University of Wisconsin Hematology

Hypercoagulable disorders

General

  1. Middeldorp et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv 2023;7:7101
  2. Moran and Bauer. Managing thromboembolic risk in patients with hereditary and acquired thrombophilias. Blood 2020;135:344
  3. Connors et al. Thrombophilia testing and venous thrombosis. NEJM 2017;377:1177
  4. Nagalla and Bray. Personalized medicine in thrombosis: back to the future. Blood 2016;127:2665(Discusses the challenges of using genetic testing in the diagnosis and management of thrombotic disorders)
  5. Ortel et al. How I treat catastrophic thrombotic syndromes. Blood 2015;126:1285
  6. Schmidt et al. Complement and the prothrombotic state. Blood 2022;139:1972
  7. Middeldorp S. Is thrombophilia testing useful? Hematology 2011:150(“Because testing for thrombophilia serves a limited purpose, this test should not be performed on a routine basis”)
  8. Gavva et al. A clinical audit of thrombophilia testing in pediatric patients with acute thromboembolic events: impact on management. Blood Adv 2017;1:2386(“Thrombophilia testing does not affect clinical management in the acute setting after a TEE in children and should be avoided”)
  9. Rosendaal F. Venous Thrombosis: The Role of Genes, Environment, and Behavior. Hematology 2005:1-12.
  10. Cushman M. Inherited Risk Factors for Venous Thrombosis. Hematology 2005:452-457
  11. Prandoni P. Acquired Risk Factors for Venous Thromboembolism in Medical Patients. Hematology 2005:458-461
  12. Ho et al. Risk of Recurrent Venous Thromboembolism in Patients With Common Thrombophilia. A Systematic Review. Arch Intern Med 2006;166:729
  13. Bauer and Rosenberg. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70:343
  14. Bauer et al. Aging-associated changes in indices of thrombin generation and protein C activation in humans. J Clin Invest 1987; 80:1527
  15. Conway et al. Suppression of Hemostatic System Activation by Oral Anticoagulants in the Blood of Patients with Thrombotic Diatheses. J Clin Invest 1987;80:1535
  16. Favaloro E. Diagnostic Issues in Thrombophilia: A Laboratory Scientist’s View. Semin Hematol 2005;31:11
  17. Rabinovich et al. Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis. J Thromb Haemost 2014;12:14(No association found)
  18. van Vlijmen et al. Oral Contraceptives and the Absolute Risk of Venous Thromboembolism in Women With Single or Multiple Thrombophilic Defects. Results From a Retrospective Family Cohort Study. Arch Intern Med 2007;167:282
  19. Brooks et al. Valves of the deep venous system: an overlooked risk factor. Blood 2009;114:1276(Variation in endothelial protein C receptor and thrombomodulin expression may be a factor in VTE pathogenesis)
  20. Undas et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009;114:4272
  21. Cieslik et al. Altered plasma clot properties increase the risk of recurrent deep vein thrombosis: a cohort study. Blood 2018;131:797(Denser clots more resistant to lysis, associated with higher risk of recurrent DVT)
  22. Lim et al. A review of global coagulation assays — Is there a role in thrombosis risk prediction? Thromb Res 2019;179:45
  23. Warny et al Arterial and venous thrombosis by high platelet count and high hematocrit: 108 521 individuals from the Copenhagen General Population Study. J Thromb Haemost 2019;17:1898 (Elevated Hct or platelet count not associated with higher VTE risk, but did increase risk of arterial events by 1.5-1.8x)

Inherited Thrombophilia

  1. Han et al. Genomic science of risk prediction for venous thromboembolic disease: convenient clarification or compounding complexity. J Thromb Haemost 2023;21:3292
  2. Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008;112:19
  3. Mannucci and Franchini. Classic thrombophilic gene variants. Thromb Haemost 2015;114:885
  4. Morange et al. Genetics of venous thrombosis: update in 2015. Thromb Haemost 2015;114:910(“Common polymorphisms are estimated to account for only about 5% of VT heritability”)
  5. Lindström et al. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. Blood 2019;134:1645(Demonstrates the polygenic nature of thrombophilia)
  6. Desch et al Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease. Blood 2020;136:533(Mutations causing increased VWF levels)
  7. Tang and Hu. Ethnic diversity in the genetics of venous thromboembolism. Thromb Haemost 2015;114:901
  8. Heit J. Thrombophilia: common questions on laboratory assessment and management. Hematology 2007:127
  9. Pabinger et al. Mortality and inherited thrombophilia: results from the European Prospective Cohort on Thrombophilia. J Thromb Haemost 2012;10:217(No increased mortality associated with inherited thrombophilia, regardless of whether there is a history of thrombosis)
  10. Bezemer et al. The Value of Family History as a Risk Indicator for Venous Thrombosis. Arch Intern Med 2009; 169:610(“Family history may be more useful for risk assessment than thrombophilia testing”)
  11. Zöller et al. Family history of venous thromboembolism (VTE) and risk of recurrent hospitalization for VTE: a nationwide family study in Sweden. J Thromb Haemost 2014;12:306(Positive family hx a modest risk factor for recurrence)
  12. Zöller et al. Family history of venous thromboembolism as a risk factor and genetic research tool. Thromb Haemost 2015;114:890
  13. Sundquist et al. Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow-up study. J Thromb Haemost 2015;13:2180(In patients with unprovoked VTE, FH of VTE associated with higher risk of recurrence, particularly in women)
  14. Couturaud et al. Factors that predict thrombosis in relatives of patients with venous thromboembolism. Blood 2014;123:2124(Unprovoked VTE or VTE at young age in proband predict VTE in relatives; FVL and PT gene variants do not)
  15. Bucciarelli et al. Influence of proband’s characteristics on the risk for venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms. Blood 2013;122:2555(Relatives of heterozygous probands and those with VTE had higher risk than relatives of homozygotes or those without VTE)
  16. Holzhauer et al. Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study. Blood 2012;120:1510(Affected relatives of children with AT, PC or PS deficiency at highest risk)
  17. Zöller et al. Age- and Gender-Specific Familial Risks for Venous Thromboembolism. A Nationwide Epidemiological Study Based on Hospitalizations in Sweden. Circulation 2011;124:1012
  18. Lijfering et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009;113:5314(Antithrombin, protein C and protein S deficiencies strongest risk factors for first VTE)
  19. Brouwer et al. The Pathogenesis of Venous Thromboembolism: Evidence for Multiple Interrelated Causes. Ann Intern Med 2006;145:807   (additive effect of thrombophilic defects)
  20. de Haan et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012;120:656
  21. Young et al. Impact of Inherited Thrombophilia on Venous Thromboembolism in Children. A Systematic Review and Meta-Analysis of Observational Studies. Circulation 2008;118:1373
  22. Lijfering et al. A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 2009; 114:2031
  23. Segal et al. Predictive Value of Factor V Leiden and Prothrombin G20210A in Adults With Venous Thromboembolism and in Family Members of Those With a Mutation. JAMA 2009;301:2472(FVL mutation, but not PT mutation, associated with higher VTE recurrence risk)
  24. Juul et al.  Factor V Leiden and the Risk for Venous Thromboembolism in the Adult Danish Population.  Ann Intern Med 2004;140:330
  25. Ryu et al. Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank. Blood 2024;143:2425
  26. Prüller et al. Activated Protein C Resistance Assay and Factor V Leiden (letter). NEJM 2014;371:685(Suggests functional testing for APC resistance more reliable and economical than DNA testing)
  27. Vasan et al. ABO Blood Group and Risk of Thromboembolic and Arterial Disease. A Study of 1.5 Million Blood Donors. Circulation 2016;133:1449(Non-O blood type increased incidence of both arterial and venous events, may account for over 30% of VTE events)
  28. Coppens et al. A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation. Blood 2006;108:2604 (Modest increased risk of VTE, no increased risk of arterial events)
  29. Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group. No Evidence of Association Between Prothrombotic Gene Polymorphisms and the Development of Acute Myocardial Infarction at a Young Age. Circulation 2003;107:1117
  30. Ridker et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. NEJM 1995;332:912
  31. Mahmoodi et al. Association of Factor V Leiden With Subsequent Atherothrombotic Events.  A GENIUS-CHD Study of Individual Participant Data.  Circulation 2020;142:546 (FVL does not increase risk of subsequent atheroembolic events or mortality in high risk cardiac patients)
  32. Pruissen et al. Prothrombotic gene variation and new vascular events after cerebral ischemia of arterial origin. J Thromb Haemost 2008; 6:1639 (inherited thrombophilia does not increase risk of stroke recurrence)
  33. Curtis et al. Thrombophilia risk is not increased in children after perinatal stroke. Blood 2017;129:2793
  34. Madonna et al. Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke. Stroke 2002;33:51 (moderate hyperhomocysteinemia, but not FV Leiden or prothrombin G20210A, associated with stroke risk in young adults)
  35. Lijfering et al. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood 2009;113:1225 (free protein S levels below 5th percentile associated with increased risk of new & recurrent VTE)
  36. Pintao et al.Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood 2013;122:3210(No significant association between total or free protein S levels < 2.5th percentile and VTE in unselected individuals)
  37. Alhenc-Gelas et al. PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency. Thromb Haemost 2016;115:465(Poor correlation between protein S levels and genotype. Protein S levels <30% associated with modest increase in VTE risk)
  38. Marlar et al. Recommendations for clinical laboratory testing for protein S deficiency: Communication from the SSC committee plasma coagulation inhibitors of the ISTH. J Thromb Haemost 2021;19:68
  39. Chaudry et al. Population-Scale Studies of Protein S Abnormalities and Thrombosis. JAMA 2025 (Epub) (Low protein S levels poor predictors of mutational status; deletion mutations markedly increase thrombosis risk)
  40. DeSancho et al. Hereditary antithrombin deficiency pilot project registry from the American Thrombosis and Hemostasis Network. J Thromb Haemost 2024;22:3183
  41. Pabinger and Thaler. How I treat patients with hereditary antithrombin deficiency. Blood 2019;134:2348
  42. Sokol et al. Mild antithrombin deficiency and risk of recurrent venous thromboembolism: results from the MEGA follow‐up study. J Thromb Haemost 2018;16:680
  43. de la Morena-Barrio et al. Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays. Blood 2022;140:140 (Antithrombin variants not deteccted by routine functional assays)
  44. Bezemer et al. No Association Between the Common MTHFR 677CT Polymorphism and Venous Thrombosis. Results From the MEGA Study. Arch Intern Med 2007;167:497
  45. Straczek et al. Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women. Impact of the Route of Estrogen Administration. Circulation 2005;112:3495(Use of oral, but not transdermal, estrogen magnified thrombotic risk in women with thrombophilia)
  46. Jilma et al. Homozygosity in the Single Nucleotide Polymorphism Ser128Arg in the E-Selectin Gene Associated With Recurrent Venous Thromboembolism. Arch Intern Med 2006;166:1655
  47. Austin et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 2007; 110:908(2-fold increased risk of VTE in sickle trait)
  48. Hernandez et al. Novel genetic predictors of venous thromboembolism risk in African Americans. Blood 2016;127:1923(Polymorphisms in thrombomodulin gene associated with decr protein expression, 2.3-fold higher VTE risk)
  49. Van Laer et al. Functional assessment of genetic variants in thrombomodulin detected in patients with bleeding and thrombosis. Blood 2025;145:1929
  50. Bezemer et al. Gene variants associated with deep vein thrombosis. JAMA 2008;299:1306(3 newly discovered polymorphisms that increase VTE risk)
  51. Ozen et al. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. NEJM 2017;377:52(Hyperactivation of complement associated with severe VTE in several patients; a letterin the same issue of the journal reports this condition responds to eculizumab treatment)
  52. Björkman et al. Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema: a family study. Blood 2024;144:435
  53. Rabinovich et al. Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis. J Thromb Haemost 2014;12:14(No association found)

Inherited Thrombophilia and Pregnancy/Contraception

  1. Quenby et al. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet 2023;402:54 (No evidence of benefit. “We advise against testing for thrombophilia in women with recurrent pregnancy loss”)
  2. Skeith et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016;127:1650 (No evidence of benefit)
  3. Gerhardt et al. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016;128:2343
  4. Croles et al. Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis. BMJ 2017;359:j4452(Suggests that women with AT, PC, PS deficiency or homozygous FVL or PT mutation be given antepartum and postpartum prophylaxis)
  5. Gris et al.  Antiphospholipid/antiprotein antibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for a first early pregnancy loss: a matched case-control study.  Blood 2003;102:3504
  6. van Vlijmen et al. Oral Contraceptives and the Absolute Risk of Venous Thromboembolism in Women With Single or Multiple Thrombophilic Defects. Results From a Retrospective Family Cohort Study. Arch Intern Med 2007;167:282
  7. van Vlijmen et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood 2011;118:2055
  8. Di Nisio et al. Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. Blood 2011;118:2670(Evidence linking failure of ART and thrombophilia is inconclusive)
  9. Rodger et al. The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies. PLOS Medicine 2010;7:e1000292(Small increase in risk for late pregnancy loss with FVL; no association with pre-eclampsia or SGA newborn)
  10. Bouvier et al. Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study. Blood 2014;123:414(Women with FVL or PT polymorphism had higher risk for early pregnancy loss; LMWH may improve pregnancy outcomes in thrombophilic women with hx of late pregnancy complications)
  11. Rodger et al. Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study. J Thromb Haemost 2014;12:469(PT polymorphism not associated with significantly higher risk of adverse pregnancy outcomes; slight increased risk of pregnancy loss with FVL)
  12. Rodger et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 2014;384:1673(No apparent benefit, increased minor bleeding with dalteparin prophylaxis)

Inherited Thrombophilia and Risk of VTE Recurrence

  1. Van den Belt A et al. Recurrence of venous thromboembolism in patients with familial thrombophila. Arch Intern Med 1997;157:2227
  2. Christiansen et al. Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events.  JAMA. 2005;293:2352(Clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy)

Antiphospholipid Antibodies

  1. Barbhaiya et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Ann Rheum Dis 2023;80:1228
  2. Song & Leaf. New definitions for antiphospholipid syndrome: ready for clinical use?. Hematology 2024;1:222
  3. Garcia and Erkan. Diagnosis and management of the antiphospholipid syndrome. NEJM 2018;378:2010
  4. Manning and Arachchillage. Dilemmas in the diagnosis and management of antiphospholipid syndrome. J Thromb Haemost 2024;22:2156
  5. Gebhart et al. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood 2015;125:3477
  6. Garcia et al. Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood 2013;122:817(“Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality”)
  7. Kearon et al. Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism. Blood 2018;131:2151(Double- or triple-antibody positive patients and patients with persistently positive tests had highest risk of recurrence in this relatively small retrospective study)
  8. Vandevelde et al. Added value of antiphosphatidylserine/prothrombin antibodies in the workup of thrombotic antiphospholipid syndrome: Communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies.  J Thromb Haemost 2022;20:2136 (May augment LAC, ACL and B2GPI assays)
  9. Ortel et al. Recurrent thrombosis in patients with antiphospholipid antibodies and an initial venous or arterial thromboembolic event: A systematic review and meta‐analysis. J Thromb Haemost 2020;18:2274(Stopping anticoagulant after VTE associated with 18% VTE recurrence rate at 2 years; recurrence rates for arterial events similar with anticoagulant vs antiplatelet therapy)
  10. Metjian and Lim. ASH evidence-based guidelines: should asymptomatic patients with antiphospholipid antibodies receive primary prophylaxis to prevent thrombosis? Hematology 2009;247(No)
  11. Garcia et al. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review. Blood 2007;110:3122
  12. Arvanitakis et al. Relation of Antiphospholipid Antibodies to Postmortem Brain Infarcts in Older People. Circulation 2015;131:182(No apparent relationship between positive premortem APL test results and brain infarcts)
  13. Miranda et al. Prevalence of confirmed antiphospholipid syndrome in 18‐50 years unselected patients with first unprovoked venous thromboembolism. J Thromb Haemost 2020;18:926(9% of patients fulfulled criteria for APS)
  14. Pengo et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011;118:4714(“Triple-positive” individuals with LAC, ACL and B2GPI antibodies had 37% incidence of thrombosis at 10 years)
  15. APASS Investigators.  Antiphospholipid Antibodies and Subsequent Thrombo-occlusive Events in Patients With Ischemic Stroke.  JAMA 2004;291:576  (presence of ACL or lupus anticoagulant in stroke patients did not predict recurrent thrombosis)
  16. Hisada et al. Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study. J Thromb Haemost 2017;9:1782(Thrombocytopenia may increase thrombotic risk)
  17. Tektonidou et al. Cognitive Deficits in Patients With Antiphospholipid Syndrome. Arch Intern Med 2006;166:2278
  18. Comellas-Kirkerup et al. Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study. Blood 2010;116:3058(<30% had either thrombosis or pregnancy morbidity during followup)
  19. Pontara et al. Thrombocytopenia in high‐risk patients with antiphospholipid syndrome. J Thromb Haemost 2018;16:529(“Triple positive” APL associated with 6% incidence of thrombocytopenia; 100% incidence in catastrophic APS)
  20. Cattini et al. Tetra positive thrombotic antiphospholipid syndrome: Major contribution of anti‐phosphatidyl‐serine/prothrombin antibodies to lupus anticoagulant activity. J Thromb Haemost 2020;18:1124

Pathophysiology

  1. Giannakopoulos and Krills. Pathogenesis of the antiphospholipid syndrome. NEJM 2013;368:1033
  2. Wolgast et al. Reduction of annexin A5 anticoagulant ratio identifies antiphospholipid antibody-positive patients with adverse clinical outcomes. J Thromb Haemost 2017;15:1412(Supports hypothesis that interference with annexin A5 activity involved in pathogenesis of APL syndrome)
  3. ß2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator. Blood 2011;118:2774
  4. Arachchillage et al. Anti-protein C antibodies are associated with resistance to endogenous protein C activation and a severe thrombotic phenotype in antiphospholipid syndrome. J Thromb Haemost 2014;12:1801
  5. Sacharidou et al. Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. Blood 2018;131:2097(Mouse model; APL antibodies bound to cell surface B2GPI trigger signaling cascade leading to decreased nitric oxide production)
  6. Müller-Calleja et al. Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis. Blood 2019;134:1119
  7. Chaturvedi et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood 2020;135:239
  8. Noordermeer et al. Anti-β2-glycoprotein I and anti-prothrombin antibodies cause lupus anticoagulant through different mechanisms of action. J Thromb Haemost 2021;19:1018

Diagnosis

  1. Hubben and McCrae. How to diagnose and manage antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program (2023): 606
  2. Devreese et al. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018;16:809
  3. Devreese et al. An update on laboratory detection and interpretation of antiphospholipid antibodies for diagnosis of antiphospholipid syndrome: guidance from the ISTH-SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2025;23:731
  4. Pengo et al. Survey of lupus anticoagulant diagnosis by central evaluation of positive plasma samples. J Thromb Haemost 2007;5:925 (High rate of false positive tests)
  5. Galli et al.  Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101:1827
  6. de Groot et and Urbanus. The significance of autoantibodies against β2-glycoprotein I. Blood 2012;120:266.
  7. Pengo et al. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J Thromb Haemost 2013;11:1527 (98% of “triple-positive” individuals remained positive after 12 weeks, vs 84% of double-positive and 40% of single-positive individuals)
  8. Galli et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood 2007;110:1178 (IgG antibodies to ß2-glycoprotein I more strongly associated with thrombosis than was IgG or IgM anticardiolipin antibody)
  9. Devreese et al. Thrombotic risk assessment in the antiphospholipid syndrome requires more than the quantification of lupus anticoagulants. Blood 2010;115:870
  10. Pengo et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010;8:237 (“Triple positive” patients with LAC, ACL, and B2GPI antibodies at high risk for recurrent thrombosis)
  11. Galli et al.  Anti–ß2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003;102:2717
  12. de Laat et al.  ß2-glycoprotein I–dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood 2004;104:3598
  13. Tripodi et al. Lupus anticoagulant detection in anticoagulated patients. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020;18:1569

Treatment

  1. Hubben and McCrae. How to diagnose and manage antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program (2023): 606
  2. Zuily et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: Guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020;18:2126
  3. Tektonidou et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296
  4. Salet et al. Targeting thromboinflammation in antiphospholipid syndrome. J Thromb Haemost 2023;21:744
  5. Skeith L. Anticoagulating patients with high-risk acquired thrombophilias. Blood 2018;132:2219 (Discusses DOAC use in APS, HIT, PNH)
  6. Cohen et al. Monitoring of anticoagulation in thrombotic antiphospholipid syndrome. J Thromb Haemost 2021;19:892
  7. Rand et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody–β2-glycoprotein I complexes to phospholipid bilayers. Blood 2008;112:1687
  8. Rand et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 2010;115:2292
  9. Canaud et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. NEJM 2014;371:303(Suggests that sirolimus treatment may prevent vascular lesions in APS; with editorial)
  10. Bala et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane Database Syst Rev 2017 (Epub)(Insufficient evidence to recommend DOACs or adding antiplatelet agents to VKA in APL syndrome)
  11. Jackson et al. Recurrent thrombosis in patients with antiphospholipid antibodies and arterial thrombosis on antithrombotic therapy. Blood Adv 2017;1:2320(Combined anticoagulant and antiplatelet therapy may decrease risk of recurrence)
  12. Crowther et al.  A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome. NEJM 2003;349:1133
  13. Cohen et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016;3:e426 (No difference in clinical outcomes between warfarin and rivaroxaban treatment)
  14. Cohen et aL. Use of direct oral anticoagulants in antiphospholipid syndrome. J Thromb Haemost 2018;16:1028
  15. Pengo et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2017;132:1365(Adverse event rate in “triple positive” APS patients 19% with rivaroxaban, 3% with warfarin; all thrombotic events on rivaroxaban were arterial; with editorial)
  16. Dufrost et al. Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmun Rev 1018 (Epub) (DOACs appear less effective than warfarin in “triple positive” patients and those with arterial thrombosis)
  17. Ordi-Ros et al. Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial. Ann Intern Med 2019 (Epub)(Higher thrombotic risk with rivaroxaban, particularly for arterial events; with editorial)
  18. Woller et al Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv 2022;6:1661 (More strokes in apixaban-treated patients)
  19. Khairani et al. Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes.  J Am Coll Cardiol 2023;81:16 (Meta-analysis suggesting higher risk of arterial events in DOAC-treated patients)
  20. Sikorska et al. Apixaban Versus Vitamin K Antagonists in Patients With Antiphospholipid Syndrome: A Cohort Study. J Cardiovasc Pharmacol 2024; 84:36 (Non-randomized study showing similar outcomes with apixaban and VKA)
  21. Branch and Lim. How I diagnose and treat antiphospholipid syndrome in pregnancy. Blood 2024;143:757
  22. Sciascia et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost 2016;115:285
  23. Erkan et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody–positive individuals. Arth Rheum 2007;56:2382(No benefit from low dose ASA. Rate of thrombosis <3%/yr, most events in setting of other risk factors for thrombosis)
  24. Lim et al. Management of Antiphospholipid Antibody Syndrome: A Systematic Review. JAMA 2006;295:1050
  25. Cohen et al. Management of anticoagulant-refractory thrombotic antiphospholipid syndrome. Lancet Haematol 2020;7:e613
  26. Cohen and Isenberg. How I treat anticoagulant-refractory thrombotic antiphospholipid syndrome. Blood 2021;137:299
  27. Hussain et al. Eculizumab for refractory thrombosis in antiphospholipid syndrome. Blood Adv 2022;6:1271

Obstetric APL syndrome

  1. Hamulyák et al. Antithrombotic therapy to prevent recurrent pregnancy loss in antiphospholipid syndrome—What is the evidence? J Thromb Haemost 2021;19:1174(Possible benefit from heparin + ASA; low quality/certainty evidence)
  2. Derksen et al.  Management of the obstetric antiphospholipid syndrome.  Arth Rheum 2004;50:1028
  3. Clark et al. The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic. Blood 2013;122:341(LAC associated with late pregnancy loss)
  4. Bouvier et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood 2014;123:404(LMWH + ASA had limited efficacy in preventing pregnancy complications; high IgM cardiolipin Ab associated with placenta-mediated complications)
  5. Marchetti et al. Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study. J Thromb Haemost 2016;14:675(anti beta2-GPI Ab associated with severe pre-eclampsia)
  6. Gris et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood 2012;119:2624(Annual incidence of DVT about 1.5%)

Catastrophic APL syndrome

  1. Chaturvedi et al. Antiphospholipid syndrome: Complement activation, complement gene mutations, and therapeutic implications. J Thromb Haemost 2021;19:607
  2. Rodríguez-Pintó et al. Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry. Autoimmune Rev 2016;15:1120
  3. Legault et al. McMaster RARE‐Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome. J Thromb Haemost 2018;16:1656(See letter questioning use of plasma exchange as first-line treatment in this setting)
  4. Canaud et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. NEJM 2014;371:303 (Suggests that sirolimus treatment may prevent vascular lesions in APS; with editorial)
  5. Cole et  al. Complement biomarkers in the antiphospholipid syndrome – Approaches to quantification and implications for clinical management. Clin Immunol 2023 (Epub)
  6. Chaturvedi et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood 2020;135:239
  7. Sjoerd et al. More about complement in the antiphospholipid syndrome. Blood 2020;136:1456 (Data inconsistent with conclusions of above article)
  8. Yelnik et al. Patients with refractory catastrophic antiphospholipid syndrome respond inconsistently to eculizumab. Blood 2020;136:2473

Homocysteine

  1. Bazzano et al. Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases. A Meta-analysis of Randomized Controlled Trials. JAMA 2006;296:2720
  2. Clarke et al. Effects of Lowering Homocysteine Levels With B Vitamins on Cardiovascular Disease, Cancer, and Cause-Specific Mortality. Meta-analysis of 8 Randomized Trials Involving 37 485 Individuals. Arch Intern Med 2010;170:1622(No significant effect on cardiovascular events or mortality)
  3. Kluijtmans et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults.  Blood 2003;101:2483
  4. Toole et al.  Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death.  The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial.  JAMA 2004;291:565(moderate reduction of homocysteine after stroke had no effect on vascular outcomes during 2 years of follow-up)
  5. HOPE 2 Investigators. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. NEJM 2006;354:1567(Vitamin supplements lowered homocysteine levels but did not decrease risk of cardiovascular events)
  6. Bønaa et al. Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. NEJM 2006;354:1578 (Vitamins did not lower risk of cardiovascular events, may have even increased risk)
  7. Frederiksen et al.Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study.  Blood 2004;104:3046. (Questions cause and effect relationship between hyperhomocysteinemia and vascular disease)
  8. Menon et al. Relationship Between Homocysteine and Mortality in Chronic Kidney Disease. Circulation 2006;113:1572 (Homocysteine not an independent risk factor for all-cause or cardiovascular mortality)
  9. den Heijer et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood 2007;109:139(Lowering homocysteine did not seem to prevent recurrent venous thrombosis)
  10. Jamison et al. Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease. JAMA 2007;298:1163 (No apparent benefit to lowering HC level)
  11. Ebbing et al. Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. JAMA 2009;302:2119 (Increased cancer incidence after treatment with folate + B12)
  12. SEARCH Collaborative Group. Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors. A Randomized Trial. JAMA 2010;303:2486 (No benefit on vascular outcomes with folate/B-12 Rx)
  13. Xu et al. Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease. The Renal Substudy of the China Stroke Primary Prevention Trial. JAMA Int Med 2016;176:1443 (Folic acid + enalapril more effective than enalapril alone in delaying progression of CKD)
  14. Caris et al. Nitrous oxide abuse leading to extreme homocysteine levels and thrombosis in young adults: a case series. J Thromb Haemost 2023;21:276

Other

  1. Tripodi et al. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood 2004;104:3631
  2. Kyrle et al. High Plasma Levels of Factor VIII and the Risk of Recurrent Venous Thromboembolism. NEJM 2000;343:457
  3. Timp et al. Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study. J Thromb Haemost 2015;13:1823(High fVIII predicts recurrence risk in a dose-dependent manner)
  4. Simioni et al. Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 2021;137: 2383(F8 levels >400%)
  5. Kuipers et al. Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers. Blood 2009;113:2064
  6. Cushman et al. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood 2009;114:2878(only elevated factor XI level associated with higher VTE risk)
  7. Rietveld et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019;17:99
  8. Wang et al. Procoagulant factor levels and risk of venous thrombosis in the elderly. J Thromb Haemost 2021;19:186(High levels of VIII, IX, XI but not II associated with VTE risk)
  9. Lentz SR. Thrombosis in the setting of obesity or inflammatory bowel disease. Blood 2016;128:2388
  10. Saadoun et al. Behçet’s Syndrome. NEJM 2024;390:640
  11. Chung et al. Systemic lupus erythematosus increases the risks of deep vein thrombosis and pulmonary embolism: a nationwide cohort study. J Thromb Haemost 2014;12:452(>10-fold increased risk of VTE, risk highest in younger pts)
  12. Weishaupt et al. Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial. Lancet Haematol 2016;3:e72 (Treatment effective in reducing pain in most patients)
  13. Hall et al. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).  Blood 2003;102:3587
  14. Prins and Hirsh. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151:1721
  15. Tefs et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood 2006;108:3021 (No increased incidence of VTE in severe plasminogen deficiency)
  16. Meltzer et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010;116:113 (Modest increase in VTE risk associated with hypofibrinolysis)
  17. Meltzer et al. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood 2010;116:529 (Elevated alpha-2 antiplasmin levels independently associated with risk of MI)
  18. Fassel et al. Reduced expression of annexin A2 is associated with impaired cell surface fibrinolysis and venous thromboembolism. Blood 2021;137:2221
  19. Samad and Ruf. Inflammation, obesity, and thrombosis. Blood 2013;122:3415
  20. Etminan et al. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ  2005;330:63
  21. Ocak et al. Mortality due to pulmonary embolism, myocardial infarction, and stroke among incident dialysis patients. J Thromb Haemost 2012;10:2484(Risk of PE, MI and stroke significantly higher in dialysis patients than in general population)
  22. White et al. Incidence of Venous Thromboembolism in the Year Before the Diagnosis of Cancer in 528 693 Adults. Arch Intern Med 2005;165:1782
  23. Chew et al. Incidence of Venous Thromboembolism and Its Effect on Survival Among Patients With Common Cancers. Arch Intern Med 2006;166:458
  24. Blom et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.  JAMA 2005;293:715
  25. Carrier et al. Systematic Review: The Trousseau Syndrome Revisited: Should We Screen Extensively for Cancer in Patients with Venous Thromboembolism? Ann Intern Med 2008;149:323(10% of pts with unprovoked VTE diagnosed w/ cancer within 12 mo; abd/pelvic CT increased diagnostic yield significantly)
  26. Smith et al. Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke? The Caerphilly Study. Circulation 2005;112:3080(High fibrinogen, D-dimer, PAI-1 activity, and factor VIIc levels all associated with higher risk of coronary disease and stroke)
  27. Simes et al. D-Dimer Predicts Long-Term Cause-Specific Mortality, Cardiovascular Events, and Cancer in Patients With Stable Coronary Heart Disease. LIPID Study. Circulation 2018;138:712
  28. Doggen et al. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII. Blood 2006; 108:4045   (Elevated VIII, IX and XI, but lower XII, found in MI patients vs controls)
  29. Schneppenheim et al. The von Willebrand factor Tyr2561 allele is a gain-of-function variant and a risk factor for early myocardial infarction. Blood 2019;133:356
  30. Ataga and Key. Hypercoagulability in sickle cell disease: new approaches to an old problem. Hematology 2007;91
  31. Kourtzelis et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 2010;116:631
  32. Hansen et al. Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism. Blood 2020;136:1863
  33. Cheung et al. Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study. J Thromb Haemost 2018;16:1743
  34. Grover et al. C1 inhibitor deficiency enhances contact pathway–mediated activation of coagulation and venous thrombosis. Blood 2023;131:2390