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. For women it is the opposite, since they have XX chromosome, one X chromosome, can neutralise the other.
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.
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.
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.
The life expectancy, earlier was 8-11 years in 1920s, but now it has gone up to 67-75 years. Though there is still no cure, it can be managed well within modern clotting factors which is manufactured now.
To effectively manage hemophilia, there can be two goals, short term and long term.
Short term goals
- Decrease the number of bleeding episodes or frequencies every year
- Normalise or improve the clotting factors
Long term goals
- Maintain joint function
- Normalise orthopedic joint score
- Normalise radiologic joint score
- Maintain qualtiy of life measurement
Non Pharmacological therapy
Supportive care – Rest Ice Compression Elevation , also called RICE therapy, can be used during bleeding episodes, following with casts, splints, crutches after the bleeding has stopped.
Surgery– Surgical arthroscopic synovectomy reduces the bleeding in a repetative manner. This particular method replaces inflammed joint tissue. Patients can experience decreased range of motion after this.
Orthotics– A supportive measure taken to provide artificial means for joint support.
DDAVP- It is based on the severity of the condition, and the type of hemorrhage, its called 1-desamino-8-D -arginine vasopressin. It is a synthetic analogue of antidiuretic hormone, vasopressin.
Factor VIII and von Willebrand factor is released from endothelial sites. This medication causes the rise of factor VIII to rise 5 fold, within 30 minutes.
For patients less than 2 years old this treatment is not recommended. Usual dose is 0.3 mcg/kg IV (in 50 ml saline solution, infused for 15-30 minutes) , the nasal route has a late effect than the IV route.
In patients with less than 50ml/min creatinine clearance, use of DDAVP is contraindicated.
GI upset, headache, facial flushing seizures related to hyponatremia and myocardial infarction are some of the side effects.
Diseases of this era are complicated and they bring along a lot of pain and suffering, hence innovation is needed.
Factor VIII Replacement
Using the existential resources to it’s fullest potential, one of the good strategy to combat a problem, incorporated by many institutions throughout the world.
Factor VIII therapy may require recombinant method( transfection of mamallian cells) or plasma derived (concentrate from factor VIII). The older generations were stabilised using a human albumin, while the newer generations were stabilised using sucrose, so it eliminates the viral infection chance.
If the bleeding episode is higher , more activity is needed. More activity means, anything beyond 0.25-0.30 IU
A method called cryoprecipitate was also used before, its a frozen plasma which is thawed, it is rich in factor viii, however, there is no way to kill the HIV virus or hepatitis virus and there is a high chance of infection.
Factor IX replacement
Again two types of therapies might be needed, recombinant or plasma derived factor IX.
The older generation of factor IX concentrates have been associated with thrombogenic side effects. This is common in vitamin K dependent proteins, which are also found along with factor IX.
Factor IX can pass through both intravascular and extravasclar spaces. This also means it has a high volume of distribution.
Half life of Factor IX is around 16-17 hours, therefore doses are given every 18-24 hours. Gene therapy is currently under trial.