Overview…Factor VIII–von Willebrand Factor Complex factor VIII–von Willebrand factor (vWF) complex…circulate as a complex
vWF also is present in the subendothelial matrix of normal blood vessels
Platelets bind via glycoprotein 1b
(GpIb) receptors to von Willebrand
factor (vWF) on exposed
extracellular matrix (ECM)
+ factor IX
…intrinsic pathway
Primary
hemostasis
Overview, cont’d • vWF & factor VIII…each encoded by a separate gene
vWF is important in preserving factor VIII, without it factor VII could be
lost and break down
• They are bound noncovalently in the circulation
• Endothelial cells are the major source of plasma vWF
• Most factor VIII is synthesized in the liver This factor is important in intrinsic pathway (PTT becomes longer when
there is anything wrong with it), as it with factor IX they stimulates factor X
• vWF is found in:
-the plasma (in association with factor VIII)
-in the subendothelium, where it binds to collagen
**vWF found in platelet aggregation and
adhesion
when an injury happens to endothelium, it’s
exposed because it is under endothelium.
Platelets attach to vWF via a receptor on the
platelets called Gp1b (glycoprotein 1b)
-in platelet granules and in endothelial cells المصنع الرئيسي within cytoplasmic vesicles
called Weibel-Palade bodies
Present in 2 places:
1. In subendothelial matrix (not exposed in
normal vessels) if there’s injury it will be
exposed
2. As multimers (multiple peptides) non-
covalently attached to factor VIII
circulating in the blood as a complex
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 vWF disease: mainly will cause problem in
platelet function (primary hemostasis)
but can cause a problem in clotting because
of its role in preserving factor VIII
We will talk about:
• von Willebrand Disease
• Hemophilia A—Factor VIII Deficiency
• Hemophilia B—Factor IX Deficiency
von Willebrand Disease • Autosomal dominant
• Usually presents as:
-spontaneous bleeding from mucous membranes same characteristics as patients with platelets problems, like who take
aspirin, so any patient who administrates aspirin is given stomach
drugs to protect them from platelets dysfunction
-excessive bleeding from wounds
-menorrhagia in females
• 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
small bleading in mucous membrane (GI) and
skin (pitchy or purpura)
على شكل نزوفات صغيرة تحت الجلد ال تؤثر بشكل كبير على المريض
Mostly not detected, because it
is simple, and hemophilia is far
worse
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 if the patient homozygous the effect on factor
VIII is more obvious now, so they will have same
symptoms of hemophilia A
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
The problem in synthesizing here is that vWF isn’t
synthesized properly (not as multimers)
von Willebrand Disease, type II
• Type IIB: …abnormal ―hyperfunctional‖ high-molecular weight
• Type IIA: …the high-molecular-weight multimers are not synthesized
…leading to a true deficiency Multimers aren’t synthesized
properly nor in sufficient numbers
(quantitative and qualitative defect)
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 Multimers are synthesized in a wrong way that led them to be hyper-functional, thus means they will be consumed
quickly before they get the chance to do their job. It could be followed by rapid consuming of platelets
thrombocytopenia , so the number and the adhesiveness of platelets is affected in this type
Hemophilia A—Factor VIII Deficiency • The most common hereditary cause of serious bleeding
The most common sever congenital bleeding disorder
• X-linked recessive disorder…primarily males
• Much less commonly excessive bleeding occurs in heterozygous females
…if unfavorable lionization the deletion of intact X in carrier females leaving them with the
diseased X (both the intact X and diseased X are exposed to the deletion, but in this particular femal most
of the X deleted was the intact ones)
• 30%...due to new mutations
…others: familial
• Severe hemophilia A: if marked deficiency in factor VIII (<1% of normal activity levels)
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 because intrinsic pathway isn’t intact
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 blood inside the joint
• Petechiae are characteristically absent petechiae found in platelet dysfunction
• Treatment??? To give the patient plasma have factor VIII, or recombinant factor
VIII (synthesitic/pure) to avoid being infected with AIDs