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Thrombophilia due to activated protein C resistance(THPH2)

MedGen UID:
396074
Concept ID:
C1861171
Disease or Syndrome
Synonyms: Activated protein C resistance; APC resistance; Factor V Cambridge Thrombophilia; Hereditary Resistance to Activated Protein C; PCCF DEFICIENCY; PROC COFACTOR DEFICIENCY; THPH2; THROMBOPHILIA DUE TO DEFICIENCY OF ACTIVATED PROTEIN C COFACTOR; THROMBOPHILIA V
 
Gene (location): F5 (1q24.2)
 
Monarch Initiative: MONDO:0008560
OMIM®: 188055

Disease characteristics

Excerpted from the GeneReview: Factor V Leiden Thrombophilia
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. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
Authors:
Jody L Kujovich   view full author information

Additional descriptions

From OMIM
Thrombophilia due to activated protein C resistance is due to a mutation in the F5 gene that renders factor V resistant to cleavage and inactivation by activated protein C (PROC; 612283) and results in a tendency to thrombosis. See also factor V deficiency (227400), an allelic disorder resulting in a hemorrhagic diathesis due to lack of factor V. The most common mutation that causes this disorder is referred to as factor V Leiden (R506Q; 612309.0001), named after the town in the Netherlands where Bertina et al. (1994) discovered the defect. Homozygosity increases the risk of thrombotic complications to a greater extent than heterozygosity. However, heterozygous presence of the mutation may be combined with defects in other genes in the clotting pathway to contribute to the disorder. Expressivity is variable and influenced by environment.  http://www.omim.org/entry/188055
From MedlinePlus Genetics
Factor V Leiden thrombophilia is an inherited disorder of blood clotting. Factor V Leiden is the name of a specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels.

People with factor V Leiden thrombophilia have a higher than average risk of developing a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the legs, although they can also occur in other parts of the body, including the brain, eyes, liver, and kidneys. Factor V Leiden thrombophilia also increases the risk that clots will break away from their original site and travel through the bloodstream. These clots can lodge in the lungs, where they are known as pulmonary emboli. Although factor V Leiden thrombophilia increases the risk of blood clots, only about 10 percent of individuals with the factor V Leiden mutation ever develop abnormal clots.

The factor V Leiden mutation is associated with a slightly increased risk of pregnancy loss (miscarriage). Women with this mutation are two to three times more likely to have multiple (recurrent) miscarriages or a pregnancy loss during the second or third trimester. Some research suggests that the factor V Leiden mutation may also increase the risk of other complications during pregnancy, including pregnancy-induced high blood pressure (preeclampsia), slow fetal growth, and early separation of the placenta from the uterine wall (placental abruption). However, the association between the factor V Leiden mutation and these complications has not been confirmed. Most women with factor V Leiden thrombophilia have normal pregnancies.  https://medlineplus.gov/genetics/condition/factor-v-leiden-thrombophilia

Clinical features

From HPO
Deep venous thrombosis
MedGen UID:
57448
Concept ID:
C0149871
Disease or Syndrome
Formation of a blot clot in a deep vein. The clot often blocks blood flow, causing swelling and pain. The deep veins of the leg are most often affected.
Prolonged partial thromboplastin time
MedGen UID:
66815
Concept ID:
C0240671
Finding
Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms.
Thrombophilia
MedGen UID:
98306
Concept ID:
C0398623
Disease or Syndrome
An abnormality of coagulation associated with an increased risk of thrombosis.
Resistance to activated protein C
MedGen UID:
109068
Concept ID:
C0600433
Disease or Syndrome
Poor anticoagulant response to activated protein C. A plasma is termed 'APC resistant' when the addition of exogenous APC fails to prolong its clotting time in an activated partial thromboplastin time assay.

Term Hierarchy

Professional guidelines

PubMed

Moore GW, Van Cott EM, Cutler JA, Mitchell MJ, Adcock DM; subcommittee on plasma coagulation inhibitors
J Thromb Haemost 2019 Sep;17(9):1555-1561. Epub 2019 Jul 17 doi: 10.1111/jth.14532. PMID: 31317658
Rolla R, Bellomo G
Clin Lab 2013;59(9-10):1187-8. doi: 10.7754/clin.lab.2013.130148. PMID: 24273947

Curated

UK NICE Guideline NG158, Venous thromboembolic diseases: diagnosis, management and thrombophilia testing, 2023

Recent clinical studies

Etiology

Santler SC, Konstantiniuk P, Schramayer G, Prüller F, Siegl G, Demel U, Cohnert T
Semin Dial 2022 Jan;35(1):58-65. Epub 2021 Dec 9 doi: 10.1111/sdi.13042. PMID: 34882835
Zöller B, Svensson PJ, Dahlbäck B, Lind-Hallden C, Hallden C, Elf J
Expert Rev Hematol 2020 Sep;13(9):971-981. Epub 2020 Aug 23 doi: 10.1080/17474086.2020.1804354. PMID: 32731838
Brooks JK, Elrafei A, Ord RA
Gen Dent 2019 May-Jun;67(3):21-24. PMID: 31199740
Van Cott EM, Khor B, Zehnder JL
Am J Hematol 2016 Jan;91(1):46-9. Epub 2015 Nov 17 doi: 10.1002/ajh.24222. PMID: 26492443
Rühl H, Schröder L, Müller J, Fimmers R, Sukhitashvili S, Welz J, Kuhn WC, Oldenburg J, Rudlowski C, Pötzsch B
Thromb Res 2014 May;133(5):886-91. Epub 2014 Feb 11 doi: 10.1016/j.thromres.2014.02.004. PMID: 24568775

Diagnosis

Yang J, Mao H, Sun L
J Clin Lab Anal 2022 Nov;36(11):e24705. Epub 2022 Sep 20 doi: 10.1002/jcla.24705. PMID: 36125894Free PMC Article
Zöller B, Svensson PJ, Dahlbäck B, Lind-Hallden C, Hallden C, Elf J
Expert Rev Hematol 2020 Sep;13(9):971-981. Epub 2020 Aug 23 doi: 10.1080/17474086.2020.1804354. PMID: 32731838
Brooks JK, Elrafei A, Ord RA
Gen Dent 2019 May-Jun;67(3):21-24. PMID: 31199740
Rühl H, Schröder L, Müller J, Fimmers R, Sukhitashvili S, Welz J, Kuhn WC, Oldenburg J, Rudlowski C, Pötzsch B
Thromb Res 2014 May;133(5):886-91. Epub 2014 Feb 11 doi: 10.1016/j.thromres.2014.02.004. PMID: 24568775
Blanco-Molina Á
Thromb Res 2012 Oct;130 Suppl 1:S16-8. doi: 10.1016/j.thromres.2012.08.263. PMID: 23026651

Therapy

Santler SC, Konstantiniuk P, Schramayer G, Prüller F, Siegl G, Demel U, Cohnert T
Semin Dial 2022 Jan;35(1):58-65. Epub 2021 Dec 9 doi: 10.1111/sdi.13042. PMID: 34882835
Zöller B, Svensson PJ, Dahlbäck B, Lind-Hallden C, Hallden C, Elf J
Expert Rev Hematol 2020 Sep;13(9):971-981. Epub 2020 Aug 23 doi: 10.1080/17474086.2020.1804354. PMID: 32731838
Van Cott EM, Khor B, Zehnder JL
Am J Hematol 2016 Jan;91(1):46-9. Epub 2015 Nov 17 doi: 10.1002/ajh.24222. PMID: 26492443
Rühl H, Schröder L, Müller J, Fimmers R, Sukhitashvili S, Welz J, Kuhn WC, Oldenburg J, Rudlowski C, Pötzsch B
Thromb Res 2014 May;133(5):886-91. Epub 2014 Feb 11 doi: 10.1016/j.thromres.2014.02.004. PMID: 24568775
Blanco-Molina Á
Thromb Res 2012 Oct;130 Suppl 1:S16-8. doi: 10.1016/j.thromres.2012.08.263. PMID: 23026651

Prognosis

Falkner F, Thomas B, Aman M, Risse EM, Wittenberg G, Gazyakan E, Harhaus L, Bigdeli AK, Kneser U, Radu CA
BMC Surg 2022 May 14;22(1):190. doi: 10.1186/s12893-022-01639-3. PMID: 35568862Free PMC Article
Gupta T, Delhi Kumar CG, Ramesh Kumar R, Adhisivam B
Indian J Pediatr 2019 Mar;86(3):241-244. Epub 2018 Dec 13 doi: 10.1007/s12098-018-2827-5. PMID: 30547428
Alshaikh NA, Rosing J, Thomassen MCLGD, Castoldi E, Simioni P, Hackeng TM
J Thromb Haemost 2017 May;15(5):950-960. Epub 2017 Mar 20 doi: 10.1111/jth.13657. PMID: 28211163
Rühl H, Schröder L, Müller J, Sukhitashvili S, Welz J, Kuhn WC, Oldenburg J, Rudlowski C, Pötzsch B
PLoS One 2014;9(8):e105007. Epub 2014 Aug 14 doi: 10.1371/journal.pone.0105007. PMID: 25121606Free PMC Article
Blanco-Molina Á
Thromb Res 2012 Oct;130 Suppl 1:S16-8. doi: 10.1016/j.thromres.2012.08.263. PMID: 23026651

Clinical prediction guides

Wei Y, He Y, Guo X
J Pediatr Hematol Oncol 2022 Mar 1;44(2):e482-e486. doi: 10.1097/MPH.0000000000002261. PMID: 34387626Free PMC Article
Zöller B, Svensson PJ, Dahlbäck B, Lind-Hallden C, Hallden C, Elf J
Expert Rev Hematol 2020 Sep;13(9):971-981. Epub 2020 Aug 23 doi: 10.1080/17474086.2020.1804354. PMID: 32731838
Gupta T, Delhi Kumar CG, Ramesh Kumar R, Adhisivam B
Indian J Pediatr 2019 Mar;86(3):241-244. Epub 2018 Dec 13 doi: 10.1007/s12098-018-2827-5. PMID: 30547428
Rühl H, Schröder L, Müller J, Sukhitashvili S, Welz J, Kuhn WC, Oldenburg J, Rudlowski C, Pötzsch B
PLoS One 2014;9(8):e105007. Epub 2014 Aug 14 doi: 10.1371/journal.pone.0105007. PMID: 25121606Free PMC Article
Rühl H, Schröder L, Müller J, Fimmers R, Sukhitashvili S, Welz J, Kuhn WC, Oldenburg J, Rudlowski C, Pötzsch B
Thromb Res 2014 May;133(5):886-91. Epub 2014 Feb 11 doi: 10.1016/j.thromres.2014.02.004. PMID: 24568775

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • NICE, 2023
      UK NICE Guideline NG158, Venous thromboembolic diseases: diagnosis, management and thrombophilia testing, 2023

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