Thrombus

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Thrombus
Other namesBlood clot
Blood clot diagram.png
Diagram of a thrombus (blood clot) that has blocked a vein valve
Specialty Vascular surgery
Symptoms abrupt change in mental status, chest pain, cramp-like feeling, fatigue, passing out (syncope), and swelling in the arm and/or leg
Complications bleeding risks from taking anticoagulants, breathing problems, heart attacks, stroke
Durationc. 3–6 months
TypesSuperficial thrombophlebiti and Thrombophlebitis migrans
Causesinjury to the artery, sepsis or viral infection, immobility
Risk factors hospitalization, immobility, obesity, pregnancy, physical trauma
Diagnostic method magnetic resonance angiography, ultrasound, and venography
Prevention smoking cessation, regular exercise, improved blood flow, management of comorbidities
Treatment Anticoagulants: edoxaban, tinzaparin, unfractionated heparin
Medication apixaban, edoxaban, and rivaroxaban
Deaths100,000–300,000 each year

A thrombus (pl.: thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through healthy blood vessels in the circulatory system.

Contents

In the microcirculation consisting of the very small and smallest blood vessels the capillaries, tiny thrombi known as microclots can obstruct the flow of blood in the capillaries. This can cause a number of problems particularly affecting the alveoli in the lungs of the respiratory system resulting from reduced oxygen supply. Microclots have been found to be a characteristic feature in severe cases of COVID-19 and in long COVID. [1]

Mural thrombi are thrombi that adhere to the wall of a large blood vessel or heart chamber. [2] They are most commonly found in the aorta, the largest artery in the body, more often in the descending aorta, and less often in the aortic arch or abdominal aorta. [2] They can restrict blood flow but usually do not block it entirely. They appear grey-red along with alternating light and dark lines (known as lines of Zahn) which represent bands of white blood cells and red blood cells (darker) entrapped in layers of fibrin. [3]

Classification

Thrombi are classified into two major groups depending on their location and the relative amount of platelets and red blood cells (RBCs). [4] The two major groups are:

  1. Arterial or white thrombi (characterized by predominance of platelets)
  2. Venous or red thrombi (characterized by predominance of red blood cells).

Microclots

In the microcirculation consisting of the very small and smallest blood vessels, the capillaries, tiny thrombi (microthrombi) [5] known as microclots can obstruct the flow of blood in the capillaries. Microclots are small clumps of blood that form within the circulation, usually as a result of a larger thrombus breaking down into smaller pieces. They can be a cause for concern as they can lead to blockages in small vessels and restrict blood flow, leading to tissue damage and potentially causing ischemic events.

Microclots can cause a number of problems particularly affecting the alveoli in the lungs of the respiratory system, resulting from reduced oxygen supply. Microclots have been found to be a characteristic feature in severe cases of COVID-19, and in long COVID. [1] [6]

Mural thrombi

Mural thrombi are thrombi that form and adhere on the inner wall of a large blood vessel or heart chamber, often as a result of blood stasis. [2] They are most commonly found in the aorta, the largest artery in the body, more often in the descending aorta, and less often in the aortic arch or abdominal aorta. [2] They can restrict blood flow but usually do not block it entirely. Mural thrombi are not usually found in vessels already damaged by atherosclerosis. [3]

A mural thrombus can affect any heart chamber. When found in the left ventricle it is often a result of a heart attack complication. The thrombus in this case can separate from the chamber, be carried through arteries and block a blood vessel. [2] They appear grey-red with alternating light and dark lines (known as lines of Zahn) which represent bands of white blood cells and red blood cells (darker) entrapped in layers of fibrin.[ citation needed ]

Cause

Illustration comparing normal artery with diseased artery with a blood clot. Blausen 0053 Artery NormalvsDiseasedVessel.png
Illustration comparing normal artery with diseased artery with a blood clot.

It was suggested over 150 years ago that thrombus formation is a result of abnormalities in blood flow, vessel wall, and blood components. This concept is now known as Virchow's triad. The three factors have been further refined to include circulatory stasis, vascular wall injury, and hypercoagulable state, all of which contribute to increased risk for venous thromboembolism and other cardiovascular diseases. [4]

Virchow's triad describes the pathogenesis of thrombus formation: [7] [8]

  1. Endothelial injury: Injury to the endothelium (interior surface of blood vessel), causing platelet activation and aggregation;
  2. Hemodynamic changes (stasis, turbulence): Blood stasis promotes greater contact between platelets/coagulative factors with vascular endothelium. If rapid blood circulation (e.g., because of tachycardia) occurs within vessels that have endothelial injuries, that creates disordered flow (turbulence) that can lead to the formation of thrombosis; [9]
    • Common causes of stasis include anything that leads to prolonged immobility and reduced blood flow such as: trauma/broken bones and extended air travel.
  3. Hypercoagulability (also called thrombophilia; any disorder of the blood that predisposes to thrombosis); [10]
    • Common causes include: cancer (leukaemia), factor V mutation (Leiden) – prevents Factor V inactivation leading to increased coagulability.

Disseminated intravascular coagulation (DIC) involves widespread microthrombi formation throughout the majority of the blood vessels. This is due to excessive consumption of coagulation factors and subsequent activation of fibrinolysis using all of the body's available platelets and clotting factors. The result is hemorrhaging and ischemic necrosis of tissue/organs. Causes are septicaemia, acute leukaemia, shock, snake bites, fat emboli from broken bones, or other severe traumas. DIC may also be seen in pregnant females. Treatment involves the use of fresh frozen plasma to restore the level of clotting factors in the blood, as well as platelets and heparin to prevent further thrombi formation.[ citation needed ]

Pathophysiology

Animation of the formation of an occlusive thrombus in a vein. A few platelets attach themselves to the valve lips, constricting the opening and causing more platelets and red blood cells to aggregate and coagulate. Coagulation of unmoving blood on both sides of the blockage may propagate a clot in both directions. Thrombosis formation.gif
Animation of the formation of an occlusive thrombus in a vein. A few platelets attach themselves to the valve lips, constricting the opening and causing more platelets and red blood cells to aggregate and coagulate. Coagulation of unmoving blood on both sides of the blockage may propagate a clot in both directions.

A thrombus occurs when the hemostatic process, which normally occurs in response to injury, becomes activated in an uninjured or slightly injured vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel (termed a mural thrombus). In a small blood vessel, blood flow may be completely cut off (termed an occlusive thrombus), resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is considered an embolus.[ citation needed ] If an embolus becomes trapped within a blood vessel, it blocks blood flow and is termed as an embolism. Embolisms, depending on their specific location, can cause more significant effects like strokes, heart attacks, or even death. [11]

Mechanism of blood clotting 1909 Blood Clotting.jpg
Mechanism of blood clotting

Some of the conditions which increase the risk of blood clots developing include atrial fibrillation (a form of cardiac arrhythmia), heart valve replacement, a recent heart attack (also known as a myocardial infarction), extended periods of inactivity (see deep venous thrombosis), and genetic or disease-related deficiencies in the blood's clotting abilities.[ citation needed ]

Formation

Platelet activation occurs through injuries that damage the endothelium of the blood vessels, exposing the enzyme called factor VII, a protein normally circulating within the vessels, to the tissue factor, which is a protein encoded by the F3 gene. The platelet activation can potentially cause a cascade, eventually leading to the formation of the thrombus. [12] This process is regulated through thromboregulation.

Prevention

Anticoagulants are drugs used to prevent the formation of blood clots, reducing the risk of stroke, heart attack and pulmonary embolism. Heparin and warfarin are used to inhibit the formation and growth of existing thrombi, with the former used for acute anticoagulation while the latter is used for long-term anticoagulation. [8] The mechanism of action of heparin and warfarin are different as they work on different pathways of the coagulation cascade. [13]

Heparin works by binding to and activating the enzyme inhibitor antithrombin III, an enzyme that acts by inactivating thrombin and factor Xa. [13] In contrast, warfarin works by inhibiting vitamin K epoxide reductase, an enzyme needed to synthesize vitamin K dependent clotting factors II, VII, IX, and X. [13] [14] Bleeding time with heparin and warfarin therapy can be measured with the partial thromboplastin time (PTT) and prothrombin time (PT), respectively. [14]

Treatment

Once clots have formed, other drugs can be used to promote thrombolysis or clot breakdown. Streptokinase, an enzyme produced by streptococcal bacteria, is one of the oldest thrombolytic drugs. [14] This drug can be administered intravenously to dissolve blood clots in coronary vessels. However, streptokinase causes systemic fibrinolytic state and can lead to bleeding problems. Tissue plasminogen activator (tPA) is a different enzyme that promotes the degradation of fibrin in clots but not free fibrinogen. [14] This drug is made by transgenic bacteria and converts plasminogen into the clot-dissolving enzyme, plasmin. [15] Recent research indicates that tPA could have toxic effects in the central nervous system. In cases of severe stroke, tPA can cross the blood–brain barrier and enter interstitial fluid, where it then increases excitotoxicity, potentially affecting permeability of the blood–brain barrier, [16] and causing cerebral hemorrhage. [17]

There are also some anticoagulants that come from animals that work by dissolving fibrin. For example, Haementeria ghilianii , an Amazon leech, produces an enzyme called hementin from its salivary glands. [18]

Prognosis

Thrombus formation can have one of four outcomes: propagation, embolization, dissolution, and organization and recanalization. [19]

  1. Propagation of a thrombus occurs towards the direction of the heart and involves the accumulation of additional platelets and fibrin. This means that it is anterograde in veins or retrograde in arteries.
  2. Embolization occurs when the thrombus breaks free from the vascular wall and becomes mobile, thereby traveling to other sites in the vasculature. A venous embolus (mostly from deep vein thrombosis in the lower limbs) will travel through the systemic circulation, reach the right side of the heart, and travel through the pulmonary artery, resulting in a pulmonary embolism. Arterial thrombosis resulting from hypertension or atherosclerosis can become mobile and the resulting emboli can occlude any artery or arteriole downstream of the thrombus formation. This means that cerebral stroke, myocardial infarction, or any other organ can be affected.
  3. Dissolution occurs when the fibrinolytic mechanisms break up the thrombus and blood flow is restored to the vessel. This may be aided by fibrinolytic drugs such as Tissue Plasminogen Activator (tPA) in instances of coronary artery occlusion. The best response to fibrinolytic drugs is within a couple of hours, before the fibrin meshwork of the thrombus has been fully developed.
  4. Organization and recanalization involves the ingrowth of smooth muscle cells, fibroblasts and endothelium into the fibrin-rich thrombus. If recanalization proceeds it provides capillary-sized channels through the thrombus for continuity of blood flow through the entire thrombus but may not restore sufficient blood flow for the metabolic needs of the downstream tissue. [7]

See also

Related Research Articles

<span class="mw-page-title-main">Thrombosis</span> Medical condition caused by blood clots

Thrombosis is the formation of a blood clot 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, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Platelet</span> Component of blood aiding in coagulation

Platelets or thrombocytes are a component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus; they are fragments of cytoplasm derived from the megakaryocytes of the bone marrow or lung, which then enter the circulation. Platelets are found only in mammals, whereas in other vertebrates, thrombocytes circulate as intact mononuclear cells.

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Disseminated intravascular coagulation</span> Medical condition where blood clots block small blood vessels

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. During the clotting process, prothrombin is proteolytically cleaved by the prothrombinase enzyme complex to form thrombin. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel. It is the first stage of wound healing. This involves coagulation, which changes blood from a liquid to a gel. Intact blood vessels are central to moderating blood's tendency to form clots. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin, and prevent platelet aggregation with nitric oxide and prostacyclin. When endothelium of a blood vessel is damaged, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor, which initiate the maintenance of hemostasis after injury. Hemostasis involves three major steps:

<span class="mw-page-title-main">Factor XII</span> Mammalian protein involved in blood clotting

Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism and in the treatment of myocardial infarction.

<span class="mw-page-title-main">Coronary thrombosis</span> Medical condition

Coronary thrombosis is defined as the formation of a blood clot inside a blood vessel of the heart. This blood clot may then restrict blood flow within the heart, leading to heart tissue damage, or a myocardial infarction, also known as a heart attack.

<span class="mw-page-title-main">Schistocyte</span> Fragmented portion of a red blood cell

A schistocyte or schizocyte is a fragmented part of a red blood cell. Schistocytes are typically irregularly shaped, jagged, and have two pointed ends.

Thromboelastography (TEG) is a method of testing the efficiency of blood coagulation. It is a test mainly used in surgery and anesthesiology, although increasingly used in resuscitations in emergency departments, intensive care units, and labor and delivery suites. More common tests of blood coagulation include prothrombin time (PT) and partial thromboplastin time (aPTT) which measure coagulation factor function, but TEG also can assess platelet function, clot strength, and fibrinolysis which these other tests cannot.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

An embolus, is described as a free-floating mass, located inside blood vessels that can travel from one site in the blood stream to another. An embolus can be made up of solid, liquid, or gas. Once these masses get "stuck" in a different blood vessel, it is then known as an "embolism." An embolism can cause ischemia—damage to an organ from lack of oxygen. A paradoxical embolism is a specific type of embolism in which the embolus travels from the right side of the heart to the left side of the heart and lodges itself in a blood vessel known as an artery. Thus, it is termed "paradoxical" because the embolus lands in an artery, rather than a vein.

<span class="mw-page-title-main">Vascular disease</span> Medical condition

Vascular disease is a class of diseases of the vessels of the circulatory system in the body, including blood vessels – the arteries and veins, and the lymphatic vessels. Vascular disease is a subgroup of cardiovascular disease. Disorders in this vast network of blood and lymph vessels can cause a range of health problems that can sometimes become severe, and fatal. Coronary heart disease for example, is the leading cause of death for men and women in the United States.

<span class="mw-page-title-main">Lines of Zahn</span> Tissue damage caused by thrombosis

Lines of Zahn are a characteristic of thrombi. They have layers, with lighter layers of platelets and fibrin, and darker layers of red blood cells. They are more present on thrombi formed with faster blood flow, more so on thrombi from the heart and aorta. They are only seen on thrombi formed before death. They are named after German–Swiss pathologist Friedrich Wilhelm Zahn.

Thromboelastometry (TEM), previously named rotational thromboelastography (ROTEG) or rotational thromboelastometry (ROTEM), is an established viscoelastic method for hemostasis testing in whole blood. It is a modification of traditional thromboelastography (TEG).

The platelet plug, also known as the hemostatic plug or platelet thrombus, is an aggregation of platelets formed during early stages of hemostasis in response to one or more injuries to blood vessel walls. After platelets are recruited and begin to accumulate around the breakage, their “sticky” nature allows them to adhere to each other. This forms a platelet plug, which prevents more blood from leaving the body as well as any outside contaminants from getting in. The plug provides a temporary blockage of the break in the vasculature. As such, platelet plug formation occurs after vasoconstriction of the blood vessels but before the creation of the fibrin mesh clot, which is the more permanent solution to the injury. The result of the platelet plug formation is the coagulation of blood. It can also be referred to as primary hemostasis.

<span class="mw-page-title-main">Feline arterial thromboembolism</span> Feline arterial thromboembolism is a domestic cat disease

Feline arterial thromboembolism is a disease of the domestic cat in which blood clots (thrombi) block arteries, causing severe circulatory problems. Relative to the total number of feline patients, the disease is rare, but relatively common in cats with heart disease: about one-sixth of cats with heart disease are affected. Heart disease is the most common underlying cause of arterial thromboembolism. It leads to the formation of blood clots in the heart, which leave it with the bloodstream and obstruct larger blood vessels, in cats mainly the aorta at the outlet of the two external iliac arteries. Arterial thromboembolism occurs suddenly and is very painful. The blockage of the terminal portion of the aorta results in an undersupply of blood to the hind legs. The result is paralysis, cold hind extremities and later severe tissue damage. Rarely, other blood vessels are also affected; the symptoms of failure then depend on the supply area of the affected artery. Since drug thrombolysis in cats does not achieve satisfactory results, the focus today is on the self-dissolution of the clot by the body's own repair processes. Accompanying pain therapy and thrombosis prevention are performed and the underlying disease is treated. The mortality of arterial thromboembolism in cats is very high. Fifty to 60% of affected animals are euthanized without attempted treatment, and only one-quarter to one-third of animals survive such an event. In about half of the recovered cats, thromboembolism recurs despite anticoagulation prophylaxis.

References

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  2. 1 2 3 4 5 Singh, Davinder P.; Basit, Hajira; Malik, Ahmad; Mahajan, Kunal (5 November 2021). "Mural Thrombi". PMID   30484999 . Retrieved 11 February 2022.
  3. 1 2 Karaolanis G, Moris D, Bakoyiannis C, Tsilimigras DI, Palla VV, Spartalis E, Schizas D, Georgopoulos S (August 2017). "A critical reappraisal of the treatment modalities of normal appearing thoracic aorta mural thrombi". Ann Transl Med. 5 (15): 306. doi: 10.21037/atm.2017.05.15 . PMC   5555985 . PMID   28856146.
  4. 1 2 "Thrombus Formation – Virchow's triad & Types of Thrombi". Thrombosis Adviser. Bayer AG. Retrieved 20 March 2020.
  5. ↑ "Medical Definition of micro thrombus". www.merriam-webster.com. Retrieved 22 February 2023.
  6. ↑ Chen W, Pan JY (January 2021). "Anatomical and Pathological Observation and Analysis of SARS and COVID-19: Microthrombosis Is the Main Cause of Death". Biological Procedures Online. 23 (1): 4. doi: 10.1186/s12575-021-00142-y . PMC   7816139 . PMID   33472576. S2CID   255608747.
  7. 1 2 Kumar, Vinay; Abbas, Abul; Aster, Jon (2014). Robbins & Cotran Pathologic Basis of Disease (9th ed.). Philadelphia: Elsevier. ISBN   9781455726134. OCLC   879416939.
  8. 1 2 "Venous thromboembolism (VTE) | McMaster Pathophysiology Review". www.pathophys.org. 26 September 2012. Retrieved 2018-11-03.
  9. ↑ Kushner, Abigail; West, William P.; Pillarisetty, Leela Sharath (2020), "Virchow Triad", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30969519 , retrieved 2020-06-18
  10. ↑ Ataga KI (10 May 2020). "Hypercoagulability and thrombotic complications in hemolytic anemias". Haematologica. 94 (11): 1481–1484. doi: 10.3324/haematol.2009.013672 . PMC   2770956 . PMID   19880774.
  11. ↑ Marieb, Elaina N. Human Anatomy and Physiology (11th ed.). Pearson.
  12. ↑ Furie, Bruce; Furie, Barbara (2008). "Mechanisms of Thrombus Formation". The New England Journal of Medicine. 359 (9): 938–49. doi:10.1056/NEJMra0801082. PMID   18753650.
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  16. ↑ Fredriksson, L.; Lawrence, D. A.; Medcalf, R. L. (2016). "TPA modulation of the blood–brain barrier: A unifying explanation for the pleiotropic effects of tPA in the CNS?". Seminars in Thrombosis and Hemostasis. 43 (2): 154–168. doi:10.1055/s-0036-1586229. PMC   5848490 . PMID   27677179.
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  18. ↑ Budzynski, A. Z. (1991). "Interaction of hementin with fibrinogen and fibrin". Blood Coagulation & Fibrinolysis. 2 (1): 149–52. doi:10.1097/00001721-199102000-00022. PMID   1772982.
  19. ↑ Kumar, Vinay; et al. (2007). Robbins Basic Pathology (8th ed.). Philadelphia: Saunders/Elsevier. ISBN   978-1-4160-2973-1.
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