Position of aPCC in the Treatment of Hemophilia A Complicated by the Development of Inhibitors

Hemophilia A and Inhibitors as a Major Complication

Congenital hemophilia A (HA) is caused by a deficiency of coagulation factor VIII (FVIII). This leads to spontaneous or traumatic bleeding. Replacing the missing FVIII with a concentrate, whether plasma-derived or recombinant, can stop bleeding or prevent it during perioperative periods, and regular administration reduces the risk of spontaneous or traumatic bleeding. However, approximately 30% of patients with severe HA develop a serious complication of factor therapy, specifically an inhibitor, which is an antibody that neutralizes the effect of administered FVIII.

Bleeding and Hemophilia A with Inhibitors

In such cases, it is necessary to control bleeding using so-called bypassing agents (BPA) - either activated prothrombin complex concentrate (aPCC) or recombinant FVIIa (rFVIIa). aPCC was introduced in practice in 1977, almost 20 years before rFVIIa. Both BPA products can be used in patients with congenital HA and inhibitors to treat and prevent bleeding.

While both BPA products are currently approved for the treatment of bleeding and perioperative management, only aPCC is globally approved also for the prevention of bleeding in patients with HA and inhibitors.

Insights into the Mechanisms of Action of aPCC

aPCC is derived from plasma and primarily contains vitamin K-dependent coagulation factors (FII, FVII, FIX, and FX) in both zymogen and active forms. The mechanism of action of aPCC operates through multiple pathways and includes three steps:

1. The FII-FXa complex leads to immediate thrombin generation (TG) on the surface of activated platelets and tissue-factor-bearing cells. This bypasses the hemostatic cascade and supports the formation of an initial fibrin clot. Additionally, fibrin-mediated reactions activate further coagulation components and additional platelet activation.
2. Endogenous inhibitors of the tissue-factor pathway slow the reaction on tissue-factor-bearing cells. Zymogens and procoagulant enzymes in aPCC directly and indirectly amplify TG on activated platelet surfaces, leading to massive thrombin formation. Due to the long half-life of zymogens, long-lasting hemostasis is achieved, helping to prevent recurrent bleeding.
3. aPCC contains natural coagulation inhibitors (protein C and protein S). The balanced increase of these factors weakens coagulation, thus preventing prothrombotic effects in the absence of additional pro-coagulant signaling.

Dosage and Optimization of Efficacy

The hemostatic efficacy of aPCC can be further improved by optimizing the dose, with dosage and treatment duration depending exclusively on the location of the bleeding, its duration, the overall condition of the patient, and particularly their response to treatment. The potency of aPCC is expressed in arbitrary units: 1 IU of aPCC shortens aPTT using reference plasma containing FVIII by 50%. The maximum daily dose should not exceed 200 IU/kg (maximum 100 IU/kg per infusion) in monotherapy with aPCC.

Experience has shown that patients can respond differently to both BPA products. This should be considered in clinical decision-making.

The Importance of aPCC in the Management of Hemophilia Patients

With evolving treatment options for patients with HA and inhibitors, including non-factor therapies, aPCC remains very important. In some patients on non-factor therapy, it can help control breakthrough bleeding or contribute to bleeding prevention during surgical procedures. In combination with non-factor therapy, it should be noted that a dose of aPCC < 50 IU/kg may be sufficient to stop bleeding. For patients undergoing classical immune tolerance therapy (ITI) without non-factor therapy, aPCC represents a key drug not only for stopping bleeding but also for its prevention. It remains important for some patients with hemophilia B complicated by inhibitors and for patients with acquired hemophilia A.

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Source: Brackmann H. H., Schramm W., Oldenburg J. et al. Origins, development, current challenges and future directions with activated prothrombin complex concentrate for the treatment of patients with congenital haemophilia with inhibitors. Hamostaseologie 2020 Jul 27, doi: 10.1055/a-1159-4273 [Epub ahead of print].