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{{Thrombophilia}}
{{Thrombophilia}}
{{CMG}} {{AE}} {{asiri}}
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==Overview==
==Overview==
* Thrombophilia may be caused by either [[Thrombophilia_classification|acquired, inherited, or, more commonly, a combination of both conditions]].
Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions.
* The most frequent forms of inherited thrombophilia are Factor V Leiden (20-50% prevalence in patients with recurrent venous thrombosis) and prothrombon G20210A (5-20% prevalence in patients with recurrent venous thrombosis).<ref name="pmid11309638">{{cite journal| author=Seligsohn U, Lubetsky A| title=Genetic susceptibility to venous thrombosis. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 16 | pages= 1222-31 | pmid=11309638 | doi=10.1056/NEJM200104193441607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11309638  }} </ref><ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360  }} </ref>


==Causes==
==Causes==
===Inherited===
*'''Virchow's triad:''' The cause of thrombosis is multifactorial which causes an imbalance in endogenous anticoagulation and hemostasis through a complex pathophysiologic mechanism. Rudolf Virchow proposed Virchow's triad in 1856 and described the three common factors which predisposes to thrombosis as follows: <ref name="pmid20739582">{{cite journal| author=Kumar DR, Hanlin E, Glurich I, Mazza JJ, Yale SH| title=Virchow's contribution to the understanding of thrombosis and cellular biology. | journal=Clin Med Res | year= 2010 | volume= 8 | issue= 3-4 | pages= 168-72 | pmid=20739582 | doi=10.3121/cmr.2009.866 | pmc=3006583 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20739582  }} </ref>
Common types:
**'''Damage to the endothelial lining of the vessel wall:''' It leads to the production of pro-inflammatory and prothrombotic cytokines, an increase in available tissue factor, the proliferation of adhesion molecules, and enhanced platelet activation. Cytokines initiate inflammation-promoting interaction between leukocytes and endothelial cells. Inflammation is a normal body reaction to unwanted stimuli such as foreign pathogens or infection and endothelial damage, whether acute (e.g., catheter placement, trauma or surgery) or chronic (underlying inflammatory disorders or peripheral vascular disease). <ref name="pmid29872658">{{cite journal| author=Mosevoll KA, Johansen S, Wendelbo Ø, Nepstad I, Bruserud Ø, Reikvam H| title=Cytokines, Adhesion Molecules, and Matrix Metalloproteases as Predisposing, Diagnostic, and Prognostic Factors in Venous Thrombosis. | journal=Front Med (Lausanne) | year= 2018 | volume= 5 | issue= | pages= 147 | pmid=29872658 | doi=10.3389/fmed.2018.00147 | pmc=5972295 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29872658 }} </ref>
* '''[[Factor V Leiden]]''': Factor V is a procoagulant which upon activation promotes the formation of thrombin. In 1994, Bertina and colleagues identified a single nucleotide polymorphism (guanine to adenine substitution in nucleotide 1691), which rendered factor V resistant to proteolytic inactivation by activated protein C (APC).<ref name="pmid8164741">{{cite journal| author=Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H et al.| title=Mutation in blood coagulation factor V associated with resistance to activated protein C. | journal=Nature | year= 1994 | volume= 369 | issue= 6475 | pages= 64-7 | pmid=8164741 | doi=10.1038/369064a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8164741 }} </ref>  
**'''Hypercoagulable state:''' It is due to a variety of alterations in the coagulation and hemostatic system, which can result from inflammatory factors, variations in the viscosity of blood and blood components, increased cytokines, and prothrombotic proteins in circulation, or deficiencies of natural or endogenous anticoagulant factors. <ref name="urlHypercoagulability - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK538251/ |title=Hypercoagulability - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref> 
* [http://emedicine.medscape.com/article/209742-overview Prothrombin G20210A]: [[Prothrombin]], or factor II, is a precursor to throbmin. A single nucleotide polymorphism (guanine to adenonine substitution in in nucleotide 20210) was first identied by Poort and colleages in 1996. The mutation was associated with elevated prothrombin, thought to be due to increased translation efficiency, and an increased risk of thrombosis.<ref name="pmid8916933">{{cite journal| author=Poort SR, Rosendaal FR, Reitsma PH, Bertina RM| title=A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. | journal=Blood | year= 1996 | volume= 88 | issue= 10 | pages= 3698-703 | pmid=8916933 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8916933 }} </ref>
**'''Arterial or venous blood stasis:''' This third aspect could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis such as residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis. Long trips with limited mobility in cases where concurrent additional risk factors are present can be considered as a relative risk factor for thrombosis. <ref name="urlThrombosis - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK538430/ |title=Thrombosis - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref> 
* Coinheritance of multiple thrombophilias is not infrequent, and does increase the thrombotic risk in affected patients.  
 
*'''Hypercoagulable states:''' Hypercoagulability disorders are either acquired or inherited. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis, thereby explaining the inter-individual differences observed in patients with inherited mutations. <ref name="urlHypercoagulability - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK538251/ |title=Hypercoagulability - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref> <ref name="pmid16968541">{{cite journal| author=Khan S, Dickerman JD| title=Hereditary thrombophilia. | journal=Thromb J | year= 2006 | volume= 4 | issue=  | pages= 15 | pmid=16968541 | doi=10.1186/1477-9560-4-15 | pmc=1592479 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16968541  }} </ref> <ref name="pmid11700155">{{cite journal| author=Thomas RH| title=Hypercoagulability syndromes. | journal=Arch Intern Med | year= 2001 | volume= 161 | issue= 20 | pages= 2433-9 | pmid=11700155 | doi=10.1001/archinte.161.20.2433 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11700155  }} </ref> <ref name="pmid10957782">{{cite journal| author=März W, Nauck M, Wieland H| title=The molecular mechanisms of inherited thrombophilia. | journal=Z Kardiol | year= 2000 | volume= 89 | issue= 7 | pages= 575-86 | pmid=10957782 | doi=10.1007/s003920070206 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10957782  }} </ref>
**'''Inherited forms''' can be identified in up to 30% of patients with venous thromboembolism and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. However, other inherited thrombophilias are rare such as antithrombin III, protein C and protein S deficiency (around 1% in the general population) but pose a higher risk for thrombosis. Mutations influencing coagulation factors can present in heterozygous or homozygous genotype. <ref name="urlHypercoagulability - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK538251/ |title=Hypercoagulability - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
**'''Acquired factors''' are far more common and influence the coagulation cascade by multitude of factors including medications (e.g., oral contraceptives, estrogen or other hormonal replacement), recent inflammatory conditions such as pregnancy, surgery, trauma, or infection, and chronic inflammatory conditions (e.g., morbid obesity, rheumatologic disease, ulcerative colitis, heavy smoking). <ref name="pmid10957782">{{cite journal| author=März W, Nauck M, Wieland H| title=The molecular mechanisms of inherited thrombophilia. | journal=Z Kardiol | year= 2000 | volume= 89 | issue= 7 | pages= 575-86 | pmid=10957782 | doi=10.1007/s003920070206 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10957782  }} </ref> <ref name="pmid15139558">{{cite journal| author=Mazza JJ| title=Hypercoagulability and venous thromboembolism: a review. | journal=WMJ | year= 2004 | volume= 103 | issue= 2 | pages= 41-9 | pmid=15139558 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15139558 }} </ref>  
**'''Malignancy''' (occult or diagnosed) can predispose to hypercoagulability as tumor cells can express a variety of procoagulant proteins including increased expression tissue factor. Some solid tumors such as pancreatic cancer are known to significantly increase the risk of thrombosis. <ref name="CaineStonelake2002">{{cite journal|last1=Caine|first1=Graham J|last2=Stonelake|first2=Paul S|last3=Lip|first3=Gregory Y H|last4=Kehoe|first4=Sean T|title=The Hypercoagulable State of Malignancy: Pathogenesis and Current Debate|journal=Neoplasia|volume=4|issue=6|year=2002|pages=465–473|issn=15228002|doi=10.1038/sj.neo.7900263}}</ref>
**Typically, '''venous thrombosis''' is initiated by endothelial damage, while '''arterial thrombosis''' starts with atherosclerosis, and acquired hypercoagulable states leading to both '''venous and arterial thrombus''' include acquired antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia & thrombosis (HITT). <ref name="urlHypercoagulability - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK538251/ |title=Hypercoagulability - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref> 


Rare forms:
*'''Venous thromboembolism (VTE):''' Stasis behind venous valves contributes to venous thrombosis and red thrombus formation. An anatomy of the '''deep veins''' of the extremities and the pulmonary system should be considered such as the deep veins of the lower extremity include the femoral, iliac, and popliteal veins; and the upper extremity veins include the subclavian, axillary, brachial veins. Other thrombosis sites include superior vena cava thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, cavernous sinus thrombosis, and retinal vein occlusion. Thrombosis of '''superficial veins''' is possible with provoking factors such as intravenous catheterization or localized cellulitis; however, the treatment of superficial vein thrombosis does not typically require any anticoagulation. <ref name="StoneHangge2017">{{cite journal|last1=Stone|first1=Jonathan|last2=Hangge|first2=Patrick |last3=Albadawi|first3=Hassan |last4=Wallace|first4=Alex |last5=Shamoun|first5=Fadi |last6=Knuttien|first6=M. Grace |last7=Naidu|first7=Sailendra |last8=Oklu|first8=Rahmi |title=Deep vein thrombosis: pathogenesis, diagnosis, and medical management|journal=Cardiovascular Diagnosis and Therapy|volume=7|issue=S3|year=2017|pages=S276–S284|issn=22233652|doi=10.21037/cdt.2017.09.01}}</ref> <ref name="LitzendorfLitzendorf2011">{{cite journal|last1=Litzendorf|first1=Maria|last2=Litzendorf|first2=Maria|title=Superficial venous thrombosis: disease progression and evolving treatment approaches|journal=Vascular Health and Risk Management|year=2011|pages=569|issn=1178-2048|doi=10.2147/VHRM.S15562}}</ref>
* [[Antithrombin|Antithrombin III]] deficiency
* [[Protein C deficiency]]
* [[Protein S deficiency]]
* [[Familial_dysfibrinogenemia|Dysfibrinogenemia]]
* [[Hyperhomocysteinemia]]
* '''APC resistance''' in the abscence of factor V leiden
**[https://www.snpedia.com/index.php/Rs1800595 HR2 haplotype]
**Additional mutations in the cleavage site of factor V by APC
* Increased levels of [[Factor_VIII|factor VIII]], [[Factor_IX|factor IX]], [[Factor_XI|factor XI]], or [[fibrinogen]]


===Acquired and Mixed/Unknown===
*'''Arterial thrombosis:''' <ref name="pmid19110086">{{cite journal| author=Insull W| title=The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. | journal=Am J Med | year= 2009 | volume= 122 | issue= 1 Suppl | pages= S3-S14 | pmid=19110086 | doi=10.1016/j.amjmed.2008.10.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19110086  }} </ref>
* Refer to [[Thrombophilia_classification|thrombophilia classification]]
**Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Arterial thrombosis and microthrombi formation typically initiates by the accumulation of lipid plaques in the arterial wall provoking chronic inflammatory cells and platelet activation.
**'''Atherosclerosis:''' The initial lipid plaques evolve into fibrous plaques. Fibrous plaques could rupture, and the erosion of the surfaces of these plaques could lead to the release of additional pro-coagulating factors. This process is called atherosclerosis which further allows the activation of platelets, causing adhesion and aggregation, and the clot formation predisposing to the ischemic heart disease and myocardial infarction.
**In the heart, microthrombi can develop as a result of blood stasis in the ventricles or atria due to underlying valvular heart disease, cardiomyopathies, or arrhythmias such as atrial fibrillation predisposing to ischemic emboli and CVA. Hence, an increased incidence of obesity, hypertension, diabetes, and hypercholesterolemia all can contribute to the risk of an arterial thrombosis. Other risk factors include underlying connective tissue or rheumatologic conditions such as SLE, vasculitis; HITT, antiphospholipid syndrome, myeloproliferative disorders, and PNH.
**Thereby, it can present as an acute stroke, myocardial infarction, or acute on the chronic peripheral arterial disease. Other less common sites can include renal arteries, mesenteric arteries, and retinal arteries. 
**'''Antiplatelet agents:''' Platelets play a significant role in the development of arterial thrombosis compared to venous thrombosis; and hence, explains why antiplatelet agents form a cornerstone of the prevention and treatment of arterial thrombosis. <ref name="urlThrombosis - StatPearls - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK538430/ |title=Thrombosis - StatPearls - NCBI Bookshelf |format= |work= |accessdate=}}</ref> 
'''Table 1: System wise causative factors of thrombophilia'''


==Causes of Thrombophilia by Organ System==
{| class="wikitable"
 
|-
{|style="width:75%; height:100px" border="1"
! '''Systemic organ''' !! '''Medical conditions'''
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
|-
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | [[Cerebral vein thrombosis]] [[Acute myocardial infarction]] [[Deep vein thrombophlebitis]] [[Portal vein thrombosis]] [[Pelvic thrombophlebitis]]
| '''Cardiovascular''' || [[Cerebral vein thrombosis]], [[Acute myocardial infarction]], [[Deep vein thrombophlebitis]], [[Portal vein thrombosis]], [[Pelvic thrombophlebitis]]
|-
| '''Drugs Adverse Effects'''|| [[Asparaginase]], [[bevacizumab]], [[combined oral contraceptive pill]], [[certolizumab pegol]], [[Ccproterone]], [[diethylstilboestrol]],[[drospirenone]], [[eltrombopag]], [[erythropoietin]], [[ethinylestradiol]], [[fosfestrol]], [[granulocyte-macrophage colony stimulating factor]], [[heparin]], [[hormone replacement therapy]], [[lenalidomide]], [[peginesatide]], [[polyestradiol]], [[raloxifene]], [[strontium ranelate]], [[tamoxifen]], [[tobacco smoking]], [[tranexamic acid]],[[vorinostat]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Endocrine'''|| [[Hyperosmolar non-ketotic diabetic coma]]
| '''Drug Side Effect'''
|bgcolor="Beige"| • [[Asparaginase]] • [[bevacizumab]] • [[combined oral contraceptive pill]] • [[certolizumab pegol]] • [[Ccproterone]] • [[diethylstilboestrol]] • [[drospirenone]] • [[eltrombopag]] • [[erythropoietin]] • [[ethinylestradiol]] • [[fosfestrol]] • [[granulocyte-macrophage colony stimulating factor]] • [[heparin]] • [[hormone replacement therapy]] • [[lenalidomide]] • [[peginesatide]] • [[polyestradiol]] • [[raloxifene]] • [[strontium ranelate]] • [[tamoxifen]] • [[tobacco smoking]] • [[tranexamic acid]] • [[vorinostat]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Gastroenterologic'''|| Acute [[pancreatitis]], [[Portal hypertension]]
| '''Endocrine'''
|bgcolor="Beige"| • [[Hyperosmolar non-ketotic diabetic coma]]
|-bgcolor="LightSteelBlue"
| '''Gastroenterologic'''
|bgcolor="Beige"| Acute [[pancreatitis]] [[Portal hypertension]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Genetic'''|| [[Congenital Dysfibrinogenemia]], [[Factor II mutation]], [[Hereditary thrombophlebitis]], [[Antithrombin III deficiency]], [[Factor V Leiden mutation]], [[Protein C deficiency]], [[Protein S deficiency]], [[Klippel-Trenaunay syndrome]], [[Klinefelter syndrome]], [[Sickle cell disease]], [[Carbohydrate-deficient glycoprotein syndrome type 1b]], [[Factor XII deficiency]], [[Haemoglobin SC disease]], [[Hyperprothrombinemia 20210G-A]], [[Plasminogen deficiency]], [[Activated protein C resistance]], [[CD59 antigen deficiency]], [[Cystathionine beta-synthase deficiency]]
| '''Genetic'''
|bgcolor="Beige"| [[Congenital Dysfibrinogenemia]] [[Factor II mutation]] [[Hereditary thrombophlebitis]] [[Antithrombin III deficiency]] [[Factor V Leiden mutation]] [[Protein C deficiency]] [[Protein S deficiency]] [[Klippel-Trenaunay syndrome]] [[Klinefelter syndrome]] [[Sickle cell disease]] [[Carbohydrate-deficient glycoprotein syndrome type 1b]] [[Factor XII deficiency]] [[Haemoglobin SC disease]] [[Hyperprothrombinemia 20210G-A]] [[Plasminogen deficiency]] [[Activated protein C resistance]] [[CD59 antigen deficiency]] [[Cystathionine beta-synthase deficiency]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Hematologic'''|| [[Polycythemia vera]], [[Essential thrombocythemia]], [[Myeloproliferative disease]], [[Hyperviscosity]] syndrome, [[Paroxysmal Nocturnal Hemoglobinuria]], [[Thrombocytosis]], Raised homocysteine levels
| '''Hematologic'''
|bgcolor="Beige"| [[Polycythemia vera]] [[Essential thrombocythemia]] [[Myeloproliferative disease]] [[Hyperviscosity]] syndrome [[Paroxysmal Nocturnal Hemoglobinuria]] [[Thrombocytosis]] Raised homocysteine levels
|-
|-
|-bgcolor="LightSteelBlue"
| '''Iatrogenic'''|| Surgical complication
| '''Iatrogenic'''
|bgcolor="Beige"| Surgical complication
|-
|-
|-bgcolor="LightSteelBlue"
| '''Infectious Disease'''|| [[Intraperitoneal abscess]], [[Acute peritonitis]], [[Visceral abscess]], [[Diverticulitis]], [[Intravenous catheter infection]]
| '''Infectious Disease'''
|bgcolor="Beige"| [[Intraperitoneal abscess]] [[Acute peritonitis]] [[Visceral abscess]] [[Diverticulitis]] [[Intravenous catheter infection]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Musculoskeletal / Ortho'''|| Orthopedic surgeries, Abdominal surgery
| '''Musculoskeletal / Ortho'''
|bgcolor="Beige"| Orthopedic surgeries Abdominal surgery
|-
|-
|-bgcolor="LightSteelBlue"
| '''Nutritional / Metabolic'''|| [[Cystathionuria]], [[Homocystinuria]], [[Methyltetrahydrofolate reductase deficiency]], [[Metabolic Syndrome]], [[Insulin resistance]], [[Folic acid deficiency]], [[Obesity]]
| '''Nutritional / Metabolic'''
|bgcolor="Beige"| [[Cystathionuria]] [[Homocystinuria]] [[Methyltetrahydrofolate reductase deficiency]] [[Metabolic Syndrome]] [[Insulin resistance]] [[Folic acid deficiency]] [[Obesity]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Obstetric/Gynecologic'''|| [[Pregnancy]], [[Puerperium period]], [[Ovarian hyperstimulation syndrome]]
| '''Obstetric/Gynecologic'''
|bgcolor="Beige"| [[Pregnancy]] [[Puerperium period]] [[Ovarian hyperstimulation syndrome]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Oncologic'''|| [[Malignancy]], [[Peritoneal metastasis]], [[Adenocarcinoma of cecum]], [[Adenocarcinoma of colon]], Occult malignancy, [[Leukemia]], [[Pancreatic cancer]], [[Glucagonoma]]
| '''Oncologic'''
|bgcolor="Beige"| [[Malignancy]] [[Peritoneal metastasis]] [[Adenocarcinoma of cecum]] [[Adenocarcinoma of colon]] Occult malignancy [[Leukemia]] [[Pancreatic cancer]] [[Glucagonoma]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Renal / Electrolyte'''|| [[Chronic renal failure]], [[Paroxysmal Nocturnal Hemoglobinuria]], [[Nephrotic syndrome]]
| '''Renal / Electrolyte'''
|bgcolor="Beige"| [[Chronic renal failure]] [[Paroxysmal Nocturnal Hemoglobinuria]] [[Nephrotic syndrome]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Rheum / Immune / Allergy'''|| [[Antiphospholipid Syndrome]], [[Circulating anticoagulant]], [[Heparin induced thrombocytopenia]], [[Inflammatory bowel disease]], [[Crohn's disease]], [[Behcet disease]], [[Hughes-Stovin syndrome]], [[Polyarteritis Nodosa]], [[SLE]]
| '''Rheum / Immune / Allergy'''
|bgcolor="Beige"| [[Antiphospholipid Syndrome]] [[Circulating anticoagulant]] [[Heparin induced thrombocytopenia]] [[Inflammatory bowel disease]] [[Crohn's disease]][[Behcet disease]] [[Hughes-Stovin syndrome]] [[Polyarteritis Nodosa]] [[SLE]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Trauma'''|| [[Trauma]], [[Abdominal trauma]]
| '''Trauma'''
|bgcolor="Beige"| [[Trauma]] [[Abdominal trauma]]
|-
|-
|-bgcolor="LightSteelBlue"
| '''Miscellaneous'''|| [[Paraneoplastic syndrome]], [[Hypereosinophilic syndrome]], [[Immobility]]
| '''Miscellaneous'''
|bgcolor="Beige"| [[Paraneoplastic syndrome]] [[Hypereosinophilic syndrome]] [[Immobility]]
|-
|-
|}
|}
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==References==
==References==
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{{reflist|2}}
{{WH}}
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Hematology]]
[[Category:Hematology]]
[[Category:FinalQCRequired]]

Latest revision as of 11:06, 7 April 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Overview

Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions.

Causes

  • Virchow's triad: The cause of thrombosis is multifactorial which causes an imbalance in endogenous anticoagulation and hemostasis through a complex pathophysiologic mechanism. Rudolf Virchow proposed Virchow's triad in 1856 and described the three common factors which predisposes to thrombosis as follows: [1]
    • Damage to the endothelial lining of the vessel wall: It leads to the production of pro-inflammatory and prothrombotic cytokines, an increase in available tissue factor, the proliferation of adhesion molecules, and enhanced platelet activation. Cytokines initiate inflammation-promoting interaction between leukocytes and endothelial cells. Inflammation is a normal body reaction to unwanted stimuli such as foreign pathogens or infection and endothelial damage, whether acute (e.g., catheter placement, trauma or surgery) or chronic (underlying inflammatory disorders or peripheral vascular disease). [2]
    • Hypercoagulable state: It is due to a variety of alterations in the coagulation and hemostatic system, which can result from inflammatory factors, variations in the viscosity of blood and blood components, increased cytokines, and prothrombotic proteins in circulation, or deficiencies of natural or endogenous anticoagulant factors. [3]
    • Arterial or venous blood stasis: This third aspect could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis such as residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis. Long trips with limited mobility in cases where concurrent additional risk factors are present can be considered as a relative risk factor for thrombosis. [4]
  • Hypercoagulable states: Hypercoagulability disorders are either acquired or inherited. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis, thereby explaining the inter-individual differences observed in patients with inherited mutations. [3] [5] [6] [7]
    • Inherited forms can be identified in up to 30% of patients with venous thromboembolism and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. However, other inherited thrombophilias are rare such as antithrombin III, protein C and protein S deficiency (around 1% in the general population) but pose a higher risk for thrombosis. Mutations influencing coagulation factors can present in heterozygous or homozygous genotype. [3]
    • Acquired factors are far more common and influence the coagulation cascade by multitude of factors including medications (e.g., oral contraceptives, estrogen or other hormonal replacement), recent inflammatory conditions such as pregnancy, surgery, trauma, or infection, and chronic inflammatory conditions (e.g., morbid obesity, rheumatologic disease, ulcerative colitis, heavy smoking). [7] [8]
    • Malignancy (occult or diagnosed) can predispose to hypercoagulability as tumor cells can express a variety of procoagulant proteins including increased expression tissue factor. Some solid tumors such as pancreatic cancer are known to significantly increase the risk of thrombosis. [9]
    • Typically, venous thrombosis is initiated by endothelial damage, while arterial thrombosis starts with atherosclerosis, and acquired hypercoagulable states leading to both venous and arterial thrombus include acquired antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia & thrombosis (HITT). [3]
  • Venous thromboembolism (VTE): Stasis behind venous valves contributes to venous thrombosis and red thrombus formation. An anatomy of the deep veins of the extremities and the pulmonary system should be considered such as the deep veins of the lower extremity include the femoral, iliac, and popliteal veins; and the upper extremity veins include the subclavian, axillary, brachial veins. Other thrombosis sites include superior vena cava thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, cavernous sinus thrombosis, and retinal vein occlusion. Thrombosis of superficial veins is possible with provoking factors such as intravenous catheterization or localized cellulitis; however, the treatment of superficial vein thrombosis does not typically require any anticoagulation. [10] [11]
  • Arterial thrombosis: [12]
    • Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Arterial thrombosis and microthrombi formation typically initiates by the accumulation of lipid plaques in the arterial wall provoking chronic inflammatory cells and platelet activation.
    • Atherosclerosis: The initial lipid plaques evolve into fibrous plaques. Fibrous plaques could rupture, and the erosion of the surfaces of these plaques could lead to the release of additional pro-coagulating factors. This process is called atherosclerosis which further allows the activation of platelets, causing adhesion and aggregation, and the clot formation predisposing to the ischemic heart disease and myocardial infarction.
    • In the heart, microthrombi can develop as a result of blood stasis in the ventricles or atria due to underlying valvular heart disease, cardiomyopathies, or arrhythmias such as atrial fibrillation predisposing to ischemic emboli and CVA. Hence, an increased incidence of obesity, hypertension, diabetes, and hypercholesterolemia all can contribute to the risk of an arterial thrombosis. Other risk factors include underlying connective tissue or rheumatologic conditions such as SLE, vasculitis; HITT, antiphospholipid syndrome, myeloproliferative disorders, and PNH.
    • Thereby, it can present as an acute stroke, myocardial infarction, or acute on the chronic peripheral arterial disease. Other less common sites can include renal arteries, mesenteric arteries, and retinal arteries.
    • Antiplatelet agents: Platelets play a significant role in the development of arterial thrombosis compared to venous thrombosis; and hence, explains why antiplatelet agents form a cornerstone of the prevention and treatment of arterial thrombosis. [4]

Table 1: System wise causative factors of thrombophilia

Systemic organ Medical conditions
Cardiovascular Cerebral vein thrombosis, Acute myocardial infarction, Deep vein thrombophlebitis, Portal vein thrombosis, Pelvic thrombophlebitis
Drugs Adverse Effects Asparaginase, bevacizumab, combined oral contraceptive pill, certolizumab pegol, Ccproterone, diethylstilboestrol,drospirenone, eltrombopag, erythropoietin, ethinylestradiol, fosfestrol, granulocyte-macrophage colony stimulating factor, heparin, hormone replacement therapy, lenalidomide, peginesatide, polyestradiol, raloxifene, strontium ranelate, tamoxifen, tobacco smoking, tranexamic acid,vorinostat
Endocrine Hyperosmolar non-ketotic diabetic coma
Gastroenterologic Acute pancreatitis, Portal hypertension
Genetic Congenital Dysfibrinogenemia, Factor II mutation, Hereditary thrombophlebitis, Antithrombin III deficiency, Factor V Leiden mutation, Protein C deficiency, Protein S deficiency, Klippel-Trenaunay syndrome, Klinefelter syndrome, Sickle cell disease, Carbohydrate-deficient glycoprotein syndrome type 1b, Factor XII deficiency, Haemoglobin SC disease, Hyperprothrombinemia 20210G-A, Plasminogen deficiency, Activated protein C resistance, CD59 antigen deficiency, Cystathionine beta-synthase deficiency
Hematologic Polycythemia vera, Essential thrombocythemia, Myeloproliferative disease, Hyperviscosity syndrome, Paroxysmal Nocturnal Hemoglobinuria, Thrombocytosis, Raised homocysteine levels
Iatrogenic Surgical complication
Infectious Disease Intraperitoneal abscess, Acute peritonitis, Visceral abscess, Diverticulitis, Intravenous catheter infection
Musculoskeletal / Ortho Orthopedic surgeries, Abdominal surgery
Nutritional / Metabolic Cystathionuria, Homocystinuria, Methyltetrahydrofolate reductase deficiency, Metabolic Syndrome, Insulin resistance, Folic acid deficiency, Obesity
Obstetric/Gynecologic Pregnancy, Puerperium period, Ovarian hyperstimulation syndrome
Oncologic Malignancy, Peritoneal metastasis, Adenocarcinoma of cecum, Adenocarcinoma of colon, Occult malignancy, Leukemia, Pancreatic cancer, Glucagonoma
Renal / Electrolyte Chronic renal failure, Paroxysmal Nocturnal Hemoglobinuria, Nephrotic syndrome
Rheum / Immune / Allergy Antiphospholipid Syndrome, Circulating anticoagulant, Heparin induced thrombocytopenia, Inflammatory bowel disease, Crohn's disease, Behcet disease, Hughes-Stovin syndrome, Polyarteritis Nodosa, SLE
Trauma Trauma, Abdominal trauma
Miscellaneous Paraneoplastic syndrome, Hypereosinophilic syndrome, Immobility

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