This document provides an overview of inherited bleeding disorders, focusing on von Willebrand disease, hemophilia A, and hemophilia B. It classifies inherited bleeding disorders and discusses their prevalence. For von Willebrand disease, it describes the classification, etiology, functions of von Willebrand factor, diagnosis of different types, and management. It also discusses the formation of the primary hemostatic plug. For hemophilia A and B, it covers clinical manifestations, diagnosis, and management, including use of factor replacement therapies.

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
1. 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
2. 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
3. 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.

13. 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

14. VWD TYPE 1-QUANTITY
• It is a partial quantitative defect
• Mild to moderate disease
• Usually autosomal dominant

15. 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.

16. 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

17. 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

18. 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

19. 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

20. 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).

21. 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.

22. 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.

24. 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

25. A “ROYAL DISEASE”

26. 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.

27. • Intrinsic and
extrinsic pathway

29. 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

30. 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)

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

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

33. 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

34. 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

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

36. 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

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

38. 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

39. 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.

40. HEMOPHILIA B (FACTOR IX DEFICIENCY)
• PT is normal
• aPTT is prolonged.
• specific assay of factor IX coagulant activity is required for definitive diagnosis.
..

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

42. Thank you,
Qs?