Primary Prophylaxis for People Suffering with Hemophilia
Major challenges in PWH with severe disease, is development of spontaneous bleeding.
Spontaneous bleeding can take place in any part of the body i.e. Mucocuta-neous bleeds during eruption of milk teeth, gastro intestinal bleeding, genitourinary bleeding or catastrophic bleeding in central nervous system. However the major cause of morbidity in PWH with severe haemophilia is due to bleeding in joints leading to acute haemarthrosis particularly knee, ankle and elbow joints with pain, swelling and repeated absentism from school and working places.  Repeated acute haemarthrosis can eventually lead to chronic synovitis, chronic arthropathy and finally fibrous or bony ankylosis leading to permanent limitation of movement & pain. This chronic anthropathy and pain also leads to atrophy of muscles surrounding the affected joints.  Spontaneous bleeding also takes place in muscles leading to disabling psoas bleed or bleeding into fore arm or leg can lead to Volkmann's ischaemic contracture and muscle paralysis if these bleeds were not immediately treated. However it was found in 1960's during concentrate therapy that on demand treatment or home treatment which is initiated only after bleeding has taken place does not prevent eventual chronic arthropathy in PWH and it needs only a few (as low as 3-5) bleeds in the joint to cause these eventual chronic arthropathy.

One of the leaders of haemophilia management Dr. Inga Marie Nielson made a seminal observation in mid 1960's that moderately severe deficiency of factor IX and factor VIII (>1%-<5%) does not lead to spontaneous bleeds and these patients bleed only on trauma. However these PWH often escapes recurrent joint bleed and chronic joint damage. Muscular bleeding and its attendant complications like haemophilic pseudotumour is also almost unheard of in these PWH with moderately severe factor deficiency. A natural corollary from this observation is if a PWH who has severe factor deficiency (<1%) is made moderately severe by regular infusion concentrates so that the lowest circulating levels of deficient factor always remains >1% then a severely affected PWH will behave like moderately affected PWH without much musculo skeletal damage. She started a trial in the earnest & showed conclusively that such primary prophylaxsis indeed prevented joint damage.

However, during that period highly purified factor which could be injected in a small volume of fluid was not available and as is true today in our country the primary objective was to be able to give some treatment to all severe PWH rather than using up concentrates on few PWH leaving others without therapy hence primary prophylaxis were not widely advocated at that time as regular therapy.

Now there is conclusive evidence that primary prophylaxis works and PWH with severe disease can grow up on primary prophylaxis without any musculoskeletal disability. However, if primary prophylaxis is so good, then why even in developed country all eligible PWH are not getting primary prophylaxis? In USA at least 1/3 of eligible PWH are outside primary prophylaxis though authorities believe every severe young eligible PWH should be on primary prophylaxis.

The difficulties in providing Primary Prophylaxis to every eligible severe PWH are :

(i) The standard primary prophylaxis with 50-100 I.U/kg of factor concentrate twice weekly (factor IX deficiency) or thrice weekly (factor VIII deficiency) consumes huge amount of factor concentrate on individual patient and tremendously increase the cost of therapy.

(II) To be effective, primary prophylaxis should start very early at around 2 years of age however, there is no unanimity about this age. In some country primary prophylaxis starts at 2 years of age, whereas in some other country prophylaxis is started only after one or two joint bleed which delay this treatment in some PWH upto 5 years of age. Moreover injecting regularly factor concentrates in such a small child is not easy and maintaining venous access (Port-a-cath) for such a young child is challenging and more so is maintaining the conduit in functional condition without infection or thrombosis.

(III) There is a fear that starting primary prophylaxis too early may stimulate inhibitor development in haemophilia A patients.

(iv) There is no consensus how long primary prophylaxis should be continued. One of the intuitive reaction is to stop the prophylaxis after 18-20 years of age when a PWH has completed his puberty and bone growth and his tendency to spontaneous bleeding is substantially reduced.

(v) As the rationale of giving primary prophylaxis is to maintain lowest circulating level of deficient coagulation factor at more than 1% level so the rational approach should be to study the half life (t1/2) of factor concentrate in individual PWH and decide the dose to be injected.

However in practical life this is too cumbersome and various regimes of primary prophylaxis is still evolving. Some studies have shown factor concentrates as low as 15-30 I.U/kg twice (for factor IX deficiency) or three times a week (for factor VIII deficiency) may maintain the desired factor level and lower the cost of therapy. Some other country builds up the dose by looking at the effects of injecting the concentrates starting once a week and increasing the frequency of injections if break through bleeding appears. Theoretically speaking we can use the least amount of factor concentrate if we are giving the injections daily e.g. to maintain factor VIII or IX in plasma at more than 1% we need to inject 2-3 but it is extremely difficult to give every day injection to a small child.

Pharmaceutical companies also understand that primary prophylaxis will have more takers if products with much longer half lives can be produced. Some of the product with long half lives are already undergoing clinical trial and will be available in near future though at a higher cost.

One pertinent question to ask is are we ready to start primary prophylaxis in our PWH?

On the one hand the country and HFI is struggling to provide on demand treatment for all our PWH on the other primary prophylaxis will allow health growth for all future under 5 year PWH in this country. Due to active struggle by HFI and its well wishers different states of India are slowly opening their doors for PWH by providing free factor concentrate for PWH making it possible to aim for primary prophylaxis in under 5 years severe PWH in those states where free factor is available.

Similar attempts should also be made by these doctors treating severe PWH where Govt. or other corporate organizations are providing free factor concentrates for their staffs. If we can make a modest beginning we can cover the whole country with primary prophylaxis in due course of time.