Hemostasis - What is Hemophilia

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Hemophilia is a sex-linked hereditary bleeding disorder caused by the deficiency of either coagulation factor VIII (FVIII) or factor IX (FIX), called hemophilia A and B respectively. The genes for FVIII and FIX are located on the X chromosome which means that, with very rare exceptions, only males are affected (Fig. 1, pdf). As females have two X chromosomes, even if one chromosome carries the hemophilia mutation, the second normal chromosome is able to produce sufficient quantities of clotting factor. It is interesting to note that up to one third of hemophiliacs have no family history and result from spontaneous mutation.

How common is hemophilia?

Hemophilia A is the most common of the hereditary clotting factor deficiencies occurring in about 1 in 5000 live male births. Hemophilia B is less common with a prevalence of about 1 in 30,000 live male births. The clinical presentation, laboratory diagnosis and management of hemophilia A and B are identical. This article will focus on hemophilia A and FVIII because it is more common, however all references to FVIII can be substituted with FIX to be applicable to hemophilia B.

What are the clinical manifestations of hemophilia?

The major clinical symptom of hemophilia is recurrent bleeding episodes. The severity of bleeding is directly related to the FVIII levels (Table 1). Patients with the lowest levels of FVIII will have more frequent bleeds and a worse clinical picture, while patients with mild hemophilia will experience far fewer bleeds and minimal or no complications. Infants may present with profuse post-circumcision hemorrhage, soft tissue bleeds and/or excessive bruising, especially when they first start crawling. Recurrent spontaneous joint bleeds and muscle hematomas are a common complication and if left untreated the joints can develop chronic arthritis progressively leading to disability. Complications from uncontrollable bleeds may arise during major trauma or surgery.

How is hemophilia diagnosed?

Prolongation of the baseline coagulation screening tests would identify a patient with a clotting factor deficiency. Clotting factor assays are needed to identify the specific factor that is deficient. In hemophilia, the deficiency of FVIII (or FIX) causes prolongation of the APTT but not the PT.

When the APTT is prolonged, correction studies should be performed by mixing the patient’s plasma with normal pooled plasma in a ratio of 1:1. This mixing study is used to determine whether the prolongation of the APTT is due to a factor deficiency or due to an inhibitor such as heparin. The addition of normal pooled plasma will replace missing factors in the patient’s plasma and, consequently, will correct the APTT to within normal range if the original prolongation was due to a factor deficiency. In contrast, if the prolonged APTT is due to an inhibitor, then no correction will take place. Individual factor assays must be performed to confirm a diagnosis of hemophilia. Because hemophilia A is far more common than hemophilia B, it is typical to first perform a FVIII assay, followed by a FIX assay if the FVIII level is normal. The test principle and method are essentially the same for both factors.

Treating hemophilia

Hemophiliacs bleed because they have a partial or complete absence of a single clotting factor; namely FVIII or FIX. It should therefore not be surprising that the mainstay of treating bleeding episodes is to replace the missing clotting factor. This is usually given in the form of a single factor concentrate (FVIII or FIX) which is either derived from human blood through a process of purification or is manufactured by means of genetic engineering (recombinant factor). The use of recombinant products is preferred as they reduce the risk of transfusion-associated complications, however, they are typically expensive and not widely available. Factor concentrates or fresh frozen plasma are produced from donor blood and are more commonly used for treatment.

The amount of clotting factor that needs to be given will depend on the severity of the bleed. For spontaneous bleeds, a FVIII level of 30 – 50% is usually adequate, but for any major trauma or surgery, a level of 100% is required. Once bleeding has stopped, FVIII levels should be maintained at about 50% until healing has occurred.

Ideally, hemophiliacs should receive factor replacement on a regular basis to prevent bleeding and long-term complications, however, this prophylactic treatment is extremely expensive and, therefore, unfeasible for the vast majority of affected patients.

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