Thrombosis is the formation of a blood clot (partial or complete blockage) within blood vessels, whether venous or arterial, limiting the natural flow of blood and resulting in clinical sequela.

Anticoagulants prevent or inhibit the clotting process by affecting one or more clotting factors in the blood, and are therefore used for the prevention and treatment of endovascular embolization or thrombosis, as well as for the prevention of stroke or other thrombotic disorders.  

Figure 1. Thrombosis

Classification of Anticoagulants and Representative Drugs

Based on their mechanism of action, anticoagulants can be categorized into four types: Vitamin K antagonists (VKA), indirect thrombin inhibitors, direct thrombin inhibitors and factor Xa inhibitors.

Vitamin K Antagonists (VKA)

Vitamin K antagonists are drugs that prevent the gamma-carboxylation of the vitamin K-dependent coagulation factors II, VII, IX and X, as well as the naturally occurring anticoagulants Protein C and Protein S.

Warfarin (Coumadin)

Warfarin consists of a racemic mixture of two active enantiomers: R and S forms. By inhibiting the vitamin K epoxide reductase (VKOR) enzyme, Warfarin limits the conversion of oxidized vitamin K to reduced vitamin K, an essential cofactor in the carboxylation of coagulation factors, hence rendering coagulation factor molecules physiologically inactive.

Warfarin has the advantages of long duration of action, easy to take, relatively few adverse effects, low price, etc. It has an irreplaceable position in oral anticoagulation therapy, especially in valvular atrial fibrillation and after mechanical valve replacement. However, warfarin has a narrow therapeutic window, large individual differences, and many interactions with other drugs and food, etc., and requires a lot of attention during daily use.

Indirect Thrombin Inhibitors

Indirect thrombin inhibitors, are drugs that indirectly inhibit thrombin by enhancing antithrombin (AT) activity. Antithrombin (AT) is a natural inhibitor of thrombin and other clotting factors.

Heparins

Heparin is a group of polysaccharides that bind to AT and accelerate its inhibition of thrombin and factor Xa. There are three common and commercially available anticoagulant heparins: unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and ultralow-molecular-weight heparin (ULMWH). 

UFH is a heterogeneous mixture of heparin chains with different molecular weights, ranging from 3,000 to 30,000 Da. UFH inhibits thrombin and factor Xa, but requires a cofactor, heparin cofactor II (HCII), to act on thrombin. UFH has a short half-life of about 1.5 hours, which can be reversed by protamine sulfate. UFH is indicated for the prophylaxis and treatment of venous thromboembolism (VTE), acute coronary syndrome (ACS), and extracorporeal circulation during cardiac surgery.

LMWH has a small molecular weight, ranging from 2,000 to 10,000 Da.LMWH has a higher affinity for factor Xa than for thrombin and does not require HCII for its action on thrombin. LMWH has a long half-life of about 4 hours, which is partially reversed by protamine sulfate. LMWH is used for the prevention and treatment of VTE, ACS, and atrial fibrillation (AF).

ULMWH has a much smaller molecular weight, ranging from 1000 to 3000 Da.ULMWH has a very high affinity for factor Xa and has little or no effect on thrombin. ULMWH has a very long half-life of approximately 12 hours and cannot be reversed by protamine sulfate. ULMWH is indicated for the prophylaxis of VTE in orthopedic surgery.

Heparin has the advantage of a rapid onset of action, a broad therapeutic range, and a low risk of immunogenicity. However, heparin has an unstable anticoagulant response, a high risk of bleeding, and the possible complication of heparin-induced thrombocytopenia (HIT), an immune-mediated adverse reaction that can cause platelet activation and paradoxical thrombosis.

Direct Thrombin Inhibitors

Direct thrombin inhibitors are drugs that bind directly to the active site of thrombin and block its interaction with the substrate. Direct thrombin inhibitors can be categorized into parenteral and oral medications.

Bivalirudin

Bivalirudin is a synthetic peptide that mimics the structure of hirudin, a natural anticoagulant extracted from the saliva of leeches.

Bivalirudin reversibly binds to and inhibits the activity of free thrombin and clot-binding thrombin. Bivalirudin has a short half-life of approximately 25 minutes and is cleared by proteolysis or renal excretion. There is no specific antidote for bivalirudin, but its effects can be reduced by hemodialysis or blood transfusion in cases of bleeding or overdose.

Bivalirudin is indicated for the prevention and treatment of thrombosis in patients undergoing percutaneous coronary intervention (PCI), especially in patients with HIT or at high risk of bleeding. Bivalirudin has a rapid onset of action, rapid offset of effects, predictable anticoagulant response, and low immunogenicity and risk of HIT (heparin-induced thrombocytopenia). However, bivalirudin requires intravenous administration, continuous infusion, and frequent monitoring.。

Dabigatran 

Dabigatran etexilate is a prodrug that is orally absorbed and completely converted to the active form dabigatran by carboxylesterases.

Dabigatran etexilate is administered orally and has a delayed onset of action, taking approximately 2 hours to reach peak blood concentrations.Dabigatran etexilate has a variable anticoagulant response as it is influenced by factors such as renal function, age, body weight, and drug-drug interactions.Dabigatran etexilate has a very long half-life of about 12 hours and is cleared by renal excretion or p-glycoprotein excretion.

Dabigatran etexilate is indicated for the prevention and treatment of thromboembolic events in patients with VTE, AF stroke, and mechanical heart valves.Dabigatran etexilate is orally available, has high bioavailability, a broad therapeutic range, and a low risk of bleeding and drug interactions. However, Dabigatran etexilate has a high cost, poor compliance, and potential complications of dyspepsia.

Factor Xa Inhibitors

Factor Xa is the key enzyme that converts plasminogen to thrombin, both in the extrinsic and intrinsic pathways.Factor Xa inhibitors can be categorized into parenteral and oral medications.

Enoxaparine

Enoxaparin is a low molecular weight heparin that binds to AT and accelerates its inhibition of factor Xa. Enoxaparin has a higher affinity for factor Xa than for thrombin, and its action on thrombin does not require HCII. Enoxaparin is administered subcutaneously, and its effect is monitored by an anti-factor Xa activity test. Enoxaparin has a long half-life of approximately 4 hours, which can be partially reversed by protamine sulfate. Enoxaparin is indicated for the prevention and treatment of VTE, ACS, and AF.

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor that reversibly binds to the active site of factor Xa and inhibits its activity. Rivaroxaban is administered orally and has a rapid onset of action, with peak blood levels reached within approximately 2 to 4 hours. Rivaroxaban has a variable anticoagulant response as it is influenced by factors such as renal function, hepatic function, age, body weight and drug interactions. Rivaroxaban has a moderate half-life of approximately 5 ~ 9 hours and is cleared by renal excretion or hepatic metabolism. Rivaroxaban can be reversed by anddexanet alfa, an antidote that binds to rivaroxaban with high affinity and displaces it from factor Xa.

Apixaban 

Apixaban is a direct factor Xa inhibitor that reversibly binds to the active site of factor Xa and inhibits its activity. Apixaban is administered orally and has a delayed onset of action, taking approximately 3 ~ 4 hours to reach peak blood levels. Apixaban also has a variable anticoagulant response as it is influenced by factors such as renal function, liver function, age, body weight and drug interactions. Apixaban has a long half-life of approximately 12 hours and is cleared by renal excretion or hepatic metabolism. Apixaban can also be reversed by andexanet alfa, an antidote that binds apixaban with high affinity and displaces it from factor Xa.

Edoxaban 

Edoxaban is a direct factor Xa inhibitor that reversibly binds to the active site of factor Xa and inhibits its activity. Edoxaban is administered orally and has a rapid onset of action, with peak blood concentrations reached in approximately 1 ~ 2 hours. Edoxaban has a variable anticoagulant response because it is affected by renal function, liver function, age, weight and other factors. Edoxaban has a long half-life of about 10 ~ 14 hours and is cleared by renal excretion or hepatic metabolism. Edoxaban can be reversed by anddexanet alfa, an antidote that binds edoxaban with high affinity and displaces it from factor Xa.

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Fondaparinux

Fondaparinux is an indirect factor Xa inhibitor that binds to AT and accelerates its inhibition of factor Xa. Fondaparinux is a synthetic pentasaccharide that mimics the structure of the heparin-binding site. Fondaparinux has a very high affinity for factor Xa and has little or no effect on thrombin. Fondaparinux is administered subcutaneously, has a very long half-life of about 17 hours, and is cleared by renal excretion.There is no specific antidote for Fondaparinux, but its effect can be reduced by blood transfusion in the case of bleeding or overdose.

Novel Anticoagulants in Clinical Trials

Novel anticoagulants in clinical trials are mainly factor XI inhibitors.Factor XI inhibitors can be categorized into monoclonal antibodies and small molecule compounds.

Small molecule inhibitors

Milvexian (BMS-986177/JNJ-70033093), co-developed by Bristol-Myers Squibb and Johnson & Johnson, is currently in a Phase 3 trial for the prevention of venous thromboembolism (VTE) in patients undergoing knee arthroplasty, as well as a Phase 2 trial for the secondary prevention of ischemic stroke .

Asundexian (BAY 2433334), developed by Bayer, is currently in a Phase 3 trial for stroke and systemic embolism prevention in patients with atrial fibrillation.

SHR2285, a small molecule factor XI inhibitor developed by Jiangsu Hengrui Medicine Co., Ltd, is currently undergoing a phase 2 clinical trial for venous thromboembolism prophylaxis after arthroplasty in adult patients.SHR2285 is the first factor XI inhibitor to enter a clinical trial in China.

Large molecule mAb inhibitors

Osocimab (BAY 1213790), developed by Bayer, is currently in a Phase 3 trial for the prevention of VTE in patients undergoing knee arthroplasty.

Abelacimab (MAA868), developed by Anthos Therapeutics, is currently in a Phase 2 trial for the prevention of VTE, as well as cancer-associated blood clots, in patients undergoing knee arthroplasty.

Xisomab 3G3 (AB023), developed by Arctic Vision Biotechnology, is currently in a Phase 2 trial for the prevention of coagulation events in dialysis access in patients with end-stage renal disease undergoing hemodialysis.

MK-2060, developed by Merck Sharp & Dohme, is currently in Phase 1 and Phase 2 trials for the prophylaxis of coagulation events in the dialysis access for patients with end-stage renal disease undergoing hemodialysis.MK-2060 is a monoclonal antibody with a novel dual activity of inhibiting coagulation factors XI and XIa.