The thrombin time (TT), also known as the thrombin clotting time (TCT) is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is used to diagnose blood coagulation disorders and to assess the effectiveness of fibrinolytic therapy. This test is repeated with pooled plasma from normal patients. The difference in time between the test and the ‘normal’ indicates an abnormality in the conversion of fibrinogen (a soluble protein) to fibrin, an insoluble protein.
The thrombin time compares the rate of clot formation to that of a sample of normal pooled plasma. Thrombin is added to the samples of plasma. If the time it takes for the plasma to clot is prolonged, a quantitative (fibrinogen deficiency) or qualitative (dysfunctional fibrinogen) defect is present. In blood samples containing heparin, a substance derived from snake venom called batroxobin (formerly reptilase) is used instead of thrombin. Batroxobin has a similar action to thrombin but unlike thrombin it is not inhibited by heparin.
Normal values for thrombin time are 12 to 14 seconds. If batroxobin is used, the time should be between 15 and 20 seconds. Thrombin time can be prolonged by heparin, fibrin degradation products, and fibrinogen deficiency or abnormality.
Platelets, also called “thrombocytes”, are blood cells whose function (along with the coagulation factors) is to stop bleeding. Thrombocytes have no nucleus: they are fragments of cytoplasm which are derived from the megakaryocytes of the bone marrow, and then enter the circulation. These unactivated platelets are biconvex discoid structures shaped like a lens, 2–3 µm in greatest diameter. Platelets are found only in mammals, an adaptation that may have evolved to offset the risk of death from hemorrhage at childbirth – a risk unique to mammals.
On a stained blood smear, thrombocytes appear as dark purple spots, about 20% the diameter of red blood cells. The smear is used to examine platelets for size, shape, qualitative number, and clumping. The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20.
The main function of thrombocytes is to contribute to hemostasis: the process of stopping bleeding at the site of interrupted endothelium. They gather at the site and unless the interruption is physically too large, they plug the hole. First, platelets attach to substances outside the interrupted endothelium: adhesion. Second, they change shape, turn on receptors and secrete chemical messengers: activation. Third, they connect to each other through receptor bridges: aggregation. Formation of this platelet plug (primary hemostasis) is associated with activation of the coagulation cascade with resultant fibrin deposition and linking (secondary hemostasis). These processes may overlap: the spectrum is from a predominantly platelet plug, or “white clot” to a predominantly fibrin clot, or “red clot” or the more typical mixture. The final result is theclot. Some would add the subsequent clot retraction and thrombocyte inhibition as fourth and fifth steps to the completion of the process and still others a sixth step wound repair.
Low thrombocyte concentration is thrombocytopenia and is due to either decreased production or increased destruction. Elevated thrombocyte concentration is thrombocytosis and is either congenital, reactive (to cytokines), or due to unregulated production: one of the myeloprolerative neoplasms or certain other myeloid neoplasms. A disorder of platelet function is a thrombocytopathy.
Normal thrombocytes can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate thrombocyte adhesion/activation and thrombosis: the formation of a clot within an intact vessel. These arise by different mechanisms than a normal clot. Examples are: extending the fibrin clot of venous thrombosis; extending an unstable or ruptured arterial plaque, causing arterial thrombosis; and microcirculatory thrombosis. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia; or completely obstruct it, causing downstream infarction.
The terms thrombocytopenia and thrombopenia refer to a disorder in which there is a relative decrease of thrombocytes, commonly known as platelets, present in the blood.
A normal human platelet count ranges from 150,000 to 450,000 platelets per microlitre of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia is a platelet count below 50,000 per microlitre.
Thrombolysis is the breakdown (lysis) of blood clots by pharmacological means, and commonly called clot busting. It works by stimulating secondary fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator (tPA), the protein that normally activates plasmin.
Thrombolytic drugs are used in medicine to dissolve blood clots in a procedure termed thrombolysis. They limit the damage caused by the blockage or occlusion of a blood vessel.
Thrombolytic agents are used for the treatment of myocardial infarction (heart attack), thromboembolic strokes, deep vein thrombosis and pulmonary embolism to clear a blocked artery and avoid permanent damage to the perfused (see perfusion) tissue (e.g. myocardium, brain, leg) and death. They may also be used to clear blocked catheters that are used in long-term medical therapy.
Thrombolytic therapy in hemorrhagic strokes is contraindicated, as its use in that situation would prolong bleeding into the intracranial space and cause further damage.
Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoagulant enzyme. Thrombomodulin is also expressed on human mesothelial cell, monocyte and a dendritic cell subset.
Thrombophilia (sometimes hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who have an episode of thrombosis (such as deep vein thrombosis in the leg) that was not provoked by other causes. A significant proportion of the population has a detectable abnormality, but most of these only develop thrombosis in the presence of an additional risk factor.
There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term preventative anticoagulation. The first major form of thrombophilia, antithrombin deficiency, was identified in 1965, while the most common abnormalities (including factor V Leiden) were described in the 1990s.
Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets(thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot that breaks free and begins to travel around the body is known as an embolus.
When a thrombus is significantly large enough to reduce the blood flow to a tissue, hypoxia (oxygen deprivation) can occur and metabolic products such as lactic acid can accumulate. A larger thrombus causing a much greater obstruction to the blood flow may result in anoxia, the complete deprivation of oxygen and infarction, tissue death. There are also a number of other conditions that can arise according to the location of the thrombus and the organs affected.
Thromboembolism is the combination of thrombosis and its main complication, embolism.
Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome) is a rare disorder of the blood-coagulation system, causing extensive microscopic clots to form in the small blood vessels throughout the body. These small blood clots, called thrombi, can damage many organs including the kidneys, heart and brain. In the era before effective treatment with plasma exchange, the fatality rate was about 90%. With plasma exchange, this has dropped to 10% at six months. Immunosuppressants, such as glucocorticoids, rituximab, cyclophosphamide, vincristine, or cyclosporine, may also be used if a relapse or recurrence follows plasma exchange.
Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating multimers of vWF increase platelet adhesion to areas of endothelial injury, particularly at arteriole-capillary junctions.
A rarer form of TTP, called Upshaw-Schülman syndrome, is genetically inherited as a dysfunction of ADAMTS13. If large vWF multimers persist, a tendency for increased coagulation exists.
Red blood cells passing the microscopic clots are subjected to shear stress which damages their membranes, leading to intravascular hemolysis, which in turn leads to anaemia and schistocyte formation. Reduced blood flow due to thrombosisand cellular injury results in end organ damage. Current therapy is based on support and plasmapheresis to reducecirculating antibodies against ADAMTS13 and replenish blood levels of the enzyme.
A thrombus, or colloquially a blood clot, is the final product of the blood coagulation step in hemostasis. Note, a thrombus is a solid or semi-solid mass formed from the constituents of blood within the vascular system during life, whereas a blood clot refers to one that is formed post-mortem. There are two components to a thrombus, aggregated platelets that form a platelet plug, and a mesh of cross-linked fibrin protein. A thrombus is a healthy response to injury intended to prevent bleeding, but can be harmful in thrombosis, when clots obstruct blood flow through healthy blood vessels.
Mural thrombi are thrombi that adhere to the wall of a blood vessel. They occur in large vessels such as heart and aorta, and can restrict blood flow but usually do not block it entirely. They appear grey-red with alternating light and dark lines (known as lines of Zahn) which represent bands of fibrin (lighter) with entrapped white blood cells and red blood cells (darker).
Tissue factor, also called platelet tissue factor, factor III, thromboplastin, or CD142 is a protein present in subendothelial tissue and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin.
Tissue factor pathway inhibitor (or TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa(Xa). While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the FVIIa-tissue factor complex. TFPI contributes significantly to the inhibition of Xa in vivo, despite being present at concentrations of only 2.5 nM.
Tissue plasminogen activator (tPA, PLAT) is a protein involved in the breakdown of blood clots. It is a serine protease (EC 126.96.36.199) found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat embolic orthrombotic stroke. Use is contraindicated in hemorrhagic stroke and head trauma. The antidote for tPA in case of toxicity is aminocaproic acid.
tPA may be manufactured using recombinant biotechnology techniques. tPA created this way may be referred to as recombinant tissue plasminogen activator (rtPA).