Coagulation disorders

Coagulation disorders, hemophilia, hemophilia B, DIC

1. Coagulation disorders Dr Vijay Shankar S

2. Learning objectives Introduction to coagulation disorders Hemophilia A Hemophilia B Disseminated Intravascular Coagulation

3. Hemostatic Process 3 main steps Primary hemostasis: local vasoconstriction & platelet plug formation Coagulation cascade Fibrinolysis

4. Hemostatic Process Platelet Plug Formation • vascular injury • release and binding of vWF to exposed blood vessel collagen • glycoprotein IB on platelet surface membrane binds to vWF • TxA 2 → vasoconstriction & platelet adhesion • platelet factor 3 (PF3) phospholipid layer (procoagulant)

5. Platelet Activation & Aggregation exposed endothelial surface platelets exposed to collagen “activated” release contents of cytoplasmic granules adenosine diphosphate (ADP) thromboxane (Tx A 2 ) accelerates platelet vasoconstriction aggregation/activation ↑ ADP release from platelets

6. Hemostatic Process Coagulation Cascade to stabilize and reinforce the weak platelet plug fibrinogen → fibrin 3 main steps: formation of prothrombin activator conversion of prothrombin into thrombin conversion of fibrinogen to fibrin

7. Figuring It Out Different factors in two pathways …I-XIII (which number is missing?) Separate but interacting pathways (which is faster, which is quantitatively more important?) anything that interferes blocks final outcome Calcium (Factor IV) required for most steps (note which) Several factors are made in liver (II, VII, IX, X)

8. Coagulation Factors I – Fibrinogen II – Prothrombin III- Thromboplastin IV- Ca++ V Proaccelerin/ labile factor VII – Proconvertin/ Stable factor. VIII - AHF IX – AHF B/Christmas factor X – Stuart- Prower factor XI – Plasma thromboplastin antecedant XII – hageman factor/Glass factor XIII- Fibrin stabilizing factor/ laki lorand factor. HMWK – Fitzgerald factor.

9. Clot Formation (Coagulation) Intrinsic Pathway Extrinsic Pathway Final Common Pathway Prothrombin Activator Substance (PAS) Prothrombin Thrombin Fibrinogen Fibrin monoomers Polymers, threads

10. Final Common Pathway Prothrombin Activator Substance (PAS ) Prothrombin Thrombin Fibrinogen Fibrin monoomers Polymers, threads Fibrin Stabilizing Factor

11. Coagulation Cascade TF =tissue factor PK = prekallikrein HK=high molecular kininogen a = activated

12. Coagulation Mechanism activation of clotting factors requires a phospholipid surface tissue factor (TF) extrinsic to the blood activated platelet (platelet factor 3 phospholipid) intrinsic to blood vitamin-K dependent factors (II, VII, IX, X) formation of reaction complex labile factors : factors V and VIII

13. Factor VIII extrahepatic origin 2 components (separate genetic control) VIII R : Ag VIII antigen + vWF VIII : C coagulant activity *absence → hemophilia A von Willebrand factor (vWF) • mediates adhesion of platelets to surface collagen • carrier of VIII:C • vWD: appears to have defect in primary hemostasis & hemophilia A

14. Coagulation Disorders

15. Common presentation Commonly manifests in the form of large ecchymosis and hematomas – delayed bleeding Bleeding from the nose, gums, GIT, GUT Joint bleeds, muscle bleeds Excessive bleeding post vaccination Post dental extraction Post surgical trauma

16. Investigations of Coagulation disorders. Screening tests APTT PT TT Special tests Coagulation factor assays

17. Laboratory Monitoring Activated Partial Prothrombin Time (aPTT) test for intrinsic and common pathways dependent on activity of all coagulation factors, except VII and XIII normal values: 30 -40 seconds monitors heparin tx & screen for hemophilia

18. Laboratory Monitoring Prothrombin Time (PT) test of extrinsic pathway activity and common pathway. measures vitamin K - dependent factors activity (factors II, VII, IX, X) thromboplastin + Ca +2 to plasma = clotting time normal values: 10-14 seconds

19. LABORATORY TEST COMPONENTS MEASURED NORMAL VALUES Bleeding time platelet function vascular integrity 3 - 10 mins PT I, II, V, VII, IX, X 10 - 14 secs PTT I, II, V, VIII, IX, X, XI, XII 30 - 40 secs Thrombin time I, II 12 - 20 secs

20. Disorders of Coagulation Hereditary Either quantitative or qualitative defect in single coagulation factor Acquired Deficiencies of Multiple coagulation factors Haemophilia A Haemophilia B VWD Vit K Def Liver Disorders Fibrinolytic defects DIC

21. Hereditary Factor Deficiencies Hemophilia A x-linked recessive disorder that is due to defective and / or deficient factor VIII molecules Incidence – 1 in 10,000 live births. The gene for hemophilia is carried on the X chromosome and the gene is recessive -- X linked recessive disorder.

22. History's most famous carrier of the gene for hemophilia was Victoria (1819-1901), Queen of England and grandmother to most of the royalty in Europe Also known as “The Royal Disease”

23. Czar Nicholas II of Russia and his family, photographed c. 1916, showing his wife Alexandra (who was a carrier of hemophilia), his four daughters, and (in the foreground) his son Alexis, perhaps the most famous European royal with hemophilia.

24. Inheritance pattern in hemophilia

25. Hemophilia A Severity linked to level of VIII:C activity 1% Severe 1%-5% Moderate 6-30% mild ( little risk of spontaneous bleeding)

26. 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

27. Hemophilia Progression

28. 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

29. Hemophilia A Management: General measures – avoidance of aspirin 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

30. Hemophilia B (Christmas Disease) Clinically indistinguishable from hemophilia A Deficiency of factor IX Incidence – 1 in 25,000 to 30,000 live births Specific assays are the only way to distinguish hemophilia A & B Factor IX preparation used in treatment Gene manipulation in animals shows promising results for the future

31. Hereditary Platelet Disorder von Willebrand Disease (vWD) most common congenital bleeding disorder quantitative or qualitative abn. of vWF VWF plays role in both formation of platelet plug as well as fibrin clot By mediating adhesion of platelets to the injured endothelium By functioning as a Protective carrier of Factor VIII

32. Clinical features Bleeding symptoms resemble those of platelet function defect, since platelet adhesion is impaired. MC symptoms are easy bruising, epistaxis , menorrhagia etc… Hemarthrosis occurs only in severely affected patients, unlike hemophilia who often have joint bleeds.

33. Type 1: most common form partial quantitative deficiency of vWF autosomal dominant mucocutaneous bleeding hematology consult prior to surgery prolonged bleeding time, normal platelet TYPES

34. Type 2: qualitative alterations in the vWF structure & function Type 3: least common and most severe Complete absence of vWF in plasma or storage organelle Autosomal recessive acquired vWD Lymphoproliferative disease ▪ cardiac/valvular disease Tumors ▪ medications (valproic acid) Autoimmune disease ▪ hypothyroidism

35. Lab Findings Increased bleeding time with normal platelet count Decreased VWF concentration in plasma Decreased factor VIII activity.

36. Treatment VWF replacement therapy “ To summarise, patients with VWD have a compound defect involving platelet function and the coagulation pathway.”

37. Disseminated Intravascular Coagulation

38. Hemostatic Balance ATIII Clotting Factors Tissue factor * PAI-1 Antiplasmin TFPI Prot. C Prot. S Procoagulant Anticoagulant Fibrinolytic System

39. DISSEMINATED INTRAVASCULAR COAGULATION Defibrination syndrome/consumptive coagulopathy “ an acute, subacute/chronic THROMBOHEMORRHAGIC disorder occuring as a secondary complication of some diseases or conditions.” “NOT A PRIMARY DISEASE” !!

40. DIC An acquired syndrome characterized by systemic intravascular coagulation Coagulation is always the initial event SYSTEMIC ACTIVATION OF COAGULATION Intravascular deposition of fibrin Depletion of platelets and coagulation factors Thrombosis of small and midsize vessels Bleeding Organ failure DEATH

41. Pathophysiology of DIC Activation of Blood Coagulation Suppression of Physiologic Anticoagulant Pathways Impaired Fibrinolysis Cytokines

42. Diagnosis of DIC Presence of disease associated with DIC Appropriate clinical setting Clinical evidence of thrombosis, hemorrhage or both. Laboratory studies no single test is accurate serial test are more helpful than single test

43. Conditions Associated With DIC Infectious/Septicemia Bacterial Gm - / Gm + Viral CMV Varicella Hepatitis Fungal Intravascular hemolysis Acute Liver Disease Tissue Injury trauma extensive surgery tissue necrosis head trauma Obstetric Amniotic fluid emboli Placental abruption Eclampsia Missed abortion

44. Conditions Associated With DIC Malignancy Leukemia Metastatic disease Cardiovascular Post cardiac arrest Acute MI Prosthetic devices Hypothermia/Hyperthermia Pulmonary ARDS/RDS Pulmonary embolism Severe acidosis Severe anoxia Collagen vascular disease Anaphylaxis

45. Clinical Manifestations of DIC Ischemic Findings are earliest! Bleeding is the most obvious clinical finding

46. Clinical Manifestations of DIC

47. Microscopic findings in DIC Fragments Schistocytes Paucity of platelets

48. Laboratory Tests Used in DIC D-dimer * Antithrombin III * F. 1+2* Fibrinopeptide A* Platelet factor 4* Fibrin Degradation Prod Platelet count Protamine test Thrombin time Fibrinogen Prothrombin time Activated PTT Protamine test Reptilase time Coagulation factor levels *Most reliable test

49. Laboratory diagnosis Thrombocytopenia plat count <100,000 or rapidly declining Prolonged clotting times (PT, APTT) Presence of Fibrin degradation products or positive D-dimer Low levels of coagulation inhibitors AT III, protein C Low levels of coagulation factors Factors V,VIII,X,XIII Fibrinogen levels not useful diagnostically

50. Treatment of DIC Stop the triggering process . The only proven treatment! Supportive therapy No specific treatments Plasma and platelet substitution therapy Anticoagulants Physiologic coagulation inhibitors

51. Summary DIC is a syndrome characterized systemic intravascular coagulation. Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality. Important link between inflammation and coagulation. Morbidity and mortality remain high. The only proven treatment is reversal or control of the underlying cause.