Thromboembolic disorders, encompassing conditions like deep vein thrombosis (DVT) and pulmonary embolism (PE), arise from a complex interplay of risk factors and comorbidities. Pinpointing the top 3 is challenging due to variations across studies and populations, but some consistently emerge as prominent contributors.

1. Active Cancer: Cancer significantly increases VTE risk, with incidence varying by cancer type. Pancreatic, liver, and non-small cell lung cancers show the highest incidence (>70 per 1000 person-years), while breast, melanoma, and prostate cancers have lower rates (<20 per 1000 person-years). The prothrombotic state in cancer is attributed to tumor-derived procoagulants, inflammatory cytokines, and interactions with the coagulation system.

2. Prior VTE: A history of VTE is a strong predictor of recurrence. The 10-year recurrence risk ranges from 30% to 50%, higher in patients with primary DVT than PE. Residual vein thrombosis and elevated D-dimer levels further increase the risk. The underlying mechanisms likely involve persistent vascular damage and ongoing activation of the coagulation system.

3. Hospitalization/Immobilization: Hospital-associated VTE (HA-VTE) is a well-known complication, with incidence around 1.2% of medical admissions. Reduced mobility during hospitalization, surgery, or prolonged illness contributes significantly to VTE risk. Immobilization promotes venous stasis, a key component of Virchow's triad (venous stasis, endothelial injury, and hypercoagulability), which describes the pathogenesis of thrombosis.

Beyond these top 3, several other factors and comorbidities consistently increase VTE risk:

• Age: Advanced age is a major risk factor, with VTE incidence increasing substantially in older individuals.
• Obesity: Obesity is linked to increased inflammation, impaired fibrinolysis, and venous stasis, all contributing to VTE risk.
• Surgery: Major surgery, especially orthopedic and cancer surgery, significantly elevates VTE risk due to tissue trauma, inflammation, and immobilization.
• Trauma and Fractures: Similar to surgery, trauma and fractures increase VTE risk through tissue damage, inflammation, and immobilization.
• Inherited Thrombophilia: Genetic conditions like Factor V Leiden and Prothrombin G20210A mutation increase the risk of thrombosis.
• Oral Contraceptives and Hormone Replacement Therapy: Estrogen-containing medications can enhance coagulation and increase VTE risk.
• Pregnancy and Puerperium: Pregnancy induces a hypercoagulable state to prevent postpartum hemorrhage, but this also increases VTE risk.
• Medical Conditions: Certain medical conditions like heart failure, diabetes, and antiphospholipid syndrome are associated with increased VTE risk.

It's crucial to consider the interplay of these risk factors and comorbidities when assessing an individual's VTE risk. The presence of multiple risk factors can synergistically increase the overall risk, necessitating appropriate preventive measures.

SRSD107 is currently being investigated for the following indications in clinical trials:

• Thrombosis: This includes both arterial and venous thrombosis.
• Venous Thrombosis: Specifically targeting venous thromboembolism (VTE).
• Thromboembolic Disorders: This encompasses a broader range of conditions related to blood clot formation, including myocardial infarction, ischemic stroke, and VTE.
• Arterial thrombosis

The intervention models for these trials are primarily:

• Randomized: Participants are randomly assigned to different treatment groups (e.g., SRSD107 vs. placebo).
• Double-blind: Both participants and researchers are unaware of the treatment assignment.
• Placebo-controlled: A control group receives a placebo to compare the effects of SRSD107 against a non-active treatment.
• Single ascending dose: Different groups of participants receive increasing doses of SRSD107 to evaluate safety and tolerability.
• Multiple ascending dose: Participants receive multiple doses of SRSD107 to assess the long-term effects and optimal dosing regimen.
• Parallel Assignment: Different treatment groups run concurrently.
• Quadruple Blind: Four parties involved in the trial are blinded to the treatment assignment.

One trial specifically mentions a Phase 2 study for the prevention of VTE in patients undergoing total knee arthroplasty. This trial aims to confirm the anticoagulant benefits of SRSD107 and inform dose selection for future pivotal trials.

It's important to note that while SRSD107 is primarily being investigated for thromboembolic disorders, its mechanism of action (inhibiting Factor XI) may have broader applications in other conditions related to blood clotting. Further research and clinical trials will be needed to explore these possibilities.