Disorders of Hemostasis

1. Disorders of Hemostasis Dr. Batizy 11/2/06

2. Primary Hemostasis • The platelet contains lysosomes, granules, and trilaminar plasma membrane, microtubules. • Granules are key in primary hemostasis and contain ADP, Thromboxane, platelet factor 4, adhesive and aggregation glycoproteins, coagulation factors, and fibrinolytic inhibitors

3. Primary Hemostasis • Dependent on Platelets and Von Willebrand Factor (vWF) • Platelets gather and attach to vWF • Platelets degranulate after attachment and release ADP and Thromboxane which attracts more platelets • Forms a platelet plug • Requires endothelial damage to adhere

4. Secondary Hemostasis • Platelet aggregation initiates secondary hemostasis through the coagulation cascade • Coagulation cascade is initiated by the intrinsic or extrinsic pathway • The final cascade results in fibrin deposition cross-linking platelets and clot formation

5. The Coagulation Cascade Common Pathway

6. A word on clotting factors • Vitamin K Dependent Factors • Intrinsic Pathway : IX, X • Common Pathway: II • Extrinsic Pathway: VII • All clotting Factors are produced in liver except vWF/VIII • VIII produced by the vascular endothelium • Sites of heparin activity • IIa, IXa, Xa ( major site), XIa, Platelet factor 3

7. A word on clotting factors • Factor VIII – A factor by any other name? • Same factor: 3 different activities • VIII:C – antihemophilic or coagulation activity • vWF – supports platelet adhesion and carries VIII in the blood • VIII:Ag – reacts with rabbit antibodies, relates to measured plasma level rather than activity

8. Fibrinolysis • The Ying to the Yang of clot formation • Tissue Plasminogen activator (tPA) • Released from endothelial cells • Converts plasminogen to plasmin which degrades fibrinogen and fibrin into fibrin degradation products • Cross linked fibrin is cleaved into D-Dimers

9. Testing the hemostatic system • CBC • H/H drops often lag behind actual RBC loss due to slow equilibration • Blood smear • Schistocytes and fragemented RBC- DIC • Teardrop-shaped or nucleated RBC – Myelophthisic disease • Characteristic WBC morphologies seen in thrombocytopenia in infectious mononucleosus, folate, B12 deficiency, or leukemia

10. Testing the hemostatic system • Platelet count • Thrombocytopenia : Less that 100,000/mL • Spontaneous bleeding possible: Less than 20,000/mL • Count does not have anything to do with functionality of platelet

11. Testing the hemostatic system • Bleeding time • Tests vascular integrity and platelet function • Incision on volar aspect of the forearm 1mm deep and 1 cm long • BP cuff inflated to 40 mmHg • Normal < 8 minutes • Borderline 8-10 minutes • Abnormal 10 + minutes • Affected by ASA (permanent) and NSAIDs

12. Testing the hemostatic system • Bleeding time • Prolonged with platelet counts below 100,000 • When prolonged with platelet count over 100,000 suggests platelet dysfunction

13. Testing the hemostatic system • Prothrombin Time • Test of extrinsic and common pathways • International Normalized Ratio used to compensate for differences in thromboplastin reagents • Used for coumadin • Elevated in patients with liver disease and abnormalities in vitamin K sensitive factors

14. Testing the hemostatic system • Partial Thromboplastin Time (PTT) • Tests intrinsic and common pathway • Average normal 25-29 • Factor levels usually less than 40% to be affected • Affected by heparin • Can be effected by coumadin at supra-therapeutic levels due to effects on the common pathway

15. Platelet Disorders More common in Women Petechiae, Purpura, mucosal bleeding More commonly acquired Coagulation Disorder More common in Men Delayed deep muscle bleeding, hemarthrosis, hematuria More commonly congenital History and Physical

16. Thrombocytopenia • Usually mucosal bleeding • Epistaxis, menorrhagia, and GI bleeding is common • Trauma does not usually cause bleeding

17. Thrombocytopenia • Three mechanisms of Thrombocytopenia • Decreased production • Usually chemotherapy, myelophthisic disease, or BM effects of alcohol or thiazides • Splenic Sequesteration • Rare • Results from malignancy, portal hypertension, or increased Splenic RBC destruction ( hereditary spherocytosis, autoimmune hemolytic anemia) • Increased Destruction

18. Thrombocytopenia • Immune thrombocytopenia • Multiple causes including drugs, lymphoma, leukemia, collagen vascular disease • Drugs Include • Digitoxin, sulfonamindes, phenytoin, heparin, ASA, cocaine, Quinine, quinidine, glycoprotein IIb-IIa antagonists • After stopping drugs platelet counts usually improve over 3 to 7 days • Prednisone (1mg/kg) with rapid taper can shorten course

19. Thrombocytopenia • HIT • Important Immunologic Thrombocytopenia • Usually within 5-7 days of Initiation of Heparin Therapy but late onset cases are 14-40 days • Occurrence 1-5% with unfractionated heparin and less than 1% with low molecular-weight heparin • Thrombotic complications in up to 50% of HIT with loss of limb in 20% and mortality up to 30%

20. ITP • Diagnosis of exclusion • Associated with IgG anti-platelet antibody • Platelet count falls to less that 20,000

21. ITP • Acute Form • Most common in children 2 to 6 years • Viral Prodrome common in the 3 weeks prior • Self Limited and > 90% remission rate • Supportive Treatment • Steroids are not helpful

22. ITP • Chronic Form • Adult disease primarily • Women more often than men • Insidious onset with no prodrome • Symptoms include: easy bruising, prolonged menses, mucosal bleeding • Bleeding complications are unpredictable • Mortality is 1% • Spontaneous remission is rare

23. ITP • Chronic Form • Hospitalization common because of a complex differential diagnosis • Multiple treatments • Platelet transfusions are used only for life threatening bleeding • Life threatening bleeding is treated with IV Immune globulin (1g/kg)

24. TTPHUS • Exist on a continuum and are likely the same disease • Diagnosed by a common pentad • Microangiopathic Hemolytic Anemia: Schistocytes membranes are sheared passing through microthrombi • Thrombocytopenia: More sever in TTP • Fever • Renal Abnormalities: More prominent in HUS: include Renal insufficiency, azotemia, proteinuria, hematuria, and renal failure • Neurologic Abnormalities: hallmark of TTP 1/3 of HUS: Sx of HA, confusion, CN palsies, seizure,coma

25. TTPHUS • Labs • PT, PTT, and fibrinogen are within reference range • Helmet Cells (Shistocytes) are common

26. TTPHUS • HUS • Most common in infants and children 6mo - 4 years • Often associated with a prodromal diarrhea • Strongest association to E. coli O157:H7 but also associated with SSYC as well as multiple virus • Prognosis • Mortality 5-15% • Younger patients do better

27. TTPHUS • HUS • Treatment • Mostly supportive • Plasma exchange reserved for sever cases • Treat hyperkalemia • Avoid antibiotics with Ecoli • May actually increase verotoxin production with TMP-SMX • May be helpful with cases of Shigella dysenteriae

28. TTPHUS • TTP • More common in adults • Untreated mortality rate of 80% 1 to 3 months after diagnosis • Aggressive plasma exchange has dropped the mortality to 17% • Splenectomy, immune globulin, vincristine all play a role in therapy

29. TTPHUS • AVOID PLATELET TRANSFUSION • May lead to additional microthrombi in circulation • Transfuse only with life threatening bleeding

30. Dilutional Thrombocytopenia • PRBC are platelet poor • Monitor platelet count with every 10 u PRBC • Transfuse when count below 50,000 • Get them upstairs before you transfuse 10 units PRBC

31. DIC • A few harmless snowflakes working together can create an avalanche of Destruction.

32. DIC • Early recognition important secondary to potentially devastating sequelae and effective therapy • DIC Sequence  Platelets and coagulation factors consumed  Thrombin directly activates fibrinogen Fibrin deposition  Fibrinolysis  Inhibition of platelets and fibrin polymerization  Decrease in inhibition levels • Entire process leads to a massive consumption of coagulation factors

33. DIC • Life threatening combination of bleeding diathesis with small vessel ischemia • There are varying levels of acuity • Recommended testing • Peripheral Smear: Low platelets, schistocytes • Platelet count: Low (<100,000) • Pt, PTT, Thrombin Time: Prolonged • Fibrinogen: Low • Fibrin degredation products: zero to large

34. DIC • Treatment • Dependent on whether bleeding or ischemia predominate • If bleeding • Platelets, FFP or Cryoprecipitate, and blood recommended • With Ischemia • Heparin has a place in treatment • Examples include Retained fetus, purpura fulminans, giant hemangioma, and acute promyelocytic leukemia

35. DIC • Treatment • Goal in ER is suspicion, aggressive pursuit of diagnosis, understanding complications, and rarely initiation of therapy

36. Coagulation Pathway Defects • Hemophilia A • Von Willebrand’s Disease • Hemophilia B ( Christmas Disease)

37. Hemophilia A

38. Hemophilia A • Variant form of Factor VIII • 60 to 80 persons per million • 70% Sex linked recessive • Severity linked to level of VIII:C activity • 1% Severe • 1%-5% Moderate • 5-10% mild ( little risk of spontaneous bleeding)

39. Hemophilia A • Bleeding can occur anywhere • Deep muscles • Joints • Urinary Tract • Intracranial • Recurrent Hemarthrosis and progressive join destruction are major cause of morbidity • Intracranial bleed is major cause of death in all hemophiliacs

40. Hemophilia A • Mucosal bleeding is rare unless associated with von Willebrands or Platelet inhibition • Unlike platelet defects Trauma initiates bleeding • Bleeding can occur usually by 8 hours but as late as 1 to 3 days after trauma

41. Hemophilia A • Management: • Home therapy is increasingly common and most report to ER only with complicated problems or Trauma • Hospitals should have files of known hemophiliacs in the area • Accepted therapy is with Factor VIII replacement or VIII:C • Newer preparation carry lower risk for Hep B and Hep C transmission

42. Hemophilia A • Management: • Multiple guidelines for therapy institution • Most important physician should believe a patient saying they are bleeding and institute early therapy

43. Hemophilia A • Prophylaxis • May require admission for anticipation of delayed bleeding • Candidates: • Deep lacerations • Soft tissue injury where hematoma could be destructive ie: eye, mouth, neck, back, and spinal column

44. Hemophilia A • Treatment of haemophilic synovitis • COX-2 important in Hemophiliacs because of anti=inflammatory,and analgesic properties but they do not affect the platelet fuction • With withdrawl of rofecoxib from the market celecoxib had become popular • Study has shown that Celecoxib gives good relief of synovitis without serious adverse effects

45. Von Willebrand’s Disease • Most common inherited bleeding disorder • Without vWF the ability of platelets to adhere is diminished • VIII:C has diminished activity • Bleeding sites are primarily mucosal • Hemarthrosis is rare • Menorrhagia and GI bleed are common

46. Von Willebrand’s Disease • Factor VIII replacement is treatment of choice • FFP may be given in extreme circumstances • Desmopressin is only useful for specific types of vWD and should only be give with advice from hematologist

47. Hemophilia B (Christmas Disease)

48. Hemophilia B (Christmas Disease) • Clinically indistinguishable from hemophilia A • Deficiency of factor IX • Factor IX preparation used in treatment • FFP and plasma prothrombin complex are also useful • Gene manipulation in animals shows promising results for the future

49. Take home message • All Bleeding stops…. Eventually

50. References • Rosen’s • Emedicine • Celecoxib in the treatment of haemophilic synovitis, target joints, and pain in adults and children with haemophilia, Haemophilia (2006), 12, 514-517