Editing Thrombus

{{Short description|Blood clot}}
{{For|the sea sponge genus|Thrombus (sponge)}}
{{Redirect2|Clot|Blood clot}}
{{Distinguish|Embolism|Thrombosis}}
{{Infobox medical condition (new)
| name          = Thrombus
| synonyms      = Blood clot
| image         = Blood clot svg hariadhi.svg
| alt           =
| caption       = Diagram of a thrombus (blood clot) that has blocked a [[Vein#Venous valves|vein valve]]
| field         = [[Vascular surgery]]
| symptoms      = abrupt change in [[mental status]], [[chest pain]], cramp-like feeling, [[fatigue]], passing out ([[Syncope (medicine)|syncope]]), and swelling in the arm and/or leg
| complications = bleeding risks from taking [[anticoagulants]], breathing problems, [[heart attacks]], [[stroke]]
| onset         =
| duration      = c. 3–6 months
| types         = [[Superficial thrombophlebitis]] and [[thrombophlebitis migrans]]
| causes        = injury to the artery, sepsis or viral infection, [[Bed rest|immobility]]
| risks         = [[hospitalization]], [[Bed rest|immobility]], [[obesity]], [[pregnancy]], [[Major trauma|physical trauma]]
| diagnosis     = [[magnetic resonance angiography]], [[ultrasound]], and [[venography]]
| differential  =
| prevention    = [[smoking cessation]], regular exercise, improved blood flow, management of comorbidities
| treatment     = [[Anticoagulants]]: [[edoxaban]], [[tinzaparin]], unfractionated heparin
| medication    = [[apixaban]], [[edoxaban]], and [[rivaroxaban]]
| prognosis     =
| frequency     =
| deaths        = 100,000–300,000 each year
}}

A '''thrombus''' ({{plural form}} '''thrombi''') is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life.<ref>{{Citation |title=Thrombosis |date=1971-01-01 |work=Thrombosis and Bleeding Disorders |pages=488–534 |editor-last=Bang |editor-first=Nils U. |url=https://www.sciencedirect.com/science/article/abs/pii/B9780120777501500155 |access-date=2025-02-27 |publisher=Academic Press |isbn=978-0-12-077750-1 |editor2-last=Beller |editor2-first=Fritz K. |editor3-last=Deutsch |editor3-first=Erwin |editor4-last=Mammen |editor4-first=Eberhard F.}}</ref><ref>{{Cite book |last=Rubin |first=Emanuel |url=https://books.google.com/books?id=7HdzBBhtxycC&pg=PA119 |title=Essentials of Rubin's Pathology |last2=Reisner |first2=Howard M. |date=2009 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7324-9 |language=en}}</ref> A '''blood clot''' is the final product of the [[blood coagulation]] step in [[hemostasis]] in or out of the circulatory system. There are two components to a thrombus: aggregated [[platelets]] and [[red blood cell]]s 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 a healthy [[blood vessel]] in the [[circulatory system]].

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 [[pulmonary alveolus|alveoli]] in the [[lung]]s 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]].<ref name="Pretorius">{{cite journal |vauthors=Pretorius E, Vlok M, Venter C, Bezuidenhout JA, Laubscher GJ, Steenkamp J, Kell DB |title=Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin |journal=Cardiovasc Diabetol |volume=20 |issue=1 |pages=172 |date=August 2021 |pmid=34425843 |pmc=8381139 |doi=10.1186/s12933-021-01359-7 |url= |doi-access=free }}</ref>

Mural thrombi are thrombi that adhere to the wall of a large [[blood vessel]] or [[heart chamber]].<ref name="Singh">{{cite web |last1=Singh |first1=Davinder P. |last2=Basit |first2=Hajira |last3=Malik |first3=Ahmad |last4=Mahajan |first4=Kunal |title=Mural Thrombi |url=https://www.ncbi.nlm.nih.gov/books/NBK534294/ |access-date=11 February 2022 |language=en |date=5 November 2021|pmid=30484999 }}</ref> 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]].<ref name="Singh"/> 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.<ref name="Karaolanis">{{cite journal |vauthors=Karaolanis G, Moris D, Bakoyiannis C, Tsilimigras DI, Palla VV, Spartalis E, Schizas D, Georgopoulos S |title=A critical reappraisal of the treatment modalities of normal appearing thoracic aorta mural thrombi |journal=Ann Transl Med |volume=5 |issue=15 |pages=306 |date=August 2017 |pmid=28856146 |pmc=5555985 |doi=10.21037/atm.2017.05.15 |url= |doi-access=free }}</ref>

==Classification==
Thrombi are classified into two major groups depending on their location and the relative amount of platelets and red blood cells.<ref name=":3">{{cite web |title=Thrombus Formation – Virchow's triad & Types of Thrombi |url=https://www.thrombosisadviser.com/en/professionals/knowledge-base/essentials/thrombus-formation |access-date=20 March 2020 |website=Thrombosis Adviser |publisher=Bayer AG}}</ref> The two major groups are:
# [[Arterial]] or white thrombi (characterized by predominance of platelets)
# [[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)<ref>{{cite web |title=Medical Definition of micro thrombus |url=https://www.merriam-webster.com/medical/microthrombus |website=www.merriam-webster.com |access-date=22 February 2023 |language=en}}</ref> known as microclots can obstruct the flow of blood in the capillaries. Microclots are small clumps of blood that form within the circulation, possibly as a result of a larger thrombus breaking down into smaller pieces or more likely by accretion. 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 [[ischemia|ischemic events]].<ref>{{cite journal |last1=Kell |first1=DB |last2=Laubscher |first2=GJ |last3=Pretorius |first3=E |title=A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. |journal=Biochem J |date=2022 |volume=479 |pages=537-559 |url=https://portlandpress.com/biochemj/article/479/4/537/230829/A-central-role-for-amyloid-fibrin-microclots-in}}</ref> This can in turn lead to a form of chronic ischaemia-reperfusion injury<ref>{{cite journal |last1=Kell |first1=DB |last2=Pretorius |first2=E |title=The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, long COVID and ME/CFS: evidence, mechanisms, and therapeutic implications |journal=Biochem J |date=2022 |volume=479 |pages=1653-1709 |url=https://portlandpress.com/biochemj/article/479/16/1653/231696/The-potential-role-of-ischaemia-reperfusion-injury/}}</ref> and to the generation of autoantibodies.<ref>{{cite journal |last1=Kell |first1=DB |last2=Pretorius |first2=E |title=Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? |journal=Biochem J |date=2023 |volume=480 |pages=1217-1240 |url=https://portlandpress.com/biochemj/article/480/15/1217/233389/Are-fibrinaloid-microclots-a-cause-of-autoimmunity}}</ref> Because of their amyloid nature<ref>{{cite journal |last1=Pretorius |first1=E |last2=Mbotwe |first2=S |last3=Bester |first3=J |last4=Robinson |first4=C |last5=Kell |first5=DB |title=Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide. |journal=J R Soc Interf |date=2016 |pages=20160539 |url=http://rsif.royalsocietypublishing.org/content/13/122/20160539}}</ref><ref>{{cite journal |last1=Kell |first1=DB |last2=Pretorius |first2=E |title=Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. |journal=Progr Biophys Mol Biol |date=2017 |volume=123 |pages=15-41 |pmid=27554450 |url=http://www.sciencedirect.com/science/article/pii/S0079610716300499}}</ref> they are somewhat resistant to thrombolytic agents, which,<ref>{{cite journal |last1=Kell |first1=DB |last2=Pretorius |first2=E |title=Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots. |journal=Int J Mol Sci |date=2024 |volume=25 |pages=10809 |url=https://www.mdpi.com/1422-0067/25/19/10809}}</ref> along with the presence of certain other proteins,<ref>{{cite journal |last1=Pretorius |first1=E |last2=Vlok |first2=M |last3=Venter |first3=C |last4=Bezuidenhout |first4=J |last5=Laubscher |first5=GJ |last6=Steenkamp |first6=J |last7=Kell |first7=DB |title=Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. |journal=Cardiovasc Diabetol |date=2021 |volume=20 |pages=172 |URL=https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7|pmid=34425843}}</ref> explains their persistence. Evidence based on the proteomes of such microclots implies<ref>{{cite journal |last1=Kell |first1=DB |last2=Pretorius |first2=E |title=The proteome content of blood clots observed under different conditions: successful role in predicting clot amyloid(ogenicity). |journal=Molecules |date=2025 |volume=30 |pages=668 |url=https://www.mdpi.com/1420-3049/30/3/668}}</ref> that the macroclots formed in other diseases should also be amyloid in character; this has been shown<ref>{{cite journal |last1=Grixti |first1=JM |last2=Chandran |first2=A |last3=Pretorius |first3=J |last4=Walker |first4=M |last5=Sekhar |first5=A |last6=Pretorius |first6=E |last7=Kell |first7=DB |title=The clots removed from ischaemic stroke patients by mechanical thrombectomy are amyloid in nature. |journal=medRxiv |date=2024 |pages=2024:10.1101/2024.1111.1101.24316555v24316551 |url=https://www.medrxiv.org/content/10.1101/2024.11.01.24316555v1}}</ref> for [[ischaemic stroke]].

Microclots can cause a number of problems particularly affecting the [[pulmonary alveolus|alveoli]] in the [[lung]]s 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]].<ref>{{cite journal |last1=Pretorius |first1=E |last2=Venter |first2=C |last3=Laubscher |first3=GJ |last4=Kotze |first4=MJ |last5=Oladejo |first5=S |last6=Watson |first6=LR |last7=Rajaratnam |first7=K |last8=Watson |first8=BW |last9=Kell |first9=DB |title=Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) |journal=Cardiovasc Diabetol |date=2022 |volume=21 |pages=148 |url=https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01579-5}}</ref><ref name="Pretorius" /><ref name="Chen">{{cite journal |vauthors=Chen W, Pan JY |title=Anatomical and Pathological Observation and Analysis of SARS and COVID-19: Microthrombosis Is the Main Cause of Death |journal= Biological Procedures Online|volume= 23|issue=1 |pages=4 |date=January 2021 |pmid= 33472576|doi=10.1186/s12575-021-00142-y |s2cid=255608747 |url=|pmc=7816139 |doi-access=free }}</ref><ref>{{cite web |title="Long COVID and the role of fibrin amyloid (fibrinaloid) microclots" |url=http://dbkgroup.org/longcovid/}}</ref><ref>{{cite journal |last1=Dalton |first1=CF |last2=de Oliveira |first2=MIR |last3=Stafford |first3=P |last4=Peake |first4=N |last5=Kane |first5=B |last6=Higham |first6=A |last7=Singh |first7=D |last8=Jackson |first8=N |last9=Davies |first9=H |last10=Price |first10=D |last11=Duncan |first11=R |last12=Tattersall |first12=N |last13=Barnes |first13=A |last14=Smith |first14=DP |title=Increased fibrinaloid microclot counts in platelet-poor plasma are associated with Long COVID |journal=medRxiv |date=2024 |pages=2024.04.04.24305318 |url=https://www.medrxiv.org/content/medrxiv/early/2024/04/05/2024.04.04.24305318.full.pdf}}</ref> Fibrinaloid microclots can be induced directly via the addition of [[SARS-CoV-2]] [[spike protein]] to 'healthy' plasma,<ref>{{cite journal |last1=Grobbelaar |first1=LM |last2=Venter |first2=C |last3=Vlok |first3=M |last4=Ngoepe |first4=M |last5=Laubscher |first5=GJ |last6=Lourens |first6=PJ |last7=Steenkamp |first7=J |last8=Kell |first8=DB |last9=Pretorius |first9=E |title=SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19 |journal=Biosci Rep |date=2021 |volume=41 |issue=8 |pages=BSR20210611 |url=https://portlandpress.com/bioscirep/article/41/8/BSR20210611/229418/SARS-CoV-2-spike-protein-S1-induces-fibrin-ogen}}</ref> and the fact that the amyloidogenic potential of the spike variant is related to its virulence<ref>{{cite journal |last1=Grobbelaar |first1=LM |last2=Kruger |first2=A |last3=Venter |first3=C |last4=Burger |first4=EM |last5=Laubscher |first5=GJ |last6=Maponga |first6=TG |last7=Kotze |first7=MJ |last8=Kwaan |first8=HC |last9=Miller |first9=JB |last10=Fulkerson |first10=D |last11=Huff |first11=W |last12=Chang |first12=E |last13=Wiarda |first13=G |last14=Bunch |first14=CM |last15=Walsh |first15=MM |last16=Raza |first16=S |last17=Zamlut |first17=M |last18=Moore |first18=HB |last19=Moore |first19=EE |last20=Neal |first20=M |last21=Kell |first21=DB |last22=Pretorius |first22=E |title=Relative hypercoagulopathy of the SARS-CoV-2 Beta and Delta variants when compared to the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness |journal=Semin Thromb Hemost |date=2022 |volume=48 |pages=858-868 |url=https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0042-1756306}}</ref> provides a strong indication that the microclots are on the [[aetiological]] pathway of [[Long Covid]].

The fibrinaloid microclots also provide a ready explanation for other phenomena such as Postural Orthostatic Tachycardia Syndrome (POTS),<ref>{{cite journal |last1=Kell |first1=DB |last2=Khan |first2=MA |last3=Kane |first3=B |last4=Lip |first4=GYH |last5=Pretorius |first5=E |title=The role of fibrinaloid microclots in Postural Orthostatic Tachycardia Syndrome (POTS): focus on Long COVID. |journal=J Personalized Med |date=2024 |volume=14 |pages=170 |url=https://www.mdpi.com/2075-4426/14/2/170}}</ref> atrial fibrillation,<ref>{{cite journal |last1=Kell |first1=DB |last2=Lip |first2=GYH |last3=Pretorius |first3=E |title=Fibrinaloid Microclots and Atrial Fibrillation. |journal=Biomedicines |date=2024 |volume=12 |pages=891 |url=https://www.mdpi.com/2227-9059/12/4/891}}</ref> and fibromyalgia.<ref>{{cite journal |last1=Kell |first1=DB |last2=Pretorius |first2=E |title=Potential roles of fibrinaloid microclots in fibromyalgia syndrome |journal=OSF |date=2024 |pages=9e2y5 |url=https://osf.io/9e2y5/}}</ref>

Fibrinaloid microclots are easily measured using techniques such as fluorescence microscopy<ref>{{cite journal |last1=Grixti |first1=JM |last2=Theron |first2=CW |last3=Salcedo-Sora |first3=JE |last4=Pretorius |first4=E |last5=Kell |first5=DB |title=Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease. |journal=J Exp Clin App Chin Med |date=2024 |volume=5 |pages=30-55 |url=https://ojs.exploverpub.com/index.php/jecacm/article/view/201}}</ref> and flow cytometry<ref>{{cite journal |last1=Turner |first1=S |last2=Laubscher |first2=GJ |last3=Khan |first3=MA |last4=Kell |first4=DB |last5=Pretorius |first5=E |title=Accelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model. |journal=Heliyon |date=2023 |volume=9 |pages=e19605 |url=https://www.cell.com/heliyon/pdf/S2405-8440(23)06813-5.pdf}}</ref> ('flow clotometry'<ref>{{cite journal |last1=Pretorius |first1=E |last2=Nunes |first2=M |last3=Pretorius |first3=J |last4=Kell |first4=DB |title=Flow Clotometry: Measuring Amyloid Microclots in ME/CFS, Long COVID, and Healthy Samples with Imaging Flow Cytometry. |journal=Research Square |pages=https://www.researchsquare.com/article/rs-4507472/v4507471 |url=https://www.researchsquare.com/article/rs-4507472/v1}}</ref>).

===Mural thrombi===
{{Further|Left ventricular thrombus}}
Mural thrombi form and adhere on the inner wall of a large [[blood vessel]] or [[heart chamber]], often as a result of blood stasis.<ref name="Singh" /> 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]].<ref name="Singh"/> They can restrict blood flow but usually do not block it entirely. Mural thrombi are usually found in vessels already damaged by [[atherosclerosis]].<ref name="Karaolanis"/>

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.<ref name="Singh"/> 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|date=September 2022}}

==Cause==
[[File:Blausen 0053 Artery NormalvsDiseasedVessel.png|thumb|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.<ref name=":3" />

[[Virchow's triad]] describes the [[pathogenesis]] of thrombus formation:<ref name=":0">{{Cite book|title=Robbins & Cotran Pathologic Basis of Disease|last1=Kumar |first1=Vinay |last2=Abbas |first2=Abul |last3=Aster |first3=Jon |isbn=9781455726134|edition= 9th |publisher=Elsevier |location=Philadelphia|oclc=879416939|year = 2014}}</ref><ref name=":1">{{Cite web|url=http://www.pathophys.org/vte/|title=Venous thromboembolism (VTE) {{!}} McMaster Pathophysiology Review|website=www.pathophys.org|date=26 September 2012 |language=en-US|access-date=2018-11-03}}</ref>

# Endothelial injury: Injury to the [[endothelium]] (interior surface of blood vessel), causing platelet activation and aggregation;
#* Common causes include: [[Injury|trauma]], [[Health effects of tobacco|smoking]], [[hypertension]], [[atheroma]].
# [[Hemodynamics|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;<ref>{{Citation|last1=Kushner|first1=Abigail|title=Virchow Triad|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK539697/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=30969519|access-date=2020-06-18|last2=West|first2=William P.|last3=Pillarisetty|first3=Leela Sharath}}</ref>
#* Common causes of stasis include anything that leads to prolonged immobility and reduced blood flow such as: [[Injury|trauma]]/[[Bone fracture|broken bones]] and extended [[air travel]].
# Hypercoagulability (also called [[thrombophilia]]; any disorder of the blood that predisposes to thrombosis);<ref>{{cite journal |vauthors=Ataga KI |date=10 May 2020 |title=Hypercoagulability and thrombotic complications in hemolytic anemias |journal=Haematologica |volume=94 |issue=11 |pages=1481–1484 |doi=10.3324/haematol.2009.013672 |pmc=2770956 |pmid=19880774 |doi-access=free}}</ref>
#* Common causes include: cancer ([[leukaemia]]), [[factor V]] mutation ([[Factor V Leiden|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 (circulatory)|shock]], snake bites, [[Fat embolism|fat emboli]] from broken bones, or other severe traumas. DIC may also be seen in [[Pregnancy|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|date=February 2021}}. Both [[Disseminated intravascular coagulation]] and [[sepsis]] are closely correlated<ref>{{cite journal |last1=Schofield |first1=J |last2=Absrams |first2=ST |last3=Jenkins |first3=R |last4=Lane |first4=S |last5=Wang |first5=G |last6=Toh |first6=CH |title=Microclots, as defined by amyloid-fibrinogen aggregates, predict risks of disseminated intravascular coagulation and mortality |journal=Blood Adv |date=2024 |volume=8 |pages=2499-2508 |pmid=38507683 |url=https://ashpublications.org/bloodadvances/article/8/10/2499/515373/Microclots-as-defined-by-amyloid-fibrinogen}}</ref> with the presence of fibrinaloid microclots in the circulation.

==Pathophysiology==
[[File:Thrombosis formation.gif|thumb|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 [[Embolism|embolus]].{{citation needed|date=February 2021}} 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.<ref>{{cite book |last1=Marieb |first1=Elaina N. |title=Human Anatomy and Physiology |publisher=Pearson |edition=11th}}</ref>
[[File:1909 Blood Clotting.jpg|thumb|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 [[myocardial infarction|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|date=February 2021}}

===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&nbsp;F3&nbsp;gene.
The platelet activation can potentially cause a cascade, eventually leading to the formation of the thrombus.<ref>{{cite journal |last1=Furie |first1=Bruce |last2=Furie |first2=Barbara |year=2008 |title=Mechanisms of Thrombus Formation |journal=The New England Journal of Medicine |volume=359 |issue=9 |doi=10.1056/NEJMra0801082 |pmid=18753650 |pages=938–49}}</ref> This process is regulated through [[thromboregulation]].
<gallery>
File:Fetal thrombotic vasculopathy - very high mag.jpg|[[Micrograph]] showing a thrombus (center of image) within a blood vessel of the [[placenta]]. [[H&E stain]].
File:Blausen 0088 BloodClot.png|Illustration depicting thrombus formation over arterial plaque.
File:Composition of a fresh thrombus.jpg|Composition of a fresh thrombus at microscopy, showing nuclear debris in a background of [[fibrin]] and [[red blood cell]]s.
</gallery>

==Prevention==
{{Main|Thrombolysis|Thrombosis prophylaxis|Reperfusion therapy}}

[[Anticoagulant]]s are drugs used to prevent the formation of blood clots, reducing the risk of [[stroke]], [[myocardial infarction|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.<ref name=":1" /> The mechanism of action of heparin and warfarin are different as they work on different pathways of the [[Coagulation|coagulation cascade]].<ref name="harter">{{cite journal|pmc=4307693|year=2015|last1=Harter|first1=K.|title=Anticoagulation Drug Therapy: A Review|journal=The Western Journal of Emergency Medicine|volume=16|issue=1|pages=11–17|last2=Levine|first2=M.|last3=Henderson|first3=S. O.|pmid=25671002|doi=10.5811/westjem.2014.12.22933}}</ref>

Heparin works by binding to and activating the enzyme inhibitor [[antithrombin|antithrombin III]], an enzyme that acts by inactivating thrombin and factor Xa.<ref name=harter/> 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.<ref name=harter/><ref name=":2">{{Cite book|title=Lippincott Illustrated Reviews: Pharmacology|isbn=9781451191776|edition= 6th|publisher=Wolters Kluwer|location=Philadelphia| oclc=881019575|last1 = Whalen|first1 = Karen|last2=Finkel|first2=Richard S.|last3=Panavelil|first3=Thomas A.|year=2015}}</ref> Bleeding time with heparin and warfarin therapy can be measured with the partial thromboplastin time (PTT) and [[prothrombin time]] (PT), respectively.<ref name=":2" />

==Treatment==
Once clots have formed, other drugs can be used to promote [[thrombolysis]] or clot breakdown. [[Streptokinase]], an enzyme produced by [[Streptococcus|streptococcal bacteria]], is one of the oldest thrombolytic drugs.<ref name=":2"/> This drug can be administered [[Intravenous therapy|intravenously]] to dissolve blood clots in [[Coronary circulation|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.<ref name=":2"/> This drug is made by transgenic bacteria and converts plasminogen into the clot-dissolving enzyme, [[plasmin]].<ref>{{cite book |last=Saladin |first=Kenneth S. |title=Anatomy & Physiology: The Unity of Form and Function |edition= 6th |location=New York |publisher=McGraw-Hill |year=2012 |page=710 |isbn=978-0-07-337825-1 }}</ref> 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,<ref>{{cite journal|pmc=5848490|year=2016|last1=Fredriksson|first1=L.|title=TPA modulation of the blood–brain barrier: A unifying explanation for the pleiotropic effects of tPA in the CNS?|journal=Seminars in Thrombosis and Hemostasis|volume=43|issue=2|pages=154–168|last2=Lawrence|first2=D. A.|last3=Medcalf|first3=R. L.|pmid=27677179|doi=10.1055/s-0036-1586229}}</ref> and causing cerebral hemorrhage.<ref>{{Cite journal|last=Medcalf|first=R.|title=Plasminogen activation-based thrombolysis for ischaemic stroke: the diversity of targets may demand new approaches|journal=Current Drug Targets|volume=12|issue=12|pages=1772–1781|doi=10.2174/138945011797635885|pmid=21707475|year=2011}}</ref>

There are also some anticoagulants that come from animals that work by dissolving [[fibrin]]. For example, ''[[Haementeria ghilianii]]'', an [[Amazon rainforest|Amazon]] [[leech]], produces an enzyme called [[hementin]] from its [[salivary gland]]s.<ref>{{cite journal|pmid=1772982|year=1991|last1=Budzynski|first1=A. Z.|title=Interaction of hementin with fibrinogen and fibrin|journal=Blood Coagulation & Fibrinolysis |volume=2|issue=1|pages=149–52|doi=10.1097/00001721-199102000-00022}}</ref>

==Prognosis==
Thrombus formation can have one of four outcomes: propagation, embolization, dissolution, and organization and recanalization.<ref>{{cite book |first=Vinay |last=Kumar |title=Robbins Basic Pathology |location=Philadelphia |publisher=Saunders/Elsevier |year=2007 |edition= 8th |isbn=978-1-4160-2973-1 |display-authors=etal}}</ref>
# 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.
# [[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 [[human leg|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.
# Dissolution occurs when the [[fibrinolysis|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.
# Organization and recanalization involves the ingrowth of [[smooth muscle]] cells, [[fibroblast]]s 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.<ref name=":0" />

==See also==
* [[Thrombogenicity]] (the tendency to clot)
* [[National Blood Clot Alliance]]
* [[Hemorrhoid]]

==References==
{{Reflist}}

== External links ==
{{Wiktionary|thrombus|clot}}
* [http://www.medicalnewstoday.com/articles/87699.php Muscle Relaxing Drugs Can Reduce Lethal Blood Clots] {{Webarchive|url=https://web.archive.org/web/20090204115537/http://www.medicalnewstoday.com/articles/87699.php |date=2009-02-04 }}
* {{usurped|1=[https://web.archive.org/web/20070925112008/http://www.planetark.com/dailynewsstory.cfm/newsid/44436/story.htm Air Pollution Triggers Blood Clots – US Study]}}.

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{{Bleeding and clotting disorders|us=y}}
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[[Category:Hematology]]
[[Category:Ischemia]]

[[es:Trombosis]]
[[it:Trombosi]]