Therapeutic Areas

Thrombosis Overview

Despite recent progress in the development of antithrombotic drugs, thromboembolic diseases remain the leading cause of morbidity and mortality in the western world. Portola’s goal is to develop “best in class” antithrombotic drugs that will improve patient care.

The formation of a blood clot, or thrombus, is a normal vascular repair mechanism that can be harmful if it is excessively or abnormally activated, causing obstructions in blood vessels that can block the blood supply to the heart, brain, lungs or legs. Thrombi occurring in veins can cause deep vein thrombosis (DVT) in the pelvic, leg and upper extremity veins, and pulmonary embolism (PE), which can result in life-threatening lung damage. Thrombi formed in arteries can cause heart attack or stroke. Portola is developing novel therapeutics that intervene in two important processes in blood clot formation - platelet thrombosis and the coagulation cascade.

Platelet Thrombosis

Platelets are specialized disk-shaped cells in the bloodstream that play a key role in blood clot formation, or hemostasis. Platelets can detect a disruption in the lining of a blood vessel and react to build a plug that will stop bleeding. Arteries injured by smoking, cholesterol or high blood pressure develop cholesterol-rich build-ups, or plaques, that line their walls. When these fatty plaques rupture, platelets are recruited to the rupture site to help repair the injury. Instead of sealing the vessel wall, as they would normally do in the case of a cut, the platelets form a clot in an intact blood vessel, causing a blockage that potentially can lead to heart attack or stroke.

When platelets first sense an injury, they begin to adhere to the blood vessel lining, forming an initial protective layer. Platelets become activated when they are brought into contact with collagen (which is exposed when the blood vessel lining is damaged), thrombin, ADP, or several other activating factors which bind to receptors expressed on the platelet surface. Once activated, the platelets change shape and begin to release substances - such as ADP - that further stimulate platelet activation, aggregation and thrombus formation and stability. Under these conditions, the coagulation cascade is triggered, leading to the activation of even more platelets and the formation of fibrin which stabilizes the platelet rich clot.

Portola scientists have made significant contributions to the field of platelet biology, including elucidating the roles of GP IIb-IIIa and ADP in platelet thrombosis and cloning P2Y₁₂, the ADP receptor responsible for thrombus stability and the target of Plavix. We are developing elinogrel, a competitive and reversible P2Y₁₂ ADP receptor antagonist against this important, validated target, in partnership with Novartis.

Coagulation Cascade

Coagulation is a complex process through which blood forms solid clots to repair injury to a blood vessel. Coagulation is initiated almost instantly after an injury occurs, covering the damaged blood vessel wall with a clot to stop bleeding and begin repair of the vessel.

Thrombosis - or the pathological development of blood clots - occurs when the coagulation process is overactivated. For example, excessive coagulation can lead to venous thromboembolism (DVT and PE) in patients following orthopedic surgery, cancer patients, medically ill (nonambulating) patients, and patients with atrial fibrillation.

The coagulation cascade is initiated when the endothelial cells lining the damaged blood vessel express tissue factor (TF). TF then binds to Factor VIIa, triggering a sequence of biochemical reactions involving the enzymes Factor Xa and thrombin. Thrombin produces fibrin and helps to activate platelets, making it an important target for the regulation of thrombosis. Prothrombin, the precursor for thrombin, is converted to the active enzyme by Factor Xa. As the sole enzyme responsible for sustained thrombin formation in the vasculature, Factor Xa is a key, validated target for preventing thrombosis.

Portola believes that Factor Xa is the preferred target for anticoagulant drug development because it occurs prior to the explosive step in thrombin generation. Also, since FXa is present in much smaller concentrations than thrombin it is relatively easier to effectively inhibit. We are developing betrixaban, an oral, direct-acting Factor Xa inhibitor with potential best-in-class pharmaceutical properties, in partnership with Merck & Co., Inc.