |
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What are the less common primary hypercoagulable states caused by?
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Inherited deficiencies of anti-coagulants:
- Anti-thrombin III - Protein C - Protein S |
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If you have an inherited deficiency of the anti-coagulants (anti-thrombin III, protein C, or protein S), how is your risk for venous thrombosis changed?
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- Affected patients typically present w/ venous thrombosis and recurrent thromboembolism in adolescence or early adult life
- Congenitally elevated levels of homocysteine contribute to arterial and venous thromboses |
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When should you really be concerned about someone having a Factor V Leiden or Prothrombin gene mutation?
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- In any setting there risk of thrombosis is mildly elevated
- However, in settings of other acquired risk factors such as pregnancy, prolonged bed rest, and lengthy airplane flights, there risk may be more apparent |
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When should you consider an inherited cause of hypercoagulability in a young patient (<50 years)?
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When they've had a thrombotic event event when other acquired risk factors are present
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How do oral contraceptive use and hyper-estrogenic state of pregnancy relate to risk for thromboses?
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- These are hypercoagulable states
- May be related to increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III |
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How does disseminated cancer relate to risk for thromboses?
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Release of procoagulant tumor products (eg, mucin from adenocarcinoma) predisposes to thrombosis
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How does advanced aging relate to risk for thromboses?
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- Increased platelet aggregation
- Reduced release of PGI2 from endothelium (anti-coagulant molecule) |
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How does smoking and obesity relate to risk for thromboses?
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Both promote hyper-coagulability by unknown mechanisms
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What are the two acquired thrombophilic states that present particularly important clinical problems?
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- Heparin-Induced Thrombocytopenic Syndrome (HIT)
- Antiphospholipid Antibody Syndrome |
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How common is Heparin-Induced Thrombocytopenic Syndrome (HIT) in patients taking Heparin?
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Up to 5% of patients taking UNFRACTIONATED heparin (for therapeutic anticoagulation)
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What is the pathophysiology of Heparin-Induced Thrombocytopenic Syndrome (HIT)?
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- Development of auto-Abs that bind complexes of heparin and platelet membrane protein (platelet factor-4)
- Abs may also bind similar complexes on platelet and endothelial surfaces leading to platelet activation, aggregation, and consumption - Leads to thrombocytopenia and endothelial cell injury - Overall result is a prothrombotic state |
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What is an alternative to decrease occurrence of Heparin-Induced Thrombocytopenic Syndrome (HIT)?
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Low-Molecular-Weight Fractionated Heparin preps induce auto-Abs less frequently (but can still cause thrombosis if antibodies have already been formed
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What are the main manifestations of Antiphospholipid Antibody Syndrome?
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- Recurrent thrombosis
- Repeated miscarriages - Cardiac valve vegetations - Thrombocytopenia |
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What is the pathophysiology responsible for Antiphospholipid Antibody Syndrome?
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- Auto-Abs directed against anionic phospholipids (eg, cardiolipin) or plasma protein antigens unveiled by binding to such phospholipids (eg, prothrombin)
- Auto-Abs induce a hypercoagulable state, possibly by inducing endothelial injury, activating platelets or complement directly, or interacting w/ catalytic domains of certain coagulation factors |
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In vitro (in absence of platelets and endothelium), how do auto-Abs in Antiphospholipid Antibody Syndrome leads to thrombosis?
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In vitro, in absence of platelets and endothelium:
- Abs interfere w/ the phospholipid complex assembly - Inhibits coagulation (lupus anticoagulant) |
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What categories can patients with Antiphospholipid Antibody Syndrome fall into? How do they differ?
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- Primary Antiphospholipid Antibody Syndrome: only demonstrate manifestations of hypercoagulable state w/o evidence of another autoimmune disorder
- Secondary Antiphospholipid Antibody Syndrome: caused by well-defined auto-immune disease, such as SLE |
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How common are anti-phospholipid antibodies in normal people? Implications?
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- 5-15% of normal persons have these anti-phospholipid Abs
- Presence of these Abs may be necessary but not sufficient to cause full-blown Antiphospholipid Antibody Syndrome |
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How does the location of arterial, cardiac, and venous thrombi differ?
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- Arterial and cardiac thrombi: usually at sites of endothelial injury or turbulence
- Venous thrombi: usually at sites of stasis |
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How does the attachment and direction of the arterial and venous thrombi differ?
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- Thrombi are focally attached to underlying vascular surface and tend to propagate TOWARD the heart
- Arterial thrombi grow in retrograde direction (against blood flow, but towards heart) - Venous thrombi extend in direction of blood flow |
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What is true about the propagating portion of a thrombus?
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- Tends to be poorly attached
- Prone to fragmentation and migration through blood as an embolus |
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What are the morphological features of thrombi?
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Laminations called Lines of Zahn:
- Pale platelet and fibrin layers - Darker RBC rich layers |
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What is the significance of Lines of Zahn on a thrombus?
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- Found in thrombi that form in flowing blood
- Usually can distinguish between antemortem thrombosis from bland non-laminated clots that form in postmortem state - Although clots forming in low-flow areas may resemble postmortem clots, careful evaluation can generally reveal ill-defined laminations |
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What is the term for thrombi that occur in the heart or aorta?
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Mural thrombi
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What conditions promote CARDIAC mural thrombi (thrombi in heart or aorta)?
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- Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or MI)
- Endomyocardial injury (myocarditis, catheter trauma) |
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What conditions promote AORTIC mural thrombi (thrombi in heart or aorta)?
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- Ulcerated atherosclerotic plaques
- Aneurysmal dilations |
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What are the characteristic contents of arterial thrombi? Locations?
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- Rich in platelets (because it is usually caused by endothelial injury which activates platelets)
- Found on ruptured atherosclerotic plaques and other vascular injuries (eg, vasculitis or trauma) |
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What are the characteristic causes and contents of venous thrombi? Locations?
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- Propagate some distance towards the heart, forming a long cast within lumen that is prone to emboli
- Increased activity of coagulation factors causes most thrombi; platelet activation is secondary (unlike in arterial thrombi) - Form in sluggish venous circulation, tend to contain more enmeshed RBCs leading to moniker Red or Stasis Thrombi - Veins of lower extremity most commonly affected (90%) - Also occur in upper extremities, periprostatic plexus, or ovarian and periuterine veins (or rarely the dural sinuses, portal vein, or hepatic vein) |
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What are the characteristics of post-mortem clots that help distinguish them from venous thrombi?
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Post-mortem clots:
- Gelatinous d/t RBC settling - Dark red dependent portion and yellow "chicken fat" upper portion - Usually not attached to vessel wall Venous / Red thrombi: - Firm and focally attached - Contain gray strands of deposited fibrin |
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What is the term for thrombi that form on heart valves?
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Vegetations
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What can happen if blood-borne infections affect the valves?
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Bacterial or fungal blood-borne infections can cause valve damage leading to development of large thrombotic masses = Infective Endocarditis
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What causes sterile vegetations to form on heart valves?
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- Non-infected valves can grow vegetations in hypercoagulable state
- Lesions are called non-bacterial thrombotic endocarditis - Less commonly, sterile, verrucous endocarditis (Libman-Sacks endocarditis) can occur in setting of SLE |
