The mechanisms of post-stroke venous thromboembolism (VTE) need to be further explored to develop new therapeutic approaches. As a leading provider of stroke research services, Ace Therapeutics has extensive experience in this areas.

What Is VTE?

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism, is a leading cause of morbidity and mortality during acute recovery from all sorts of conditions, stroke being one of them. VTE is a leading cause of morbidity and mortality during the acute recovery period. Limb paralysis, limb paralysis, and blood coagulability are all relevant features linked to the pathology of DVT.

Risk Factors of VTE

Risk factors for VTE in stroke are multifactorial and can vary based on the type and severity of the stroke, as well as specific characteristics. Key risk factors include:

Older Age

The risk factor for VTE is age, because circulation and endothelial function naturally decline with age, and due to the presence of comorbidities that can contribute to clots.

Greater Limb Weakness

Anxiety arising from strokes (especially in the lower limbs) reduces movement and increases susceptibility to stasis, a main risk factor for DVT, leading to pulmonary embolism if untreated.

Greater Stroke Severity

The more severe the stroke, especially the large infarct, the higher the risk for VTE. When neurological impairment is severe, the patient will remain paralyzed for longer periods and the blood flow is less, making clots more likely.

Types of VTE Prophylaxis

Post-stroke VTE and Neutrophil Activation

Neutrophils are the first immune cells recruited to sites of inflammation, playing a significant role in thrombus formation. Studies have shown that activated neutrophils and NETs contribute to thrombus development in animal models and are elevated in VTE. The role of neutrophils and NETs in long-term outcomes after VTE is an ongoing investigation. 

Neutrophil-Platelet Interactions

The thrombus is initiated by neutrophils via the platelet interaction. These interactions were augmented in symptomatic carotid stenosis, but inhibition of GPIIb/IIIa and selectin adhesion molecules lowered leukocyte-platelet aggregates. This process could be used as a biomarker and target for ischemic stroke.

Neutrophil Adhesion to Endothelium

Leukocyte function-associated antigen (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) attract neutrophils to the injured walls of blood vessels first. Interfering with this process would minimize cerebral thrombosis.

Proteases and Thrombosis

The neutrophils secrete proteases such as cathepsin G that attack coagulation factors to cause clots and thus exacerbate brain damage during ischemic stroke. When cathepsin G is suppressed, thrombus formation has been reduced and neurobehavioural functioning improved in animal models. On the other hand, neutrophils secrete ADAMTS13, which splits ultralarge von Willebrand factor and suppresses stroke inflammation.

Neutrophil Extracellular Traps (NETs)

Another way that neutrophils thrombosis is by producing NETs (DNA, histones, and granule proteins). They can also bind bacteria and cleave platelets. The platelets' engagement with NETs (most significantly P-selectin and its receptor on neutrophils) increases NET turnover and kickstarts the extrinsic coagulation pathway, leading to increased thromboinflammation. In stroke models, the treatment with DNase I, which destroys NETs, was protective.

Fig. 1 Neutrophil hyperactivation following stroke in preclinical models. (Dhanesha, et al., 2023)

1. Dhanesha, N., et al. (2023). Poststroke venous thromboembolism and neutrophil activation: an illustrated review. Research and Practice in Thrombosis and Haemostasis, 7(4).