Deep vein thrombosis (DVT) takes place when a thrombus also known as blood clot forms in a deep vein, usually in the leg; it can cause swelling and redness or be asymptomatic. The cause of DVT can be found in certain medical conditions that affect the blood favouring the creation of blood cloths, it can occur after surgery, due to long time repose in bed, or because of other cause that block the free blood flow in main veins. The majority of pulmonary thromboembolism results from blood clots that break loose from the main veins of lower limb affected with DVT and travel through the bloodstream to the lungs. The blockage of the blood flow there cause a pulmonary embolism (PE) accounting for 30% mortality rate within one month, is usually the main and most serious complication associated with DVT.
Traditionally, a DVT was immediately treated using blood-thinning drugs. However, anticoagulants do not actively dissolve a blood clot; they just prevent new clots from forming. The body will sometimes dissolve a clot, eventually, but often the vein becomes damaged.
DVT treatment options include the commonly used anticoagulants or blood thinners, which although do not break up existing blood clots, can prevent them from growing bigger and reduce the risk of developing more clots. Treatment with anticoagulation is the accepted standard of care for DVT involving the proximal leg veins, specifically, the popliteal, femoral, and iliac veins. In order to be ideal, an anticoagulant has to be efficient, safe, and easy to administer; it should require minimal monitoring and have a low cost.
There are currently a good number of anticoagulants used in clinic, including intravenous heparin; Lovenox, Fragmin, Arixtra or Enoxaparin, injectable under the skin; or injectable blood thinners followed by warfarin or Pradaxa. As warfarin which requires periodic checking blood tests, Xarelto, Eliquis or Savaysa can be administered as a pill.
The protective system of blood coagulation to prevent excessive blood loss after injury in normal hemostasis is based in a cascade of enzyme activations proenzymes and procofactors initiated by serine proteases with limited proteolysis, which results in the polymerization of fibrin and the activation of platelets, leading to a blood clot formation.
While hemostasis is the normal process by which the clotting cascade stops vascular damage by limiting blood loss after an injury, pathologic thrombosis triggers the clotting cascade in the lumen of a blood vessel, leading to the formation of a blood clot or thrombus that can obstruct the flow of blood. Furthermore, severe thrombosis can block the blood flow to a tissue, leading to ischemia and tissue death.
The blood clotting system which can be triggered by two mechanisms: the tissue factor pathway that functions in normal hemostasis; and the contact pathway, which seems to act in host pathogen defences can lead to pathologic thrombosis. These unwanted blood clots contribute to substantial disability and death in the developed world.
The tissue factor pathway or Extrinsic Pathway is triggered by a cell-surface protein known as tissue factor (TF). When cells expressing TF are exposed to blood, it immediately triggers the clotting cascade and the formation of blood clots.
TF also known as thromboplastin, coagulation factor III, or CD142 is a glycosylated, integralmembrane protein that does not need proteolysis to be activated; it is present in adventitial cells surrounding blood vessels and organ capsules, and is particularly abundant at anatomic sites where hemorrhage can result in disastrous consequences, such as kidney and brain, but usually absents in circulating blood cells and endothelial cells.
In atherosclerosis, only a thin monolayer of endothelial cells separate blood from TF. Since myocardial infarction is considered to be triggered by the rupture of an atherosclerotic plaque in a coronary artery, as a result of that burst, TF is exposed to the catalytic serine protease enzyme coagulation factor VIIa (fVIIa) within the blood. Myocardial infarction occurs if the process of coagulation activation is big enough to form an occlusive thrombosis within the coronary vessel. Epidemiologic studies suggest that elevated plasma fVII may be a risk factor for thrombotic disease; high levels of circulating fVIIa have also been found with angina, transient ischemic attacks, diabetes, uremia, and peripheral vascular disease.
The contact pathway or Intrinsic Pathway is triggered when plasma meets some artificial surfaces like glass test tubes or finely ground clay. This pathway does not contribute to normal hemostasis, but it is thought to participate in thrombotic diseases.
The role of contact activation pathway seems to involve the generation of bradykinin an inflammatory mediator involved in vasodilation, vascular permeability, pain, and neutrophil chemotaxis, the contribution to fibrinolysis, and the inhibition of thrombininduced platelet activation and angiogenesis. This pathway of coagulation is initiated by activation of factor XII (fXII) in a process involving kininogen (HK) and plasma pre-kallikrein (PK) producing active factor XII (fXIIa), which activates PK to kallikrein, leading to thrombin generation and blood clots.
There is therefore a fine but complex relationship between hemostasis and pathological thrombosis. Classical anticoagulant drugs that interfere in both pathways too much anticoagulation presents the risk of bleeding, and to little have the risk of thrombosis are some of the most widely prescribed medications today. However, drugs that inhibit initiation of the contact pathway by using antisense oligonucleotides to inhibit the biosynthesis of fXI or with a monoclonal antibody targeting the active site of fXIIa may be more effective antithrombotics with little or no bleeding side effects.
Inhibition of the contact pathway as a method of anticoagulation not only carries less risk of bleeding than current therapeutics, it also has the potential to reduce the often-damaging connections between coagulation and inflammation in human disease.