Understanding Anticoagulation

What is coagulation, and what are anticoagulants used for?

Blood clotting is a central process in healing, enabling limitation of blood loss following damage to the vasculature.1 In normal physiology, however, blood flow needs to remain fluid, i.e. blood clotting should be controlled. The regulation of coagulation is ensured by various endogenous proteins and enzymes, which either promote or inhibit coagulation. The balance production of pro- and anti-coagulant factors is shifted in a vascular injury to induce coagulation in a process called hemostasis.1 However, coagulation can also occur in the lumen of a blood vessel in the absence of injury. This process, called thrombosis, leads to the formation of clots that might disrupt the bloodstream, causing conditions like deep vein thrombosis (DVT) or pulmonary embolism (PE).1

Blood clotting can be induced via two pathways: the tissue factor pathway, and the contact pathway. Though they involve different factors and enzymes, both trigger the conversion of the coagulant factor prothrombin to its active form thrombin. This induces the polymerisation of the protein fibrin to form a mesh that retains erythrocytes, and leads to the agglomeration of platelets – this forms the blood clot.2

Various genetic defects have been associated with over-clotting; specifically, those affecting enzymes and factors involved in the coagulation process. One notable example is the G20210A mutation of the prothrombin gene, which results in its overexpression, leading to excess clotting.3 Other risk factors commonly associated with excess coagulation are age, and comorbid conditions like obesity or cancer. However, many thromboses, especially among young people, are idiopathic, (i.e. not explained).3

Anticoagulants, commonly called blood thinners, are medicines that help reduce blood clotting. Today, in the USA, more than eight million people take routine anticoagulants to treat or prevent thromboses.2 As opposed to antiplatelet drugs that solely focus on preventing platelet aggregation, anticoagulants’ action is more diverse, preventing thrombus formation. Since the discovery of heparin in 1916, numerous anticoagulant drugs, targeting diverse proteins and aspects of the blood clotting process, have been developed and are increasingly used in practice.

Classes of anticoagulants and their mechanisms

Each class of anticoagulant has its own way of bringing about a blood-thinning effect by intervening in the clotting cascade.4 We can sort anticoagulants into general categories based on where and how this intervention occurs. Even within these groups, however, there is variation in the mode of action.

Heparins are a widely used anticoagulant class based on Unfractionated Heparin (UFH), a molecule consisting of an alternating chain of amino and uronic sugars produced in the mast cells of mammals.5 Heparins work by binding to an enzyme called Antithrombin III (AT-III), inducing a conformational change. The AT-III then sets to work inactivating Thrombin, Factor Xa and Factor IXa, which are important enzymes in the coagulation cascade.6

Vitamin K antagonists (VKA, also called couramins) are anticoagulants that target Vitamin K, which is critical in the production of blood clotting proteins, such as thrombin. Vitamin K is modified in this process and an enzyme called vitamin K epoxide reductase reverts it to its original form, ready to be used again. Vitamin K antagonists do not act on Vitamin K directly, but obstruct the action of the epoxide reductase, impeding the recycling of Vitamin K. In this way, the production of clotting proteins is impaired.7

A particularly important step in the clotting cascade is the cleaving of prothrombin into thrombin. Thrombin is involved in the activation of Factors V, VIII, and XI (which in turn contribute to the generation of more thrombin) and acts to stimulate platelets. Most importantly, thrombin converts fibrinogen into fibrin – a long, sticky protein that meshes platelets together to form a clot and helps indirectly to stabilize fibrin crosslinks in a clot. The cleaving of prothrombin is carried out by Factor Xa, either on its own or more efficiently as part of the prothrombinase protein complex. Factor Xa inhibitors intervene at this crucial step in the cascade, ultimately impeding the formation of fibrin.8

Thrombin has two main sites crucial to its function that are targeted by inhibitors: the active site, and exosite 1. The active site is the region on the protein where the controlled conversion of fibrinogen to fibrin takes place. With an inhibitor bound to the active site, the protein is disabled.9 Once an inhibitor binds to exosite 1, it becomes much more difficult for thrombin to capture fibrinogen molecules, impeding the formation of fibrin.10 Inhibitors can also act in other ways to interfere with the action of Factor Xa. One synthetic agent, Fondaparinux, for example, promotes the sequestering of Factor Xa by a protein called antithrombin.5

As such, thrombin inhibitors hamper the action of a critical clotting protein essential for the conversion of fibrinogen to fibrin, and so impair the formation of blood clots.

Current research and future directions

Heparins and VKAs have traditionally been the main treatments for PE. However, the use of these agents can be complex, and they are often associated with an increased risk of major and potentially life-threatening bleeding – a common characteristic amongst all anticoagulants.11 Multiple clinical trials have, and are, being performed in the field of thromboembolism to determine the safety and efficacy of new medications and provide patients with more and better treatment options.

One such study, the randomized, double-blind trial PADIS-PE investigated the optimal duration of anticoagulation after the first episode of an unprovoked PE and the benefits and harms of an additional coagulant as a form of treatment for PE.12 In this study, patients who had experienced episodes of symptomatic unprovoked PE were given VKA for 6 uninterrupted months, then randomized to receive an additional 18-month course of VKA or placebo. Results showed that patients randomized to an additional 18 months of treatment had reduced rates of PE/DVT during those 18 months, though this effect was not sustained after discontinuation of anticoagulation.12

Another study, STOP-APE, is investigating whether anticoagulation is necessary following an isolated or incidental subsegmental PE for preventing recurrent VTE.13 Subjects will be randomized to either receive at least three months of standard anticoagulation or no coagulation.13

These are only some examples of the many clinical trials relating to PE across the globe. Despite the efforts of clinical researchers and medical teams to resolve fundamental issues about anticoagulation in PE, numerous key questions remain unanswered. Future research will continue to answer these questions to improve patient care and therapy for PE.


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