In the Sunday series, today we get you, from our archives, Haematology expert, Dr Abhay Bhave, who takes you on an interesting journey of the past, present and the future of haemophilia.

 

 

 

 

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Going back in time

The word ‘Haemophilia’ first appears in a description of the condition written by Hopff at the University of Zurich in 1828, but haemophilia was recognized, though not named, since ancient times. The Talmud, a collection of Jewish Rabbinical writings from the 2nd century AD, stated that male babies did not have to be circumcised if two brothers had already died from the procedure.

The Arab physician Albucasis, who lived in the 12th century, wrote of a family whose males died of bleeding after minor injuries. In 1803, a Philadelphia physician named Dr. John Conrad Otto wrote about a ‘haemorrhagic disposition existing in certain families’ and thought it to be hereditary and affecting males. But, around World War II, doctors learned that haemophilia A was caused by a blood deficiency, which was later termed as factor VIII.

Haemophilia has been called a "royal disease" as the gene was passed from Queen Victoria, who became Queen of England in 1837, to the ruling families of Russia, Spain, and Germany through the marriages of her daughters. Queen Victoria's gene for haemophilia was caused by a spontaneous mutation. The X-linked recessive inherited bleeding disorder due to deficiency of a coagulation factor in the blood and has been divided into haemophilia A for factor VIII deficiency and haemophilia B for factor IX deficiency.

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Presentation

Haemophilia presents clinically in a mild, moderate or severe form in males; and in a carrier state with a variable degree of bleeding risks in females. Haemophilia A accounts for about 1 in 5,000 male births while factor IX deficiency accounts for 1 in 30,000 male births

Sometimes the moderate and mild forms of haemophilia are a challenge to diagnose as they don't present earlier in life and maybe picked up only at the time of surgery and can be completely unanticipated either by the patient or by the medical team. In such cases, a detailed history of bleeding in the family is essential in the pre-operative assessment to provide a clue.

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Diagnosis

The diagnosis of this condition is suspected by a history of bleeding either into joints (haemarthrosis) or deep sites (gastrointestinal tract or the nervous system) or into deep muscles (ileo-psoas, calf muscles or the rectus muscle). Mucocutaneous (oral/nasal) bleeds are rare.

In haemophilia the platelet count is normal. There is isolated prolongation of the aPTT (activated partial thromboplastin time) but the PT (prothrombin time) is normal.

Mixing study

A mixing study should be performed, to differentiate prolongation of aPTT due to factor deficiency and presence of inhibitors. In mixing studies, the patient's plasma is mixed with an equal volume of pooled plasma (normal plasma) and the aPTT is performed on the mixed sample. If the aPTT gets corrected then this confirms a deficiency which in clinical terms would either be factor VIII or factor IX deficiency, followed by calculation of factor VIII or factor IX assay by automation to confirm the diagnosis.

The site, nature, and type of bleeding clinically cannot differentiate between factor VIII and factor IX bleeding. Prolonged aPTT could also be due to other deficiencies such as factor XI and factor XII deficiency, but they are rare and hence to be assessed only if factor VIII or factor IX are normal.

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Treatment options

Since the diagnosis in severe haemophilia is usually made at the time of bleeding actively, it is imperative that the patient receives a rapid and adequate management of the bleeding event to minimize blood loss and target tissue damage.

Almost 70 to 80% of the time, Haemarthrosis is the common bleeding event at presentation. Doctors recommend rest, immobilization, compression, and elevation of the involved limb (RICE). Oral tranexamic acid is given for 1 to 3 days to minimize the bleeding and the patient is given either reconstituted intravenous factor VIII or factor IX based on the diagnosis.

Factor therapy

Factor VIII and factor IX are available as lyophilized powders which needs to be reconstituted with water for injection and given as a slow intravenous infusion. These factors are available as high purity plasma derived products (now by Double viral inactivation method, some having von Willebrands factor) or as recombinant factors the latter being more expensive.

The dose of factor therapy would depend upon the innate factor level, degree of bleeding, site of bleeding, need of surgery and the time needed for rehabilitation (physiotherapy).

For example, 1 unit/kg body weight of factor VIII increases the native factor VIII level in the blood by 2 percent, so if we want to achieve 100% level in a 50 kg patient then we need to give him 2500 units. On the other hand, 1 unit/kg body weight of factor IX increases the native factor IX level in the blood by 1%, so if we want to achieve 100% level in a 50 kg patient then we need to give him 5000 units of factor IX concentrate.

We can measure the factor level half an hour to one hour after completion of the infusion to confirm that we have achieved the desired level of factor VIII or IX to either prevent further bleeding and promote joint healing or for fitness for surgery. However, if the desired factor level is not obtained after infusion of factor this could be due to inadequate correction (calculation error), lab error or presence of inhibitors in the patient's plasma preventing the expected rise of factor levels.

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Dosing & duration

Dose and duration of factor therapy would depend on the site of bleeding, such that deeper sites will need higher and longer duration of therapy. CNS and deeper bleeds need 80 to 100% factor correction for 3 to 7 days while Haemarthrosis needs 30 to 50% factor correction.

Factor VIII has to be given 3 times a day because of its half-life of about 8 hours as opposed to factor IX which could be given twice a day due to its half-life of 9 to 12 hours. However, some of the new plasma derived factors have von Willebrands factor in addition to the factor VIII which protects fast degradation of the factor VIII increasing its half-life to 16 hours.

Hence it is imperative that the entire dose calculation is done appropriately based on the patient's weight, factor level along with the site of bleeding. More factors will be necessary for prevention of anticipated bleeding during rehabilitation. The use of fresh frozen plasma (FFP) and cryoprecipitate should be avoided and done only in cases where factors are not available.

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Risks

One of the problems in haemophilia is acquiring infections related to blood transfusion (fresh frozen plasma) such as the HIV, HCV, or HbsAg infections in those not affording factor therapy or needing plasma in an emergency till factors are available. However, with high standards of testing these events are now rare. Still there are other immunological reactions that preclude FFP as a modality of therapy.

Another issue that complicates Haemophilia management is the development of factor VIII or IX inhibitors that need either large factor therapy to swamp these inhibitors or use of FEIBA (factor VIII inhibitor bypass activity) or APCC (activated prothrombin complex concentrates), or rFVIIa (activated recombinant factor VII) concentrates.

In extreme cases, Immunoglobulins, high dose steroids, and plasmapheresis may be needed.

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Recent advances

Conceptually, changes have taken place in the last 5 years which have changed the outcomes of patients with this condition.

Prophylactic Therapy

The concept of being able to provide factors maybe 2 or 3 times a week to the patient to maintain a factor level more than 1% so that he is no more in severe haemophilia.This will significantly reduce the risk of bleeding and the need for factor replacement therapy especially in children so that they can grow normally without disabilities.

This prophylaxis can either be; 

• primary, which is around the first or second year of age after having one episode of joint bleeding,
•  secondary, when such prophylaxis was given after the second joint bleed,
•  tertiary prophylaxis, when such prophylaxis was given when joint deformity is suspected to be taking place in the patient.

Gene Therapy

 Another concept in which the gene that is responsible for the production of factor VIII /factor IX is incorporated into the nucleus with the help of a vector (an adenovirus) allowing enough production of factor VIII / factor IX to convert the patient permanently into a moderate or mild haemophiliac. This is the most exciting part of haemophilia which can make a tremendous difference to the patient's quality of life and convert him to be a normal person being productive in society without having to lose his self-esteem.

This article was originally published on 3.05.18

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Dr Abhay Bhave on past present &future of #hemophilia,
recognised, though not named, since ancient times.https://t.co/nkksiAj5GP pic.twitter.com/iXt85PmYF6

— M3 India (@m3_india) May 4, 2018