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Acquired Bleeding Disorders
M2 Hematology/Oncology Sequence Steven Pipe, MD
Winter 2009
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Acquired Bleeding Disorders
• Can be a recognized manifestation of a known disorder
• Can prompt a differential diagnosis to identify an underlying disease
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or
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Promoters and Inhibitors of Coagulation
• Coagulation cascade – Tissue factor (Extrinsic) Pathway – Intrinsic Pathway – Fibrinogen, Factor XIII and Fibrinolysis
• Inhibitors – Physiologic – Acquired – Therapeutic
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PTT PT
6 Mechanisms In Hematology Israel
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7 Mechanisms In Hematology Israel
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Protein C - Protein S System
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Mechanisms In Hematology Israel
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9 Mechanisms In Hematology Israel
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Acquired Bleeding Disorders associated with PT and aPTT
• Various Medical Conditions – Anticoagulation – Disseminated Intravascular Coagulation – Vitamin K Deficiency – Liver Disease – Massive Transfusion
• Dysfibrinogenemias • Acquired Inhibitors to Factors V, II & X
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Disseminated Intravascular Coagulation (DIC)
• DIC is evidence for the simultaneous presence of: – thrombin(procoagulation) – plasmin(fibrinolysis)
• Presentations: – an acute hemorrhagic disorder – an indolent, subacute thrombotic disorder
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Primary Events in DIC
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Underlying Disorder
Systemic Activation of Coagulation
Widespread Intravascular Fibrin Deposition
Consumption of Platelets and Clotting Factors
Thrombosis Bleeding
K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009
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Pathophysiology of DIC
Blue (dotted) indicates inhibitors of coagulation 13 K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009
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Etiology of DIC
• Acute DIC – Infection: Gram -ve sepsis, viremia, parasitic – Obstetric: Abruption, amniotic fluid embolism, eclampsia – Malignancy: Acute promyelocytic leukemia – Trauma: Crush injury, freshwater drowning, heat stroke,
snakebite – Other: Homozygous protein C and S deficiency (infants), severe
liver disease, HIT • Subacute DIC
– Malignancy: mucinous adenocarcinoma (Trousseau syndrome) – Obstetric: retained dead fetus – Vascular: hemangioendothelioma (Kasabach-Merritt), venous
thromboembolic disease, chronic renal failure
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Post-varicella purpura fulminans
15 DeLoughery, ASH Image Bank, 2004
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Diagnosis of DIC
• Screening tests: – Activated partial thromboplastin time (prolonged) – Prothrombin time (prolonged) – Fibrinogen (decreased) – Platelet count (decreased)
• Confirmatory tests: – D-dimer (elevated) – Fibrin degradation products (elevated)
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17 Mechanisms In Hematology Israel
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Value of the D-dimer • Measure of D-dimers liberated from fibrin by
action of plasmin – Evidence of prior thrombin activity followed by
fibrinolysis • Should be part of evaluation of DIC • Also now an important screening and prognostic
tool in venous thromboembolic disease – Good positive predictive value for DVT and PE – Very high negative predictive value
18 Source: Wells et al., NEJM, 2003;349:1227-1235 Eichinger et al., JAMA, 2003;290:1071-1074
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Treatment of DIC
• Treat the underlying condition first! – Antibiotics, surgery, chemotherapy, embolization – disease-specific therapy
• APML - all trans-retinoic acid (ATRA)
• Replacement therapy – Platelets, FFP, cryoprecipitate
• Heparin – May be useful in certain situations
• Acral cyanosis and digital ischemia, purpura fulminans, retained dead fetus, migratory thrombophlebitis
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Microangiopathic Hemolytic Anemia
1. Shistocyte 2. Microcyte
* Note absence of platelets 20
K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009
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Microangiopathic Hemolytic Anemias Pathophysiology
• Hallmarks are red cell fragmentation (shistocytes, microcytes) on peripheral blood smear, often accompanied by thrombocytopenia
• Intravascular hemolysis as red cells are damaged traversing small blood vessels with fibrin deposition or platelet aggregates – Can also occur in areas of high turbulence (eg. Aortic
stenosis) • Red cell fragments are targeted for destruction in
the reticuloendothelial system (eg. spleen) 21
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Microangiopathic Hemolytic Anemias Differential Diagnosis
• Disseminated intravascular coagulation (DIC) • Thrombotic thrombocytopenic purpura (TTP) • Hemolytic uremic syndrome (HUS) • Malignant hypertension • Aortic stenosis • HELLP syndrome and eclampsia • Heparin-induced thrombocytopenia • Severe glomerulonephritis
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Thrombotic Thrombocytopenic Purpura
• Classic pentad: – Microangiopathic hemolytic anemia – Thrombocytopenia – Renal involvement – Neurologic signs – Fever
• Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves vWF within platelet-rich thrombi – Congenital form (Upshaw-Schulman syndrome) is the result of a
deficiency of ADAMTS13 • Treatment is plasma exchange +/- immunosuppression
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Pathogenesis of Idiopathic TTP caused by ADAMTS13 Deficiency
24
Sadler, J. E. Blood 2008;112:11-18
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DIC vs TTP
Abnormality DIC TTP
Abnormal PT/PTT Y N
Hemolysis Y Y
Thrombocytopenia Y Y
Abnormal Renal Tests N Y
25 Source Undetermined
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Acquired Bleeding Disorders associated with PT and aPTT
• Various Medical Conditions – Anticoagulation – Disseminated Intravascular Coagulation – Vitamin K Deficiency – Liver Disease – Massive Transfusion
• Dysfibrinogenemias • Acquired Inhibitors to Factors V, II & X
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Vitamin K deficiency
• Vitamin K cycle • Mechanisms of Vitamin K deficiency • Warfarin action
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28 Mechanisms In Hematology Israel
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Mechanisms of Vitamin K deficiency
• Nutritional depletion – Alcoholics, long-term IV nutrition
• Antibiotic administration – Interfere with bacteria synthesis and
absorption • Warfarin
– Inhibition of epoxide reductase and (to a lesser degree) quinone reductase
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Liver Disease
• Liver synthesizes and clears both procoagulants and inhibitors
• Paradoxically factor VIII is often elevated – Likely due to decreased clearance
• Reduced factor V helps distinguish liver synthetic dysfunction from vitamin K deficiency
• Fibrinogen the last to fall • Structural manifestations of liver disease contribute to
bleeding – Portal hypertension, varices, gastritis, hemorrhoids
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Massive Transfusion
• Defined as transfusion of more than 1.5 times the patient’s blood volume in 24 h
• Acquired coagulopathy results from dilution of plasma and platelets and excess anticoagulant – 10% of transfusion is anticoagulant
• Prevention: – Administer 1 unit FFP and calcium chloride for
every 4-6 units PRBC’s
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Other uncommon acquired coagulation protein defects
• Dysfibrinogenemia – Acquired liver disease (EtOH, immunologic, toxic, viral)
• Inhibitors to X, V, II and fibrinogen • Hypergammaglobulinemia
– Multiple myeloma (IgG) – Waldenstrom macroglobulinemia (IgM)
• Systemic amyloidosis – Decreased factor X or IX
• Heparinoids – Heparin-like anticoagulants produced in patients with an
underlying malignancy • Factitious
– Self-administered heparin/warfarin
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Acquired bleeding disorders associated with prolonged aPTT only
• Inhibitors to factor VIII – Elderly, post-partum, connective tissue disorder, B cell
malignancy – Prolonged aPTT but normal PT – Skin ecchymoses and tissue hematomas – Respond to immunosuppressive therapy – “bypassing agents” to treat bleeding
• Activated prothrombin complex concentrates • Recombinant factor VIIa (Novoseven)
– Prognosis generally favorable
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Slide 6: Mechanisms In Hematology Israel Slide 7: Mechanisms In Hematology Israel Slide 8: Mechanisms In Hematology Israel Slide 9: Mechanisms In Hematology Israel Slide 12: K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 – From the chapter “Disseminated Intravascular Coagulation” Slide 13: K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 – From the chapter “Disseminated Intravascular Coagulation” Slide 15: DeLoughery, ASH Image Bank, 2004 Slide 17: Steven Pipe Slide 20: K. McInerny. American Academy of Pediatrics textbook of pediatric care. 2009 – From the chapter “Disseminated Intravascular Coagulation” Slide 24: Sadler, J. E. Blood 2008;112:11-18, http://bloodjournal.hematologylibrary.org/cgi/content/full/112/1/11/F2, 2008 American Society of
Hematology Slide 25: Source Undetermined Slide 28: Mechanisms In Hematology Israel
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