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Thrombophilia(THPH1)

MedGen UID:
98306
Concept ID:
C0398623
Disease or Syndrome
Synonyms: Factor V R2 Mutation Thrombophilia; Prothrombin-Related Thrombophilia; Prothrombin-Related Thrombophilia (Factor II); THPH1; THROMBOPHILIA DUE TO FACTOR 2 DEFECT; Thrombosis susceptibility; VENOUS THROMBOEMBOLISM; VENOUS THROMBOSIS
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Hypercoagulability state (76612001); Hypercoagulable state (76612001); Hypercoagulability (76612001); Thrombophilia (234467004)
 
Genes (locations): F13A1 (6p25.1); F2 (11p11.2); HABP2 (10q25.3); MTHFR (1p36.22)
Related genes: PROS1, PROC, F5, SERPINC1
OMIM®: 188050
HPO: HP:0100724

Disease characteristics

Excerpted from the GeneReview: Prothrombin-Related Thrombophilia
Prothrombin-related thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism. The clinical expression of prothrombin-related thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A (G20210A or c.*97G>A) allele in F2 never develop thrombosis, and while most heterozygotes who develop thrombotic complications remain asymptomatic until adulthood, some have recurrent thromboembolism before age 30 years. The relative risk for DVT in adults heterozygous for the 20210G>A allele is two- to fivefold increased; in children, the relative risk for thrombosis is three- to fourfold increased. 20210G>A heterozygosity has at most a modest effect on recurrence risk after a first episode. Although prothrombin-related thrombophilia may increase the risk for pregnancy loss, its association with preeclampsia and other complications of pregnancy such as intrauterine growth restriction and placental abruption remains controversial. Factors that predispose to thrombosis in prothrombin-related thrombophilia include: the number of 20210G>A alleles; presence of coexisting genetic abnormalities including factor V Leiden; and acquired thrombophilic disorders (e.g., antiphospholipid antibodies). Circumstantial risk factors for thrombosis include pregnancy and oral contraceptive use. Some evidence suggests that the risk for VTE in 20210G>A heterozygotes increases after travel. [from GeneReviews]
Authors:
Jody L Kujovich   view full author information

Additional descriptions

From OMIM
Thrombophilia is a multifactorial disorder of inappropriate clot formation resulting from an interaction of genetic, acquired, and circumstantial predisposing factors. Venous thromboembolism most commonly manifests as deep vein thrombosis, which may progress to pulmonary embolism if the clot dislodges and travels to the lung. Other manifestations include thromboses of the cerebral or visceral veins and recurrent pregnancy loss (summary by Seligsohn and Lubetsky, 2001 and Varga and Kujovich, 2012). Genetic Heterogeneity of Thrombophilia THPH2 (188055) is caused by mutation in the F5 gene (612309) on chromosome 1q23; THPH3 (176860) and THPH4 (612304) are both caused by mutation in the PROC gene (612283) on 2q; THPH5 (612336) and THPH6 (614514) are caused by mutation in the PROS1 gene (176880) on 3q11; THPH7 (613118) is caused by mutation in the AT3 gene (107300) on 1q25; THPH8 (300807) is caused by mutation in the F9 gene (300746) on Xq27; THPH9 (612348) is associated with decreased release of tissue plasminogen activator (PLAT; 173370); THPH10 (612356) is caused by mutation in the HCF2 gene (142360) on 22q11; THPH11 (613116) is caused by mutation in the HRG gene (142640) on 3q27; and THPH12 (614486) is associated with variation in the THBD gene (188040) on 20p11. Susceptibility to thrombosis has also been associated with variation in additional genes, including MTHFR (607093.0003); F13B (134580.0003); plasminogen activator inhibitor (SERPINE1; 173360); and several genes encoding fibrinogen (FGA, 134820; FGB, 134830; FGG, 134850). Variation in the SERPINA10 (see 605271.0001), KNG1 (612358) and HABP2 (603924) genes has also been reported. Protection against venous thrombosis is associated with variation in the F13A1 gene (134570) on 6p25.  http://www.omim.org/entry/188050
From GHR
Prothrombin thrombophilia is an inherited disorder of blood clotting. Thrombophilia is an increased tendency to form abnormal blood clots in blood vessels. People who have prothrombin thrombophilia are at somewhat higher than average risk for a type of clot called a deep venous thrombosis, which typically occurs in the deep veins of the legs. Affected people also have an increased risk of developing a pulmonary embolism, which is a clot that travels through the bloodstream and lodges in the lungs. Most people with prothrombin thrombophilia never develop abnormal blood clots, however.Some research suggests that prothrombin thrombophilia is associated with a somewhat increased risk of pregnancy loss (miscarriage) and may also increase the risk of other complications during pregnancy. These complications may include pregnancy-induced high blood pressure (preeclampsia), slow fetal growth, and early separation of the placenta from the uterine wall (placental abruption). It is important to note, however, that most women with prothrombin thrombophilia have normal pregnancies.  https://ghr.nlm.nih.gov/condition/prothrombin-thrombophilia

Clinical features

Pulmonary Embolism
MedGen UID:
11027
Concept ID:
C0034065
Disease or Syndrome
A pulmonary embolism is a sudden blockage in a lung artery. The cause is usually a blood clot in the leg called a deep vein thrombosis that breaks loose and travels through the bloodstream to the lung. Pulmonary embolism is a serious condition that can cause. -Permanent damage to the affected lung . -Low oxygen levels in your blood . -Damage to other organs in your body from not getting enough oxygen . If a clot is large, or if there are many clots, pulmonary embolism can cause death. . Half the people who have pulmonary embolism have no symptoms. If you do have symptoms, they can include shortness of breath, chest pain or coughing up blood. Symptoms of a blood clot include warmth, swelling, pain, tenderness and redness of the leg. The goal of treatment is to break up clots and help keep other clots from forming. . NIH: National Heart, Lung, and Blood Institute.
Embolism and Thrombosis
MedGen UID:
43147
Concept ID:
C0085307
Disease or Syndrome
The formation of a blood clot inside a blood vessel that subsequently travels through the blood stream from the site where it formed to another location in the body, generally leading to vascular occlusion at the distant site.
Deep venous thrombosis
MedGen UID:
57448
Concept ID:
C0149871
Disease or Syndrome
Deep vein thrombosis, or DVT, is a blood clot that forms in a vein deep in the body. Most deep vein clots occur in the lower leg or thigh. If the vein swells, the condition is called thrombophlebitis. A deep vein thrombosis can break loose and cause a serious problem in the lung, called a pulmonary embolism. Sitting still for a long time can make you more likely to get a DVT. Some medicines and disorders that increase your risk for blood clots can also lead to DVTs. Common symptoms are . - Warmth and tenderness over the vein . - Pain or swelling in the part of the body affected . - Skin redness . Treatment includes medicines to ease pain and inflammation, break up clots and keep new clots from forming. Keeping the affected area raised and applying moist heat can also help. If you are taking a long car or plane trip, take a break, walk or stretch your legs and drink plenty of liquids.
Cerebral venous thrombosis
MedGen UID:
57743
Concept ID:
C0151945
Disease or Syndrome
Formation of a blood clot (thrombus) inside a cerebral vein, causing the obstruction of blood flow.
Recurrent thrombophlebitis
MedGen UID:
763064
Concept ID:
C3550150
Finding
Repeated episodes of inflammation of a vein associated with venous thrombosis (blood clot formation within the vein).

Conditions with this feature

Thrombophilia due to activated protein C resistance
MedGen UID:
396074
Concept ID:
C1861171
Disease or Syndrome
Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep venous thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that a heterozygous factor V Leiden mutation has at most a modest effect on recurrence risk after initial treatment of a first VTE. Heterozygosity for factor V Leiden is associated with a two- to threefold increase in relative risk for pregnancy loss, and possibly other pregnancy complications such as preeclampsia, fetal growth retardation, and placental abruption. The clinical expression of factor V Leiden thrombophilia is influenced by: The number of factor V Leiden alleles (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk); Coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk; Acquired thrombophilic disorders: antiphospholipid antibodies, hyperhomocysteinemia, high factor VIII levels, malignancy; and Circumstantial risk factors: travel, central venous catheters, pregnancy, oral contraceptive use, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), organ transplantation, advancing age, and surgery.
Thrombophilia due to thrombomodulin defect
MedGen UID:
348286
Concept ID:
C1861173
Disease or Syndrome
The role of thrombomodulin in thrombosis is controversial. Although there have been several reports of THBD mutations in patients with venous thrombosis, clear functional evidence for the pathogenicity of these mutations is lacking. In a review, Anastasiou et al. (2012) noted that thrombomodulin has a major role in capillary beds and that THBD variation may not be associated with large vessel thrombosis. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis. However, variation in the THBD gene may be associated with increased risk for arterial thrombosis and myocardial infarction. This association may be attributed to the fact that thrombomodulin can modulate inflammatory processes, complement activity, and fibrinolysis.
Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant
MedGen UID:
436138
Concept ID:
C2674321
Disease or Syndrome
Heterozygous protein C deficiency is characterized by recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic (Millar et al., 2000). Individuals with decreased amounts of protein C are classically referred to as having type I deficiency and those with normal amounts of a functionally defective protein as having type II deficiency (Bertina et al., 1984). Acquired protein C deficiency is a clinically similar disorder caused by development of an antibody against protein C. Clouse and Comp (1986) reviewed the structural and functional properties of protein C and discussed both hereditary and acquired deficiency of protein C.
Thrombophilia, familial, due to decreased release of tissue plasminogen activator
MedGen UID:
393574
Concept ID:
C2676721
Disease or Syndrome
Protein S deficiency
MedGen UID:
436762
Concept ID:
C2676728
Disease or Syndrome
Heterozygous protein S deficiency, like protein C deficiency (176860), is characterized by recurrent venous thrombosis. Bertina (1990) classified protein S deficiency into 3 clinical subtypes based on laboratory findings. Type I refers to deficiency of both free and total protein S as well as decreased protein S activity; type II shows normal plasma values, but decreased protein S activity; and type III shows decreased free protein S levels and activity, but normal total protein S levels. Approximately 40% of protein S circulates as a free active form, whereas the remaining 60% circulates as an inactive form bound to C4BPA (120830). Zoller et al. (1995) observed coexistence of type I and type III PROS1-deficient phenotypes within a single family and determined that the subtypes are allelic. Under normal conditions, the concentration of protein S exceeds that of C4BPA by approximately 30 to 40%. Thus, free protein S is the molar surplus of protein S over C4BPA. Mild protein S deficiency will thus present with selective deficiency of free protein S, whereas more pronounced protein S deficiency will also decrease the complexed protein S and consequently the total protein S level. These findings explained why assays for free protein S have a higher predictive value for protein S deficiency. See also autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514), which is a more severe disorder.
Thrombophilia, hereditary, due to protein C deficiency, autosomal recessive
MedGen UID:
394120
Concept ID:
C2676759
Disease or Syndrome
Autosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000).
Thrombophilia, X-linked, due to factor IX defect
MedGen UID:
411730
Concept ID:
C2749016
Disease or Syndrome
Thrombophilia, histidine-rich glycoprotein-related
MedGen UID:
416465
Concept ID:
C2751090
Disease or Syndrome
Thrombophilia due to protein S deficiency, autosomal recessive
MedGen UID:
482722
Concept ID:
C3281092
Disease or Syndrome
Autosomal recessive thrombophilia due to protein S deficiency is a very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al., 2010), whereas others have recurrent thromboses later in childhood (Comp et al., 1984). See also autosomal dominant thrombophilia due to protein S deficiency (THPH5; 612336), a less severe disorder caused by heterozygous mutation in the PROS1 gene.

Professional guidelines

PubMed

Hickey SE, Curry CJ, Toriello HV
Genet Med 2013 Feb;15(2):153-6. Epub 2013 Jan 3 doi: 10.1038/gim.2012.165. PMID: 23288205
Lockwood C, Wendel G; Committee on Practice Bulletins— Obstetrics.
Obstet Gynecol 2011 Sep;118(3):730-40. doi: 10.1097/AOG.0b013e3182310c6f. PMID: 21860314
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.
Genet Med 2011 Jan;13(1):67-76. doi: 10.1097/GIM.0b013e3181fbe46f. PMID: 21150787
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Pinette MG, Wax JR
Obstet Gynecol 2010 Jan;115(1):188-9; author reply 189. doi: 10.1097/AOG.0b013e3181c8b21d. PMID: 20027064

External

Don't order MTHFR genetic testing for the risk assessment of hereditary thrombophilia.

Recent clinical studies

Etiology

Garcia-Horton A, Kovacs MJ, Abdulrehman J, Taylor JE, Sharma S, Lazo-Langner A
Thromb Res 2017 Jan;149:76-80. Epub 2016 Dec 1 doi: 10.1016/j.thromres.2016.11.023. PMID: 27931012
Aracic N, Roje D, Jakus IA, Bakotin M, Stefanovic V
Yonsei Med J 2016 Sep;57(5):1230-5. doi: 10.3349/ymj.2016.57.5.1230. PMID: 27401656Free PMC Article
Gils C, Nybo M
Int J Gynaecol Obstet 2016 Aug;134(2):156-9. Epub 2016 Apr 8 doi: 10.1016/j.ijgo.2015.12.007. PMID: 27113416
Pahus SH, Hansen AT, Hvas AM
Thromb Res 2016 Jan;137:108-12. Epub 2015 Nov 10 doi: 10.1016/j.thromres.2015.11.006. PMID: 26585761
Meyer MR, Witt DM, Delate T, Johnson SG, Fang M, Go A, Clark NP
Thromb Res 2015 Dec;136(6):1160-4. Epub 2015 Oct 21 doi: 10.1016/j.thromres.2015.10.019. PMID: 26477821Free PMC Article

Diagnosis

Garcia-Horton A, Kovacs MJ, Abdulrehman J, Taylor JE, Sharma S, Lazo-Langner A
Thromb Res 2017 Jan;149:76-80. Epub 2016 Dec 1 doi: 10.1016/j.thromres.2016.11.023. PMID: 27931012
Gils C, Nybo M
Int J Gynaecol Obstet 2016 Aug;134(2):156-9. Epub 2016 Apr 8 doi: 10.1016/j.ijgo.2015.12.007. PMID: 27113416
Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M, Lim W, Douketis JD
J Thromb Thrombolysis 2016 Jan;41(1):154-64. doi: 10.1007/s11239-015-1316-1. PMID: 26780744Free PMC Article
Pahus SH, Hansen AT, Hvas AM
Thromb Res 2016 Jan;137:108-12. Epub 2015 Nov 10 doi: 10.1016/j.thromres.2015.11.006. PMID: 26585761
Meyer MR, Witt DM, Delate T, Johnson SG, Fang M, Go A, Clark NP
Thromb Res 2015 Dec;136(6):1160-4. Epub 2015 Oct 21 doi: 10.1016/j.thromres.2015.10.019. PMID: 26477821Free PMC Article

Therapy

Garcia-Horton A, Kovacs MJ, Abdulrehman J, Taylor JE, Sharma S, Lazo-Langner A
Thromb Res 2017 Jan;149:76-80. Epub 2016 Dec 1 doi: 10.1016/j.thromres.2016.11.023. PMID: 27931012
Skelley JW, White CW, Thomason AR
J Thromb Thrombolysis 2017 Jan;43(1):24-30. doi: 10.1007/s11239-016-1428-2. PMID: 27734187
Ata B, Urman B
J Assist Reprod Genet 2016 Oct;33(10):1305-1310. Epub 2016 Jul 16 doi: 10.1007/s10815-016-0771-8. PMID: 27423663Free PMC Article
Aracic N, Roje D, Jakus IA, Bakotin M, Stefanovic V
Yonsei Med J 2016 Sep;57(5):1230-5. doi: 10.3349/ymj.2016.57.5.1230. PMID: 27401656Free PMC Article
Meyer MR, Witt DM, Delate T, Johnson SG, Fang M, Go A, Clark NP
Thromb Res 2015 Dec;136(6):1160-4. Epub 2015 Oct 21 doi: 10.1016/j.thromres.2015.10.019. PMID: 26477821Free PMC Article

Prognosis

Garcia-Horton A, Kovacs MJ, Abdulrehman J, Taylor JE, Sharma S, Lazo-Langner A
Thromb Res 2017 Jan;149:76-80. Epub 2016 Dec 1 doi: 10.1016/j.thromres.2016.11.023. PMID: 27931012
Gils C, Nybo M
Int J Gynaecol Obstet 2016 Aug;134(2):156-9. Epub 2016 Apr 8 doi: 10.1016/j.ijgo.2015.12.007. PMID: 27113416
Delate T, Hsiao W, Kim B, Witt DM, Meyer MR, Go AS, Fang MC
Thromb Res 2016 Jan;137:97-102. Epub 2015 Nov 10 doi: 10.1016/j.thromres.2015.11.009. PMID: 26585762Free PMC Article
Sundquist K, Sundquist J, Svensson PJ, Zöller B, Memon AA
J Thromb Haemost 2015 Dec;13(12):2180-6. Epub 2015 Oct 29 doi: 10.1111/jth.13154. PMID: 26407905
Ergul Y, Kiplapinar N, Tanidir IC, Ozturk E, Guzeltas A, Haydin S, Akcay A, Erek E, Yeniterzi M, Odemis E, Bakir I
Pediatr Int 2015 Dec;57(6):1072-7. Epub 2015 Nov 10 doi: 10.1111/ped.12727. PMID: 26096312

Clinical prediction guides

Garcia-Horton A, Kovacs MJ, Abdulrehman J, Taylor JE, Sharma S, Lazo-Langner A
Thromb Res 2017 Jan;149:76-80. Epub 2016 Dec 1 doi: 10.1016/j.thromres.2016.11.023. PMID: 27931012
Delate T, Hsiao W, Kim B, Witt DM, Meyer MR, Go AS, Fang MC
Thromb Res 2016 Jan;137:97-102. Epub 2015 Nov 10 doi: 10.1016/j.thromres.2015.11.009. PMID: 26585762Free PMC Article
Berks D, Duvekot JJ, Basalan H, De Maat MP, Steegers EA, Visser W
Eur J Obstet Gynecol Reprod Biol 2015 Nov;194:199-205. Epub 2015 Sep 28 doi: 10.1016/j.ejogrb.2015.09.021. PMID: 26444331
Sundquist K, Sundquist J, Svensson PJ, Zöller B, Memon AA
J Thromb Haemost 2015 Dec;13(12):2180-6. Epub 2015 Oct 29 doi: 10.1111/jth.13154. PMID: 26407905
Weingarz L, Schindewolf M, Schwonberg J, Hecking C, Wolf Z, Erbe M, Lindhoff-Last E, Linnemann B
Vasa 2015 Jul;44(4):313-23. doi: 10.1024/0301-1526/a000447. PMID: 26314364

Recent systematic reviews

Kirkegaard K, Heegaard S, Hvas AM
Acta Ophthalmol 2017 Feb;95(1):12-19. Epub 2016 Aug 29 doi: 10.1111/aos.13214. PMID: 27573507
Skeith L, Carrier M, Kaaja R, Martinelli I, Petroff D, Schleußner E, Laskin CA, Rodger MA
Blood 2016 Mar 31;127(13):1650-5. Epub 2016 Feb 2 doi: 10.1182/blood-2015-12-626739. PMID: 26837697
Areia AL, Fonseca E, Areia M, Moura P
Arch Gynecol Obstet 2016 Jan;293(1):81-6. Epub 2015 Jun 10 doi: 10.1007/s00404-015-3782-2. PMID: 26059084
Torres VM, Saddi VA
J Pediatr (Rio J) 2015 Jan-Feb;91(1):22-9. Epub 2014 Oct 16 doi: 10.1016/j.jped.2014.08.004. PMID: 25451211
de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S
Cochrane Database Syst Rev 2014 Jul 4;(7):CD004734. doi: 10.1002/14651858.CD004734.pub4. PMID: 24995856

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