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Hemostasis/Thrombosis

Factor V Leiden Genotype

Factor V Leiden (FVL) is a genetic variant of the gene encoding the protein factor V, a cofactor in the blood-clotting process. This variant confers a hypercoagulable state and is the most common inherited risk factor for venous thromboembolism (VTE).1 A single FVL allele (the heterozygous state, with one copy of the variant gene and one copy of the normal gene (Arg/Glyn) is found in 1–5% of the US population, while homozygotes (two copies of the altered gene) are rare (~1 in 5000 individuals).2

VTE is typically seen in the veins (deep vein thrombosis or DVT). The clot may migrate and cause pulmonary embolism, myocardial infarction, or stroke. Both FVL and prothrombin G20210A heterozygosity and homozygosity are predictive of recurrent VTE among individuals who have had a prior VTE, and in women who are using oral contraceptives or hormone replacement therapy, or are pregnant.3-5  Rare compound heterozygotes, individuals heterozygous for both the FVL mutation and the prothrombin mutation, have a much greater risk of VTE, similar to individuals homozygous for either mutation but occurring at a younger age.Other contributing thrombogenic factors to the importance of these two SNPs in any given individual include smoking, prolonged sitting, dehydration, surgery, hyperhomocysteinemia, varicose veins, obesity, diabetes, age,  and malignancy.

Simple lifestyle modifications can reduce the risk of VTE: avoiding prolonged periods of sitting or immobilization, remaining hydrated, regular exercise (especially walking), weight loss, and for smokers, smoking cessation. A lower estrogen-content oral contraceptive or alternative birth control measures may be a consideration in heterozygous carrier women. Surgery is a main cause of DVT (through increased clotting), so it is important that FVL or prothrombin G20210A carriers inform surgeons of their need for anticoagulation therapy ahead of time.

  1. Cott EM, et al. Factor V Leiden. Am J Hematol 2016;91:46–49.
  2. Price DT, Ridker PM. Ann Intern Med 1997;127(10):895–903.
  3. Segal JB, et al. J Am Med Assoc 2009;301(23):3698-3703.
  4. Kujovich J (updated March 9, 2010). Factor V Leiden thrombophilia. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2010. Available at https://www.ncbi.nlm.nih.gov/books/NBK1368/.
  5. Gadelha T, et al. Thromb Res 2010;126:283.
  6. Lim MY, et al. Eur J Haematol 2016;97(4):353–360.

Prothrombin G20210A Genotype

The prothrombin G20210A variant results from an alteration in the 3’-untranslated region of the prothrombin gene and is the second most common inherited risk factor for first VTE. This DNA variant leads to increased circulating levels of prothrombin (30% higher in heterozygotes, 70% in homozygotes). As prothrombin is the precursor to thrombin, this enhances the potential for clot formation. 1 The prothrombin G20210A SNP is fairly common, with a heterozygote carrier frequency of approximately 1–2% in American populations.2 Homozygous individuals are rare (< 20 per 100,000), although this SNP is present in ~6% of those who present with a VTE.3

VTE is typically seen in the veins (deep vein thrombosis or DVT). The clot may migrate and cause pulmonary embolism, myocardial infarction, or stroke. Both FVL and prothrombin G20210A heterozygosity and homozygosity are predictive of recurrent VTE among individuals who have had a prior VTE, and in women who are using oral contraceptives or hormone replacement therapy, or are pregnant.4-6 Rare compound heterozygotes, individuals heterozygous for both the FVL mutation and the prothrombin mutation, have a much greater risk of VTE, similar to individuals homozygous for either mutation but occurring at a younger age.7 Other contributing thrombogenic factors to the importance of these two SNPs in any given individual include smoking, prolonged sitting, dehydration, surgery, hyperhomocysteinemia, varicose veins, obesity, diabetes, age, and malignancy.

Simple lifestyle modifications can reduce the risk of VTE: avoiding prolonged periods of sitting or immobilization, remaining hydrated, regular exercise (especially walking), weight loss, and for smokers, smoking cessation. A lower estrogen-content oral contraceptive or alternative birth control measures may be a consideration in heterozygous carrier women. Surgery is a main cause of DVT (through increased clotting), so it is important that FVL or prothrombin G20210A carriers inform surgeons of their need for anticoagulation therapy ahead of time.

  1. Poort SR, et al. Blood 1996;88(10):3698–3703.
  2. Kujovich JL. Prothrombin-Related Thrombophilia. 2006 Jul 25 [Updated 2014 Aug 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.Available at https://www.ncbi.nlm.nih.gov/books/NBK1148/.
  3. EGAPP working group. Genet Med 2011;13(1):67–76.
  4. Segal JB, et al. J Am Med Assoc 2009;301(23):2472–2485.
  5. Kujovich J (updated March 9, 2010). Factor V Leiden thrombophilia. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2010. Available at https://www.ncbi.nlm.nih.gov/books/NBK1368/.
  6. Gadelha T, et al. Thromb Res 2010;126:283.
  7. Lim MY, et al. Eur J Haematol 2016;97(4):353–360.

Antiphospholipid Antibodies

Antiphospholipid antibodies (APA) are immunoglobulins of IgG, IgM and IgA isotypes that target phospholipid and/or phospholipid-binding plasma proteins. The repeated finding of APA in association with abnormal blood clotting and a multitude of neurological, obstetrical, and rheumatic disorders, often compounded by autoimmune diseases, has led to the diagnosis term antiphospholipid syndrome (APS).1 APS is a largely underdiagnosed autoimmune disorder that is associated with venous and arterial thrombosis. Diagnosis of APS involves testing for medium-to-high levels of anticardiolipin and anti-β2 glycoprotein I (GPI) antibodies (or lupus anticoagulant) and screening for clinical symptoms of vascular thrombosis or history of pregnancy morbidity. It is an important women’s health issue; the 75–90% of APS patients who are women comprise ~0.4% of the US population.2 APS antibody testing can help determine the cause of unexplained thrombotic episode, thrombocytopenia, or recurrent miscarriages, and may be considered for women with a strong family history of stroke, especially prior to pregnancy.

Cardiolipin is a phospholipid found in the inner mitochondrial membrane, where it is essential for the optimal function of enzymes involved in mitochondrial energy metabolism, as well as in circulating plasma, bound to lipoproteins. Anticardiolipin antibodies (ACA) have been strongly associated with venous and arterial thrombosis and are commonly present in patients with systemic lupus erythematosus (SLE).1,3 β2-GPI is a 50kD serum cofactor required for cardiolipin antibodies induced in SLE or APS patients to bind to cardiolipin. Combining the β2-GPI antibody test with the traditionally used ACA provides a more specific assay for detecting thrombosis risk in patients with clinical manifestations of APS or SLE.4

Many infections may be accompanied by APA elevations (particularly ACA) through the process of molecular mimicry and, in some instances, these elevations may be accompanied by clinical manifestations of APS. For example, APA have been associated with skin infections, HIV infection, pneumonia, HCV infections, and urinary tract infections.5 Several studies have indicated that APAs trigger an inflammatory cascade and have been implicated in the pathogenesis of atherosclerosis associated with APS, SLE, and rheumatoid arthritis, as well as cerebrovascular and peripheral arterial diseases.7-11

  1. Chaturvedi S, McCrae KR. Hematology Am Soc Hematol Educ Program 2015;2015:53–60.
  2. APS Foundation of America. Available at http://www.apsfa.org/aps.htm. Accessed November 28, 2016.
  3. Krone KA, et al. Curr Rheumatol Rep 2010;12:53–57.
  4. De Groot PG, Urbanus RT. Blood 2012;120(2):266–274.
  5. Cervera R, et al. Ann Rheum Dis2004;63(10):1312–1317.
  6. Willis R, Pierangeli SS. Ann NY Acad Sci 2013;1285:44–58.
  7. Hasunuma Y, et al. Clin Exp Immunol 1997;107:569–573.
  8. Gladd DA, Olech E. Curr Rheumatol Rep 2009;11(1):43–51.
  9. Sherer, Shoenfeld. Nat Clin Pract Rheumatol 2006;2(2):99–106.
  10. Artenjak A, et al. Autoimmun Rev 2012;11:873–882.
  11. Matsuura E, et al. Autoimmun Rev 2012;12:241–249.

 

 

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