Human plasma‐derived concentrates: preventing thrombosis and controlling haemorrhage

The use of human plasma-derived products to prevent thrombosis and control haemorrhage exemplifies the delicate balance between clotting and bleeding. Plasma-derived antithrombin (pdAT) concentrates are indicated for the treatment of venous thromboembolism (VTE) associated with congenital antithrombin (AT) deficiency. Prothrombin complex concentrates (PCCs), on the other hand, are primarily used in clinical practice today to reverse anticoagulation [1]. Antithrombin is a natural anticoagulant that inhibits serine proteases, notably thrombin and activated factor X, in the coagulation cascade [2]. Inherited AT deficiency is an uncommon autosomal dominant disorder with a prevalence of 1:2000–1:3000 [3]. Most cases are heterozygous (homozygosity is usually fatal in utero [4]), and affected individuals have a 50–70% lifetime risk of VTE [5, 6]. While thrombosis is uncommon during the first two decades of life, by age 50 years, approximately half of all individuals with AT deficiency will have experienced a thrombotic event [7-9]. Primary prophylaxis with anticoagulant therapy is not recommended for asymptomatic individuals with AT deficiency because the risk of serious or fatal bleeding outweighs the risk of a fatal VTE [10]. Short-term thromboprophylaxis is essential during periods of transient risk, such as surgery, trauma or immobilization, as 42% of VTE episodes associated with AT deficiency occur these settings [10]. Unfractionated heparin or low-molecular-weight heparin is typically used for anticoagulation followed by an oral vitamin K antagonist (e.g. warfarin) [4]. Some patients with very low AT levels may be resistant to heparin therapy and require higher doses of heparin or treatment with fondaparinux [11]. Alternatively AT concentrates may be used to normalize AT levels and decrease the risk of thrombosis. Case reports suggest that AT concentrates are useful for surgical procedures with a high VTE risk when anticoagulation prophylaxis cannot be given because of the potential for serious bleeding [12-14]. AT concentrates may also be appropriate for: (i) patients undergoing operations associated with a high rate of VTE despite prophylaxis with heparin or fondaparinux, such as total knee and hip replacement, and (ii) those with clinically symptomatic VTE. In addition, to pdAT, a recombinant human AT (rhAT) has been available for clinical use in Europe since 2006 and subsequently received US approval. This product, which is produced in the milk of transgenic goats, differs from pdAT in terms of its glycosylation pattern, which results in a 4-fold greater heparin-binding affinity for rhAT [2, 11]. pdAT and rhAT also differ in terms of their half-lives [11]. Studies in healthy volunteers [15] and in patients undergoing cardiopulmonary bypass [12] have shown that the half-life of rhAT is 10.5 h compared with approximately 60 h for pdAT. Thus, depending on the clinical situation, rhAT may require more frequent dosing than pdAT. It is difficult to establish the appropriate dose of the oral anticoagulant warfarin, the most commonly used coumarin derivative in North America and the United Kingdom [16, 17], because dosing can vary by a factor of 10 among patients [18]. Over-anticoagulation can lead to major or life-threatening bleeding, in particular intracerebral haemorrhage (ICH). An estimated 14–20% of all spontaneous ICHs are related to the use of oral anticoagulants [19, 20], and mortality rates for anticoagulation-associated ICH (AAICH) are as high as 67% [21, 22]. Moreover, the number of new cases of AAICH is increasing. In the period from 1989 to 1999, the annual incidence per 100 000 persons more than quadrupled from 0.8 to 4.4, with this growth chiefly attributable to increasing warfarin use for the prevention of stroke and myocardial infarction in an ageing population [23]. Patients presenting with AAICH require complete and rapid warfarin reversal to reduce the risk of haematoma expansion, an independent determinant of morbidity and mortality [24], and allow emergency surgery [17, 25]. Current practice is to administer vitamin K concomitantly with fresh frozen plasma (FFP) or PCCs to replace exogenous factors II, VII, IX and X [26]. FFP is widely available, allows partial reversal of the coagulopathy, [27] and is considered the general standard of care in the United States. However, there are significant number of drawbacks to its use, including the need for compatibility testing and thawing and the potential for infectious transmission [28]. The intravenous infusion of large volumes is a slow process and frequently leads to pulmonary complication, especially for patients with marginal cardiac function [28-30]. Furthermore, in patients with very high international normalized ratios (INRs) who have profound decreases in vitamin K-dependent factors, replacement of haemostatic levels of these factors cannot be achieved with tolerable FFP doses [28-30]. Prothrombin complex concentrates provide a rapid, effective and specific method for replacing deficient clotting factors and correcting INR and may require significantly smaller volumes compared with FFP [29, 31]. The first successful use of PCCs to reverse over-anticoagulation was described in 1976 [32], and numerous reports from other investigators have followed. Consequently, PCCs have become the preferred agents for warfarin reversal in some centres [16, 17, 33]. A recent review of the published literature over the last 30 years found these agents to be superior to FFP for urgent reversal of warfarin-induced coagulopathy and to have a low risk of thrombotic events [28]. Several PCCs are variably marketed in Europe, Australia and Japan, but only 1 product is still available in the United States (Profilnine® SD; Grifols Biologicals Inc, Los Angeles, CA, USA). Whether a recombinant equivalent will be developed and its impact on clinical care are unknown. Novel oral anticoagulants, specifically oral direct thrombin inhibitors (DTIs) and oral factor Xa (FXa) inhibitors, are in advanced stages of development. Within the next few months, at least one of these investigational drugs is expected to be approved for use in the United States [34]. DTIs and oral FXa inhibitors have predictable pharmacokinetic and pharmacodynamic parameters and will not require the routine monitoring necessary with warfarin. Nonetheless, the experience with the oral DTI ximelagatran, which was withdrawn from the market in 2006 because of concerns about severe liver toxicity and the potential for rebound hypercoagulability, underscores the need for long-term safety data once these drugs reach the market. Thus, the use of warfarin will persist for the foreseeable future, and the need for PCCs to reverse warfarin-induced coagulopathy will continue. The role of AT replacement therapy in patients with congenital AT deficiency cannot be evaluated in large randomized clinical trials because of the rarity of the condition and the ethical questions posed by the use of alternatives to AT concentrates in surgical and other high-risk patients. Such trials are necessary, however, to determine the optimal management of patients with AAICH. The authors stated that they had no interests which might be perceived as posing a conflict or bias.