Unveiling the Great Therapeutic Potential of MASPs as Hemostatic Agents.

Abstract

The lectin complement pathway (LP) is an important effector arm of innate immunity and exemplary pattern recognition artist that draws a fine line between friend and foe (host defense) and between innocuous and noxious (homeostasis). Intriguingly, the proteolytic activity of the LP is attributed to proteolytic enzymes, called mannan-binding lectin (MBL)-associated serine proteases (MASPs). MASPs are central components of the LP that resemble the serine proteases, C1r and C1s, of the classical complement pathway (CP). Recently, the MASPs’ important role in the coagulation cascade was unmasked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [1-6]. MASPs (mainly MASP-1) are actually key elements that connect both complement and coagulation systems [7]. So far, research into complement-coagulation interactions focusing merely on MASP inhibition had offered promising targets for novel preventive and therapeutic strategies [8]. Conversely, here I propose that the fibrinolytic activity of MASPs can be explored in the management of bleeding disorders. In particular, traumatic and surgical bleeding are life-threating but potentially avoidable causes of death [9, 10]. Johnston et al showed that postsurgical bleeding is associated with substantial increases in postprocedural length of stay, days spent in critical care, and the risks of infection, vascular events, acute renal failure, and in-hospital mortality [11]. In addition, use of anticoagulants and antiplatelets increases the surgical bleeding risk, creates a need for multiple pharmacologic approaches and poses potential problems in managing surgical patients [1215]. On the other hand, approximately one-third of all trauma patients with bleeding present with a coagulopathy on hospital admission [16, 17]. This subset of patients has a significantly increased incidence of multiple organ failure and death compared to patients with similar injury patterns in the absence of a coagulopathy [18]. Coagulopathy frequently occurs early in the postinjury period and is an independent predictor of mortality. Compared to patients whose initial prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal, trauma patients have 35% and 326% increased risk of mortality when their initial PT and aPTT are abnormal, respectively [19]. It is important to emphasize that trauma-induced coagulopathy, also called acute traumatic coagulopathy, is distinct from massive transfusion coagulopathy that occurs in the context of loss and dilution coagulopathy [20, 21] or disseminated intravascular coagulation [22]. Hitherto, measures to reduce intraoperative blood loss have been limited to enhancement of coagulation by recombinant activated coagulation factor VII (rFVIIa), desmopressin, fibrinogen, prothrombin complex concentrates, inhibition of fibrinolysis comprising lysine analogues (tranexamic acid and epsilon aminocaproic acid) and a broad-spectrum serine protease inhibitor (aprotinin) in order to avoid or minimize the need for blood transfusions, which is directly proportional to perioperative complications and mortality [23]. Moreover, since FXa is at a critical point of the coagulation cascade (FXa is the trypsin-like proteinase of coagulation that catalyses prothrombin activation) [24], several pharmacological strategies have been developed to modulate its function [25]. These endeavours paved the way for a new era of non-vitamin K oral anticoagulants that not only produce more predictable/less labile anticoagulant effect than oral vitamin K antagonists (such as warfarin), but are also equally safe and effective [26]. These non-vitamin K oral anticoagulants have been termed direct oral anticoagulants that include the factor Xa inhibitors (i.e., rivaroxaban, apixaban, edoxaban, and betrixaban) and direct thrombin inhibitors (i.e., dabigatran) [27]. Contrarily, harnessing FXa for its procoagulant effect in the context of prothrombin activation can prove challenging due to two main factors. Firstly, the ability of Xa to activate prothrombin (FII) is markedly low without its activated cofactor, FVa. Actually, the catalytic efficiency of FXa activation of prothrombin increases by 100,000-fold when FXa incorporates into the prothrombinase complex, a composition of phospholipids, Ca2+, FVa cofactor and FXa, which cleaves prothrombin at Arg271 and Arg320 [28]. To put it simply, the prothrombinase complex is essential for hemostasis as it is the only physiologic producer of thrombin [29]. Secondly, despite its negligible contribution to the catalytic process, the membrane surface is obligately required. Normally, the prothrombinase complex is physiologically assembled on phospholipid membranes at the site of tissue damage; the most relevant of which is the activated platelet surface [30]. The membrane surface provides an environment in which both the FVa/FXa complex and prothrombin (the prothrombinase substrate) can co-concentrate. Activated platelets also provide FVa, the essential nonenzymatic cofactor of the Manuscript submitted September 22, 2022, accepted October 31, 2022 Published online December 1, 2022