Disorders of Coagulation and Hemostasis

1. Disorders of Coagulation and Hemostasis Jeffrey T. Reisert, DO University of New England Physician Assistant Program 25 FEB 2010

2. Contact Information Jeffrey T. Reisert, DO Tenney Mountain Internal Medicine, PLLC 16 Hospital Rd. Plymouth, NH 03264 603-536-6355 603-536-6356 (fax) Jeffrey.T.Reisert@Hitchcock.org

3. Objectives • Understand major features of normal coagulation cascade • Know effect on coagulation by common drugs • Recognize common disorders affecting platelet and factor hemostasis

4. Case study • A patient, 35 years old female presents to the ED • Cc: Swollen Left leg

5. Case study work-up • What are physical exam findings? • What else do you want to know? • What is considered a thorough work-up? • What is the treatment, if any?

6. Agenda • Normal vascular, fibrinogen, and platelet coagulation • Aspirin, heparin, and warfarin • Disorders of hemostasis--->Bleeding • Hypercoagulability-Excessive clotting

7. Phases of clotting-Delicate balance • Vascular phase • Platelet adhesion/aggregation/ retraction • White thrombus • Coagulation phase • Intrinsic pathway • Extrinsic pathway • Common pathway • Remodeling

8. Physical exam • Bleeding • Purpura-Big bruise • Petechiae (Platelet diseases) • Punctate, little bruise

9. Lab testing • Platelets • Screening tests • Platelet count, PT, PTT • Specific tests • Thrombin, etc. • Factor assays

10. Tests of Platelets • Platelet count • Off CBC or separately • Platelet volume • Bleeding time (BT) • Tests vascular and platelet phase of clotting • Abnormal if low platelets, vWD, DIC, Liver disease • Platelet aggregation

11. Other tests • PT (Prothrombin time) • PT-INR (Standardizes between labs) • PTT (Partial thromboplastin time) • Fibrinogen • Thrombin time

12. Prothrombin Time (PT) • Use: Monitor warfarin, test liver function, vitamin K deficiency • Tests Extrinsic pathway • VII (first to drop), X, V, II (thrombin), I (fibrinogen) • PT prolonged with nl PTT-Usually liver disease (or on warfarin)

13. PT-INR • International Normalized Ratio • Standardizes the PT across different labs • (Patient’s PT/Normal PT) I • Where I is a fudge factor (close to 1.0) that is different at each lab depending on which method is used to measure • This has become the standard for interpreting the protime

14. Warfarin (Coumadin®, Jantoven®) • Decreases synthesis of Vitamin K dependent factors • INR

15. D con • http://www.d-conproducts.com/

16. PT-INR • Normally 1 • When treating with warfarin • Goal 2-3 if atrial fibrillation, stroke, etc. • Goal of 2.5-3.5 if artificial (mechanical) valve

17. Partial thromboplastin time (PTT) • Use: Monitor continuous IV heparin • Need full tube • Tests intrinsic and common pathways • XII, XI, IX, VIII, X, V, II, I • Doesn’t measure Factor VII • IF PTT prolonged and PT normal problem is intrinsic pathway

18. Heparin • Inhibit factor activation • Given as continuous IV or sc injection • ADR: • Thrombocytopenia (Antiplatelet Ab produced) • Heparin induced thrombocytopenia (HIT) • Paradoxical thrombocytosis • Like an allergic reaction • Lose fingers • Can die • Requires monitoring both PTT and platelets and bleeding

19. Low Molecular Weight Heparin • Enoxaparin (Lovenox®), Dalteparin (Fragmin®) others • Have found new utility in preventing abnormal clotting • Post operative DVT prophylaxis • Post MI • Atrial fibrillation • Other uses • Easy to administer-sc • Effect can’t be measured with PTT/Effect need not be measured! • Weight adjusted dosing

20. Factor Xa Inhibitors • Synthetic inhibitors of Factor X activation • Binds antithrombin III which inhibits formation of Xa • Thus decreases thrombin III formation • Fondaparinux (Arixtra®) • Use for DVT prophylaxis • Not a heparin (advantage if HIT)

21. Fibrinogen (Factor I) • Decreased • Acquired • DIC (Most common, as this uses up fibrinogen) • Liver disease (Dysfibrinogenemia) • Bleed • Congenital • Elevated • Pregnancy, oral contraceptive pills, Acute inflammation, Malignancy

22. Thrombin time • Mix patient plasma with commercially supplied thrombin and measure time to clot • Fibrinogen is converted to fibrin • Estimates the rate of formation of fibrin • Measures if enough fibrinogen in plasma

23. Thrombin time-cont • Tests last stage of coagulation • Test for presence of heparin • Also tests for fibrinolysis • Presence of fibrin split products prevent fibrin monomer polymerization • In case of clot breakdown, thrombin time prolongs

24. Factor assays • Exist for all factors except XIII • Measured as % of normal activity • VIII • IX

25. Platelet disorders-Overview • Quantitative disorders (Low number) • Qualitative disorders (Ineffective function)

26. Platelet count • Normal 150,000-450,000 • Risk for bleeding if less than 50,000 • Danger zone less than 10,000 • Risk for spontaneous cerebral hemorrhage

27. Platelet disorders-Quantitative • Autoimmune, Lupus • Drugs • Heparin, Quinidine, sulfa, others • Infection (HIV, Mono) • CLL, Sarcoidosis • Thrombocytopenic purpuras

28. Thrombocytopenic purpuras • Low platelets with big bruises • Immune thrombocytopenic purpura (ITP) • Thrombotic thrombocytopenic purpura (TTP)

29. Idiopathic thrombocytopenic purpuras (ITP) • Immune reaction often • Post infection • HIV • Lupus • Children common (viral origin) • Adults may be chronic (especially young women) • Malignancies may cause, and must be excluded

30. ITP-Treatment • Glucocorticoids • IV immunoglobulin • Splenectomy • Don’t forget pneumovax! • Chemotherapy

31. Thrombotic thrombocytopenic purpuras (TTP) • Due to unknown mechanism, develop platelet aggregation in microcirculation • What results is a form of intravascular hemolysis with a consumptive thrombocytopenia • Increased LDH and Indirect bilirubin • Thrombocytopenia • Purpura • Fever

32. TTP-II • Resultant renal and neurological sequelae due to hypoxia • Etiology unknown • May respond to plasmapheresis, steroids • Hemolytic uremic syndrome (TTP with manifestations limited to the kidney)

33. Platelet disorders-Qualitative Platelet. dysfunction • ASA/NSAIDS/Hespan/Others • Renal failure/Uremia • Dysproteinemias • Myeloproliferative syndromes • Cirrhosis • DIC

34. Aspirin affect on clotting • Inactivate cyclooxygenase • Platelets can’t produce thromboxane A2 • Lifelong for each platelet • Doesn’t stop surgery!

35. Non Platelet disorders • Congenital • Acquired

36. Non Platelet disorders-Congenital • Hemophilias • Gene for Factor VIII and IX lie on X chromosome • When mutation present, X linked recessive trait • May also be due to spontaneous mutation • Two majors (A and B)

37. Hemophilia • Hemophilia A-Deficiency of VIII (“Classic hemophilia”) • 1:5000 live births • Hemophilia B-Deficiency of IX (Christmas disease) • 1:30,000 live births

38. Hemophilias-Grading • Based on amount of factor present • Mild • Bleed with surgery/trauma perhaps • Mucosal bleeding • Moderate or • Severe • Frequent spontaneous bleeds into joints (hemarthrosis) and muscles

39. Hemophilia-Treatment • Fresh frozen plasma (FFP) • Contains II, V, VII, VIII, IX, X, XI, XIII • Problematic • Used pooled blood products, starting in 1970’s • Many/most developed hepatitis B and C • Later, HIVmany died • Now safer • Recombinant factors • Gene therapy?

40. Pseudo hemophilia-von Willebrand’s disease • MC inherited hemophilia • 1:1000 live births • vWF helps to adhere platelets and carries Factor VIII • Affects platelets and factor VIII • Prolongs BT by affecting aggregation • Treatment: Cryoprecipitate (Plasma with extra vWF and VIII) or vasopressin (DDAVP) IV or sc

41. Non Platelet disorders-Acquired • DIC (Consumptive) • Liver disease • Transfusion induced

42. Non Platelet. disorders-Acquired-II • Vitamin K deficiency • Malabsorption, Antibiotics • Circulating anticoagulant • Lupus, pregnancy, penicillin • Heparin • Warfarin/Coumadin

43. Disseminated intravascular coagulation (DIC) • A disease of excess clotting AND of bleeding • Trigger is typically a massive event such as surgical catastrophe or sepsis • Begins thrombotic followed by consumptive and fibrinolytic process • Prolonged PT and PTT, Thrombocytopenia • Decreased fibrinogen • Increased fibrin degradation products (Elevated D-Dimer which is cross linked fibrin)

44. DIC-Treatment • Treat cause-Most important for survival • FFP • Platelets • Red cells

45. Hypercoagulability

46. Hypercoagulability • Predisposition to clot formation (all of them to various degrees) • “Thromboembolic disease” • Deep vein thrombosis • Pulmonary embolism • Often missed, based on autopsy studies • Suspect genetic cause in patients • Young who develops 2+ clots • Family history (the importance of taking family history, particularly if surgery planned!)

47. How do we prevent abnormal clotting? • Maintaining homeostasis requires ability of clotting to be balanced with breakdown of clots (fibrinolysis) and prevention of abnormal/inappropriate clotting • Protein C • Protein S • Anti-thrombin III • Absence of the above allows abnormal clotting • Fibrinolytic system

48. Fibrinolytic system • Breaks down clot after formation • Prevents abnormal clotting/Keeps system in check • Allows wound reparation and healing

49. Causes of hypercoagulability • Inherited disorders • Dysfibrinogenemias/Fibrinolytic defects

50. Inherited prothrombotic disorders • Defects in coagulation inhibitors (5-15% of cases) • All are autosomal dominant traits • Anti-thrombin deficiency • Protein C deficiency • Protein S deficiency • Point mutations • Factor V Leiden (12-40% of cases) • Prothrombin gene mutation (6-10% of the cases)