Thrombosis

Thrombosis
Cyanosis of the lower right extremity, resulting from acute arterial thrombosis of the right leg (on the left side of the image)
Classification and external resources
Specialty Vascular surgery
ICD-10 I80-I82
ICD-9-CM 437.6, 453, 671.5, 671.9
MeSH D013927

Thrombosis (Greek: θρόμβωσις) is the formation of a blood clot (thrombus; Greek: θρόμβος) 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.[1][2]

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.

Causes

Main article: Virchow's triad

The main causes of thrombosis are given in Virchow's triad which lists hypercoagulability, endothelial cell injury, and disturbed blood flow.

Hypercoagulability

Main article: Thrombophilia

Hypercoagulability or thrombophilia, is caused by, for example, genetic deficiencies or autoimmune disorders. Recent studies indicate that neutrophils play a pivotal role in deep vein thrombosis, mediating numerous pro-thrombotic actions.[3][4][5]

Endothelial cell injury

Causes of injury to the vessel's wall include trauma, surgery, infection, or turbulent flow at bifurcations. The main mechanism is exposure of tissue factor to the blood coagulation system.[6]

Disturbed blood flow

Further information: Blood flow

Causes of disturbed blood flow include stagnation of blood flow past the point of injury, or venous stasis which may occur in heart failure,[6] in or after long periods of sedentary behavior, such as sitting on a long airplane flight. Also, atrial fibrillation, causes stagnant blood in the left atrium (LA) or left atrial appendage (LAA), and can lead to a thromboembolism.[6] Cancers or malignancies such as leukemia 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).[6] Also, treatments for cancer (radiation, chemotherapy) often cause additional hypercoagulability.[6] 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.[7]

Classification

There are two distinct forms of thrombosis, venous thrombosis and arterial thrombosis, each of which can be presented by several subtypes.

Venous thrombosis

Main article: Venous thrombosis

Venous thrombosis is the formation of a thrombus (blood clot) within a vein. There are several diseases which can be classified under this category:

Deep vein thrombosis

Main article: Deep vein thrombosis

Deep vein thrombosis (DVT) is the formation of a blood clot within a deep vein. It most commonly affects leg veins, such as the femoral vein. Three factors are important in the formation of a blood clot within a deep vein—these are the rate of blood flow, the thickness of the blood and qualities of the vessel wall. Classical signs of DVT include swelling, pain and redness of the affected area.

Portal vein thrombosis

Portal vein thrombosis affects the hepatic portal vein, which can lead to portal hypertension and reduction of the blood supply to the liver.[8] It usually has a pathological cause such as pancreatitis, cirrhosis, diverticulitis or cholangiocarcinoma.

Renal vein thrombosis

Main article: Renal vein thrombosis

Renal vein thrombosis is the obstruction of the renal vein by a thrombus. This tends to lead to reduced drainage from the kidney. Anticoagulation therapy is the treatment of choice.

Jugular vein thrombosis

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, and papilledema. Though characterized by a sharp pain at the site of the vein, it can prove difficult to diagnose, because it can occur at random.[9]

Budd-Chiari syndrome

Main article: Budd-Chiari syndrome

Budd-Chiari syndrome is the blockage of the hepatic vein or the inferior vena cava. This form of thrombosis presents with abdominal pain, ascites and hepatomegaly. Treatment varies between therapy and surgical intervention by the use of shunts.

Paget-Schroetter disease

Paget-Schroetter disease is the obstruction of an upper extremity vein (such as the axillary vein or subclavian 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.

Cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis (CVST) is a rare form of stroke which results from the blockage of the dural 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 and seizures. The diagnosis is usually made with a CT or MRI scan. The majority of persons affected make a full recovery. The mortality rate is 4.3%.[10]

Cavernous sinus thrombosis

Cavernous sinus thrombosis is a specialised form of cerebral venous sinus thrombosis, where there is thrombosis of the cavernous sinus of the basal skull dura, due to the retrograde spread of infection and endothelial damage from the danger triangle of the face. The facial veins in this area anastomose with the superior and inferior ophthalmic veins of the orbit, which drain directly posteriorly into the cavernous sinus through the superior orbital fissure. Staphyloccoal or Streptococcal infections of the face, for example nasal or upper lip pustules may thus spread directly into the cavernous sinus, causing stroke-like symptoms of double vision, squint, as well as spread of infection to cause meningitis.

Arterial thrombosis

Arterial thrombosis is the formation of a thrombus within an artery. In most cases, arterial thrombosis follows rupture of atheroma, and is therefore referred to as atherothrombosis.

Another common cause of arterial occlusion is atrial fibrillation, which causes a blood stasis within the atria with easy thrombus formation. In addition, it is well known that the direct current cardioversion of atrial fibrillation carries a great risk of thromboembolism, especially if persisting more than 48 hours. Thromboembolism strikes approximately 5% of cases not receiving anticoagulant therapy. When cardiac rhythm is restored clots are pushed out from atria to ventricles and from these to the aorta and its branches.[11]

Arterial thrombosis can embolize and is a major cause of arterial embolism, potentially causing infarction of almost any organ in the body.

Stroke

Main article: Stroke
Acute thrombus in the right MCA M1 branch

A stroke is the rapid decline of brain function due to a disturbance in the supply of blood to the brain. This can be due to ischemia, thrombus, embolus (a lodged particle) or hemorrhage (a bleed). In thrombotic stroke, a thrombus (blood clot) usually forms around atherosclerotic plaques. Since blockage of the artery is gradual, onset of symptomatic thrombotic strokes is slower. Thrombotic stroke can be divided into two categories—large vessel disease and small vessel disease. The former affects vessels such as the internal carotids, vertebral and the circle of Willis. The latter can affect smaller vessels such as the branches of the circle of Willis.

Myocardial infarction

Main article: Myocardial infarction

Myocardial infarction (MI) or heart attack, is caused by ischemia, (restriction in the blood supply), often due to the obstruction of a coronary 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 the infarct. MI can quickly become fatal if emergency medical treatment is not received promptly. If diagnosed within 12 hours of the initial episode (attack) then thrombolytic therapy is initiated.

Other sites

Hepatic artery thrombosis usually occurs as a devastating complication after liver transplantation.[12]

An arterial embolus can also form in the limbs.[13]

Natural history

If a thrombus forms inside a blood vessel, without medical intervention the thrombosis may proceed to several possible outcomes:

  1. Embolisation: the thrombus detaches from the underlying endothelial wall, leading to distal embolisation and vessel occlusion. An arterial thromboembolus may lead to a stroke, central retinal artery occlusion, ischaemic limb, mesenteric ischaemia or some form of localised ischaemia depending on the arterial circulation of the embolus. A venous thromboembolus may occlude the pulmonary artery leading to pulmonary embolism.
  2. Lysis: the thrombus may be acutely lysed by circulatory plasmin. This is essentially the physiological equivalent to pharmacological thrombolysis performed in the hospital.
  3. Ischaemia/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 local ischaemia or infarction will result. A venous thrombus may or may not be ischaemic, since veins distribute deoxygenated blood that is less vital for cellular metabolism. Nevertheless, non-ischaemic venous thrombosis may still be problematic, due to the swelling caused by blockage to venous drainage. In deep vein thrombosis this manifests as pain, redness, and swelling; in retinal vein occlusion this may result in macular oedema and visual acuity impairment, which if severe enough can lead to blindness.
  4. 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 collagenous scar tissue, where the scar tissue will either permanently obstruct the vessel, or contract down with myofibroblastic activity to unblock the lumen. 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 classic wound healing mechanism. Instead, the platelet-derived growth factor degranulated by the clotted platelets will attract a layer of smooth 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 the vasa vasorum.

Embolization

Further information: Embolus

If a bacterial infection is present at the site of thrombosis, the thrombus may break down, spreading particles of infected material throughout the circulatory system (pyemia, septic embolus) and setting up abscesses of a metastatic nature wherever they come to rest. Without an infection, the thrombus may become detached and enter circulation as an embolus, finally lodging in and completely obstructing a blood vessel, which unless treated very quickly will lead to tissue necrosis (an infarction) in the area past the occlusion. If the occlusion is in the coronary artery, myocardial ischaemia is likely to occur, whereby cardiac myocytes cannot function properly due to lack of oxygen. This lack of oxygen is then likely to result in a myocardial infarction.

Most thrombi, however, become organized into fibrous tissue, and the thrombosed vessel is gradually unblocked.

Prevention

Prophylaxis of venous thromboembolism with heparin in medical patients does not appear to decrease mortality and while it may decrease the risk of pulmonary embolism and deep vein thrombosis it increases the risk of bleeding and thus results in little or no overall clinical benefit.[14][15] Mechanical measures also appeared of little benefit in this group and in those with a stroke resulted in harm.[14] Evidence supports the use of heparin following surgery which has a high risk of thrombosis to reduce the risk of DVTs; however the effect on PEs or overall mortality is not known.[16][17][18]

Generally, a risk-benefit analysis is required, as all anticoagulants lead to a small increase in the risk of major bleeding. In atrial fibrillation, for instance, the risk of stroke (calculated on the basis of additional risk factors, such as advanced age and high blood pressure) needs to outweigh the small but known risk of major bleeding associated with the use of warfarin.[19]

In people admitted to hospital, thrombosis is a major cause for complications and occasionally death. In the UK, for instance, the Parliamentary Health 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.[20] Hence thromboprophylaxis (prevention of thrombosis) is increasingly emphasized. In patients admitted for surgery, graded compression stockings are widely used, and in severe illness, prolonged immobility and in all orthopedic surgery, professional guidelines recommend low molecular weight heparin (LMWH) administration, mechanical calf compression or (if all else is contraindicated and the patient has recently suffered deep vein thrombosis) the insertion of a vena cava filter.[21][22] In patients with medical rather than surgical illness, LMWH too is known to prevent thrombosis,[22][23] and in the United Kingdom the Chief Medical Officer has issued guidance to the effect that preventative measures should be used in medical patients, in anticipation of formal guidelines.[20]

However, thromboprophylaxis can lead to complications such as bleeding. There are new, non-invasive ways to stratify bleeding risk for patients with VTE and PE, by using tools like the RIETE Registry. The RIETE registry is an interactive database which uses data from previous and current patients, even groups not typically recruited like women and elderly as well as those with pre-existing conditions like Cancer or renal failure. The RIETE Registry offers more personalized options for patients with clotting risk, and it also has created a predictive calculator based on the registry's findings.[24]

Treatment

Warfarin and Vitamin K antagonists, are anticoagulants 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 the international 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).[25]

See also

References

  1. ↑ Furie B, Furie BC (2008). "Mechanisms of thrombus formation". New England Journal of Medicine. 359 (9): 938–949. doi:10.1056/NEJMra0801082. PMID 18753650.
  2. ↑ Handin RI (2005). "Chapter 53: bleeding and thrombosis". In Kasper DL, Braunwald E, Fauci AS, et al. Harrison's Principles of Internal Medicine (16th ed.). New York, NY: McGraw-Hill. ISBN 0-07-139140-1.
  3. ↑ Fuchs, TA; Brill, A, Duerschmied, D, Schatzberg, D, Monestier, M, Myers DD, Jr, Wrobleski, SK, Wakefield, TW, Hartwig, JH, Wagner, DD (Sep 7, 2010). "Extracellular DNA traps promote thrombosis.". Proceedings of the National Academy of Sciences of the United States of America. 107 (36): 15880–5. doi:10.1073/pnas.1005743107. PMC 2936604Freely accessible. PMID 20798043.
  4. ↑ Brill, A; Fuchs, TA, Savchenko, A, Thomas, GM, Martinod, K, De Meyer, SF, Bhandari, AA, Wagner, DD (Nov 1, 2011). "Neutrophil Extracellular Traps Promote Deep Vein Thrombosis in Mice". Journal of thrombosis and haemostasis : JTH. 10 (1): 136–44. doi:10.1111/j.1538-7836.2011.04544.x. PMC 3319651Freely accessible. PMID 22044575.
  5. ↑ Borissoff, JI; ten Cate, H (September 2011). "From neutrophil extracellular traps release to thrombosis: an overshooting host-defense mechanism?". Journal of thrombosis and haemostasis : JTH. 9 (9): 1791–4. doi:10.1111/j.1538-7836.2011.04425.x. PMID 21718435.
  6. 1 2 3 4 5 labtestsonline > Hypercoagulable Disorders This article was last reviewed on May 23, 2007 and was last modified on March 6, 2010.
  7. ↑ van der Hulle, T; den Exter, PL; Kooiman, J; van der Hoeven, JJ; Huisman, MV; Klok, FA (2014). "Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism.". J Thromb Haemost. 12 (7): 1116–20. doi:10.1111/jth.12605. PMID 24819040.
  8. ↑ Webster, GJ; Burroughs AK, Riordan SM (January 2005). "Review article: portal vein thrombosis – new insights into aetiology and management". Alimentary Pharmacology & Therapeutics. 21 (1): 1–9. doi:10.1111/j.1365-2036.2004.02301.x. PMID 15644039.
  9. ↑ eMedicine Article on Internal Jugular Vein Thrombosis by Dale K. Mueller|http://www.emedicine.com/med/topic2762c.htm
  10. ↑ Canhão, P; Ferro JM, Lindgren AG; et al. (August 2005). "Causes and predictors of death in cerebral venous thrombosis". Stroke. 36 (8): 1720–1725. doi:10.1161/01.STR.0000173152.84438.1c. PMID 16002765.
  11. ↑ Hatzinikolaou-Kotsakou E, Kartasis Z, Tziakas D, et al. (March 2005). "Clotting state after cardioversion of atrial fibrillation: a haemostasis index could detect the relationship with the arrhythmia duration". Thromb J. 3 (1): 2. doi:10.1186/1477-9560-3-2. PMC 555849Freely accessible. PMID 15748296.
  12. ↑ Bekker J, Ploem S, de Jong KP. Early hepatic artery thrombosis after liver transplantation: a systematic review of the incidence, outcome and risk factors. Am J Transplant 2009; 9(4):746-57.
  13. ↑ MedlinePlus > Arterial embolism Update Date: 5/8/2008. Updated by: Sean O. Stitham, MD and David C. Dugdale III, MD. Also reviewed by David Zieve, MD
  14. 1 2 Lederle, FA; Zylla, D, Macdonald, R, Wilt, TJ (2011-11-01). "Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an american college of physicians clinical practice guideline". Annals of Internal Medicine. 155 (9): 602–15. doi:10.1059/0003-4819-155-9-201111010-00008. PMID 22041949.
  15. ↑ Alikhan, R; Cohen, AT (2009-07-08). Alikhan, Raza, ed. "Heparin for the prevention of venous thromboembolism in general medical patients (excluding stroke and myocardial infarction)". Cochrane database of systematic reviews (Online) (3): CD003747. doi:10.1002/14651858.CD003747.pub2. PMID 19588346.
  16. ↑ Oates-Whitehead, RM; D'Angelo, A, Mol, B (2003). "Anticoagulant and aspirin prophylaxis for preventing thromboembolism after major gynaecological surgery". Cochrane database of systematic reviews (Online) (4): CD003679. doi:10.1002/14651858.CD003679. PMID 14583989.
  17. ↑ Handoll, HH; Farrar, MJ, McBirnie, J, Tytherleigh-Strong, G, Milne, AA, Gillespie, WJ (2002). Handoll, Helen HG, ed. "Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures". Cochrane database of systematic reviews (Online) (4): CD000305. doi:10.1002/14651858.CD000305. PMID 12519540.
  18. ↑ Roderick, P; Ferris, G, Wilson, K, Halls, H, Jackson, D, Collins, R, Baigent, C (December 2005). "Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis". Health technology assessment (Winchester, England). 9 (49): iii–iv, ix–x, 1–78. PMID 16336844.
  19. ↑ National Institute for Health and Clinical Excellence. Clinical guideline 36: Atrial fibrillation. London, June 2006.
  20. 1 2 Hunt BJ (March 2008). "Awareness and politics of venous thromboembolism in the United kingdom". Arterioscler. Thromb. Vasc. Biol. 28 (3): 398–9. doi:10.1161/ATVBAHA.108.162586. PMID 18296598.
  21. ↑ National Institute for Health and Clinical Excellence. Clinical guideline 46: Venous thromboembolism (surgical). London, April 2007.
  22. 1 2 Geerts WH, Pineo GF, Heit JA, et al. (September 2004). "Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest. 126 (3 Suppl): 338S–400S. doi:10.1378/chest.126.3_suppl.338S. PMID 15383478.
  23. ↑ Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA (February 2007). "Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients" (PDF). Ann. Intern. Med. 146 (4): 278–88. doi:10.7326/0003-4819-146-4-200702200-00007. PMID 17310052.
  24. ↑ "Information about the Registry". S&H Medical Science Service. Retrieved 2014-08-15.
  25. ↑ Heneghan C, Ward A, Perera R (2012). "Self-monitoring of oral anti-coagulation: systematic review and meta-analysis of individual patient data". The Lancet. 379 (9813): 322–334. doi:10.1016/S0140-6736(11)61294-4. PMID 22137798.
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