DONE BY: Muntaha Al-khazalleh

EDITED BY: RASha rakan

Congenital bleeding disorders

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

Hemophilia B—Factor IX Deficiency