Haemophilia A is a rare congenital bleeding disorder characterised by a deficient coagulation protein, named factor VIII, and affecting 1 out of 10’000 people. Severity of clotting defects correlates with phenotypic manifestation of these diseases, characterized by post-traumatic and spontaneous bleeds. One of the major complication of the treatment of Haemophilia A is the development of antibody against factor VIII (called inhibitors) that inhibits factor VIII activity (FVIII:C) and leading to a poor control of bleeding. The risk of inhibitors production is higher in patients with severe Haemophilia A than in patients with mild or moderate disease. The prevalence of patients with severe haemophilia A is estimated to be about 3 out of 100,000 people in the general population.

The occurrence of inhibitors in previously untreated patients should be seen as a natural response of the immune system to a non-self protein.

Inhibitor development is the most challenging complication of haemophilia treatment and the highest economic burden for a chronic disease (Gringeri et al, 2003). It is important to know whether plasma-derived and recombinant products are associated with a different risk of inhibitor development in previously untreated patients (PUPs) or not. Unfortunately, no randomized clinical trials are available to provide the evidence we need.

A very accurate and systematic review on the epidemiology of inhibitors in haemophilia A has been carried out by the School of Health and Related Research of the University of Sheffield, UK (Wight and Paisley 2003). This review evaluated the role of the different FVIII products on the risk of inhibitor development. The cumulative risk in previously untreated patients (PUPs) treated with different plasma-derived products of low or intermediate purity was reported to range from 20.3 (Lorenzo et al, 2001) to 33.0% (Ehrenforth et al, 1992; Addiego et al, 1993). By contrast, for patients treated with a single plasma-derived concentrate, the cumulative risk ranged from 0 (Schimpf, et al 1995) to 12.4% (Guerois, et al 1995). The cumulative risk for patients treated with a single recombinant product was reported to range from 36.0 (Lusher, et al 1993) to 38.7% (Rothschild, et al 1998). More recent papers have shown that in patients treated with a 2nd generation rFVIII products the incidence of inhibitors was ranging from to 16.7 to 32% (Kreuz et al, 2005; Courter et al, 2001).

The analysis of concentrate immunogenicity is complicated by several factors:

  1. the different modality of inhibitor testing
  2. the heterogeneity of study population, not only because of the different severity of enrolled patients’ FVIII defects but also because of the different risk factors that might play a role in inhibitor development, such as ethnicity, type of gene mutation, age at first treatment (Scharrer & Ehrlich 2004)
  3. the multiplicity of FVIII products used

In particular, some confusion is introduced when the observations involve intermediate and high purity products, which differ in particular with respect to their content in von Willebrand factor (VWF) but also in other plasma protein that may exert an immunomodulating effect. In fact, the presence of VWF has been suggested to play a role in the immunogenicity of FVIII products since 1995 (Amano et al 1995; Auerswald et al 2003; Gringeri et al 2006). On the other hand, other plasma proteins have been suggested to play a role.

In 2007, Dasgupta and colleagues demonstrated that VWF protects FVIII from being endocytosed by human dendritic cells and subsequently presented to FVIII-specific T cells. These Authors proposed that VWF may reduce the immunogenicity of FVIII by preventing, upstream from the activation of immune effectors, the entry of FVIII in professional antigen-presenting cells.

Furthermore, a French study has compared a cohort of severe haemophilia A previously untreated patients given a single high-purity plasma-derived FVIII containing VWF (VWF/FVIII) or first generation full-length rFVIII concentrates and has shown a 2.4 higher risk of inhibitor development in patients treated with a rFVIII compared to those treated with a plasma-derived VWF/FVIII (Goudemand, et al, 2006). On the other hand, a retrospective international cohort study (Gouw et al, 2007) showed no difference in the rate of inhibitor development with the two different FVIII sources, at variance with another cohort study carried out in UK (Chalmers et al, 2007) which showed that VWF/FVIII products were less immunogenic than rFVIII products. All these studies are, however in accord that switching between different products, and particularly from a plasma-derived to recombinant concentrates, represents no risk of inhibitor development.

More recently, Lillicrap’s research group examined the hypothesis that the cytokine microenvironment induced by plasma-derived FVIII (pdFVIII) has a critical influence on the reduction of anti-FVIII antibody titers in hemophilia A mice (Waters, et al, 2009). These Authors found that pdFVIII causes a different immune gene expression profile than rFVIII administration. Both treatments caused the up regulation of pro-inflammatory gene expression. However, the rFVIII and pdFVIII treatments caused the up regulation of genes that induce Th1 and Th2 responses, respectively. Moreover, after administering rFVIII or pdFVIII concentrates to mice, each treatment induced a distinct T cell splenic cytokine micro-environment. Recombinant FVIII induced the release of Th1 cytokines and IL10, while pdFVIII induced the release of Th2 cytokines and TGF-a.

Very recently, another study supports the evidence that rFVIII products can be at higher risk of inhibitor development: Israeli Authors (Strauss et al, 2008) have in fact reported at the 2008 World Federation of Haemophilia Congress in Istanbul that they found inhibitors in 14 out of 43 (32.5%) haemophilia A patients neonatally exposed to rFVIII, whereas among all other Israeli haemophilia A patients previously treated with plasma-derived products, inhibitor had occurred in 22 out of 415 patients (5.3%).

These contradictory findings emphasize the need of a randomized clinical trial in order to provide a definite answer on the different immunogenicity of FVIII products.

This study aims to test the hypothesis that plasma-derived VWF/FVIII products are less immunogenic than rFVIII products. For this reasons we will compare two classes of products and not two specific products belonging to these 2 classes. This approach will also facilitate to generalise the findings of the study to all the patients who are going to be treated with any product belonging to the class of rFVIII products or to that of plasma-derived VWF/FVIII products.

The SIPPET study was sponsored by the Fondazione Angelo Bianchi Bonomi

The contract research organization of SIPPET study was Sintesi Research

© 2019