Hemophilia

X- linked recessive hemorrhagic disease due to the mutation in the F8 gene ( Hemophilia A ), and F9 gene is responsible for Hemophilia B. Since it is an X linked disorder males are clinically more affected than females. Males have XY chromosome, so if the X chromosome is affected the Y isn’t able to carry over the function, this is in a very lay man term. For women it is the opposite, since they have XX chromosome, one X chromosome, can neutralise the other.

 

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Clinically , hemophilia A and B are indistinguishable, it can be classified as

  • severe ( <1%)
  • moderate ( 1-5%)
  • mild (6-30 %)

Hemophilia A–  Is also called Classic Hemophilia, they do not have clotting factor 8, most common

Hemophilia B– Factor IX deficiency, also called Christmas factor

Hemophilia C– Factor XI deficiency, accounts for less than 5 % of all hemophilia patients.


Laboratory Findings

Individuals will have prolonged a PTT, except in some cases of mild deficiency.

The diagnosis is confirmed by finding decreased factor VIII activity, with normal vWF activity. Around two-thirds of the families of hemophilia, females are the carriers, and some are mildly symptomatic.

The ratio of factor VIII  activity to vWF antigen and definitely diagnosed by molecular genetic techniques. In a new-born baby in whose family hemophilia is prevalent, a cord blood sampling for factor VIII activity is accurate and important making a confirmed statement.

When the child starts to walk or crawl, this condition is more apparent, causes recurrent hemarthroses, and bleeding into limb muscles, hematuria, retroperitoneal hemorrhages, CNS bleeds, gum bleeds occur.


Hemostasis  Path

The two pathway intrinsic and extrinsic unlike before is considered whole now.

Clotting cascade acts sequentially with each element working in perfect harmony with each other. This amplifies the system and gives a response to action.

Tissue factor- it is a glycoprotein that is inducible on the endothelial and other cells by IL-1, TNF and endotoxin, especially if the cells are damaged. It can act as a co-factor with Factor VII to initiate a cascade.

  • Factor VII-Tfr complex activates Fr IX and Fr X
  • Forms Fr IX a and Xa
  • Fr Xa reacts with Fr Va and forms a Tenase complex

 

Fr V → Fr Va, to generate additional tenase complex

Fibrinogen → fibrin

Fr XIII → Fr XIIIa, which in turn crosslinks the fibrin fibres, forming a stable clot matrix

Fr XI → Fr XIa, which then converts Fr IX → IXa , VIII→VIIIa,

Fr VIIIa- Fr IXa converts Fr X → Fr Xa

Now to limit the excessive coagulation, Tissue Factor Plasminogen Inhibitor is needed.

So that is formed when Fr X is activated to Xa providing an additional source for the tenase complex that is required because it elicits the production of a tissue factor pathway inhibitor, and inactivates FrVIIa-TFr.

 

All of this is confusing and that’s why I recommend reading twice thrice may be. Until a clear picture is formed in mind it’s difficult to comprehend the clotting cascade.

 


Management of Hemophilia

During the 1990’s and 1980’s  efforts were made to use the freeze-died factor concentrations , which were prepared from large donor pools, but it was soon realized that it was risk associated due to the transfer of viruses such has Hepatitis and HIV.

This was taken care by carefully selecting the donor pool and viral inactivation by irradiation and immunization against hepatitis. However the transfer is reduced and eliminated by using recombinant DNA technology and using the recombinant human FrVIII and FrIX.

So this recombinant method also comes with a little bit of a problem, and that is developing an antibody. Our cells don’t want any foreign particles to enter about which we know already, and this is the case when vaccines or serums are introduced too.

About 10 % of the treated patients can or may develop antibodies, and it is active against both endogenous factors and those given therapeutically and can cause severe problems in treatment. The rhFr VIII is not complexed with its carrier molecule (vWFr) – Willebrand Factor , and hence it is more immunogenic.

 

 

 

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