Inherited Bleeding Disorders

Von-Willbrand disease
Hemophilia A
Hemophilia B

1. INHERITED BLEEDING DISORDERS Advanced hematology Dr. ahmed silmi Ahmed Adel Abdallah IUGAZA

2. Classification of inherited bleeding disorders X-Linked recessive trait - hemophilia A (factor VIII def.) - hemophilia B (factor IX def.) Autosomal recessive trait Afibrinogenemia & Hypofibrinogenemia Glanzmann thrombasthenia Bernard–Soulier syndrome Factor XIII deficiency Factor V and VIII Combined Deficiency Autosomal dominant trait Von-Willbrand disease (Type III recessive ) Dysfibrinogenemia Ehlers-Danlos syndrome Hereditary hemorrhagic telangiectasia Marfan syndrome

3. Prevalence of bleeding disorders The most common congenital bleeding disorders include : Von Willbrand disease Hemophilia A Hemophilia B Patients with inherited bleeding disorders recorded in the NRCC-2015

4. 1 . Von Willbrand disease In 1926, Erik von Willebrand first described a hemorrhagic disorder characterized by a prolonged bleeding time and an autosomal inheritance pattern that distinguished the disease from classic hemophilias . In the early 1950s, an additional component of the disease was identified: a deficiency of factor VIII procoagulant activity These observations distinguish von Willebrand disease from classic factor VIII deficiency (hemophilia A ) In addition, evaluation of the multimeric structures of vWF has aided in the classification of the variant forms of von Willebrand disease . Three major types of von Willebrand disease have been identified.

5. Von Willbrand disease von Willebrand disease is recognized as one of the most common hereditary bleeding disorders in humans. The exact incidence is difficult to determine because milder forms are often not clinically recognized, but it has been estimated to have a prevalence as high as 1% in the general population. No racial or ethnic predisposition Both genders are affected, but women have a higher frequency of clinical manifestation. the primary source of the synthesis and release of plasma vWF is Vascular endothelium, and stored in Weibel-Palade bodies, while the other cell that synthesizes vWF is the megakaryocyte .

6. functions of vWF 1. Stabilization of FVIII vWF serves as carrier for FVIII in plasma protecting FVIII from proteolytic degradation and localizing FVIII to sites of vascular injurie . (independent of higher multimers) 2. Support of platelet adhesion vWF mediates platelet adhesion to the vascular endothelium, and plays a role in platelet aggregation . (dependent on higher multimers)

7. Etiology von Willebrand disease may be an acquired or inherited disorder. The congenital disorder is autosomally dominant in most cases. Inherited abnormalities in von Willebrand disease are associated with a defect of the vWF gene on chromosome 12 More than 20 distinct clinical and laboratory subtypes of von Willebrand disease have been described, and Three broad types of von Willebrand disease are recognized.

8. Etiology Variant forms of von Willebrand disease can be identified by their patterns of genetic transmission and the vWF abnormalities in the plasma and the cellular compartment. Distinguishing between various subtypes of von Willebrand disease is important in determining appropriate therapy

9. formation of primary hemostatic plug Adhesion Damage to the endothelium of a blood vessel leads to exposed sub endothelial collagen von Willebrand factor is released by damaged endothelial cells and will bind tightly to the exposed collagen. The platelets have a GPIb receptor, bind to the von Willebrand factor which is bound to the collagen .

10. formation of primary hemostatic plug Activation The interaction between GPIb platelet receptors and vWF leads to platelets activation This will lead to platelet degranulation of their content ADP and thromboxane A2 will bind to other platelets and activate them to the site of injury. Thromboxane and serotonin also serve as vasoconstrictors to reduce the bleeding that is occurring. Morphological changes of platelets shape from discs to spiny spheres

11. formation of primary hemostatic plug Aggregation As platelets continue to adhere and become activated at the site of injury, they need a method to bind to each other in order to strengthen the platelet plug. When platelets are activated they express GPIIb / IIIa receptors that serve to bind fibrinogen to create a cross-link between 2 platelets. This will further solidify and strengthen the platelet plug.

12. Classification of VWD subclasses Type I ( 70% of cases) Partial quantitative deficiency of vWF Mild-moderate disease Type II ( 25 %) Qualitative deficiency of vWF Mild to moderate disease Type III ( 5 %) Total or near total deficiency of vWF Severe disease Additional subclass Acquired vWD

13. vWD TYPE 1-QUANTITY It is a partial quantitative defect Mild to moderate disease Usually autosomal dominant

14. TYPE 2A, 2B, 2M, 2N – QUALITY Accounts for 15-30% of the population. It’s the quality of the VWD, and its Usually autosomal dominant. Type 2A: there is reduced levels of HMW and intermediate sized multimers This stops the platelet from making a good plug. Type 2B : increase affinity of the large vWF multimers for platelet binding (to GpIb) vWF binds to platelets in the bloodstream, and these large bundles of platelets are removed from circulation with resultant thrombocytopenia. This causes a shortage of both platelets and VWF in the blood.

15. TYPE 2A, 2B, 2M, 2N – QUALITY Type 2M : the VWF is not able to stick to the platelets and a good platelet plug does not form. In this disorder, there is mutation in the A1 region (which forms the principal binding site for platelet) resulting in decreased platelet-dependent function. The multimers are present but dysfunctional. - vWF antigen, FVIII, and multimer analysis are found to be within reference range

16. TYPE 2A, 2B, 2M, 2N – QUALITY Type 2N : the VWF is not able to be the carrier of factor VIII . The level of factor VIII in the body will become low the body has trouble making a fibrin  clot due to low levels of factor VIII .   A person with Type 2N can appear to have mild hemophilia with some of the same symptoms . FVIII levels reduce to usually around 5% of the reference range

17. vWD Type 3-QUANTITY Autosomal recessive The rarest type where patients have total deficiency of vWF resulting in sever form of disease. This will lead to a secondary deficiency of FVIII The patient can have spontaneous bleed

18. Acquired vWD This condition typically presents as a sudden onset of mucocutaneous bleeding in a previously asymptomatic patient. occurs mostly often in individuals over 40 years. Mechanisms include Antibody formation against vWF with resultant increased clearance of the from circulation or inhibition of function Adsorption of vWF by tumor cells. Tumor cells may have aberrant GP Iba receptor expression Defective synthesis and release of vWF Increased proteolysis of vWF

19. Diagnosis of various types CBC (in certain subtypes, type 2B and platelet thrombocytopenia may be present ). Bleeding time should be prolonged as vWF is required for platelet adhesion. PTT (PTT should be prolonged due to low levels of factor VIII ) FVIII level is low in type 2N and type 3 individuals (below 10 IU/dl).

20. Diagnosis of various types VWF:Ag the plasma concentration of VWF is measured by enzyme-linked immunosorbent assay (ELISA) or automated latex immunoassay (LIA) Normal range of VWF:Ag is 50-200 IU/dl  In type 1, 2A, 2B individuals, the levels are decreased. (type 3: absent) VWF:RCo it is the most widely accepted test for evaluating VWF function. ristocetin induces von Willebrand and Gp1b interaction causing platelet aggregation. Normal range is 50-200 IU/dl. type 2N individuals have normal levels of VWF:RCo.

21. Diagnosis of various types FVIII:C It’s a Functional assay used to measure the ability of VWF to serve as a carrier protein for FVIII. Decreased in type 2N and type 3 VWD. RIPA It is mainly used to diagnose type 2B VWD using low concentration ristocetin (usually <0.6 mg/ml ). Platelets aggregation means either type 2B or mutations in the platelet VWF receptor ( pseudo VWD). Multimer analysis by electrophoresis, allows typing and sub-typing of VWD according to size.

22. Management Desmopressin ( dDAVP) a synthetic analogue of antidiuretic hormone. causing release of von Willebrand factor (VWF) from endothelial storage sites Cryoprecipitate Plasma-derived FVIII/vWF

23. A “Royal Disease”

24. 2. Hemophilia A ( factor VIII deficiency) Hemophilia A is an X-chromosome-linked recessive coagulation disorder included among the rare diseases and caused by mutations in the factor VIII ( FVIII) gene, which is an essential component of the intrinsic pathway of blood coagulation. The incidence of hemophilia A is 1 in 5000 male live births and affected individuals have severe, moderate, and mild forms of the disease The majority of FVIII is synthesized in liver . Factor VIII is a plasma glycoprotein consisting of six domains. The encoding gene is located on the long arm of the X chromosome (Xq28 ). Multiple mutations leading to hemophilia A have been described, the most common genetic defect is a large inversion and translocation of exons 1 or 22, which completely disrupts the gene.

25. Intrinsic and extrinsic pathway

26. Clinical manifestations patients with a mild form of the disease (6–30% of normal FVIII activity) unlikely to have unprovoked hemorrhages and experience major bleeding only with trauma or surgery. moderate disease patients (1–5% of normal FVIII activity) will occasionally demonstrate spontaneous hemorrhages. while patients with severe disease (<1% of normal FVIII activity) will develop spontaneous hemorrhages since early infancy. Neither factor VIII nor factor IX crosses the placenta therefore, bleeding symptoms may occur from birth or in the fetus

27. Clinical manifestations Primary; early joint and muscle bleeds bleeding in the mouth, gums, and nose. GIT and urinary hemorrhage neck/throat , eye, hip, joint and muscle , testicles, and retro peritoneum bleeds Secondary; Chronic joint deformities from recurrent bleeding Antibodies to transfused factor VIII (inhibitors develop in 20-30% of severe patients) AIDS - Over half of hemophilia patients treated with plasma concentrates in the early 1980s became HIV + Never purpura and petechiae (because primary hemostasis is not affected)

28. After repeated bleeding episodes in the joint, patients may develop a "target" joint.

29. Hemophilic arthropathy. The chronic effects of repeated hemorrhage into the knees

30. Diagnosis Hemoglobin/hematocrit Prothrombin time (PT) Extrinsic coagulation pathway screen Normal range Activated partial thromboplastin time (aPTT) Intrinsic pathway screen Elevated values expected May be normal range in mild disease Platelet count normal range

31. Diagnosis Factor VIII & IX level percentage activity (normal 50-150%). Expect severe disease with less than 1%, moderate disease with 1-5%, and mild disease with greater than 5% Factor VIII & IX inhibitors

32. Insertion of human factor VIII DNA into vector system allowing incorporation into non-human mammalian cell lines for continued propagation Recombinant Factor VIII

33. Management Cryoprecipitate and fresh frozen plasma Hemophilia care should deliver virally inactivated clotting factor concentrates , in absence of FVIII concentrate, cryoprecipitate can be used as the source of FVIII. (each cryoprecipitate unit contains 80–100 IU of FVIII) And In the absence of FIX concentrates, fresh frozen plasma should be Used for hemophilia B patients. Desmopressin (DDAVP) DDAVP is a vasopressin analogue that can release stored VWF from endothelial cells and results in a secondary increase in FVIII levels Can be used in mild hemophilia A , and type 1 VWD

34. Management Tranexamic acid anti fibrinolytic agent Avoid all products that cause platelet dysfunction ( ASA, NSAIDs ) Avoid intramuscular injections.

35. 3. Hemophilia B ( Factor IX Deficiency) Known as Christmas disease, first reported in the medical literature in 1952 in a patient with the name of Stephen Christmas. occurs in one of every 25,000 to 30,000 live male births. As with hemophilia A, hemophilia B is found in all ethnic groups. The factor IX gene is located on the long arm of the X chromosome Factor IX inhibitor antibodies less common in hemophilia B

36. Hemophilia B ( Factor IX Deficiency) Factor IX is a vitamin K-dependent. It is activated by the factor VIIa–tissue factor complex, or factor XIa, forming the active enzyme factor Ixa factor IXa activates factor X in the presence of factor VIIIa , phospholipid and calcium. Factor VIIIa is a necessary cofactor for activity of factor IXa. Therefore, deficiency of either factor IX or VIII leads to a similar lack of factor X-activating activity on the platelet surface. Factor Xa converts prothrombin to thrombin in the presence of factor Va, activated platelets, and calcium .

37. Hemophilia B ( Factor IX Deficiency) PT is normal aPTT is prolonged. specific assay of factor IX coagulant activity is required for definitive diagnosis. ..

38. references Thomas G. DeLoughery (eds .), Hemostasis and Thrombosis. Hoffman and Abeloff’s, HEMATOLOGYONCOLOGY REVIEW. Hussain I. Saba, Harold R. Roberts, Hemostasis and Thrombosis Practical Guidelines in Clinical Management. K. Pavani Bharati * and U. Ram Prashanth , Von Willebrand Disease: An Overview

39. Thank you, Qs ?