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Biochemistry of Coagulation
Ahmad Shihada Silmi Msc, FIBMS Staff Specialist in Hematology Medical Technology Department Islamic University of Gaza 2012
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The Protein C Anticoagulant Pathway Thrombus at site of injury
Blood Flow Thrombomodulin Protein C APC Anticoagulation downstream Thrombin Thrombin Thrombus Thrombus at site of injury
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The Protein C Anticoagulant Pathway
Blood Flow VIIIa Va Thrombus Vai VIIIai Factor V Leiden PS APC APC
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Proposed Mechanism of AT III-Heparin System
Th Lysine sites Serine site H Arginine site Heparin Thrombin Antithrombin III H AT III Th
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Fibrinolytic Pathway Fibrinolysis is initiated when fibrin is formed and eventually dissolves the clot.
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degradation products (FDP)
Fibrinolytic Pathway PAI-1 Plasminogen Tissue Plasminogen Activator (t-PA) Urokinase (uPA) Exogenous: streptokinase Plasmin Inhibitor XL-Fibrin, fibrinogen Plasmin XL- fibrin degradation products (FDP)
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Degradation of Fibrin/Fibrinogen
Fibrinogen or Fibrin Fragment X Small Peptides Fragment Y Fragment D Fragment E Plasmin Plasmin Plasmin
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Approach to evaluate Fibrinolysis
D-Dimer, a measure of fibrin degradation products, is the final product formed during the fibrinolysis process by plasmin
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Approach to evaluate Fibrinolysis cont,
Elevated levels of D-Dimer are indicative of on-going fibrinolysis Found high in : (DVT) (PE) (DIC) D-Dimer levels also rise during the normal pregnancy and very high levels are associated with complications.
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Bleeding Disorders
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Clinical Features of Bleeding Disorders
Platelet disorders Coagulation factor disorders Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract) Petechiae Yes No Ecchymoses (“bruises”) Small, superficial Large, deep Hemarthrosis / muscle bleeding Extremely rare Common Bleeding after cuts & scratches Yes No Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe
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Hematologic disorders causing bleeding
Coagulation factor disorders Platelet disorders
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Coagulation factor disorders
Inherited bleeding disorders Hemophilia A and B Von Willebrands disease Other factor deficiencies Acquired bleeding disorders Liver disease Vitamin K deficiency/warfarin overdose DIC
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Hemophilia A and B Hemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX Inheritance X-linked X-linked recessive recessive Incidence 1/10,000 males 1/50,000 males Severity Related to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 5-25% - Mild - bleeding with surgery or trauma Complications Soft tissue bleeding
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Hemophilia Clinical manifestations (hemophilia A & B are indistinguishable) Hemarthrosis (most common) Fixed joints Soft tissue hematomas (e.g., muscle) Muscle atrophy Shortened tendons Other sites of bleeding Urinary tract CNS, neck (may be life-threatening) Prolonged bleeding after surgery or dental extractions
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Hemarthrosis (acute)
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von Willebrand Disease: Clinical Features
von Willebrand factor Synthesis in endothelium and megakaryocytes Forms large multimer Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets Inheritance - autosomal dominant Incidence - 1/10,000 Clinical features - mucocutaneous bleeding
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Laboratory evaluation of von Willebrand disease
Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency Diagnostic tests: vonWillebrand type Assay ___________________________________________________ vWF antigen ß Normal ßß vWF activity ß ß ßß Multimer analysis Normal Normal Absent
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Vitamin K deficiency Source of vitamin K Green vegetables Synthesized by intestinal flora Required for synthesis Factors II, VII, IX ,X,Protein C and S Causes of deficiency Malnutrition Biliary obstruction Malabsorption Antibiotic therapy Treatment Vitamin K Fresh frozen plasma
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Common clinical conditions associated with Disseminated Intravascular Coagulation
Activation of both coagulation and fibrinolysis Triggered by Obstetrical complications Amniotic fluid embolism Abruptio placentae Vascular disorders Reaction to toxin (e.g. snake venom, drugs) Immunologic disorders Severe allergic reaction Transplant rejection Sepsis Trauma Head injury Fat embolism Malignancy
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Disseminated Intravascular Coagulation (DIC) Mechanism
Systemic activation of coagulation Depletion of platelets and coagulation factors Intravascular deposition of fibrin Thrombosis of small and midsize vessels with organ failure Bleeding
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Release of thromboplastic material into
Pathogenesis of DIC Release of thromboplastic material into circulation Consumption of coagulation factors; presence of FDPs aPTT PT TT Fibrinogen Presence of plasmin FDP Intravascular clot Platelets Schistocytes Coagulation Fibrinolysis Fibrinogen Thrombin Plasmin Fibrin Monomers Fibrin(ogen) Degradation Products Fibrin Clot (intravascular) Plasmin
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Classification of platelet disorders
Quantitative disorders Abnormal distribution Dilution effect Decreased production Increased destruction Qualitative disorders Inherited disorders (rare) Acquired disorders Medications Chronic renal failure Cardiopulmonary bypass
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Laboratory Evaluation of Bleeding Overview
CBC and smear Platelet count Thrombocytopenia RBC and platelet morphology TTP, DIC, etc. Coagulation Prothrombin time Extrinsic/common pathways Partial thromboplastin time Intrinsic/common pathways Coagulation factor assays Specific factor deficiencies 50:50 mix Inhibitors (e.g., antibodies) Fibrinogen assay Decreased fibrinogen Thrombin time Qualitative/quantitative fibrinogen defects FDPs or D-dimer Fibrinolysis (DIC) Platelet function von Willebrand factor vWD Bleeding time In vivo test (non-specific) Platelet function analyzer (PFA) Qualitative platelet disorders and vWD Platelet function tests Qualitative platelet disorders
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Laboratory Evaluation of the Coagulation Pathways
Partial thromboplastin time (PTT) Prothrombin time (PT) Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium Thromboplastin Tissue factor Phospholipid Calcium Intrinsic pathway Extrinsic pathway Common pathway Thrombin time Thrombin Fibrin clot
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Pre-analytic errors Problems with blue-top tube
Partial fill tubes Vacuum leak and citrate evaporation Problems with phlebotomy Heparin contamination Wrong label Slow fill Underfill Vigorous shaking Biological effects Hct ≥55 or ≤15 Lipemia, hyperbilirubinemia, hemolysis Laboratory errors Delay in testing Prolonged incubation at 37°C Freeze/thaw deterioration
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Initial Evaluation of a Bleeding Patient - 1
Normal PT Normal PTT Abnormal Urea solubility Factor XIII deficiency Normal Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (a2 anti-plasmin def) Vascular disorder Elevated FDPs
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Initial Evaluation of a Bleeding Patient - 2
Normal PT Abnormal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)
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Initial Evaluation of a Bleeding Patient - 3
Abnormal PT Normal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare) 50:50 mix is normal Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)
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Initial Evaluation of a Bleeding Patient - 4
Abnormal PT Abnormal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)
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Coagulation factor deficiencies Summary
Sex-linked recessive Factors VIII and IX deficiencies cause bleeding Prolonged PTT; PT normal Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding Prolonged PT and/or PTT Factor XIII deficiency is associated with bleeding and impaired wound healing PT/ PTT normal; clot solubility abnormal Factor XII, prekallikrein, HMWK deficiencies do not cause bleeding
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Thrombin Time Bypasses factors II-XII
Measures rate of fibrinogen conversion to fibrin Procedure: Add thrombin with patient plasma Measure time to clot Variables: Source and quantity of thrombin
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Causes of prolonged Thrombin Time
Heparin Hypofibrinogenemia Dysfibrinogenemia Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies
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Approach to the thrombocytopenic patient
History Is the patient bleeding? Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) Is there a history of medications, alcohol use, or recent transfusion? Are there risk factors for HIV infection? Is there a family history of thrombocytopenia? Do the sites of bleeding suggest a platelet defect? Assess the number and function of platelets CBC with peripheral smear Bleeding time or platelet aggregation study
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Bleeding time and bleeding
5-10% of patients have a prolonged bleeding time Most of the prolonged bleeding times are due to aspirin or drug ingestion Prolonged bleeding time does not predict excess surgical blood loss Not recommended for routine testing in preoperative patients
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Special Coagulation is a specialized, complex and dynamic field!
Conclusion Special Coagulation is a specialized, complex and dynamic field!
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