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Thrombophilia

MedGen UID:
98306
Concept ID:
C0398623
Disease or Syndrome
Synonym: Hypercoagulability
SNOMED CT: Hypercoagulability state (76612001); Hypercoagulable state (76612001); Hypercoagulability (76612001); Thrombophilia (234467004)
 
HPO: HP:0100724
Monarch Initiative: MONDO:0002305
Orphanet: ORPHA64738

Definition

An abnormality of coagulation associated with an increased risk of thrombosis. [from HPO]

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 vein 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 heterozygosity for the Leiden variant has at most a modest effect on risk for recurrent thrombosis after initial treatment of a first VTE. It is unlikely that factor V Leiden thrombophilia (i.e., heterozygosity or homozygosity for the Leiden variant) is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes (preeclampsia, fetal growth restriction, and placental abruption). The clinical expression of factor V Leiden thrombophilia is influenced by the following: The number of Leiden variants (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 antibody (APLA) syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travel, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and advancing age.
Thrombophilia 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 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 9 defect
MedGen UID:
411730
Concept ID:
C2749016
Disease or Syndrome
A hemostatic disorder characterized by a tendency to thrombosis that has X-linked recessive inheritance, and can be caused by a gain-of-function mutation in the gene encoding factor IX (F9).
Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency
MedGen UID:
416465
Concept ID:
C2751090
Disease or Syndrome
Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency is a rare, genetic, coagulation disorder characterized by a tendency to develop thrombosis, resulting from decreased histidine-rich glycoprotein (HRG) plasma levels. Manifestations are variable depending on location of thrombosis, but may include headaches, diplopia, progressive pain, limb swelling, itching or ulceration, and brownish skin discoloration, among others.
Thrombophilia due to protein S deficiency, autosomal dominant
MedGen UID:
479841
Concept ID:
C3278211
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.
Thrombomodulin-related bleeding disorder
MedGen UID:
482606
Concept ID:
C3280976
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 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

Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton D, James AH, Lang E, Moll S, Myers T, Bhatt M, Chai-Adisaksopha C, Colunga-Lozano LE, Karam SG, Zhang Y, Wiercioch W, Schünemann HJ, Iorio A
Blood Adv 2023 Nov 28;7(22):7101-7138. doi: 10.1182/bloodadvances.2023010177. PMID: 37195076Free PMC Article
Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA
J Clin Endocrinol Metab 2018 May 1;103(5):1715-1744. doi: 10.1210/jc.2018-00229. PMID: 29562364
Ferro JM, Bousser MG, Canhão P, Coutinho JM, Crassard I, Dentali F, di Minno M, Maino A, Martinelli I, Masuhr F, Aguiar de Sousa D, Stam J; European Stroke Organization
Eur J Neurol 2017 Oct;24(10):1203-1213. Epub 2017 Aug 20 doi: 10.1111/ene.13381. PMID: 28833980

Recent clinical studies

Etiology

Middeldorp S, Naue C, Köhler C
Hamostaseologie 2022 Feb;42(1):54-64. Epub 2022 Feb 23 doi: 10.1055/a-1717-7663. PMID: 35196731
Dautaj A, Krasi G, Bushati V, Precone V, Gheza M, Fioretti F, Sartori M, Costantini A, Benedetti S, Bertelli M
Acta Biomed 2019 Sep 30;90(10-S):44-46. doi: 10.23750/abm.v90i10-S.8758. PMID: 31577252Free PMC Article
Campello E, Spiezia L, Adamo A, Simioni P
Expert Rev Hematol 2019 Mar;12(3):147-158. Epub 2019 Feb 26 doi: 10.1080/17474086.2019.1583555. PMID: 30773075
Applegate JS, Gronefeld D
Radiol Technol 2019 Jan;90(3):259-273. PMID: 30635457
Connors JM
N Engl J Med 2017 Sep 21;377(12):1177-1187. doi: 10.1056/NEJMra1700365. PMID: 28930509

Diagnosis

Asmis L, Hellstern P
Clin Lab 2023 Apr 1;69(4) doi: 10.7754/Clin.Lab.2022.220817. PMID: 37057948
Middeldorp S, Naue C, Köhler C
Hamostaseologie 2022 Feb;42(1):54-64. Epub 2022 Feb 23 doi: 10.1055/a-1717-7663. PMID: 35196731
Dautaj A, Krasi G, Bushati V, Precone V, Gheza M, Fioretti F, Sartori M, Costantini A, Benedetti S, Bertelli M
Acta Biomed 2019 Sep 30;90(10-S):44-46. doi: 10.23750/abm.v90i10-S.8758. PMID: 31577252Free PMC Article
Applegate JS, Gronefeld D
Radiol Technol 2019 Jan;90(3):259-273. PMID: 30635457
Connors JM
N Engl J Med 2017 Sep 21;377(12):1177-1187. doi: 10.1056/NEJMra1700365. PMID: 28930509

Therapy

Quenby S, Booth K, Hiller L, Coomarasamy A, de Jong PG, Hamulyák EN, Scheres LJ, van Haaps TF, Ewington L, Tewary S, Goddijn M, Middeldorp S; ALIFE2 Block Writing Committee; ALIFE2 Investigators
Lancet 2023 Jul 1;402(10395):54-61. Epub 2023 Jun 1 doi: 10.1016/S0140-6736(23)00693-1. PMID: 37271152
Asmis L, Hellstern P
Clin Lab 2023 Apr 1;69(4) doi: 10.7754/Clin.Lab.2022.220817. PMID: 37057948
Morris G, Talaulikar V
Post Reprod Health 2023 Mar;29(1):33-41. Epub 2022 Dec 27 doi: 10.1177/20533691221148036. PMID: 36573625
Middeldorp S, Naue C, Köhler C
Hamostaseologie 2022 Feb;42(1):54-64. Epub 2022 Feb 23 doi: 10.1055/a-1717-7663. PMID: 35196731
Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S, Murad MH
Chest 2012 Feb;141(2 Suppl):e195S-e226S. doi: 10.1378/chest.11-2296. PMID: 22315261Free PMC Article

Prognosis

Klok FA, Ageno W, Ay C, Bäck M, Barco S, Bertoletti L, Becattini C, Carlsen J, Delcroix M, van Es N, Huisman MV, Jara-Palomares L, Konstantinides S, Lang I, Meyer G, Ní Áinle F, Rosenkranz S, Pruszczyk P
Eur Heart J 2022 Jan 25;43(3):183-189. doi: 10.1093/eurheartj/ehab816. PMID: 34875048Free PMC Article
Kichloo A, Dettloff K, Aljadah M, Albosta M, Jamal S, Singh J, Wani F, Kumar A, Vallabhaneni S, Khan MZ
Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620962853. doi: 10.1177/1076029620962853. PMID: 33074732Free PMC Article
Liew NC, Alemany GV, Angchaisuksiri P, Bang SM, Choi G, DE Silva DA, Hong JM, Lee L, Li YJ, Rajamoney GN, Suviraj J, Tan TC, Tse E, Teo LT, Visperas J, Wong RS, Lee LH
Int Angiol 2017 Feb;36(1):1-20. Epub 2016 Sep 8 doi: 10.23736/S0392-9590.16.03765-2. PMID: 27606807
Pasupathy S, Air T, Dreyer RP, Tavella R, Beltrame JF
Circulation 2015 Mar 10;131(10):861-70. Epub 2015 Jan 13 doi: 10.1161/CIRCULATIONAHA.114.011201. PMID: 25587100
Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A, Hunt BJ, Hylek EM, Kakkar A, Konstantinides SV, McCumber M, Ozaki Y, Wendelboe A, Weitz JI; ISTH Steering Committee for World Thrombosis Day
Arterioscler Thromb Vasc Biol 2014 Nov;34(11):2363-71. doi: 10.1161/ATVBAHA.114.304488. PMID: 25304324

Clinical prediction guides

Asmis L, Hellstern P
Clin Lab 2023 Apr 1;69(4) doi: 10.7754/Clin.Lab.2022.220817. PMID: 37057948
Chopard R, Albertsen IE, Piazza G
JAMA 2020 Nov 3;324(17):1765-1776. doi: 10.1001/jama.2020.17272. PMID: 33141212
Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M; Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis
J Thromb Haemost 2019 Nov;17(11):1989-1994. Epub 2019 Aug 13 doi: 10.1111/jth.14578. PMID: 31410983
Moll S
J Thromb Thrombolysis 2015 Apr;39(3):367-78. doi: 10.1007/s11239-015-1197-3. PMID: 25724822
Wypasek E, Undas A
Adv Clin Exp Med 2013 Jul-Aug;22(4):459-67. PMID: 23986205

Recent systematic reviews

Asmis L, Hellstern P
Clin Lab 2023 Apr 1;69(4) doi: 10.7754/Clin.Lab.2022.220817. PMID: 37057948
Chiasakul T, De Jesus E, Tong J, Chen Y, Crowther M, Garcia D, Chai-Adisaksopha C, Messé SR, Cuker A
J Am Heart Assoc 2019 Oct;8(19):e012877. Epub 2019 Sep 24 doi: 10.1161/JAHA.119.012877. PMID: 31549567Free PMC Article
Croles FN, Nasserinejad K, Duvekot JJ, Kruip MJ, Meijer K, Leebeek FW
BMJ 2017 Oct 26;359:j4452. doi: 10.1136/bmj.j4452. PMID: 29074563Free PMC Article
van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K
J Thromb Haemost 2016 Jul;14(7):1393-403. Epub 2016 Jun 16 doi: 10.1111/jth.13349. PMID: 27121914
Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A, Hunt BJ, Hylek EM, Kakkar A, Konstantinides SV, McCumber M, Ozaki Y, Wendelboe A, Weitz JI; ISTH Steering Committee for World Thrombosis Day
Arterioscler Thromb Vasc Biol 2014 Nov;34(11):2363-71. doi: 10.1161/ATVBAHA.114.304488. PMID: 25304324

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