Thrombotic diseases are caused by two pathological processes: thrombosis and thromboembolism, and are mainly manifested as venous thromboembolism (VTE), myocardial infarction, and ischemic stroke. Deaths caused by thrombotic diseases account for about 4% of global mortality, posing a great burden of public health (1). The elderly become the high-risk population of thrombotic diseases due to the changes of lifestyle and pathophysiological characteristics of the body. The main changes of physiological factors in the elderly are as follows: (1) the different degrees of endothelial damage and vascular sclerosis; (2) increased platelet aggregation; (3) increased blood viscosity; (4) hypercoagulation and increased coagulation factors (2). In addition, the risk factors of thromboembolism such as atrial fibrillation, malignancy, total knee arthroplasty, atherosclerosis, ischemic stroke, end-stage renal disease, and long-term bedridden are more common in the elderly. Therefore, The elderly are the key population in the prevention and treatment of thrombotic diseases.

Anticoagulant therapy is an important cornerstone for the prevention and treatment of thrombotic diseases. Traditional oral anticoagulants have commonly used in clinical practice, such as warfarin, which has good antithrombotic efficacy. But the dose-effect relationship of warfarin is affected by many factors. Close monitoring of international normalized ratio (INR) is necessary during warfarin treatment. Even if INR is maintained within the therapeutic range, there is still a high risk of intracranial hemorrhage (3–5). In recent years, the direct oral anticoagulants (DOACs) such as rivaroxaban, apixaban and dabigatran etexilate have better safety and efficacy than warfarin (6–9). However, bleeding was still considered an inevitable side effect of DOACs therapy, with the most common sites being the gastrointestinal and urinary tract (10–13). Due to the deterioration of physical functions, the elderly are not only with high risk of thrombosis, but also with high risk of bleeding during anticoagulant treatment. The high risk of bleeding limits the intensity of anticoagulant therapy tolerated by patients, leading to inadequate anticoagulation therapy, which increases the incidence of thromboembolic events. Therefore, it is of great clinical value to find a therapeutic target that effectively reduces thrombosis without increasing bleeding risk.

Epidemiological and numerous research data have shown that factor Ⅺ plays an important role in thrombosis, but little role in physiological hemostasis (14, 15). Therefore, factor Ⅺ has become an emerging and popular target for the development of new anticoagulants. The existing phase Ⅰ and phase Ⅱ clinical trial data indicated that compared with DOACs, factor Ⅺ inhibitors could be more effective to reduce the incidence of thromboembolic events without increasing the risk of bleeding (16). Therefore, factor Ⅺ inhibitors have significant potential value in the prevention and treatment of thrombotic diseases. In this review, we summarize the biological functions of factor Ⅺ, and the types and clinical research progress of factor Ⅺ inhibitors.

In the last decade, DOACs have been regarded as the optimal choice therpy for the prevention of thromboembolic events. It has been shown that DOACs were at least as effective as heparins and warfarin for preventing stroke and VTE, associated with lower rates of intracranial bleeding (45, 46). However, DOACs also have some limitations including: causing a high risk of bleeding, mainly gastrointestinal (46); areas where no clinical benefit was reported, such as the prevention of stroke in patients with mechanical heart valves (47), rheumatic heart disease-associated AF (48), transcatheter aortic valve implantation (49), the VTE prevention in patients with antiphospholipid antibody syndrome (50); no available data of DOACs in specific areas (e.g., kidney failure, thrombocytopenia, hypohepatia and extremes of body weight) (51, 52).

In recent years, factor Ⅺ has been an attractive target to explore the advantages of anticoagulation in specific clinical settings and overcome the limitations of the DOACs. Given the biological functions, targeting inhibition of factor Ⅺ can uncouple thrombosis from hemostasis and block the activation of the contact pathway in the process of thrombogenesis. The repression of factor Ⅺ seems to be rational in cases when thrombosis is triggered by artificial surfaces exposed to blood (e.g., haemodialysis circuits, mechanical valves, catheters, and cardiopulmonary bypass). At present, the research and development of factor Ⅺ inhibitors has been vigorously carried out, and a variety of factor Ⅺ inhibitors have entered the clinical trial stage (Table 2). A number of phase Ⅰ and phase Ⅱ clinical studies have indicated that factor Ⅺ inhibitors were more effective than DOACs for the prevention of VTE in patients with TKA and the improvement of dialyzer clotting in those with ESRD requiring long-term hemodialysis, without a significant increase in bleeding events (32, 34, 36, 38, 40). The safety of factor Ⅺ inhibitors compared with DOACs in AF patients has been researched (42), however, the differences in efficacy have not been studied. Among the factor Ⅺ inhibitors, abelacimab and asundexian have entered phase III clinical trails and have the potential to become novel safe and effective anticoagulants.

Moreover, the fact is that the average age of subjects was greater than 65 years in multiple studies involved in patients with TKA, AF, and acute noncardiac ischemic stroke (32, 34, 36, 40, 42, 43). Those studies have consistently shown that the efficacy of factor Ⅺ inhibitors was better than and without no increase in bleeding risk. Therefore, we can conclude that the factor Ⅺ inhibitors may be a promising anticoagulants in the treatment of thrombotic diseases in the elderly patients.

Current factor Ⅺ inhibitors have varieties of advantages and limitations. Both ASOs and monoclonal antibodies have long half-lives, infrequent dosing, and stable efficacy, making them suitable for the prevention of cancer-associated thrombosis. However, these drugs may require the development of antidotes and reversal strategies. At present, there are potential difficulties in antagonising these drugs: the administration of factor Ⅺ concentrates can be thrombogenic, and prothrombin complex concentrates may not be sufficiently effective (53). ASOs take approximately 1 month to reach therapeutic levels and are therefore not suitable for acute situations. Among monoclonal antibodies, AB023 is an exception because of its short half-life and thus the potential for use in the periinterventional period, such as in the setting with indwelling catheter or extracorporeal circuit. ASOs and monoclonal antibodies are not metabolized by the kidney and therefore may be more suitable for patients with renal insufficiency. In addtion, the metabolism of small molecules depend on the liver, mainly interacted with cytochrome P450 3A4, thus, there may be potential drug-drug interactions (54).

Given the success of DOACs, factor XI inhibitors face a formidable challenge. there are some areas remaining to explore the safty and efficacy of factor XI inhibitors where DOACs have failed or where were not evaluated, such as stroke prevention in patients with mechanical prosthetic valves, rheumatic valve disease and TAVI, VTE treatment in patients with antiphospholipid antibody syndrome. Moreover, the effect of factor Ⅺ inhibitors in the setting of coronary thrombosis has not been elucidated (55). Ultimately, as with any new drug, the safety concerns may arise and have to be addressed. The long-term safety and effective antidotes of factor Ⅺ inhibitors need to be further investigated. In addition, the optimal dosage and safety profile in older populations remain to be established through ongoing and future large-scale phase III trials.