Forgotten Steps in the Coagulation Cascade

Great progress has been made in the treatment of haemophilia with improved factor concentrates, the advent of FVIII mimetics, gene therapy and rebalancing agents [1]. Also for von Willebrand disease, efforts are ongoing to improve the management of patients [2]. However, rare coagulation disorders have not yet benefited from these developments. In particular, patients with severe factor II (FII) and factor V (FV) deficiencies, affecting less than 1 in 1 million and around 1 in 1 million people respectively [3], currently do not have access to dedicated factor concentrates. In contrast to haemophilia, these disorders are autosomal recessive, and affect both men and women, with women facing heavy menstrual bleeding and pregnancy-related haemorrhagic complications. For FII deficiency, three-factor or four-factor prothrombin complex concentrates (PCC) are available. These also contain factor IX and factor X with or without factor VII. Supplementing the other vitamin K-dependent coagulation factors in addition to FII increases the risk of thrombotic events. In case of FV, options are even scarcer, and fresh frozen plasma (FFP) is the standard treatment option for these patients. FFP is typically given at 15–20 mL/kg, but repeated administration may cause circulatory overload and transfusion reactions. Furthermore, the relatively short half-life of FV of approximately 16–36 h makes it harder to achieve sufficiently high trough levels without a significant burden for the patient. In addition, platelets contain FV and transfusion may provide some haemostatic benefit [4], but carries the risk of alloimmunization. In most cases, patients are treated episodically. However, Pasca et al. [5]. reported several published cases in need of prophylaxis in a recent issue of Haemophilia. The authors described two additional previously unpublished cases from Italy in more detail. These cases highlight the need for prophylaxis in a subset of patients with rare coagulation factor deficiencies. Moreover, they exemplify the hurdles that are currently encountered in managing these patients. A first patient with severe FII deficiency received four-factor PCC in prophylaxis following an intracranial haemorrhage at the age of six months. Upon developing a cerebral vein thrombosis, he was temporarily treated with FFP, but this regimen was soon halted because of frequent muscle and joint bleeds, and allergic reactions to FFP. The boy subsequently received an experimental FII concentrate in compassionate use aiming at trough levels of 4%–5%. At the age of 8, he developed a splanchnic vein thrombosis. After a new episode of intracranial haemorrhage, treatment with the FII concentrate was restarted with satisfactory bleed control until the current age of 23 years. A second patient had a severe FV deficiency and also developed an intracranial haemorrhage at 3 months of age. Long-term prophylaxis with a solvent-detergent-treated plasma product was initiated with subsequent haemostatic control throughout childhood. However, biweekly plasma treatment posed a huge burden on this child. These cases demonstrate that the current goal in haemophilia care of zero bleeds and a normalization of life cannot be achieved in patients with severe FII and FV deficiencies. The most obvious improvement would be the development of specific FII and FV concentrates, similar to the existing concentrates for other rare coagulation factor deficiencies. In addition, it may be possible to design FV mimetics that mimic the cofactor function of FV by bridging activated factor X and prothrombin, in similar vein to the existing factor VIII mimetic emicizumab. A FV mimetic would have a longer half-life and in general, antibodies can be produced at lower cost than many other molecules including factor concentrates. However, the rarity of these patients hinders the development of dedicated products. Therefore, an easier choice would be to test drugs that have been developed for haemophilia, thereby redirecting the therapeutic innovations in haemophilia to these ultrarare bleeding disorders. Rebalancing agents represent a very interesting option. These subcutaneously administered drugs target the natural anticoagulants in order to restore the disequilibrium in haemostasis [6]. Fitusiran, targeting antithrombin, and marstacimab and concizumab, inhibiting tissue factor pathway inhibitor (TFPI), have gone through phase 3 trials and have received regulatory approval for the treatment of haemophilia. Following their mechanism of action, rebalancing agents are not specific to deficiencies in factor VIII or factor IX, and could have beneficial effects in other coagulation factor deficiencies. However, FII and FV are situated at the end of the coagulation cascade, rendering these deficiencies more resistant to upstream inhibition of anticoagulants (Figure 1). Therefore, TFPI inhibitors, which target a more proximal anticoagulant, are expected to have less effect than fitusiran, which releases the brakes on both factor X and FII. Supporting this hypothesis, marstacimab increased thrombin generation ex vivo in plasma of patients with factor XI deficiency, but not in FV-deficient plasma [7]. Furthermore, patients with severe FV deficiency have lower levels of TFPI [8], which already rebalances the bleeding phenotype to some extent. Similarly, VGA039, which targets protein S, the cofactor for inhibition of FV and factor VIII, did not increase thrombin generation in FV-deficient plasma [9]. In contrast, in silico modelling predicted an increase in thrombin generation in FV deficiency when antithrombin levels were lowered to 20% [10], suggesting that fitusiran may be more promising than TFPI or protein S inhibitors in this setting. Whether fitusiran may increase thrombin generation in patients with FV deficiency remains to be established though. In severe FII deficiency however, the substrate for thrombin generation is itself depleted, limiting the potential benefit of rebalancing agents. For FV deficiency in particular, non-replacement therapies are needed to overcome the issue of FV's short half-life (Table 1). However, caution is needed when using these agents, because of their inherent thrombotic risk [11], which has been observed in clinical trials in haemophilia. The review by Pasca et al. makes the therapeutic gap in FII and FV deficiency impossible to ignore. First, regulatory authorities should accelerate the market access of specific factor concentrates considering the low number of patients affected, making these diseases a healthcare priority. Second, we urge pharmaceutical companies to incorporate these ultrarare inherited bleeding disorders in their development programs. In particular, we encourage the inclusion of patients with rare coagulation deficiencies in clinical trials with rebalancing agents. Finally, registries play a pivotal role in collecting systematic outcome data to acquire more evidence on these ultrarare disorders. Establishing a dedicated European registry may be a step in the right direction. In summary, the current possibilities in haemophilia, including innovative subcutaneous treatments and gene therapy, are in stark contrast to the use of decades-old plasma products in patients with FII and FV deficiency. After transforming the lives of people with haemophilia, it is time for the haemostasis community to remember the forgotten steps in the coagulation cascade. Both authors are members of ERN-EuroBloodNet. Artificial intelligence (Claude, Anthropic) was used for linguistic editing of the submitted manuscript. The authors have nothing to report. Quentin Van Thillo has received consultancy fees from Pfizer and Roche, research support from Octapharma, Roche, CSL Behring, and travel support from CSL Behring. CH has obtained consultancy fees from Pfizer, Bayer, Shire, Novo Nordisk, CSL Behring, Octapharma, Sobi Biogen, LFB, CAF-DCF, and Roche; Cedric Hermans has been invited to give guest lectures at different conferences by Pfizer, Bayer, Shire, Novo Nordisk, CSL Behring, Octapharma, Sobi Biogen, LFB, CAF-DCF, Roche; and Kedrion.