Hemostasis Disorders


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Hemostasis Disorders

  1. 1. Hemostasis The process of blood clotting and then the subsequent dissolution of the clot, following repair of the injured tissue, is termed hemostasis.
  2. 2. BV Injury Contact/ Tissue Factor Neural Blood Vessel Constriction Haemostasis overview: Platelet Aggregation Coagulation Cascade Primary hemostatic plug Reduced Blood flow Platelet Activation Stable Hemostatic Plug Fibrin formation
  3. 3. Hemostasis - major events 1. Vascular constriction. 2. Platelets become activated by thrombin and aggregate at the site of injury, forming a temporary, loose platelet plug. 3. To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug. 4. The clot must be dissolved in order for normal blood flow to resume following tissue repair.
  4. 4. HK = high molecular wt. kininogen. PK = prekallikrein. PL = phospholipid.
  5. 5. Endogeneous anticoagulants • AT lll – (binds to thrombin and prevents fibrinogen-fibrin) • Heparin co-factor II – (homologous with AT lll) • Prot C – (inhibits activity of factors V and Vll) • Prot S – (enhances the effect of protein C). • TFPI – (tissue factor pathway inhibitor - inhibits the tissue factor-Vlla complex)
  6. 6. Vitamin K Dependent Factors • Factors II, VII, lX, X. • Protein C and Protein S
  7. 7. Role of the liver Loss of liver parenchyma decreases: – all coagulation factors - except F Vlll and von Willebrand co-factor . – physiologic inhibtors of the coagulation (AT lll, Prot C and Prot S) – components of the fibrinolytic system ( mainly plasminogen, and a2 anti plasmines). • Liver dysfunction induces: – platelet dysfunction – dysfibrinogenemia – accelerated fibrinolysis (impaired clearance of tissue plasminogen activators t-PA)
  8. 8. Disorders of Hemostasis
  9. 9. Hematologic disorders causing bleeding • Vascular disorders – Scurvy, easy bruising, • Platelet disorders – Low Number or abnormal function • Coagulation disorders – Factor deficiency. • Mixed/Consumption – DIC
  10. 10. Approach to Bleeding Disorders HISTORY • Is the patient bleeding? • Surrogate markers of bleeding – declining hemoglobin • Age of onset • Surgical procedures • Medications – Aspirin, anticoagulants, etc. • Birth & Family
  11. 11. Approach to Bleeding Disorders Platelet Disorder •Petechiae, • Echymoses, • Menorrhagia • GI bleeding Coagulation Disorders • Echymoses • Late wounds bleeding • Extensive hemorrhage ( joint spaces, after immu.) D.I.C. • • Bleeding from multiple sites in an ill patient
  12. 12. Approach to Bleeding Disorders If a patient has tolerated tonsillectomy and / or adenoidectomy or extraction of multiple wisdom teeth without major hemorrhage, a significant bleeding disorder is unlikely.
  13. 13. Clinical aspects of bleeding Petechiae - (typical of platelet disorders) • • Do not blanch with pressure (cf. angiomas) Not palpable (cf. vasculitis)
  14. 14. Platelet Petechiae, Purpura Coagulation Hematoma, Joint bl.
  15. 15. Clinical aspects of bleeding Platelet factor disorders Coagulation disorders Site of bleeding Skin, Mucous membranes (epistaxis, gum, vaginal, GIT) Deep in soft tissues 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, usually mild Delayed (1-2 days), often severe Mucus membrane bleeds Spontaneous With trauma
  16. 16. Investigations Platelet count 150,000 to 450,000 platelets per ml of blood. < 20,000 per mL - spontaneous bleeding Bleeding time Test for platelet function in Normal : 2 - 5 minutes Prothrombin Time measures the clotting activity of factors I, II, V, VII, and X Normal : 12-15 seconds Activated Partial Thromboplastin Time Measures clotting activity of factors I, II, V, VIII, IX, X, XI, and XII Normal : 25 - 39 sec Factor assays Measure the amount of specific clotting factors FDPs Fibrin degradation products
  17. 17. Activated partial thromboplastin time (aPTT or APTT) • is a performance indicator measuring the efficacy of both the "intrinsic" (now referred to as the contact activation pathway) and the common coagulation pathways. • It is also used to monitor the treatment effects with heparin, a major anticoagulant.
  18. 18. aPTT - Interpretation • Normal = 25 to 39 sec • Prolonged APTT may indicate: • heparin, • direct thrombin inhibitors, • a deficiency or inhibitor for factors in the intrinsic and common pathway • factors II, V, VIII, IX, X, XI, XII, • lupus anticoagulant, • vitamin K deficiency, or • severe liver disease
  19. 19. (Inaccurate) Whole blood clotting time • 5 ml of blood is placed in a glass container, kept at body temperature and observed • A clot should occur in 5 to 15 minutes • Prolonged = Severe deficiency of any of the coagulation proteins • The clot should retract in 30 to 60 minutes • Weak friable clot = hypofibrinogenaemia • Early dissolution = enhanced fibrinolysis
  20. 20. Prothrombin time • The time taken for plasma to clot after addition of tissue factor (obtained from animals) and calcium to citrated blood. • This measures the quality of the extrinsic pathway (as well as the common pathway) of coagulation.
  21. 21. Prothrombin time • The reference range for prothrombin time is usually around 12-15 seconds; • Prolonged • Deficiencies of factors II, V, VII, X or fibrinogen; • Liver disease; • Vitamin K deficiency and • Oral anticoagulants (warfarin)
  22. 22. International normalized ratio • Each manufacturer gives an ISI (International Sensitivity Index) for any tissue factor they make. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 1.4 • The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the control sample used.
  23. 23. Thrombin time • Time to clot formation after the addition of thrombin to citrated blood • Prolonged by • • • • • Heparin, Direct thrombin inhibitors, Fibrin degradation products (FDPs), Paraproteins, and Fibrinogen deficiency (both qualitative and quantitative)
  24. 24. Bleeding time - Ivy method • A blood pressure cuff is placed on the upper arm and inflated to 40 mm Hg. A lancet is used to make a stab wound on the underside of the forearm. • The time from when the stab wound is made until all bleeding has stopped is measured and is called the bleeding time. • Every 30 seconds, filter paper or a paper towel is used to draw off the blood. • Normal values fall between 2 - 5 minutes depending on the method used
  25. 25. FDPs • Fragments resulting from the action of plasmin on fibrin or fibrinogen • Reflect high fibrinolysis states (such as DIC) when they are elevated
  26. 26. Platelet Count • In an adult, a normal count is about 150,000 to 450,000 platelets / µL of blood. • Platelet levels fall below 20,000/µL, spontaneous bleeding may occur and is considered a life-threatening risk. • Increased platelet counts (thrombocytosis) • Myeloproliferative disorder
  27. 27. Others Tests • Von Willebrand factor antigen (vWF:Ag): immunoassay for circulating vWF. • Von Willebrand factor activity (vWF:RCo): measures the functional ability of a patient's vWF to agglutinate platelets in the presence of Ristocetin. • Factor VIII C activity: is functional assay for factor VIII. It is measured by mixing normal plasma with factor VIII-deficient plasma • Platelet function studies • Bone marrow examination – plt
  28. 28. 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 Thrombin time Common pathway Thrombin Fibrin clot
  29. 29. Extrinsic Pathway Intrinsic Pathway II X VI I * IX * I X Prolonged PTT * V III X Prolonged PT Abnormal PTT, PT & TT V II - - - - - - - - - - I - - - - - XIII Both Urea PTT & PT Stability Abnormal or DIC Test
  30. 30. Correction Tests Only PTT abnormal : XI, IX & VIII (XII never presents clinically) Abnormal PTT corrected by Plasma Adsorbed Serum VIII Yes No IX No Yes
  31. 31. Some Rules of Thumb
  32. 32. Both aPTT and PT Elevated
  33. 33. Only PT prolonged
  34. 34. Only aPTT prolonged
  35. 35. von Willebrand Disease An inherited bleeding disorder described by Finnish Physician Erik Adolf von Willebrand Low levels of a protein called von Willebrand factor that helps the blood to clot Von Willebrand factor that doesn’t work properly
  36. 36. Platelet Activation and von Willebrand Factor (vWF) In order for hemostasis to occur, platelets must adhere to exposed collagen, release the contents of their granules, and aggregate. The adhesion of platelets to the collagen exposed on endothelial cell surfaces is mediated by von Willebrand factor (vWF).
  37. 37. Platelet Activation and von Willebrand Factor (vWF) The function of vWF is to act as a bridge between a specific glycoprotein on the surface of platelets (GPIb/IX) and collagen fibrils. vWF binds to and stabilizes coagulation factor VIII. Binding of factor VIII by vWF is required for normal survival of factor VIII in the circulation.
  38. 38. von Willebrand Disease Type 1 Low level of von Willebrand factor. The level of factor VIII may also be lower than normal Mildest and most common form of the disease. About 3 out of 4 people diagnosed with vWD have type 1 disease. Type 2 Defect in von Willebrand factor causes it to not work properly. Type 2 is divided into 2A, 2B, 2M, and 2N. Each is treated differently, so knowing the exact type is important. Type 3 No von Willebrand factor and very low factor VIII. Type 3 is severe and very rare.
  39. 39. von Willebrand Disease Incidence roughly about 1 in 100 individuals. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. It may be more severe or apparent in people with blood type O.
  40. 40. von Willebrand Disease Genetics vWF gene is located on chromosome twelve (12p13.2). o Types 1 and 2 are inherited as autosomal dominant traits and o type 3 is inherited as autosomal recessive. o Occasionally type 2 also inherits recessively.
  41. 41. von Willebrand Disease
  42. 42. Weibel-Palade bodies  Organelles in the endothelial cells  There are two major constituents 1. von Willebrand factor (vWF), a multimeric protein involved in blood coagulation 2. The second is P-selectin - binds to passing immune cells (leukocytes).
  43. 43. von Willebrand Disease Manifestations: Bruising that's unusual in location or frequency Abnormal menstrual bleeding Bleeding in the mucous membranes Excessive or prolonged bleeding after a tooth extraction or tonsillectomy
  44. 44. Investigations  Bleeding time  Factor VIII level test (factor VIII coagulant)  von Willebrand factor antigen test (factor VIII antigen) - which measures the amount of von Willebrand factor. ( mild if a person has 20% to 40% of the normal, severe if the amount is less than 10% of normal. )  Ristocetin co-factor activity test  measures how well the von Willebrand factor is working  von Willebrand factor multimers test - to classify the type of vWD  Platelet function tests  which determine how well the platelets work and help identify the type of vWD or the presence of another disorder Tests may need to be done more than once because these levels may rise and fall over time in an individual.
  45. 45. von Willebrand Disease Treatment: No regular treatment  Prophylactic treatment is sometimes given for patients are scheduled for surgery.  They can be treated with human derived medium purity factor VIII concentrates complexed to vWF  Mild cases - treated with desmopressin (1-desamino 8-D-arginine vasopressin, DDAVP)  Rises patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells
  46. 46. Than Q