Congenital bleeding disorders

Transcription

1 Congenital bleeding disorders

2 Overview Factor VIII von Willebrand Factor Complex factor VIII von Willebrand factor (vwf) complex circulate as a complex + factor IX intrinsic pathway Platelets bind via glycoprotein 1b (GpIb) receptors to von Willebrand factor (vwf) on exposed extracellular matrix (ECM) 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

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