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| {{Infobox_Disease |
| | __NOTOC__ |
| Name = {{PAGENAME}} |
| | {{Thrombophilia}} |
| Image = |
| | {{CMG}}; {{AE}} [[User:Kashish Goel|Kashish Goel, M.D.]], {{asiri}},{{M.B}}, {{MKA}}, {{S.G.}}, {{JK}} |
| Caption = |
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| DiseasesDB = 29080 |
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| ICD10 = |
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| ICD9 = |
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| ICDO = |
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| OMIM = 188050 |
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| MedlinePlus = |
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| eMedicineSubj = |
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| eMedicineTopic = |
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| MeshID = D019851 |
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| }} | |
| {{SI}} | |
| {{CMG}};'''Associate Editor(s)-In-Chief:''' [[Kashish Goel|Kashish Goel, M.D.]] | |
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| '''''Synonyms and Keywords:''''' Hypercoagulability, coagulability, hypercoagulable state
| | {{SK}} Hypercoagulability, coagulability, hypercoagulable state; thrombosis risk elevation; thrombotic tendency; prothrombotic state; clotting disorder; |
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| ==Overview== | | == [[Thrombophilia overview|Overview]] == |
| '''Thrombophilia''' is defined as an increased risk of [[thrombosis]] in the body, due to an abnormality in the system of [[coagulation]]. Thrombophilia can be inherited or acquired. More than 50% of the cases of [[thrombosis]] are associated with an underlying thrombophilia. Thrombophilias are mostly associated with venous thromboembolism like [[deep vein thrombosis]] in lower extremities or [[pulmonary embolism]]. Relatively less is known about thrombophilias that predispose to arterial thromboembolism<ref name="pmid11309638">{{cite journal |author=Seligsohn U, Lubetsky A |title=Genetic susceptibility to venous thrombosis |journal=N. Engl. J. Med. |volume=344 |issue=16 |pages=1222–31 |year=2001 |month=April |pmid=11309638 |doi=10.1056/NEJM200104193441607 |url=}}</ref>.
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| ==Classification== | | == [[Thrombophilia historical perspective|Historical Perspective]]== |
| Thrombophilia can be classified in various forms.
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| * The most common classification is by the nature of the thrombosis: [[artery|arterial]], [[vein|venous]] or combined.
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| * Crowther & Kelton (2003) propose to classify the abnormality by the molecular deficiency, type I being the (severe) deficiencies of inhibitors, and type II being the less severe elevation of coagulation factors.<ref>{{cite journal |author=Crowther MA, Kelton JG |title=Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system |journal=Ann. Intern. Med. |volume=138 |issue=2 |pages=128-34|year=2003 |pmid=12529095 |doi= |url=http://www.annals.org/cgi/reprint/138/2/128}}</ref>
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| * Inherited vs. acquired
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| ==Pathophysiology== | | == [[Thrombophilia classification|Classification]] == |
| The Virchow's triad has been described classically as the patho-physiologic mechanism responsible for any thrombosis, which includes 3 components:
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| * [[Endothelial dysfunction]]
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| * [[Venous stasis]]
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| * [[Hypercoaguability]]
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| The mechanism of thrombophilia involves affecting the pathway of thrombosis<ref name="pmid11309638">{{cite journal |author=Seligsohn U, Lubetsky A |title=Genetic susceptibility to venous thrombosis |journal=N. Engl. J. Med. |volume=344 |issue=16 |pages=1222–31 |year=2001 |month=April |pmid=11309638 |doi=10.1056/NEJM200104193441607 |url=}}</ref>:
| | == [[Thrombophilia pathophysiology|Pathophysiology]] == |
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| [[Image: Figure_thrombophilia_mechanism.jpg]] | | == [[Thrombophilia causes|Causes]] == |
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| Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.
| | == [[Thrombophilia differential diagnosis|Differentiating Thrombophilia from Other Diseases]] == |
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| ==Epidemiology and Demographics== | | == [[Thrombophilia epidemiology and demographics|Epidemiology and Demographics]]== |
| ===Prevalence of various inherited thrombophilias and their clinical impact===
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| {| border="1" cellpadding="5" cellspacing="0" align="center" class="sortable"
| | == [[Thrombophilia risk factors|Risk Factors]] == |
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| ! Disorder
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| ! Healthy subjects/General population (%)
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| ! Patients with known thrombosis (%)
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| ! Estimated increase in thrombosis risk
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| |-
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| | [[Antithrombin deficiency]]
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| | 0.02
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| | 1 - 4
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| | 10 - 20X
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| |-
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| | [[Dysfibrinogenemia]]
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| | <1
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| | <1
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| | Variable
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| |-
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| | [[Protein C deficiency]]
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| | 0.2 - 0.4
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| | 3 - 5
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| | 10X
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| |-
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| | [[Protein S deficiency]]
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| | 0.3 - 0.13
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| | 2 - 4
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| | 10X
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| |-
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| | [[Factor V Leiden]]
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| | 1 - 15
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| | 18 - 40
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| | 5X
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| |-
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| | G20210A [[prothrombin]] gene mutation
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| | 2 - 5
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| | 7 - 16
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| | 3X
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| |-
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| | [[Hyperhomocystenemia]]
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| | 5
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| | 10
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| | 3X
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| |-
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| | Elevated [[factor VIII]] levels
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| | 11
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| | 25
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| | 5X
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| |-
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| |}
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| The table has been adapted from Best Pract Res Clin Obstet Gynaecol. 2003 Jun;17(3):397-411<ref name="pmid12787534">{{cite journal |author=Buchanan GS, Rodgers GM, Ware Branch D |title=The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation |journal=Best Pract Res Clin Obstet Gynaecol |volume=17 |issue=3 |pages=397–411 |year=2003 |month=June |pmid=12787534 |doi= |url=}}</ref> and data has been obtained from references<ref name="pmid11309638">{{cite journal |author=Seligsohn U, Lubetsky A|title=Genetic susceptibility to venous thrombosis |journal=N. Engl. J. Med. |volume=344 |issue=16 |pages=1222–31 |year=2001 |month=April |pmid=11309638|doi=10.1056/NEJM200104193441607 |url=}}</ref><ref name="pmid11702218">{{cite journal |author=Franco RF, Reitsma PH |title=Genetic risk factors of venous thrombosis |journal=Hum. Genet. |volume=109 |issue=4 |pages=369–84 |year=2001 |month=October |pmid=11702218 |doi=10.1007/s004390100593 |url=}}</ref><ref name="pmid7740487">{{cite journal |author=Haverkate F, Samama M |title=Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen |journal=Thromb. Haemost. |volume=73 |issue=1 |pages=151–61 |year=1995 |month=January |pmid=7740487 |doi= |url=}}</ref>.
| | == [[Thrombophilia screening|Screening]]== |
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| ==Causes== | | == [[Thrombophilia natural history, complications and prognosis|Natural History, Complications and Prognosis]] == |
| ===Inherited===
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| Common types:
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| * G1691A mutation in factor V gene ([[Factor V Leiden|Factor V, Leiden type]]; 5% of the population are [[heterozygous]] for FVL)
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| * [[Prothrombin]] (factor II) mutation (G20210A, 5'UTR)
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| * Homozygous C677T mutation in the [[MTHFR]] gene
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| Rare forms:
| | == Diagnosis == |
| * [[Plasminogen]] and [[fibrinolysis]] disorders
| | [[Thrombophilia history and symptoms|History and Symptoms]] | [[Thrombophilia physical examination|Physical Examination]] | [[Thrombophilia laboratory findings|Laboratory Findings]] | [[Thrombophilia x ray|X Ray]] | [[Thrombophilia CT|CT]] | [[Thrombophilia MRI|MRI]] | [[Thrombophilia echocardiography or ultrasound|Ultrasound]] | [[Thrombophilia other imaging findings|Other Imaging Studies]] | [[Thrombophilia other diagnostic studies|Other Diagnostic Studies]] |
| * [[Paroxysmal nocturnal hemoglobinuria]]
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| * [[Protein C deficiency]]
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| * [[Protein S deficiency]]
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| * [[Antithrombin|Antithrombin III]] deficiency
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| * [[Dysfibrinogenemia]]
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| * Homozygous [[homocystinuria]]
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| * Increased levels of factor VIII, factor IX, factor XI, or [[fibrinogen]].
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| ===Acquired=== | | == Treatment == |
| * [[Antiphospholipid antibodies]]
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| ** [[anti-cardiolipin antibodies]] and/or
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| ** [[lupus anticoagulant]]s
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| * [[Kidney|Renal disease]] (renal loss of antithrombin)
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| * High [[homocysteine]] levels due to vitamin deficiency (vitamins B6, B12 and folic acid).
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| * Immobility
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| * [[Pregnancy]] and [[puerperium]]
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| * [[Oral contraceptive pills]]
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| * [[Malignancy]]
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| * [[Obesity]]
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| * African American race
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| * [[Hormone replacement therapy]]
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| * Surgery and trauma
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| * Older age
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| * [[Myeloproliferative disorders]]
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| * Previous thrombosis
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| ==Differential diagnosis of thrombophilia==
| | [[Thrombophilia medical therapy|Medical Therapy]] | [[Thrombophilia surgery|Surgery]] | [[Thrombophilia primary prevention|Primary Prevention]] | [[Thrombophilia secondary prevention|Secondary Prevention]] | [[Thrombophilia future or investigational therapies|Future or Investigational Therapies]] | [[Thrombophilia cost-effectiveness of therapy | Cost Effectiveness of Therapy]] |
| (By organ system)
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| {|style="width:75%; height:100px" border="1"
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| |style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
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| |style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | • [[Cerebral vein thrombosis]] • [[Acute myocardial infarction]] • [[Deep vein thrombophlebitis]] • [[Portal vein thrombosis]] • [[Pelvic thrombophlebitis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Drug Side Effect'''
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| |bgcolor="Beige"| • [[Asparaginase]] • [[Bevacizumab]] • [[Combined oral contraceptive pill]] • [[Cyproterone]] • [[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]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Endocrine''' | |
| |bgcolor="Beige"| • [[Hyperosmolar non-ketotic diabetic coma]]
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| |-bgcolor="LightSteelBlue" | |
| | '''Gastroenterologic'''
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| |bgcolor="Beige"| • Acute [[pancreatitis]] • [[Portal hypertension]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Genetic'''
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| |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]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Hematologic'''
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| |bgcolor="Beige"| • [[Polycythemia vera]] • [[Essential thrombocythemia]] • [[Myeloproliferative disease]] • [[Hyperviscosity]] syndrome • [[Paroxysmal Nocturnal Hemoglobinuria]] • [[Thrombocytosis]] • Raised homocysteine levels
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Iatrogenic'''
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| |bgcolor="Beige"| • Surgical complication
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Infectious Disease'''
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| |bgcolor="Beige"| • [[Intraperitoneal abscess]] • [[Acute peritonitis]] • [[Visceral abscess]] • [[Diverticulitis]] • [[Intravenous catheter infection]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Musculoskeletal / Ortho'''
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| |bgcolor="Beige"| • Orthopedic surgeries • Abdominal surgery
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Nutritional / Metabolic'''
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| |bgcolor="Beige"| • [[Cystathionuria]] • [[Homocystinuria]] • [[Methyltetrahydrofolate reductase deficiency]] • [[Metabolic Syndrome]] • [[Insulin resistance]] • [[Folic acid deficiency]] • [[Obesity]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Obstetric/Gynecologic''' | |
| |bgcolor="Beige"| • [[Pregnancy]] • [[Puerperium period]] • [[Ovarian hyperstimulation syndrome]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Oncologic'''
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| |bgcolor="Beige"| • [[Malignancy]] • [[Peritoneal metastasis]] • [[Adenocarcinoma of cecum]] • [[Adenocarcinoma of colon]] • Occult malignancy • [[Leukemia]] • [[Pancreatic cancer]] • [[Glucagonoma]] | |
| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Renal / Electrolyte'''
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| |bgcolor="Beige"| • [[Chronic renal failure]] • [[Paroxysmal Nocturnal Hemoglobinuria]] • [[Nephrotic syndrome]]
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| |- | |
| |-bgcolor="LightSteelBlue"
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| | '''Rheum / Immune / Allergy'''
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| |bgcolor="Beige"| • [[Antiphospholipid Syndrome]] • [[Circulating anticoagulant]] • [[Heparin induced thrombocytopenia]] • [[Inflammatory bowel disease]] • [[Crohn's disease]]• [[Behcet disease]] • [[Hughes-Stovin syndrome]] • [[Polyarteritis Nodosa]] • [[SLE]]
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| |-
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| |-bgcolor="LightSteelBlue" | |
| | '''Trauma'''
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| |bgcolor="Beige"| • [[Trauma]] • [[Abdominal trauma]]
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| |-
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| |-bgcolor="LightSteelBlue" | |
| | '''Miscellaneous'''
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| |bgcolor="Beige"| • [[Paraneoplastic syndrome]] • [[Hypereosinophilic syndrome]] • [[Immobility]]
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| |-
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| |}
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| ==Laboratory testing== | | ==Case Studies== |
| ===Indications for screening===
| | :[[Thrombophilia case study one|Case #1]] |
| Routine screening is not indicated in those individuals with an obvious acquired cause. For example, if the thrombosis is due to immobilisation after recent [[orthopedic surgery]], it is unlikely that an underlying cause is found. Comprehensive testing in any patient should include complete assessment of risk factors and its effect on long-term therapy. Some of the indications of further testing may include<ref name="pmid19289024">{{cite journal |author=Foy P, Moll S |title=Thrombophilia: 2009 update |journal=Curr Treat Options Cardiovasc Med |volume=11 |issue=2 |pages=114–28 |year=2009 |month=April |pmid=19289024 |doi= |url=}}</ref><ref name="pmid11309638">{{cite journal |author=Seligsohn U, Lubetsky A |title=Genetic susceptibility to venous thrombosis |journal=N. Engl. J. Med. |volume=344 |issue=16 |pages=1222–31 |year=2001 |month=April |pmid=11309638 |doi=10.1056/NEJM200104193441607 |url=}}</ref>:
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| * Unexplained venous thromboembolism at an age of less than 50 years
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| * Recurrent spontaneous thrombosis
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| * Unusual sites like portal, splenic, mesenteric, hepatic or renal veins
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| * Family history in first-degree relatives
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| * Recurrent pregnancy losses<ref>Dawood, F., Farquharson, R., Quenby, S.''Recurrent miscarriage.'' Current Obstetrics & Gynaecology, 2004; 14:247-253.</ref>
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| * Recurrence of venous thromboembolism while adequately anticoagulated
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| * Warfarin-induced skin necrosis
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| * Unexplained arterial thromboembolism in a younger patient without significant arteriosclerosis risk factors and no cardioembolic source
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| ===Timing===
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| The timing of tests is very important as it influences the levels of various thrombogenic factors in the body.
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| * Testing at the time of acute venous thrombosis is not indicated or during ongoing anti-coagulation.
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| * Best time to test is 4 weeks after completion of anticoagulation.
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| * Avoid intercurrent severe illness
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| * Pregnancy, oral contraceptives, hormone replacement therapy and cancer chemotherapy may also affect some tests.
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| * Factor V Leiden and Prothrombin mutation can be done in patients on anticoagulants and even in acute phase, as these are PCR tests. However, other tests can be done only at a later stage to rule out two disorders.
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| ===Type of tests===
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| Tests for thrombophilia are categorized according to their priority, as discussed below:
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| '''1. General tests:''' These include [[prothrombin time]], INR, and [[partial thromboplastin time]].
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| '''2. High priority tests:'''
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| * Activated protein C resistance
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| * Factor V Leiden (Homozygosity or heterozygosity)
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| * Prothrombin gene mutation (G20210A)
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| * Homocysteine levels
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| * Factor VIII
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| * Lupus anticoagulant
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| '''3. Intermediate priority'''
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| * Protein C activity
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| * Protein S activity
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| * Antithrombin activity
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| * Anticardiolipin antibodies
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| '''4. Low priority'''
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| * Thrombin time
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| * Fibrinogen levels
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| * Factor IX activity
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| * Factor X activity
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| * [[MTHR]] gene
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| '''High priority and intermediate priority tests''' should be performed in those with an unprovoked thrombotic event and have a recurrent event, cerebral-or visceral thrombosis, stillbirth, three or more unexplained spontaneous abortions, family history of venous thrombosis, or are younger than 45 years.
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| '''High priority tests''' only should be conducted in those who have a first unprovoked event, age > 45 years, event provoked by pregnancy/puerperium/use of oral contraceptives or hormone-replacement therapy, proximal-vein thrombosis, pulmonary embolism, or both provoked by surgery, trauma, or immobilization.
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| It is recommended that all these patients be treated with anticoagulation for at least 6 months, unless contraindicated.
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| ==Treatment==
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| ==References==
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| {{Reflist|2}}
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| [[Category:Hematology]] | | [[Category:Hematology]] |
| | | [[Category:Disease]] |
| [[de:Thrombophilie]] | |
| [[fr:Thrombophilie]]
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| [[no:Trombofili]]
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| [[pl:Trombofilia]]
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |