1. Congenital bleeding disorders
Ali Al Khader, M.D.
Faculty of Medicine
Al-Balqa’ Applied University

2. Overview…Factor VIII–von Willebrand Factor Complex
factor VIII–von Willebrand factor (vWF) complex…circulate as a complex
Platelets bind via glycoprotein 1b (GpIb) receptors to von Willebrand factor (vWF) on exposed extracellular matrix (ECM)
+ factor IX
…intrinsic pathway
vWF also is present in the subendothelial matrix of normal blood vessels

3. Overview, cont’d vWF & factor VIII…each encoded by a separate gene
They are bound noncovalently in the circulation
Endothelial cells are the major source of plasma vWF
Most factor VIII is synthesized in the liver
vWF is found in:
-the plasma (in association with factor VIII)
-in platelet granules and in endothelial cells within cytoplasmic vesicles called:
Weibel-Palade bodies
-in the subendothelium, where it binds to collagen

4. Overview, cont’d
The most important function of vWF is to facilitate the adhesion of
platelets to damaged blood vessel walls
…inadequate platelet adhesion is believed to underlie the bleeding
tendency in von Willebrand disease
vWF also stabilizes factor VIII…thus, vWF deficiency leads to a
secondary deficiency of factor VIII

5. We will talk about: von Willebrand Disease
Hemophilia A—Factor VIII Deficiency
Hemophilia B—Factor IX Deficiency

6. von Willebrand Disease
Autosomal dominant
Usually presents as:
-spontaneous bleeding from mucous membranes
-excessive bleeding from wounds
-menorrhagia
This disease is surprisingly prevalent, particularly in persons of European descent:
…It is estimated that approximately 1% of people in the United States have von
Willebrand disease
…the most common inherited bleeding disorder

7. von Willebrand Disease, cont’d
This disease is underrecognized, because:
-the diagnosis requires sophisticated tests
-the clinical manifestations often are quite mild
The problem is mainly due to platelet dysfunction
…but rare patients who are homozygous: also deficiency of factor VIII
…they will have manifestations resembling
hemophilia

8. von Willebrand Disease, variants
The classic and most common variant (type I):
-autosomal dominant disorder
-quantity of circulating vWF is reduced
-there is also a measurable but clinically insignificant decrease in factor VIII
levels
The other, less common varieties produce both qualitative and quantitative defects in
vWF (Type II):
-several subtypes
-characterized by the selective loss of high molecular-weight multimers of vWF
…these large multimers are the most active form…so: there is a functional
deficiency of vWF…see next slide

9. von Willebrand Disease, type II
Type IIA: …the high-molecular-weight multimers are not synthesized
…leading to a true deficiency
Type IIB: …abnormal “hyperfunctional” high-molecular weight
multimers are synthesized that are rapidly removed from
the circulation
…some people with type IIB von Willebrand disease have
mild chronic thrombocytopenia, presumably due to
platelet consumption

10. Hemophilia A—Factor VIII Deficiency
The most common hereditary cause of serious bleeding
X-linked recessive disorder…primarily males
Much less commonly excessive bleeding occurs in heterozygous females
…if unfavorable lionization
30%...due to new mutations
…others: familial
Severe hemophilia A: if marked deficiency in factor VIII (<1% of normal activity
levels)

11. Hemophilia A, cont’d
Milder deficiencies may only become apparent when other predisposing conditions, such as trauma, are also present
The varying degrees of factor VIII deficiency are explained by the existence of many different causative mutations
Sometimes, the mutation causes dysfunction not decreased quantity
PTT is prolonged

12. Hemophilia A, clinical notes
Tendency toward easy bruising and massive hemorrhage after trauma or operative
procedures
“Spontaneous” hemorrhages frequently are encountered in tissues that
normally are subject to mechanical stress, particularly the joints, where
recurrent bleeds (hemarthroses) lead to progressive deformities that can be
crippling
Petechiae are characteristically absent
Treatment???

13. Hemophilia B—Factor IX Deficiency

14. Thank You