Thrombosis (from Ancient Greek θρόμβωσις (thrómbōsis)'clotting') is the formation of ablood clot inside ablood vessel, obstructing the flow ofblood through thecirculatory system. When a blood vessel (avein or anartery) is injured, the body usesplatelets (thrombocytes) andfibrin to form ablood 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, or a piece of the clot, that breaks free and begins to travel around the body is known as anembolus.[1][2]
Thrombosis may occur inveins (venous thrombosis) or inarteries (arterial thrombosis). Venous thrombosis (sometimes called DVT,deep vein thrombosis) leads to a blood clot in the affected part of the body, while arterial thrombosis (and, rarely, severe venous thrombosis) affects the blood supply and leads to damage of the tissue supplied by that artery (ischemia andnecrosis). A piece of either an arterial or a venous thrombus can break off as anembolus, which could then travel through the circulation and lodge somewhere else as anembolism. This type of embolism is known as athromboembolism. Complications can arise when a venous thromboembolism (commonly called a VTE) lodges in the lung as apulmonary embolism. An arterial embolus may travel further down the affected blood vessel, where it can lodge as an embolism.[citation needed]
Thrombosis is generally defined by the type of blood vessel affected (arterial or venous thrombosis) and the precise location of the blood vessel or the organ supplied by it.[citation needed]
Paget-Schroetter disease or upper extremity DVT (UEDVT) is the obstruction of anarm vein (such as theaxillary vein orsubclavian vein) by a thrombus. The condition usually comes to light after vigorous exercise and usually presents in younger, otherwise healthy people. Men are affected more than women.[4]
Cerebral venous sinus thrombosis (CVST) is a rare form ofstroke which results from the blockage of thedural venous sinuses by a thrombus. Symptoms may include headache, abnormal vision, any of the symptoms of stroke such as weakness of the face and limbs on one side of the body andseizures. The diagnosis is usually made with aCT orMRI scan. The majority of persons affected make a full recovery. Themortality rate is 4.3%.[9]
Jugular vein thrombosis is a condition that may occur due to infection, intravenous drug use or malignancy. Jugular vein thrombosis can have a varying list of complications, including:systemic sepsis,pulmonary embolism, andpapilledema. Though characterized by a sharp pain at the site of the vein, it can prove difficult to diagnose, because it can occur at random.[10]
Cavernous sinus thrombosis is a specialised form of cerebral venous sinus thrombosis, where there is thrombosis of thecavernous sinus of the basal skull dura, due to the retrograde spread of infection and endothelial damage from thedanger triangle of the face. The facial veins in this area anastomose with thesuperior andinferior ophthalmic veins of the orbit, which drain directly posteriorly into the cavernous sinus through thesuperior orbital fissure.Staphyloccoal orStreptococcal infections of the face, for example nasal or upper lip pustules may thus spread directly into the cavernous sinus, causing stroke-like symptoms ofdouble vision,squint, as well as spread of infection to causemeningitis.[11]
Arterial thrombosis is the formation of a thrombus within anartery. In most cases, arterial thrombosis follows rupture ofatheroma (a fat-rich deposit in the blood vessel wall), and is therefore referred to asatherothrombosis.Arterial embolism occurs when clots then migrate downstream and can affect any organ.[12] Alternatively, arterial occlusion occurs as a consequence of embolism of blood clots originating from the heart ("cardiogenic" emboli). The most common cause isatrial fibrillation, which causes a blood stasis within the atria with easy thrombus formation, but blood clots can develop inside the heart for other reasons too as infective endocarditis.[citation needed]
A stroke is the rapid decline of brain function due to a disturbance in the supply of blood to the brain.[13] This can be due toischemia, thrombus,embolus (a lodged particle) orhemorrhage (a bleed).[13]
In thrombotic stroke, a thrombus (blood clot) usually forms aroundatherosclerotic plaques. Since blockage of the artery is gradual, the onset of symptomatic thrombotic strokes is slower. Thrombotic stroke can be divided into two categories — large vessel disease or small vessel disease. The former affects vessels such as theinternal carotids,vertebral and thecircle of Willis. The latter can affect smaller vessels, such as the branches of the circle of Willis.[citation needed]
Myocardial infarction (MI), or heart attack, is caused by ischemia (restriction in the blood supply), which is often due to the obstruction of acoronary artery by a thrombus. This restriction gives an insufficient supply of oxygen to the heart muscle which then results in tissue death (infarction). A lesion is then formed which is theinfarct. MI can quickly become fatal if emergency medical treatment is not received promptly. If diagnosed within 12 hours of the initial episode (attack) thenthrombolytic therapy is initiated.[citation needed]
Some risk factors predispose for venous thrombosis while others increase the risk of arterial thrombosis.[citation needed] Newborn babies in the neonatal period are also at risk of a thromboembolism.[19]
The main causes of thrombosis are given inVirchow's triad which liststhrombophilia,endothelial cell injury, and disturbedblood flow. Generally speaking the risk for thrombosis increases over the life course of individuals, depending on life style factors like smoking, diet, and physical activity, the presence of other diseases like cancer or autoimmune disease, while also platelet properties change in aging individuals which is an important consideration as well.[31]
Hypercoagulability orthrombophilia, is caused by, for example,genetic deficiencies orautoimmune disorders. Recent studies indicate that white blood cells play a pivotal role in deep vein thrombosis, mediating numerous pro-thrombotic actions.[32]
Any inflammatory process, such as trauma, surgery or infection, can cause damage to theendothelial lining of the vessel's wall. The main mechanism is exposure oftissue factor to the blood coagulation system.[33] Inflammatory and other stimuli (such ashypercholesterolemia) can lead to changes ingene expression in endothelium producing to a pro-thrombotic state.[34] When this occurs, endothelial cellsdownregulate substances such asthrombomodulin, which is a key modulator of thrombin activity.[35] The result is a sustained activation of thrombin and reduced production ofprotein C and tissue factor inhibitor, which furthers the pro-thrombotic state.[34]
Endothelial injury is almost invariably involved in the formation of thrombi in arteries, as high rates of blood flow normally hinder clot formation. In addition, arterial and cardiac clots are normally rich in platelets–which are required for clot formation in areas under high stress due to blood flow.[34]
Cancer-associated thrombosis can result from: (1) stasis, i.e., direct pressure on blood vessels by the tumor mass, poor performance status, and bed rest following surgical procedures; (2) iatrogenic, due to treatment with antineoplastic medications; and (3) secretion of heparanase from malignant tumors that results in degradation of endogenous heparin.[36]
Causes of disturbed blood flow include stagnation of blood flow past the point of injury, orvenous stasis which may occur in heart failure,[33] or after long periods of sedentary behaviour, such as sitting on a long airplane flight. Also,atrial fibrillation, causes stagnant blood in the left atrium (LA), orleft atrial appendage (LAA), and can lead to athromboembolism.[33]Cancers ormalignancies such asleukemia may cause increased risk of thrombosis by possible activation of the coagulation system by cancer cells or secretion of procoagulant substances (paraneoplastic syndrome), by external compression on a blood vessel when a solid tumor is present, or (more rarely) extension into the vasculature (for example, renal cell cancers extending into the renal veins).[33] Also, treatments for cancer (radiation, chemotherapy) often cause additional hypercoagulability.[33] There are scores that correlate different aspects of patient data (comorbidities, vital signs, and others) to risk of thrombosis, such as the POMPE-C, which stratifies risk of mortality due to pulmonary embolism in patients with cancer, who typically have higher rates of thrombosis.[37] Also, there are several predictive scores for thromboembolic events, such as Padua,[38] Khorana,[39][40] andThroLy score.[41]
Organisation: following the thrombotic event, residual vascular thrombus will be re-organised histologically with several possible outcomes. For an occlusive thrombus (defined as thrombosis within a small vessel that leads to complete occlusion),wound healing will reorganise the occlusive thrombus into collagenousscar tissue, where the scar tissue will either permanently obstruct the vessel, or contract down withmyofibroblastic activity to unblock thelumen. For a mural thrombus (defined as a thrombus in a large vessel that restricts the blood flow but does not occlude completely), histological reorganisation of the thrombus does not occur via the classicwound healing mechanism. Instead, theplatelet-derived growth factor degranulated by the clottedplatelets will attract a layer ofsmooth muscle cells to cover the clot, and this layer of mural smooth muscle will be vascularised by the blood inside the vessel lumen rather than by thevasa vasorum.[citation needed]
Ischemia/infarction: if an arterial thrombus cannot be lysed by the body and it does not embolise, and if the thrombus is large enough to impair or occlude blood flow in the involved artery, then localischemia orinfarction will result. Avenous thrombus may or may not be ischemic, since veins distribute deoxygenated blood that is less vital for cellular metabolism. Nevertheless, non-ischemic venous thrombosis may still be problematic, due to the swelling caused by blockage to venous drainage. Indeep vein thrombosis this manifests as pain, redness, and swelling; inretinal vein occlusion this may result inmacular oedema andvisual acuity impairment, which if severe enough can lead to blindness.[citation needed]
A thrombus may become detached and enter circulation as anembolus, finally lodging in and completely obstructing a blood vessel, which unless treated very quickly will lead to tissue necrosis (aninfarction) in the area past the occlusion. Venous thrombosis can lead to pulmonary embolism when the migrated embolus becomes lodged in the lung. In people with a "shunt" (a connection between the pulmonary and systemic circulation), either in the heart or in the lung, a venous clot can also end up in the arteries and cause arterial embolism.[citation needed]
Arterial embolism can lead to obstruction of blood flow through the blood vessel that is obstructed by it, and a lack of oxygen and nutrients (ischemia) of the downstream tissue. The tissue can become irreversibly damaged, a process known asnecrosis. This can affect any organ; for instance, arterial embolism of the brain is one of the causes of stroke.[citation needed]
The use ofheparin following surgery is common if there are no issues with bleeding. Generally, a risk-benefit analysis is required, as all anticoagulants lead to an increased risk of bleeding.[42] In people admitted to hospital, thrombosis is a major cause for complications and occasionally death. In the UK, for instance, the ParliamentaryHealth Select Committee heard in 2005 that the annual rate of death due to thrombosis was 25,000, with at least 50% of these being hospital-acquired.[43] Hencethromboprophylaxis (prevention of thrombosis) is increasingly emphasized. In patients admitted for surgery, gradedcompression stockings are widely used, and in severe illness, prolonged immobility and in allorthopedic surgery,professional guidelines recommendlow molecular weight heparin (LMWH) administration, mechanical calf compression or (if all else is contraindicated and the patient has recently developed deep vein thrombosis) the insertion of avena cava filter.[44][45] In patients with medical rather than surgical illness, LMWH too is known to prevent thrombosis,[45][46] and in the United Kingdom theChief Medical Officer has issued guidance to the effect that preventative measures should be used in medical patients, in anticipation of formal guidelines.[43]
The treatment for thrombosis depends on whether it is in a vein or an artery, the impact on the person, and the risk of complications from treatment.[citation needed]
Warfarin andvitamin K antagonists areanticoagulants that can be taken orally to reduce thromboembolic occurrence. Where a more effective response is required, heparin can be given (by injection) concomitantly. As a side effect of any anticoagulant, the risk of bleeding is increased, so theinternational normalized ratio of blood is monitored. Self-monitoring and self-management are safe options for competent patients, though their practice varies. In Germany, about 20% of patients were self-managed while only 1% of U.S. patients did home self-testing (according to one 2012 study).[47] Other medications such asdirect thrombin inhibitors anddirect Xa inhibitors are increasingly being used instead of warfarin.[citation needed]
Thrombolysis is the pharmacological destruction of blood clots by administeringthrombolytic drugs includingrecombinant tissue plasminogen activator, which enhances the normal destruction of blood clots by the body's enzymes. This carries an increased risk of bleeding so is generally only used for specific situations (such as severe stroke or a massive pulmonary embolism).[48]
Arterial thrombosis is platelet-rich, and inhibition of platelet aggregation withantiplatelet drugs such asaspirin may reduce the risk of recurrence or progression.[50]
With reperfusion comes ischemia/reperfusion (IR) injury (IRI), which paradoxically causes cell death in reperfused tissue[51] and contributes significantly to post-reperfusion mortality and morbidity.[52][53] For example, in a feline model of intestinal ischemia, four hours of ischemia resulted in less injury than three hours of ischemia followed by one hour of reperfusion.[51] In ST-elevation myocardial infarction (STEMI), IRI contributes up to 50% of final infarct size despite timely primary percutaneous coronary intervention. This is a key reason for the continued high mortality and morbidity in these conditions, despite endovascular reperfusion treatments and continuous efforts to improve timeliness and access to these treatments. Hence, protective therapies are required to attenuate IRI alongside reperfusion in acute ischemic conditions to improve clinical outcomes.[54] Therapeutic strategies that have potential to improve clinical outcomes in reperfused STEMI patients includeremote ischemic conditioning (RIC), exenatide, and metoprolol. These have emerged amongst a multitude of cardioprotective interventions investigated with largely neutral clinical data.[55] Of these, RIC has the most robust clinical evidence, especially in the context of STEMI, but also emerging for other indications such as acute ischemic stroke and aneurysmal subarachnoid hemorrhage.[54]
Treatment options for full-term and preterm babies who develop thromboembolism include expectant management (with careful observation), nitroglycerin ointment,pharmacological therapy (thrombolytics and/or anticoagulants), and surgery.[19] The evidence supporting these treatment approaches is weak. For anticoagulant treatment, it is not clear if unfractionated and/or low molecular weight heparin treatment is effective at decreasing mortality and serious adverse events in this population.[19] There is also insufficient evidence to understand the risk of adverse effects associated with these treatment approaches in term or preterm infants.[19]
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