Thrombosis is the formation, development or presence of a blood clot (thrombus) in a blood vessel. It is the most common severe medical disorder.  The most fequent example of arterial thrombosis is coronary thrombosis, which leads to occlusion of the coronary arteries and often to myocardial infarction (heart attack). The standard therapy is adminsitration of a thromboytic protein by infusion.

Another important example of arterial thrombosis is cerebral thrombosis. 

Venous thrombosis is a frequent complication of surgical procedures such as hip and knee athroplasties.

Mechanisms of Action/Pathogenesis

Role of complement: Studies have shown a role of complement in procoagulant pathways. For example, interception of C5a and C5aR results in distinct changes in pro/antifibrinnoytic proteins and in the induciton of tissue factor (TF) in endothelial cells and monocytes. Ritis (J. Immunology, 2006, 177, 4794-4802) also show that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the inudction of tissue factor (TF), a key initiating component of the blood coagulation cascade. Inhibition studies using the complement inhibitor compstatin showed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF dependent coagulant activity. Blockage using a selective C5a receptor antagonist and stimulation of neutrophils wiht recombinant human C5a also showed that C5a and C5aR mediate the expression of TF in nuetrophils. 

Thrombus associated diseases:

Thrombus associated diseases are vascular conditions that develop due to the presence of a clot.

Abdominal Aortic Aneurysm (rupture of an abdominal aortic aneurysm (RAAA)): is a lethal event in 90% of patietns. In hospital mortality rates of 10-70% account for a large proportion of these deaths and are due primarily to multiple organ failure after successful repair.

Boyd (“a CD18 monoclonal antibody reduces multiple organ injury in a model of ruptured abdominal aortic aneurysm, 1999) discloses that a CD18 m antibody reduces multiple organ injury in a model of ruptured abdominal aortic aneurysm.

Acquired thrombotic thrombocytopenic purpura: is a rare, life threatening autoimmune blood clotting disorder.

Cablivi (sold by Sanofi), a humanized, 259 aino acid, 27.78 kDa bivalent nanobody produced in E. coli that binds to von Willebrand factor, a key protein in hemostasis, which in turn inhibits the itneraction of von Willebrand factor with blood platelets, preventing platelet adhesion and hence the clotting characteristic of the condition, has been approved in Europe for treatment. (Gary Wash “Biopharmaceutical benchmarks 2018” Nature Biotechnology, 36(12), 2018)

Deep-vein thrombosis (DVT): is a condition in which blood clots form in the deep blood vessels of the legs and groin. These clots can block the flow of blood from the legs back to the heart and sometimes a piece of a clot is detached and carried by the bloodstream through the heart to a blood vessel, where it lodges and reduces, or blocks the flow of blood to a vascular tissue. This is called an embolism. If the clot lodges in pulmonary blood vessel (see below) it can be fatal.

Pulmonary embolism: In the US alone an estimated 600k patients suffer from PE’s each year. Many of these cases go undetected and many of these patients later die due to complications associated with the disease.

Thrombus: is a circumscribed blood solidification that forms in arteries or veins by intravascular clotting. A typical example of an arterial thrombosis is that of the coronary arteries. If a thrombus detaches from the vessel wall, it can be carrierd by the blood stream which can obstruct a downstream smaller vessel. The brain supplying aerteries are a typical example of thromboembolisms in arteries. 

Ischemic Stroke (see outline)

Hemorrhagic Stroke: See outline

Treatment

Anti-thrombotic agents are those agents that inhibit or reduce blood clot formation and/or stimulate thromboysis (thrombus dissolution). They include aspirin, protaglandin E1, selective thromoxane A2 inhibitors, selective thrombin inhibitors, platelet receptor GPIIb/IIIa blockers, streptokinase, heparin, complement inhibitors and kistrin. (Lipton, US 6,503,947).

Annexins: have shown anticoagulant activity in several in vitro thrombin dependent assays. Allison (US 2006/0105952) discloses methods for preventing arterial or venous thrombosis by adminnistering to a subject a modified annexin protein.

Intravenous recombinant tissue plasminogen activator (rtPA) is the only treatment for acute ischemic stroke that is approved by the FDA. The earlier it is adminsitered the better.

Factor Xa inhbitors:

–Apixaban (Eliquis): is an anticoagulant medicaito used to treat and prevent blood clots and to prevent stroke in people with novalvular atrial defibrillation through direclty inhibiting factor Xa. It is used as an anlternative to warfarin to prevent blood clots following hip or kee replacement and in those with a histoyr of prior clots. 

–Rivaroxaban (Xarelto): is an anticoagulant medication (blodo thinner) used to treat nad prevent blood clots. Specifically it is used to reat deep vein thrombosis and pulmonary emboli and to prevent blood clots in atrial fibrillation. Rvaroxaban appears to be as effective as warfarin in preventing strokes and embolic events in patients who are classified as moderate to high risk. It inhbitors both free and bound Factor Xa in the prothrombinase complex. It is a selective direct factor Xa inhibitor with an onset of action of 2.5-4 hours.