Thrombus

Last updated
Thrombus
Other namesBlood clot
Blood clot diagram.png
Diagram of a thrombus (blood clot) that has blocked a blood vessel valve
Specialty Vascular surgery

A thrombus, 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 prevent bleeding, but can be harmful in thrombosis, when clots obstruct blood flow through healthy blood vessels.

Contents

Mural thrombi are thrombi that adhere to the wall of a blood vessel. They occur in large vessels such as the 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 entrapped white blood cells and red blood cells (darker).

Cause

Virchow's triad describes the pathogenesis of thrombus formation: [1] [2]

  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; [3]
    • 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 [4] (also called thrombophilia; any disorder of the blood that predisposes to thrombosis);
    • 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 end result is hemorrhaging and ischaemic 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.

Classification

Thrombi are classified into two major groups depending on their location and the relative amount of platelets and red blood cells (RBCs). [5] 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).

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.

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.

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. [6] This process is regulated through thromboregulation.

Prevention and treatment

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. [2] The mechanism of action of heparin and warfarin are different as they work on different pathways of the coagulation cascade. [7] Heparin works by binding to and activating the enzyme inhibitor antithrombin III, an enzyme that acts by inactivating thrombin and factor Xa. [7] 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. [7] [8] Bleeding time with heparin and warfarin therapy can be measured with the partial thromboplastin time (PTT) and prothrombin time (PT), respectively. [8]

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. [8] 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. [8] This drug is made by transgenic bacteria and converts plasminogen into the clot-dissolving enzyme, plasmin. [9] 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, [10] and causing cerebral hemorrhage. [11]

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. [12]

Prognosis

Thrombus formation can have one of four outcomes: propagation, embolization, dissolution, and organization and recanalization. [13]

  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. [1]

See also

Related Research Articles

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

Thrombosis Vascular disease caused by the formation of a blood clot inside a blood vessel

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.

Platelet Component of blood aiding in coagulation

Platelets, also called 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 that are derived from the megakaryocytes of the bone marrow, which then enter the circulation. Circulating unactivated platelets are biconvex discoid (lens-shaped) structures, 2–3 µm in greatest diameter. Activated platelets have cell membrane projections covering their surface. Platelets are found only in mammals, whereas in other vertebrates, thrombocytes circulate as intact mononuclear cells.

Venous thrombosis Blood clot (thrombus) that forms within a vein

A venous thrombosis is a thrombosis in a vein, caused by a thrombus. A common type of venous thrombosis is a deep vein thrombosis (DVT), which is a blood clot usually found in the deep veins of the leg. It is increasingly found in the deep veins of the arm, accounting for more than 10% of all deep vein thromboses. If the thrombus breaks off (embolizes) and flows towards the lungs, it can become a pulmonary embolism (PE), a blood clot in the lungs. This combination is called venous thromboembolism. Various other forms of venous thrombosis also exist; some of these can also lead to pulmonary embolism.

Coagulation Process by which blood changes from a liquid to a gel, forming a blood clot

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.

Disseminated intravascular coagulation pathological process characterized by the widespread activation of the clotting cascade that results in the formation of blood clots in the small blood vessels throughout the body

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.

Antiphospholipid syndrome Human disease

Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia. The diagnostic criteria require one clinical event and two positive blood test results spaced at least three months apart that detect lupus anticoagulant, anti-apolipoprotein antibodies, or anti-cardiolipin antibodies.

Thrombin Enzyme in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. 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. This process has two types: primary fibrinolysis and secondary fibrinolysis. The primary type is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

Thrombolysis breakdown (lysis) of blood clots formed in blood vessels, using medication

Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism.

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, blood changing 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 endothelial injury occurs, 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 has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a fibrin clot. These processes seal the hole until tissues are repaired.

Endothelium Cells that line the Inner surface of blood vessels

Endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels, and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Coronary thrombosis Human disease

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.

Urokinase mammalian protein found in Homo sapiens

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.

Thrombophilia abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels)

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

Schistocyte

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,INR) 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.

Renal vein thrombosis

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.

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). TEM investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis. The rheological conditions mimic the sluggish flow of blood in veins.

The platelet plug, also known as the hemostatic plug or platelet thrombus, is an aggregation of platelets formed during the earlier stage of hemostasis in response to blood vessel wall injury. 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.

References

  1. 1 2 Kumar, Vinay; Abbas, Abul; Aster, Jon (2014). Robbins & Cotran Pathologic Basis of Disease (9th ed.). Philadelphia, PA: Elsevier. ISBN   9781455726134. OCLC   879416939.
  2. 1 2 "Venous thromboembolism (VTE) | McMaster Pathophysiology Review". www.pathophys.org. Retrieved 2018-11-03.
  3. Kushner, Abigail; West, William P.; Pillarisetty, Leela Sharath (2020), "Virchow Triad", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30969519 , retrieved 2020-06-18
  4. Ataga KI (10 May 2020). "Hypercoagulability and thrombotic complications in hemolytic anemias". 94 (11). Haematologica. doi: 10.3324/haematol.2009.013672 . Retrieved 2 May 2020.Cite journal requires |journal= (help)
  5. "Thrombus Formation - Virchow's triad & Types of Thrombi". www.thrombosisadviser.com. Bayer AG. Retrieved 20 March 2020.
  6. 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.
  7. 1 2 3 Harter, K.; Levine, M.; Henderson, S. O. (2015). "Anticoagulation Drug Therapy: A Review". The Western Journal of Emergency Medicine. 16 (1): 11–17. doi:10.5811/westjem.2014.12.22933. PMC   4307693 . PMID   25671002.
  8. 1 2 3 4 Whalen, Karen; Finkel, Richard S.; Panavelil, Thomas A. (2015). Lippincott Illustrated Reviews: Pharmacology (6th ed.). Philadelphia: Wolters Kluwer. ISBN   9781451191776. OCLC   881019575.
  9. Saladin, Kenneth S. (2012). Anatomy & Physiology: The Unity of Form and Function (6th ed.). New York, NY: McGraw-Hill. p. 710. ISBN   978-0-07-337825-1.
  10. 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.
  11. Medcalf, R. (2011). "Plasminogen activation-based thrombolysis for ischaemic stroke: the diversity of targets may demand new approaches". Current Drug Targets. 12 (12): 1772–1781. doi:10.2174/138945011797635885. PMID   21707475.
  12. Budzynski, A. Z. (1991). "Interaction of hementin with fibrinogen and fibrin". Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis. 2 (1): 149–52. doi:10.1097/00001721-199102000-00022. PMID   1772982.
  13. Kumar, Vinay; et al. (2007). Robbins Basic Pathology (8th ed.). Philadelphia: Saunders/Elsevier. ISBN   978-1-4160-2973-1.
Classification
D