Blood clot disorders are estimated to cause 1 in 4 deaths. Blood clots are associated with pulmonary embolism, most cases of heart attack and stroke, and are a major cause of morbidity and mortality in the US. Anticoagulation therapy is the foundation for the prevention and treatment of blood clots. For many years, warfarin, or Vitamin K antagonist, was the only oral blood thinner available. It is usually effective but needs periodic monitoring (INR) to ensure levels are in the desired range and there are some dietary restrictions. If the INR is too low, there is an increased risk of forming a blood clot. If the INR is too high, there is an increased risk of bleeding. The most feared complication is an intracranial bleed which is 10-fold higher in patients taking warfarin, even if their INR is within the therapeutic range. There is a need for better and safer anticoagulants.
What is factor XI? Decoding the coagulation cascade :
Before talking about factor XI, let’s discuss why and how blood clots form. Blood clotting, also known as coagulation, is a complex physiological process that helps control bleeding when a blood vessel is damaged. It involves a series of interactions among various components in the blood to form a clot, which prevents excessive blood loss. The process of blood clotting or hemostasis can be summarized in the following steps:
- When a blood vessel is injured, it constricts or narrows to reduce blood flow to the site of injury. This constriction helps in slowing down the blood flow and limiting blood loss.
- Platelet Activation: Platelets are small, disc-shaped cell fragments present in the blood. They play a crucial role in clot formation. When a blood vessel is damaged, platelets adhere to the site of injury and become activated. This activation causes the platelets to change shape, release chemical signals, and stick to one another, forming a platelet plug.
- Formation of Fibrin: The activated platelets trigger a cascade of chemical reactions known as the coagulation cascade. This cascade involves the activation of several clotting factors, which ultimately convert a protein called fibrinogen into fibrin. Fibrin forms a mesh-like network that reinforces the platelet plug and traps red blood cells, creating a stable blood clot.
- Clotting Factor Activation: The coagulation cascade involves a series of enzymatic reactions that rely on various clotting factors, which are proteins present in the blood. These factors work sequentially, activating one another in a cascade. The cascade is triggered by the release of certain substances at the site of injury, such as tissue factors. Activated clotting factors VII, X, V, and II (thrombin) promote the conversion of fibrinogen to fibrin. Factors VIII and IX amplify the process, while factor XI helps consolidate the clot. Except for bleeding in the oropharynx or urinary tract area, the role of factor XI in hemostasis is minimal
When is blood clotting abnormal?
Blood clotting is considered abnormal or problematic when it occurs inappropriately or excessively, leading to various health complications. Here are a few scenarios where blood clotting is considered abnormal:
- Thrombosis: Thrombosis refers to the formation of a blood clot within a blood vessel, obstructing the normal blood flow. It can occur in both arteries and veins. Deep vein thrombosis (DVT) is a common form of venous thrombosis, where a clot forms in the deep veins of the legs. Abnormal clotting can occur due to factors like immobility, injury to blood vessels, or underlying medical conditions such as clotting disorders. When a blood clot breaks free from its original location, usually a deep vein in the leg (DVT), and travels to the lungs, blocking the blood vessels there. This is called a pulmonary embolism or “killer clot”. It can cause chest pain, and shortness of breath, and, in severe cases, can be life-threatening.
- Arterial thrombosis can lead to conditions such as heart attack or stroke. The rupture or erosion of the atherosclerotic plaque in the coronary or cerebral artery triggers platelet activation and exposes tissue factor, which initiates the coagulation cascade and leads to thrombin generation and fibrin formation. A crucial step in the amplification of thrombin generation is the feedback activation of factor XI by thrombin. In patients with coronary, peripheral, or cerebrovascular atherosclerosis, thromboembolic complications are the main causes of mortality worldwide. The risk of recurrent cardiovascular events such as a heart attack, stroke, or mortality remains high at more than 5% in the first year after myocardial infarction.
- The prevalence of atrial fibrillation increases with age and carries a 5-fold increase in the risk of stroke. In patients with afib and not on anticoagulation, a clot or thrombus can be found in the left atrial appendage in >90% of cases. Interestingly, despite anticoagulation, a clot can still be found in 3-5% of patients when a trans-oesophageal echo is performed.
What are the therapies available to prevent abnormal blood clots?
There are several therapies available to prevent blood clots, and the choice of treatment depends on various factors such as the individual’s risk factors, the presence of underlying medical conditions, and the specific situation. Here are some commonly used therapies to prevent blood clots:
Antiplatelet Medications: Antiplatelet drugs inhibit the activation and aggregation of platelets, thus reducing the risk of clot formation. Aspirin inhibits thromboxane and is often prescribed for individuals at risk of cardiovascular events, or in those with a history of heart attack or stroke. P2Y12 antagonists are another class of antiplatelet drugs that inhibit the adenosine diphosphate (ADP) receptor (or P2Y12 inhibitors) such as the thienopyridines (clopidogrel and prasugrel) and the nonthienopyridines (ticagrelor). Most heart attacks are treated by opening the infarct-related coronary artery with a coronary stent. Patients are then treated with dual antiplatelet therapy (DAPT= ASA and a P2Y12 antagonist) for a period varying from 1 month to years depending on the clinical setting and the risk of bleeding. Similarly, after a stroke, patients are treated long-term with ASA and with a P2Y12 antagonist for usually 3 months.
Anticoagulant Medications: Anticoagulants, also known as blood thinners, are the most common type of medication used to prevent blood clots. These medications work by inhibiting the clotting process and reducing the ability of the blood to form clots. Examples of parenteral anticoagulants include heparin and low molecular weight heparin (LMWH) that inhibit factor X and thrombin (factor IIa). Oral anticoagulants include warfarin which competitively inhibits Vitamin K, thus reducing the synthesis of several coagulation factors: thrombin or factor II, factor VII, factor IX and factor X. It is the only approved oral anticoagulation in patients with mechanical prosthetic heart valves. The advent of direct oral anticoagulants (DOACS) has resulted in significant advances in the prevention of thromboembolic events in patients with non-valvular afib and in patients with venous thrombosis (DVT/PTE). In patients with non-valvular afib, DOACS that include factor X inhibitors (apixaban and rivaroxaban) reduced mortality by 10% and hemorrhagic stroke by 50% compared to warfarin. All DOACS, including dabigatran (factor II inhibitor), reduce bleeding events by an average of 30% compared to warfarin. Despite these results, there is still an increased risk of bleeding in the elderly, and frail, when associated with DAPT or in patients with renal failure. The fear of bleeding restrains patients from taking lifesaving medications and physicians from prescribing them. A study found that over 13% of patients with Afib who had a stroke, had been deemed unsuitable for anticoagulation.
Why Factor XI is a promising anticoagulant?
As previously discussed, factor XI plays a subsidiary role in hemostasis while playing a pivotal role in thrombosis. This means that factor XI inhibitor could potentially prevent a clot from forming while minimizing the risk of bleeding. To this point, patients that are born with a factor XI deficiency reduced incidence of DVT/PTE and ischemic stroke compared to the normal population, while those with a high level of factor XI carry more than twice the risk of venous thrombosis. Phase 2 clinical studies are emerging on inhibition of factor XI in different clinical scenarios: prevention of DVT after knee surgery, stroke prevention in afib, after MI, and after a stroke. Factor XI inhibitors studied include antisense oligonucleotides given SC once a week, inhibitory antibodies given SC/IV with an effect lasting 1 month, and small molecules (asundexian, milvexian) given orally once or twice a day.
In the area of stroke prevention in afib, PACIFIC-AF, a phase 2 study of asundexian compared to apixaban in patients with non-valvular afib found less bleeding with the new factor XI. LIBREXIA-AF, is a phase 3 study of milvexian vs apixaban, which will study 15,500 patients with non-valvular afib over a period of 6 yrs. LILAC-TIMI 76 will study the safety and efficacy of abelacimab, 150 mg SC monthly, in high-risk patients with afib who are deemed unsuitable for oral anticoagulation.
In the area of stroke prevention after a stroke, AXIOMATIC-SSP and PACIFIC-stroke, phase 2 clinical studies of milvexian and asundexian respectively, found no excess of intracranial hemorrhage when given in patients recovering from a noncardioembolic stroke treated with ASA and clopidogrel for 3 weeks followed by ASA thereafter. LIBREXIA-STROKE will enroll 15,000 patients after an acute ischemic stroke or high-risk TIA to milvexian, twice a day vs placebo in addition to single antiplatelet therapy or DAPT.
In the field of recurrent ischemic events following an AMI, PACIFIC-AMI, a phase 2 study, evaluated the safety of asundexian, 10-50 mg daily, in addition to background DAPT with ASA and P2Y12 inhibitor in patients with recent MI and found no excess bleeding. LIBREXIA-ACS, a phase 3 study, will enroll approximately 16,000 patients within 7 days of an acute coronary syndrome ( STEMI, NSTEMI, or unstable angina with positive troponin), to milvexian vs placebo with background antiplatelet therapy (DAPT for < or > 90 days) with or without de-escalation to single antiplatelet therapy.