HomeCirculationVol. 129, No. 2Inherited and Secondary Thrombophilia Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBInherited and Secondary Thrombophilia Kevin P. Cohoon, DO, MSc and John A. Heit, MD Kevin P. CohoonKevin P. Cohoon From the Divisions of Cardiovascular Diseases (K.P.C., J.A.H.) and Hematology (J.A.H.), Department of Internal Medicine, Mayo Clinic, Rochester, MN. Search for more papers by this author and John A. HeitJohn A. Heit From the Divisions of Cardiovascular Diseases (K.P.C., J.A.H.) and Hematology (J.A.H.), Department of Internal Medicine, Mayo Clinic, Rochester, MN. Search for more papers by this author Originally published14 Jan 2014https://doi.org/10.1161/CIRCULATIONAHA.113.001943Circulation. 2014;129:254–257IntroductionCase Presentation 1: A healthy 19-year-old man presented with new chest pain and near syncope. Computed tomography pulmonary angiography showed a saddle pulmonary embolus. The patient denied recent travel, trauma, surgery, or hospitalization. His mother had 2 miscarriages at 10 weeks of gestation, and his maternal grandfather had deep venous thrombosis at 60 years of age.Case Presentation 2: A healthy 45-year-old woman reported new dyspnea and left calf pain. Computed tomography pulmonary angiography and compression venous duplex ultrasonography showed bilateral pulmonary emboli and acute left leg deep vein thrombosis, respectively. The patient denied exogenous hormone use, recent travel, trauma, surgery, or hospitalization. Her health maintenance was current, and she gave a family history of pernicious anemia, Grave disease, and amyotrophic lateral sclerosis. Laboratory analyses showed reduced hemoglobin (11.4 g/dL; normal, 12.0–15.5 g/dL), increased red blood cell distribution width (18.9%; normal, 11.9%–15.5%), and mild thrombocytopenia.Neither patient had previous venous thromboembolism, and both were referred to the Mayo Clinic Thrombophilia Center for apparent idiopathic venous thromboembolism.Thrombophilia is defined as a predisposition (susceptibility) to thrombosis. Thrombophilia is not a disease per se, but may be associated with a disease (eg, cancer), drug exposure (eg, oral contraceptives) or condition (eg, pregnancy or postpartum, secondary thrombophilia; Table 1), and thrombophilia may be inherited (Table 2).1 This concept is important because disease susceptibility does not imply an absolute requirement for primary or secondary prevention, or for treatment. Most persons with a thrombophilia do not develop thrombosis. Thus, thrombophilia must be considered in the context of other risk factors for incident thrombosis, or predictors of recurrent thrombosis, when estimating the need for primary or secondary prophylaxis, respectively.Table 1. Secondary Thrombophilia1Active cancer (including myeloproliferative and myelodysplastic disorders)Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody, anti–β2-glycoprotein-1 antibody)Autoimmune disorders (eg, Behçet syndrome, celiac disease, inflammatory bowel disease, ITP, multiple sclerosis, myasthenia gravis, pernicious anemia, polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus, thromboangiitis obliterans [Buerger disease], systemic sclerosis, thyroiditis, TTP, vasculitis, Wegener granulomatosus)Chemotherapy (l-asparaginase, antiangiogenesis therapy, aromatase inhibitors, cytotoxic and immunosuppressive therapy, growth factor therapy [eg, erythropoietin], immunomodulatory therapy)EstrogenTamoxifen and raloxifene (selective estrogen receptor modulator [SERM])DehydrationDyslipidemiaHeparin-induced thrombocytopenia (HIT)HyperhomocysteinemiaInfection (HIV, sepsis, urinary tract infection)Intravascular coagulation and fibrinolysis/disseminated intravascular coagulation (ICF/DIC)Microalbuminuria, nephrotic syndrome and possibly chronic kidney diseaseObesityParoxysmal nocturnal hemoglobinuria (PNH)ProgestinPregnancy/postpartum stateHIV indicates human immunodeficiency virus; ITP, immune/idiopathic thrombocytopenic purpura; and TTP, thrombotic thrombocytopenic purpura.Table 2. Inherited Thrombophilia1Antithrombin deficiency (SERPINC1)Protein C deficiency (PROC)Protein S deficiency (PROS)Factor V Leiden (F5 rs6025; activated protein C resistance)Prothrombin G20210A (F2 rs1799963)ABO blood group non-O (ABO rs8176719)Fibrinogen gamma (FGG rs2066865)Factor XI (F11 rs2036914)HomocystinuriaIncreased plasma factors I (fibrinogen), II (prothrombin), VIII, IX, XIDysfibrinogenemiaSickle cell diseaseWeakly supportive data:HypofibrinolysisHypoplasminogenemia and dysplasminogenemiaReduced tissue plasminogen activator (tPA)Increased plasminogen activator inhibitor (PAI-1)Reduced protein Z and Z-dependent protease inhibitor [ZPI]Reduced tissue factor pathway inhibitor (TFPI)Factor XIII polymorphismsIncreased thrombin-activatable fibrinolysis inhibitor (TAFI)The role of special coagulation testing for an acquired or inherited thrombophilia is controversial. Thrombophilia testing should only be done if the results are likely to change medical management. There are no absolute indications for thrombophilia testing. Relative indications could include selected screening of asymptomatic or symptomatic family members of patients with a known inherited thrombophilia, populations at increased risk for thrombosis (eg, before pregnancy, oral contraception or estrogen therapy, high-risk surgery, or chemotherapy with angiogenesis inhibitors), patients with an incident thrombotic event (eg, incident venous thromboembolism, stillbirth or another complication of pregnancy, incident arterial thrombosis in a young person without other arterial disease), recurrent thrombosis, idiopathic thrombosis, thrombosis at a young age (eg, ≤40–45 years for venous thrombosis, ≤50–55 years for arterial thrombosis), or thrombosis in unusual vascular territories (eg, cerebral vein, portal vein, hepatic vein, mesenteric vein or artery, renal vein or artery). All of these potential indications are controversial and must be considered in the context of the clinical presentation.Timing of Diagnostic Thrombophilia Testing: When Should I Test?Many of the natural anticoagulant and procoagulant plasma proteins are acute-phase reactants. Acute thrombosis can transiently reduce the levels of antithrombin and, occasionally, proteins C and S. Consequently, testing is usually not recommended during the acute phase of thrombosis or during pregnancy. A delay of at least 6 weeks after the acute thrombosis or childbirth allows sufficient time for acute-phase reactant proteins to return to baseline. Heparin therapy can lower antithrombin activity and antigen levels and can impair the interpretation of clot-based assays for a lupus anticoagulant. A delay of at least 5 days after heparin is stopped before testing is usually feasible. Warfarin therapy reduces the activity and antigen levels of the vitamin K–dependent factors, including proteins C and S. Rarely, warfarin may also increase antithrombin levels into the normal range in individuals with a hereditary deficiency. Novel oral anticoagulants may cause false-positive lupus anticoagulant (dilute Russell viper venom time) testing and falsely low antithrombin activity. Many authorities recommend delaying testing until the effects of warfarin or novel oral anticoagulant therapy have resolved. The effect of warfarin on protein S levels may not resolve for up to 6 weeks. Direct leukocyte genomic DNA testing for the factor V Leiden and prothrombin G20210A mutations is unaffected by anticoagulation therapy; such testing can be performed at any time.Diagnostic Thrombophilia Testing: For What Should I Test?Unfortunately, there is no single laboratory assay or simple set of assays that will identify all thrombophilias. Consequently, a battery of complex and potentially expensive assays is usually required. Many of these laboratory analytes are affected by other conditions such that the correct interpretation of the results can be complicated and require clinical correlation. The laboratory evaluation for individuals with thrombosis should be selective and based on the history and physical examination, and may include a complete blood cell count with peripheral smear, serum protein electrophoresis, serum chemistries for electrolytes and liver and renal function, serology, and urinalysis. Testing for inherited deficiency of antithrombin, protein C, and protein S should be considered in patients with thrombosis at a young age. Patients who develop arterial thrombosis should be considered for testing for antiphospholipid antibodies (eg, lupus anticoagulant, anticardiolipin antibodies, anti–β2-glycoprotein-1 antibodies), heparin-induced thrombocytopenia, myeloproliferative disorders, homocystinuria, and hyperhomocysteinemia.A young patient with organ or skin infarction in the absence of risk factors for atherosclerosis or cardioembolism should be carefully evaluated for esoteric or occult arterial disease. An inherited thrombophilia is an unusual cause of stroke, myocardial infarction, or other organ or skin infarction. Detailed inquiry into constitutional or specific symptoms of vasculitis (primary or secondary), infection (systemic [eg, endocarditis], local [eg, infected aneurysm with artery-to-artery embolism]), atheroembolism, trauma (accidental, thermal, or occupational), dissection, vasospasm, or vascular anomaly is required. In addition to a careful pulse examination (including an examination for aneurysmal disease), evidence of microcirculatory occlusive disease of the hand (eg, livedo, skin or fingernail-bed infarction, or ulcer) should prompt a search for endocarditis (infectious and noninfectious), thoracic outlet syndrome, or other causes of repetitive arterial trauma (eg, hypothenar hammer hand syndrome, jackhammer or volleyball hand), atheroembolism, and thermal injury. Such physical findings in the foot should include a similar search plus an evaluation for abdominal aortic or popliteal artery aneurysmal disease with athero- or thromboembolism.How Do I Manage Patients With Thrombophilia?Acute TherapyIn general, patients with an inherited or acquired thrombophilia and a first-lifetime venous thromboembolism should be managed in standard fashion with intravenous unfractionated heparin, low-molecular-weight heparin, fondaparinux, or rivaroxaban.2,3 An acute treatment duration of 6 weeks to 3 months appears to be adequate for thrombosis related to transient risk factors, whereas patients with persistent risk factors require a longer duration of acute treatment.Secondary ProphylaxisSecondary prophylaxis may be recommended after completion of acute treatment for patients at high risk for venous thromboembolism (VTE) recurrence and acceptable risk for a bleeding complication. Recommendations of life-long or indefinite secondary prophylaxis are inappropriate, because the risks and benefits of such prophylaxis may change over time. In general, secondary prophylaxis is not recommended after a first-lifetime episode if the event was associated with a transient (eg, surgery, hospitalization for acute medical illness, trauma, oral contraceptive use, pregnancy, or the puerperium) clinical risk factor.Secondary prophylaxis may be recommended for idiopathic, recurrent, or life-threatening VTE (eg, pulmonary embolism, especially in association with persistently reduced cardiopulmonary functional reserve owing to chronic cardiopulmonary disease, phlegmasia with threatened venous gangrene, or purpura fulminans), persistent clinical risk factors (eg, active cancer, chronic neurological disease with leg paresis, or other persistent secondary causes of thrombophilia), a persistent lupus anticoagulant, high-titer anticardiolipin, or anti– β2-glycoprotein-1 antibody, antithrombin, protein C or protein S deficiency, increased basal factor VIII activity or hyperhomocysteinemia, combined heterozygous carriers for >1 familial thrombophilia (eg, heterozygous for the factor V Leiden and prothrombin G20210A mutations), or homozygous carriers (Table 3), a persistently increased plasma fibrin d-dimer, and possibly residual vein thrombosis. The risk of recurrence among isolated heterozygous carriers for either the factor V Leiden or prothrombin G20201A mutations is relatively low and insufficient to warrant secondary prophylaxis. A family history of VTE is not a predictor of VTE recurrence and should not influence the decision regarding secondary prophylaxis. Because of the high risk of recurrent VTE among active cancer patients owing to warfarin failure, low-molecular-weight heparin is recommended over warfarin as secondary prophylaxis as long as the cancer remains active. The risk of VTE recurrence decreases with time following the incident event, and the risk of anticoagulant-related bleeding also may vary over time. Consequently, the benefits and risks of secondary prophylaxis must be continually reevaluated.Table 3. Inherited or Secondary Thrombophilia: Estimated Prevalence by Population, and Incidence and Relative Risk of Incident or Recurrent Venous Thromboembolism by Thrombophilia1ThrombophiliaPrevalence (Whites, %)Incident VTERecurrent VTENormalIncident VTERecurrent VTEIncidence* (95% CI)Relative Risk (95% CI)Incidence* (95% CI)Relative Risk (95% CI)Antithrombin deficiency0.02–0.041–22–5500 (320–730)17.5 (9.1–33.8)10 500 (3800–23 000)2.5Protein C deficiency0.02–0.052–55–10310 (200–470)11.3 (5.7–22.3)5100 (2500–9400)2.5Protein S deficiency0.01–11–35–10710 (530–930)32.4 (16.7–62.9)6500 (2800–11 800)2.5Factor V Leiden†3–712–2050–50150 (80–260)4.3‡ (1.9–9.7)3500 (1900–6100)1.3 (1.0–3.3)Prothrombin G20210A†1–33–815–203501.9 (0.9–4.1)1.4 (0.9–2.0)Combined---840 (560–1220)32.4 (16.7–62.9)5000 (2000–10 300)-Hyperhomocysteinemia------2.5Antiphospholipid Ab------2.5Factor VIII (>200 IU/dL)------1.8 (1.0–3.3)CI indicates confidence interval; VTE, and venous thromboembolism.*Per 100 000 person-years.†Heterozygous carriers.‡Homozygous carriers relative risk ≈80.Case ResolutionCase 1: Special coagulation testing for an inherited or acquired thrombophilia showed reduced plasma antithrombin activity (46%; normal, 80%–130%) and antigen (41%; normal, 80%–130%). SERPINC1 (antithrombin gene) sequencing revealed a heterozygous cytosine to thymine transition at nucleotide 9839 in exon 6 resulting in a premature stop codon at arginine 359, consistent with a novel inherited type I antithrombin deficiency. Secondary prophylaxis was recommended after acute treatment was completed.Case 2: A sensitive thyroid-stimulating hormone was increased (6.6 mIU/L; normal, 0.3–5.5 mIU/L) as were thyroid peroxidase antibodies (469 mIU/mL; normal, <9 mIU/mL), consistent with incipient hypothyroidism from Hashimoto thyroiditis. Special coagulation testing for thrombophilia showed normal results, with the exception of an increased plasma homocysteine (99 μmol/L; normal, ≤13 μmol/L). The methylmalonic acid was increased (19 nmol/mL; normal, ≤0.4 nmol/mL) as were antiparietal cell antibodies (84.4 U; normal, <20 U), consistent with vitamin B12 deficiency due to pernicious anemia. Repeat plasma homocysteine and thyroid-stimulating hormone were normal after treatment with B12 and thyroid replacement, and no secondary prophylaxis was recommended after acute treatment was completed.ConclusionsHomocystinuria is associated with childhood features of mental retardation, ectopia lentis, marfanoid habitus, premature atherosclerosis, and VTE. As opposed to normal fasting plasma homocysteine levels of 13 to 15 μmol/L, patients with homocystinuria have levels in the range of 100 to 400 μmol/L. Hyperhomocysteinemia is a weak risk factor for incident and recurrent VTE.4–7 In 1 study, VTE patients with plasma homocysteine above the 90th percentile (20.1 μmol/L) had a 1.8-fold increased risk for VTE recurrence.8 Finally, in 1 study, Hashimoto thyroiditis and pernicious anemia were associated with 5.3- and 3.9-fold increased risk for VTE.9 For both of these cases, thrombophilia testing identified treatable and acquired important risk factors for VTE and guided recommendations for secondary prophylaxis.Sources of FundingThis work was funded, in part, by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL66216, HL83797, K12HL83141) to Dr Heit, and by the Mayo Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.DisclosuresNone.FootnotesCorrespondence to John A. Heit, MD, Stabile 6-Hematology Research, Mayo Clinic, 200 First St, SW, Rochester, MN 55905. E-mail [email protected]