Thrombophilia: Difference between revisions

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	Thrombophilia;
OMIM	188050
DiseasesDB	29080
MeSH	D019851

VisualWikitext

Revision as of 18:19, 7 May 2012

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-In-Chief: Kashish Goel, M.D.

Synonyms and Keywords: Hypercoagulability, coagulability, hypercoagulable state

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^[1].

Classification

Thrombophilia can be classified in various forms.

The most common classification is by the nature of the thrombosis: arterial, venous or combined.
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.^[2]
Inherited vs. acquired

Pathophysiology

The Virchow's triad has been described classically as the patho-physiologic mechanism responsible for any thrombosis, which includes 3 components:

The mechanism of thrombophilia involves affecting the pathway of thrombosis^[1]:

Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.

Epidemiology and Demographics

Prevalence of various inherited thrombophilias and their clinical impact

Disorder	Healthy subjects/General population (%)	Patients with known thrombosis (%)	Estimated increase in thrombosis risk
Antithrombin deficiency	0.02	1 - 4	10 - 20X
Dysfibrinogenemia	<1	<1	Variable
Protein C deficiency	0.2 - 0.4	3 - 5	10X
Protein S deficiency	0.3 - 0.13	2 - 4	10X
Factor V Leiden	1 - 15	18 - 40	5X
G20210A prothrombin gene mutation	2 - 5	7 - 16	3X
Hyperhomocystenemia	5	10	3X
Elevated factor VIII levels	11	25	5X

The table has been adapted from Best Pract Res Clin Obstet Gynaecol. 2003 Jun;17(3):397-411^[3] and data has been obtained from references^[1]^[4]^[5].

Causes

Inherited

Common types:

G1691A mutation in factor V gene (Factor V, Leiden type; 5% of the population are heterozygous for FVL)
Prothrombin (factor II) mutation (G20210A, 5'UTR)
Homozygous C677T mutation in the MTHFR gene

Rare forms:

Plasminogen and fibrinolysis disorders
Paroxysmal nocturnal hemoglobinuria
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Dysfibrinogenemia
Homozygous homocystinuria
Increased levels of factor VIII, factor IX, factor XI, or fibrinogen.

Acquired

Antiphospholipid antibodies
- anti-cardiolipin antibodies and/or
- lupus anticoagulants
Renal disease (renal loss of antithrombin)
High homocysteine levels due to vitamin deficiency (vitamins B6, B12 and folic acid).
Immobility
Pregnancy and puerperium
Oral contraceptive pills
Malignancy
Obesity
African American race
Hormone replacement therapy
Surgery and trauma
Older age
Myeloproliferative disorders
Previous thrombosis

Differential diagnosis of thrombophilia

(By organ system)

Cardiovascular	• Cerebral vein thrombosis • Acute myocardial infarction • Deep vein thrombophlebitis • Portal vein thrombosis • Pelvic thrombophlebitis
Drug Side Effect	• 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
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

Indications for testing

Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious other 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^[6]^[1]:

Unexplained venous thromboembolism at an age of less than 50 years
Recurrent spontaneous thrombosis
Unusual sites like portal, splenic, mesenteric, hepatic or renal veins
Family history in first-degree relatives
Recurrent pregnancy losses^[7]
Recurrence of venous thromboembolism while adequately anticoagulated
Warfarin-induced skin necrosis
Unexplained arterial thromboembolism in a younger patient without significant arteriosclerosis risk factors and no cardioembolic source

Tests for thrombophilia include prothrombin time and INR, partial thromboplastin time, thrombin time, fibrinogen levels, antiphospholipid antibody levels (IgG- and IgM-anticardiolipin, dilute Russell viper venom time and lupus anticoagulant), protein C, protein S and antithrombin (both levels and activity), activated protein C resistance (APC resistance), factor V Leiden and prothrombin mutation. Many laboratories add on various other tests, depending on local policy and guidelines.

Treatment

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis". N. Engl. J. Med. 344 (16): 1222–31. doi:10.1056/NEJM200104193441607. PMID 11309638. Unknown parameter |month= ignored (help)
↑ Crowther MA, Kelton JG (2003). "Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system". Ann. Intern. Med. 138 (2): 128–34. PMID 12529095.
↑ Buchanan GS, Rodgers GM, Ware Branch D (2003). "The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation". Best Pract Res Clin Obstet Gynaecol. 17 (3): 397–411. PMID 12787534. Unknown parameter |month= ignored (help)
↑ Franco RF, Reitsma PH (2001). "Genetic risk factors of venous thrombosis". Hum. Genet. 109 (4): 369–84. doi:10.1007/s004390100593. PMID 11702218. Unknown parameter |month= ignored (help)
↑ Haverkate F, Samama M (1995). "Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen". Thromb. Haemost. 73 (1): 151–61. PMID 7740487. Unknown parameter |month= ignored (help)
↑ Foy P, Moll S (2009). "Thrombophilia: 2009 update". Curr Treat Options Cardiovasc Med. 11 (2): 114–28. PMID 19289024. Unknown parameter |month= ignored (help)
↑ Dawood, F., Farquharson, R., Quenby, S.Recurrent miscarriage. Current Obstetrics & Gynaecology, 2004; 14:247-253.

de:Thrombophilie no:Trombofili

Template:WH Template:WS

[pmid11309638-1] 1.0 ^1.1 ^1.2 ^1.3 Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis". N. Engl. J. Med. 344 (16): 1222–31. doi:10.1056/NEJM200104193441607. PMID 11309638. Unknown parameter |month= ignored (help)

[2] Crowther MA, Kelton JG (2003). "Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system". Ann. Intern. Med. 138 (2): 128–34. PMID 12529095.

[pmid12787534-3] Buchanan GS, Rodgers GM, Ware Branch D (2003). "The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation". Best Pract Res Clin Obstet Gynaecol. 17 (3): 397–411. PMID 12787534. Unknown parameter |month= ignored (help)

[pmid11702218-4] Franco RF, Reitsma PH (2001). "Genetic risk factors of venous thrombosis". Hum. Genet. 109 (4): 369–84. doi:10.1007/s004390100593. PMID 11702218. Unknown parameter |month= ignored (help)

[pmid7740487-5] Haverkate F, Samama M (1995). "Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen". Thromb. Haemost. 73 (1): 151–61. PMID 7740487. Unknown parameter |month= ignored (help)

[pmid19289024-6] Foy P, Moll S (2009). "Thrombophilia: 2009 update". Curr Treat Options Cardiovasc Med. 11 (2): 114–28. PMID 19289024. Unknown parameter |month= ignored (help)

[7] Dawood, F., Farquharson, R., Quenby, S.Recurrent miscarriage. Current Obstetrics & Gynaecology, 2004; 14:247-253.

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@@ Line 196: / Line 196: @@
 ==Indications for testing==
-Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious other 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 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>:
+Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious other 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>:
 * Unexplained venous thromboembolism at an age of less than 50 years
 * Recurrent spontaneous thrombosis
 * Unusual sites like portal, splenic, mesenteric, hepatic or renal veins
 * Family history in first-degree relatives
-* Recurrent pregnancy losses
+* Recurrent pregnancy losses<ref>Dawood, F., Farquharson, R., Quenby, S.''Recurrent miscarriage.'' Current Obstetrics & Gynaecology, 2004; 14:247-253.</ref>
 * Recurrence of venous thromboembolism while adequately anticoagulated
 * Warfarin-induced skin necrosis
 * Unexplained arterial thromboembolism in a younger patient without significant arteriosclerosis risk factors and no cardioembolic source
-Conversely, although thrombosis itself may occur in any person, repeated (two or more) unprovoked episodes of thrombosis and unusual sites and types of thrombosis (e.g. [[Budd-Chiari syndrome]]) may point towards a coagulation disorder.
-Increasingly, [[habitual abortion|recurrent miscarriage]] is seen as an indication for thrombophilia screening. <ref>Dawood, F., Farquharson, R., Quenby, S.''Recurrent miscarriage.'' Current Obstetrics & Gynaecology, 2004; 14:247-253.</ref>
 Tests for thrombophilia include [[prothrombin time]] and INR, [[partial thromboplastin time]], [[thrombin time]], [[fibrinogen]] levels, [[antiphospholipid antibody]] levels (IgG- and IgM-anticardiolipin, dilute Russell viper venom time and lupus anticoagulant), [[protein C]], [[protein S]] and [[antithrombin]] (both levels and activity), activated protein C resistance (APC resistance), [[factor V Leiden]] and [[thrombin|prothrombin]] mutation. Many laboratories add on various other tests, depending on local policy and guidelines.