HEMOPHILIA AND OTHER COAGULOPATHIES

1. HEMOPHILIA AND OTHER COAGULOPATHIES Prof. Dr. Filiz Bakar Yeditepe Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı

2. Outline • Normal hemostasis • Hemophilia • Differential diagnostic tests to coagulation disorders • Treatment

3. Normal hemostasis

11. HEMOSTATIC MECHANISMS • Vascular response • Platelet adhesion • Platelet agregation • Clot formation • Clot stabilization • Limitation of clotting to the site of injury by regulatory anticoagulants • Re-establishment of vascular patency through fibrinolysis • Vascular healing

12. Stages of hemostasis • Primary hemostasis • Von Willebrand factor, platelets, fibrinogen • Secondary hemostasis • Coagulation cascade • Tertiary hemostasis • Cross-linking of fibrin strands • Clot maturation and wound healing

14. Anticoagulants • All procoagulant proteins are balanced by an anticoagulant protein. • Four clinically important anticoagulants: • Antithrombin III X F Xa and thrombin • Protein C X F Va and F VIIIa • Protein S • Tissue factor pathway inhibitor X F Xa

15. Hemophilia

16. Definition • Hemophilias are a group of related bleeding disorders that most commonly are inherited • Inherited bleeding disorders include: • Abnormalities of coagulation factors • Abnormalities of platelet function • The term ‘hemophilia’ refers • Factor VIII deficiency (hemophilia A) • Factor IX deficiency (hemophilia B)

17. Incidince • Combinedincidence of hemophilia A and B is 1/5000 • 80% hemophilia A; 2/3 have severe disease • Hemophilia B; ½ severe disease

18. Mild : > 5% factor level • Moderate: 1–5% factor level • Severe: < 1% factor level • Within each kindred, similar severity of disease • Multiple genetic defects • Factor IX > 800 • Factor VIII > 700

19. Genetics • Hemophilia A F VIII (X-linked) • Hemophilia B F IX (X-linked) • Hemophilia C F XI (Autosomal)

22. Clinical manifestations • Bleeding may occur anywhere • Most common sites: • Joints (80%) • Ankles; most common in children • Knees, elbows, and ankles; most common in adolescents • Muscles • Gastrointestinal tract

23. Mild • Bleeding only with response to injury/trauma or surgery • Moderate • Bleeding with response to intercurrent injury or surgery • Severe • Spontaneously and at an early age

24. Initial presentation • Neonates; • Intracranial hemorrhage • Bleed with circumcision • Infant; • easy bruising, intramuscular hematomas, hemarthroses • Older child; • hemarthroses

25. Sites of bleeding • Central nervous system • Most frequent in neonates, spontaneous • Hemarthrosis • Painful and physically debilitating manifestation • Originates from the synovial vessels • Hemorrhage occurs within the joint cavity • Hallmark is hemarthroses (ankle, knees, elbows) • In severe hemophilia ‘target joint’

26. Sites of bleeding • Skeletal muscle • Bleeding into muscles with hematoma formation, most often quadriceps, iliopsoas (important), and forearm • Head and neck • May be life-threatening hemorrhages • Epistaxis, mucosal bleeding, posterior pharynx • Gastrointestinal tract • Genitourinary tract • Hematuria • Posttraumatic bleeding

34. Late complications • Joint destruction due to hemarthroses • Hemophilic arthropathy; tissue deposition of iron and dense fibrozis of the joint with contractures, pain, limitation of motion • Transmission of blood-borne infections • Hepatitis A, B, C, and D, HIV • Development of inhibitor antibodies • 25% of patients with severe hemophilia A, 3-5% with severe hemophilia B • Complicate bleeding episodes

36. Hemophilia C • F XI deficiency • Autosomal recessive, frequently in Ashkenazi Jews • Mild-moderate bleeding, not correlated with the amount of F XI.

37. Deficiencies of the Contact Factors • Extremely prolonged PTT, but no evidence of clinical bleeding • Factor XII, prekallikrein, high molecular weight kininogen

38. Other Factor Deficiencies • F VII deficiency, AR • F X deficiency, AR • F II (Prothrombin) deficiency, AR • F V deficiency (parahemophilia), AR

39. Fibrinogen disorders • Severe or mild. • Congenital afibrinogenemia • Rare, AR • Clinical manifestations similar to hemophilia A • Bleeding from minor cuts is prolonged because of the lack of fibrinogen to support platelet aggregation. • Hypofibrinogenemia (AD or AR) • Dysfibrinogenemia (AD) • Mild to moderate bleeding symptoms or may be asymptomatic • Risk for venous thrombosis. • Diagnosis is based on kinetic and antigenic protein levels, thrombin time is usually prolonged

40. Factor XIII Deficiency • F XIII, responsible for cross linking of fibrin or the stabilization of fibrin clot • Delayed and prolonged bleeding • Autosomal recessive • Clinical symptoms • Umblical bleeding • Intracranial bleeding • Poor wound healing • Delayed separation of umblical cord • Coagulation tests are normal • Clot solubility test (5 M urea)

41. von Willebrand Disease (vWD)

42. Von Willebrand disease • Most common hereditary bleeding disorder, incidence 1-2% of general population • Autosomal • Function: Platelet adhesion, F VIII stability • Mucocuteneous hemorrhage, excessive bruising, epistaxis, menorrhagia, postoperative bleeding • Laboratory: long bleeding time, long PTT • Classified as: • Tip 1 (Partial deficiency), 85% • Tip 2 (Functional defect) • Tip 3 (Complete vWF deficiency)

43. Hereditary predisposition to thrombosis • The newborn infant, because of physiologic deficiency, particulary predisposed to thrombosis. • Deficiencies of regulatory proteins: • Protein C (homozygous protein C deficiency, fatal purpura fulminans in the neonatal period) • Protein S • AT-III • Plasminogen • Synthesis of a procoagulant protein: • F V Leiden • Elevated levels of procoagulant protein: • Prothrombin mutation • Elevated levels of toxic organic acid: • Homocystinuria

44. Diagnosis

45. Clinical diagnosis • A coagulation disorder is suspected with any of the following: • Hemarthrosis, especially with mild or no antecedent trauma • Deep-muscle hematomas • Intracranial bleeding in the absence of major trauma • Cephalohematoma or intracranial bleeding at birth • Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision • Prolonged bleeding or renewed bleeding following surgery or trauma • Unexplained GI bleeding or hematuria • Menorrhagia, especially at menarche • Prolonged nosebleeds, especially recurrent and bilateral • Excessive bruising, especially with firm, subcutaneous hematomas

46. History • To differentiate hereditary disorders from acquired • Hereditary • Start early in age • Recurrent in nature • Positive family history • Acquired • Occur at any age • Underlying predisposing cause

47. Physical Examination • Mucocutaneous bleeding (mucous membranes or skin) OR • Deep bleeding (muscles and joints) • Presence of: • petechia, • ecchymoses, • hematomas, • hemartroses, • mucous membrane bleeding

48. Type of Bleeding for Differential Diagnosis Unilateral epistaxis Non-hematologic Bruises arms and legs Mucose membrane bleeding Platelet disorder, vWD Bleeding into joint and soft tissue Hemophilia A, B, vWD Bilateral epistaxis Excessive menstruel bleeding Umblical bleeding F XIII deficiency

49. Type of Bleeding for Differential Diagnosis

50. Laboratory Investigation in Patients with Bleeding Diathesis • CBC (platelet count) • Bleeding time • Prothrombin time (PT) • Activated partial thromboplastin time(aPTT) If the results are normal: • Thrombin Time (TT) • vWF testing • Clot stability Further spesific work-up: • F XIII • Factor Activity • Platelet Functions • Antiphospholipid antibodies