1. Inherited Coagulation Disorders Dr Galila Zaher Consultant Hematologist KAUH

2. BLOOD CLOTTING Blood clotting interactions Plasma protein clotting factors Platelets Vascular endothelium

3. Hemostasis Subendothelial matrix Platelets Hemostatic plug Fibrin Endothelial cell RBC WBC WBC Hemostasis Subendothelial matrix Platelets Hemostatic plug Fibrin Endothelial cell RBC WBC WBC

4. COAGULOPATHIES Bleeding Thrombosis Clotting factors Natural anticoagulant platelets

5. Clot formation Platelet activation Primary hemostasis No &count (immediate) Fibrin generation plasma clotting Secondary hemostasis factors (delayed)

6. Adhesion GpIIb/IIIa Platelet Activation Pathways (1) GpIIb/IIIa Aggregation ADP Adrenaline Platelet GpIb Exposed Collagen Endothelium vWF COLLAGEN GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation Adhesion ADP Adrenaline THROMBIN

7. Clotting factor production Liver: source of plasma clotting factors except VWF Factor VIII: produced by liver & endothelium VWF: endothelial cells & megakaryocytes Vitamin K dependent clotting factors are: II, VII, IX, X

8. COAGULATION PATHWAYS Intrinsic & extrinsic pathways “conclude” in the common pathway Intrinsic pathway clotting factors Extrinsic pathway clotting factors Common pathway clotting factors

9. NORMAL COAGULATION PATHWAYS Intrinsic pathway clotting factors Factor XII Factor IX Factor VIII Factor XI Extrinsic pathway clotting factors Tissue factor (TF)* Factor VII Common pathway clotting factors Factor X Factor V Factor IIProthrombin Factor IFibrinogen

10. Intrinsic pathway XII ---> XIIa v XI---------XIa v IX --------> IXa + VIII v X----------------------> Xa[Common pathway] v Xa + V prothrombin -------------> thrombin v fibrinogen--------------> fibrin Extrinsic pathway VII + TF ----->VIIa/TF v IXase (“crossover”) Xase (minor)

11. Fibrin XIIIa Cross-linked fibrin

12. DefectTimeClinical Platelet disorders function or number “immediate” (mins):Mucosal bruising,petechia, epistaxis, childhood menorrhagia, post-op Coagulation factor“delayed” (hrs - days): joint (hemarthrosis), muscle, skin (soft tissue hematomas) fibrinolytic disorders

13. Deficiencies of:  Factor XII  High molecular weight kininogen  Prekallikrein  - Do NOT produce bleeding diatheses

14. COAGULATION TESTS  Platelet tests <150,000thrombocytopenia >400,000thrombocytosis  Tests of clotting factors

15. Platelet tests Test Comment Platelet count Part of routine CBC, normal count: 150,000 - 400,000/uL Mean platelet volumeMPVSome analyzers provide MPV measurement; in healthy individuals, MPV varies inversely with platelet count Platelet aggregationNot routine tests, and secretion tests used only in special circumstances

16. Tests of clotting factors TestAbbreviationComment Prothrombin timePTextrinsic & common pathways Functional test VII X, V, II, I Partial thromboplastin PTT intrinsic & common pathways Functional test prekallikrein, HMWK XII, XI, IX, VIII X, V, II, I Thrombin timeTTFibrinogen concentration Quantitative test

17. Hemophilia A = Factor VIII deficiency  B = Factor IX deficiency  Affects one in 6000 males  A is 5 X > B  Mild > 5 % normal amount of factor  Moderate 2 - 5 %, severe < 2 %  Levels remain stable throughout life

18. Inheritance  Both HA & HB are X linked  Only men can have the disease  Women are carriers

19. Clinical presentation  < 2 years: joint bleeds Rare Only bruising or mouth bleeds are seen Head injuries are a major concern  > 2 years joint and muscle bleeds become more common

20. Clotting factor deficiencies

21. Laboratory Diagnosis Isolated prolongation of APTT Microcytic hypochromic anemia Normal platelets count Mixing studies :corrected.

22. When to treat  All joint bleeds: Pain, swelling,warmth or loss of movement.  Muscle bleeds that cause severe pain or are in a dangerous location  Bruises usually don’t need treatment  When in doubt.

23. Treatment  Keep weight off of joint  Ice pack  Factor replacement - the sooner the better  Amicar or tranexamic acid : mouth bleed  CVL s :Frequent bleeds or factor given on a regular basis  Port-a-catheters

24. Dose & Duration  1 IU/kg of factor VIII increases the level by 2%  1 IU/kg of factor IX increases the level by 1%  Every 12 hours the level decreases by half

25. Prophylaxis  To prevent bleeds  Started after developing a target joint  Usually it is administered 3/week  Stepwise approach: Initially 1/week, increasing to 2-3/week if needed  Goal is to prevent long-term joint damage

26. Team Approach  We all work together Child and parents Doctor and nurses Physiotherapy Social work  Everyone has an essential role  The aim is to get life to be as normal as possible

27. Factor VIII Replacement  Mechanism of action : activate FX  Mode of administration : IV  Monitoring : no predict the effectiveness of treatment  Indications :HA & HB  Severe surgical bleeding  Factor VII deficiency

28. Factor VIII  Derived from pooled human plasma  Derived from pig (porcine) plasma  Recombinate products

29. Porcine factor VIII  Hyate:C  Apparently no pig viruses present  Can replace human Factor VIII in clotting cascade  Minimal cross reactivity with AHF antibodies  Minimal von Willebrand factor present

30. von Willebrand Factor (V W F)  VWF bridges platelets to collagen exposure from blood vessel injury  VWF contributes to primary hemostasis  Factor VIII circulates bound to VWF.  VWD: clinically similar to platelet disorders  Most common inherited bleeding disorder

31. VWD  Inherited as a dominant or recessive.  Most common congenital bleeding disorder  Affecting 1-3% of the population.  Personal and family bleeding history.  Highly heterogeneous  Ranging from asymptomatic to a life threatening bleeding.  The most common bleeding symptoms ever were epistaxis, bruising  Menorrhagia is one of the most important and frequent complications in women

32. Platelet disorders

33. DIAGNOSIS  The condition is caused by a quantitative or qualitative deficiency of vWF.  Prolonged bleeding time (BT) & activated partial thromboplastin time (APTT)  iron deficiency anemia.  type 1 vWD

34. Managment  The aim of treatment is to correct the dual defect of hemostasis ( low VIII:C & prolonged bleeding time).  DDAVP is the treatment of choice for the mild forms of type 1 and 2 VWD  Unresponsive to DDAVP, plasma virally inactivated concentrates of factor VIII  Tranexamic acid

35. Increased PT Deficient, function or inhibition : Liver disease production/ vit K malabsorption vit. K antagonistswarfarin (blocks carboxylation) Heparin the PTT is a more sensitive test FDPs inhibits coagulation lupus anticoagulant PTT is a better test (LA)

36. Increased PTT Heparinunfractionated heparin inhibits Xa and IIa vit K antagonists PT is a more sensitive fibrin/fibrinogen inhibits coagulation degradation products lupus anticoagulant PTT is a better than PT

37. TT increased  Congenital disorders afibrinogenemia homozygous def. hypofibrinogenemia heterozygous def. dysfibrinogenemia dysfunctional fibrinogen  Acquired disorders hypofibrinogenemia liver disease, (disseminated intravascular coagulation), thrombolytic therapy dysfibrinogenemia liver disease, hepatic malignancy Fibrin degradation inhibits coagulation products Heparin inactivates IIa

38. Fibrinogen level hypofibrinogenemia) Liver disease decreased production Consumption disseminated intravascular coagulation (DIC) Thrombolytic therapy Congenital def.afibrinogenemia: homo. def. hypofibrinogenemia: hetero.

39. Fibrinogen assay quantitative immunoassay: Functional “immunologic” or “antigenic” fibrinogen Increased:Estrogen Pregnancy Acute phase response Estrogen Pregnancy Acute phase response decreasedhypofibrinogenemia) hypofibrinogenemia) also - dysfunctional fibrinogen (dysfibrinogenemia

40. Problem solving PTPTTTT Incr.NLNL_____________ NLIncr.NL_____________ Incr.Incr.NL_____________ Incr.Incr.Incr._____________

41. Intrinsic pathway XII ---> XIIa v XI---------XIa v IX --------> IXa + VIII v X----------------------> Xa[Common pathway] v Xa + V prothrombin -------------> thrombin v fibrinogen--------------> fibrin Extrinsic pathway VII + TF ----->VIIa/TF v IXase (“crossover”) Xase (minor) v XIII ---> XIIIav cross-linked fibrin ---> VIIIa ---> Va Actions of thrombin