Hemophilia pathophysiology: Difference between revisions

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Revision as of 00:18, 25 August 2015

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pathophysiology

factor VIII production, processing and structure

FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver. Hemophilia A has been corrected by liver transplantation.[10] Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor. Upon activation by thrombin, (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot. No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.

Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.

Von Willebrand Factor[vWF] synthesis structure and function

vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large vWF in endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.The basic vWF monomer is a 2050-amino acid protein. Every monomer contains a number of specific domains with a specific function.Von Willebrand factor's primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. It is not an enzyme and, thus, has no catalytic activity. vWF binds to a number of cells and molecules. The most important ones are:

Factor VIII is bound to vWF while inactive in circulation; factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin.
vWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel.
vWF binds to platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stress (i.e., rapid blood flow in narrow blood vessels, see below).
vWF binds to other platelet receptors when they are activated, e.g., by thrombin (i.e., when coagulation has been stimulated).

vWF plays a major role in blood coagulation. Therefore, vWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets. Calcium enhances the refolding rate of vWF A2 domain, allowing the protein to act as a shear force sensor.

References

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 ==Overview==
 ==Pathophysiology==
-Genetic deficiencies and a rare [[autoimmune disorder]] may lower plasma [[clotting factor]] levels needed for a normal clotting process.  When a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation which is necessary to maintain the blood clot.  Therefore, there is no increase in bleeding time with haemophilia because platelets are intact, allowing the formation of these temporary hemostatic plugs (clots).  However, "late" bleeding is affected, because these hemostatic plugs are not able to be maintained.
+===factor VIII production, processing and structure===
+FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver. Hemophilia A has been corrected by liver transplantation.[10] Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor. Upon activation by thrombin, (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot. No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.
-===Genetic structure===
-[[Image:XlinkRecessive.jpg|left|thumb|150px|X-linked recessive inheritance]]
-Females possess two X-chromosomes, whereas males have one X and one [[Y chromosome]]. Since the mutations causing the disease are [[recessive gene|recessive]], a woman carrying the defect on one of her X-chromosomes may not be affected, as the equivalent [[allele]] on her other chromosome should express itself to produce the necessary clotting factors. However the Y-chromosome in men has no [[gene]] for factors VIII or IX.
-If the genes responsible for production of [[factor VIII]] or [[factor IX]] present on a male's X-chromosome is deficient then there is no equivalent on the Y-chromosome, so the deficient gene is not masked by the [[autosomal|dominant]] allele and he will develop the disease.
-Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with hemophilia, he will have a 100% chance of being a haemophiliac.
-In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a hemophiliac himself). Hence hemophilia is far more common among males than females. However it is possible for female carriers to become mild hemophiliacs due to [[lyonisation]] of the X chromosomes.
-Hemophiliac females are more common than they once were, as improved treatments for the disease have allowed more hemophiliac males to survive to adulthood and become parents. Adult females may experience [[menorrhagia]] (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in [[color blindness]].
-As with all genetic disorders, it is also possible for a human to acquire it spontaneously ([[mutation|de novo]]), rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about ⅓ of all [[hemophilia A]] and 20% of all [[hemophilia B]] cases.
-If a female gives birth to a hemophiliac child, either the female is a carrier for the disease or the hemophilia was the result of a [[mutation|spontaneous mutation]]. Until modern direct [[Genetic fingerprinting|DNA testing]], it was impossible to determine if a female with only healthy children was a carrier or not. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier. If the [[Rhesus blood group system|RH factor]] of the born male is different from the mother, the child will not be affected.
-If a male is afflicted with the disease and has children, his daughters will be carriers for hemophilia.  His sons, however, will not be affected with the disease.  This is because the disease is X-linked and the father can not pass hemophilia through the Y chromosome.
+Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.
+==Von Willebrand Factor[vWF] synthesis structure and function==
+vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large vWF in endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.The basic vWF monomer is a 2050-amino acid protein. Every monomer contains a number of specific domains with a specific function.Von Willebrand factor's primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. It is not an enzyme and, thus, has no catalytic activity. vWF binds to a number of cells and molecules. The most important ones are:
+*Factor VIII is bound to vWF while inactive in circulation; factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin.
+*vWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel.
+*vWF binds to platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stress (i.e., rapid blood flow in narrow blood vessels, see below).
+*vWF binds to other platelet receptors when they are activated, e.g., by thrombin (i.e., when coagulation has been stimulated).
+vWF plays a major role in blood coagulation. Therefore, vWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets. Calcium enhances the refolding rate of vWF A2 domain, allowing the protein to act as a shear force sensor.
 ==References==