eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli

Author: Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Coauthor(s): Barbara P Schick, PhD, Professor, Department of Medicine, Cardeza Foundation; Professor, Department of Biochemistry and Molecular Pharmacology, Professor, Department of Biochemistry and Molecular Biology, Jefferson Medical College of Thomas Jefferson University
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

Background

Venous thrombosis and pulmonary embolism are hypercoagulable states associated with significant morbidity and mortality. The most common predisposing conditions for venous thrombosis and pulmonary embolism are such risk factors as the following1 :

  • Advanced age
  • Immobilization
  • Inflammation
  • Pregnancy
  • Oral contraception use
  • Obesity
  • Diabetes
  • Hormonal replacement therapy
  • Cancer

The incidence of venous thrombosis in the United States is likely to increase due to the aging population.

Idiopathic venous thrombosis is defined as the occurrence of venous thrombosis in the absence of any of the risk factors mentioned above. About 50% of patients presenting with a first idiopathic venous thrombosis have an underlying thrombophilia.

Thrombophilias are hereditary conditions that are risk factors for venous thrombosis (see Table 1). Lupus anticoagulants are acquired risk factors for venous as well as arterial thrombosis. Several thrombophilic conditions have been reviewed in other eMedicine articles. The objectives of this article are to review current indications for testing for thrombophilia, the appropriate choice of tests, when tests should be ordered, and the interpretation of the results. The authors also discuss the options for anticoagulant therapy and prophylaxis, as well as the advantages and side effects of low molecular weight heparin (LMWH) and antithrombin agents.

For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Deep Vein Thrombosis (Blood Clot in the Leg, DVT).

Pathophysiology

Hemostasis is highly regulated to maintain a delicate balance between controlling bleeding in response to injury and avoiding excess procoagulant activity to prevent hypercoagulability and thrombosis.

The most common risk factors that tip the balance toward thrombosis are listed in Background. Any or all of the Virchow triad of underlying factors in venous thrombosis (hypercoagulability, venous stasis, and vascular damage) can occur. Procoagulants can be released in patients with cancer. Immobilization, obesity, and advanced age and the associated decrease in physical activity with any of these conditions can lead to reduced blood flow and venous stasis.

Thrombosis during pregnancy can be due to increased procoagulant factors, impaired fibrinolysis, venous stasis, and endothelial cell injury.2 The risk of thrombosis is increased in patients on hormonal replacement therapy. However, whether this risk is due to increased procoagulants or the presence of an underlying thrombophilia is not clear.3

Several underlying hereditary risk factors exist for thrombosis. A pathway that neutralizes activated factor V may be impaired by deficiencies in protein C and protein S or activated protein C (APC) resistance.4 Factor V Leiden is the most common basis for APC resistance, and its neutralization is impaired even if the proteins C and S are intact. The neutralization of activated factor Xa and thrombin are impaired with antithrombin III (ATIII) deficiency. A mutant prothrombin is associated with an increase in venous thrombosis.5

Lupus anticoagulants are antiphospholipid antibodies that result in acquired hypercoagulability due to poorly understood actions, possibly the alteration of the regulation of hemostasis and endothelial cell injury.6,7,8

Frequency

United States

Lupus anticoagulants (and antiphospholipid syndromes) are present in 4-14% of the population.

Table 1 shows the incidence of thrombophilic or hereditary hypercoagulable disorders in the general population and the risk for thrombosis and recurrent thrombosis.9,10 Other underlying risk factors are elevated factor VIII, fibrinogen, and other coagulation factors. Increases in type-1 plasminogen activator inhibitor (PAI-1), D-dimers, and homocysteine are also reported to be risk factors.

Table 1. Thrombophilic or Hereditary Hypercoagulable Disorders in the General Population and in Persons With Venous Thrombosis9

Open table in new window

[ CLOSE WINDOW ]
Table
ConditionPrevalence in General Population, %Relative Risk of VTE, %Relative Risk of Recurrent VTE, %
Factor V Leiden3-74.31.3
Prothrombin 20210A1-31.91.4
Protein C0.02-0.0511.32.5
Protein S0.01-132.42.5
Antithrombin III0.02-0.0417.52.5
ConditionPrevalence in General Population, %Relative Risk of VTE, %Relative Risk of Recurrent VTE, %
Factor V Leiden3-74.31.3
Prothrombin 20210A1-31.91.4
Protein C0.02-0.0511.32.5
Protein S0.01-132.42.5
Antithrombin III0.02-0.0417.52.5

VTE = Venous thromboembolism.

A study by Couturaud et al sought to identify risk factors for, and quantify the risk of, venous thromboembolism in 1916 first-degree relatives of patients of 378 unselected patients with a first episode of unprovoked venous thromboembolism.10 The investigators found a prevalence of 5.3% of previous venous thromboembolism in the first-degree relatives (102 episodes), with the strongest predictor of venous thromboembolism in relatives thrombosis at a young age. However, the presence of factor V Leiden or the G20210A prothrombin gene in patients was a weak independent predictor of venous thromboembolism in relatives.10

Mortality/Morbidity

Morbidity and mortality in patients with hypercoagulable states and thrombophilia are primarily due to venous thrombosis and pulmonary embolism. Although the incidence of factor V Leiden and prothrombin 20210A is significantly greater than that of protein C, protein S, and antithrombin III (ATIII) deficiencies, the risk of venous thrombosis in the case of the latter 3 (protein C, protein S, and antithrombin III (ATIII) deficiencies) is greater than in the former 2 abnormalities (factor V Leiden and prothrombin 20210A), as shown in Table 1, above.

The risk for thrombosis can be markedly increased in patients with 2 hereditary thrombophilias, in individuals who are homozygous for the factor V Leiden or prothrombin mutation, or in patients with a hereditary thrombophilia who develop an acquired risk factor for thrombosis.

Race

See articles on Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy for greater detail on the effect of race and sex on these conditions.11,12

Sex

See Race.

Age

The risk for thrombosis increases with age and associated immobility.

Clinical

History

See Physical.

Physical

There are no specific clinical symptoms or signs directly attributable to thrombophilic disorders. Rather, the clinical expressions of an underlying thrombophilia are predominantly venous thrombosis and pulmonary embolism.
  • Hereditary thrombophilia
    • These disorders should be suspected if the patient has a history of recurrent venous thromboembolism, a venous thrombosis occurring in a person younger than 40 years, a familial history of venous thromboembolism or thrombosis at an unusual site (eg, mesenteric vein, renal vein, hepatic and cerebral thrombosis).
    • Purpura fulminans in infancy could suggest protein C deficiency.
    • Thrombophilic disorders are usually associated with venous thrombosis. However, protein S, protein C, and ATIII deficiencies have been rarely associated with arterial thrombosis.
    • Patients with protein C and S deficiencies can develop warfarin-induced skin necrosis when placed on warfarin, because protein C and S are vitamin K–dependent factors.
  • Lupus anticoagulants (acquired, but sometimes classified as thrombophilia)
    • These antibodies occur in about 20% of patients with systemic lupus erythematosus (SLE), but they are also associated with other autoimmune diseases. Lupus anticoagulants may occur in patients taking phenothiazines, phenytoin, phenytoin, hydralazine, quinine, amoxicillin, and oral contraceptives.
    • Clinical criteria for indicating the presence of lupus anticoagulants (Sapporo criteria for the antiphospholipid syndrome) are as follows:
      • One or more arterial, venous, or small vessel thrombosis, affecting any organ or tissue
      • Pregnancy morbidity (10th wk or later; increases the risk for maternal and fetal morbidity and fetal mortality in pregnancy [spontaneous abortions, prematurity, stillbirths])
      • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation

Causes

See Background for risk factors. The most common acquired causes for hypercoagulability are immobilization, diabetes, advanced age, pregnancy, obesity, oral contraception use, inflammation, hormonal replacement therapy, and cancer. However, patients with the common acquired causes can have an underlying thrombophilia. Lupus anticoagulants and the diverse causes for hereditary thrombophilias should also be considered.

More on Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli

Overview: Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
Differential Diagnoses & Workup: Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
Treatment & Medication: Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
Follow-up: Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
References
Further Reading
[ CLOSE WINDOW ]

References

  1. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. Apr 3 1999;353(9159):1167-73. [Medline].

  2. Colman-Brochu S. Deep vein thrombosis in pregnancy. MCN Am J Matern Child Nurs. May-Jun 2004;29(3):186-92. [Medline].

  3. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 suppl):844S-886S. [Medline].

  4. Hillarp A, Dahlback B, Zoller B. Activated protein C resistance: from phenotype to genotype and clinical practice. Blood Rev. Dec 1995;9(4):201-12. [Medline].

  5. Eroglu A, Egin Y, Cam R, Akar N. The 19-bp deletion of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) C677T, Factor V Leiden, prothrombin G20210A polymorphisms in cancer patients with and without thrombosis. Ann Hematol. Jan 2009;88(1):73-6. [Medline].

  6. Rand JH, Senzel L. Antiphospholipid antibodies and the antiphospholipid syndrome. In: Colman RW, Marder VJ, Clowes AW, et al, eds. Hemostasis and Thrombosis. 5th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006:1621-36.

  7. Ortel TL. Thrombosis and the antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2005;462-8. [Medline]. [Full Text].

  8. Triplett DA. Antiphospholipid antibodies. Clin Adv Hematol Oncol. Dec 2003;1(12):726-30. [Medline].

  9. Heit JA. Thrombophilia: common questions on laboratory assessment and management. Hematology Am Soc Hematol Educ Program. 2007;127-35. [Medline]. [Full Text].

  10. Couturaud F, Leroyer C, Julian JA, et al. Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism. Chest. Jul 10 2009;epub ahead of print. [Medline].

  11. Lijfering WM, Veeger NJ, Middeldorp S, 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. Sep 3 2009;114(10):2031-6. [Medline]. [Full Text].

  12. Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol. Aug 2009;146(4):369-83. [Medline].

  13. Cushman M. Inherited risk factors for venous thrombosis. Hematology Am Soc Hematol Educ Program. 2005;452-7. [Medline]. [Full Text].

  14. Aiach M, Emmerrich J. Thrombophilia genetics. In: Colman RW, Marder VJ, Clowes AW, et al, eds. Hemostasis and Thrombosis. 5th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006:779-93.

  15. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. Sep 2004;126(3 suppl):188S-203S. [Medline]. [Full Text].

  16. Straczek C, Oger E, Yon de Jonage-Canonico MB, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. Nov 29 2005;112(22):3495-500. [Medline]. [Full Text].

  17. Bates SM. Management of pregnant women with thrombophilia or a history of venous thromboembolism. Hematology Am Soc Hematol Educ Program. 2007;143-50. [Medline]. [Full Text].

  18. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. Dec 1 2008;112(12):4432-6. [Medline]. [Full Text].

  19. Hanley JP. Warfarin reversal. J Clin Pathol. Nov 2004;57(11):1132-9. [Medline]. [Full Text].

  20. Keeney M, Allan DS, Lohmann RC, Yee IH. Effect of activated recombinant human factor 7 (Niastase) on laboratory testing of inhibitors of factors VIII and IX. Lab Hematol. 2005;11(2):118-23. [Medline].

  21. Baglin T, Barrowcliffe TW, Cohen A, Greaves M. Guidelines on the use and monitoring of heparin. Br J Haematol. Apr 2006;133(1):19-34. [Medline]. [Full Text].

  22. Harenberg J. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? Yes. J Thromb Haemost. Apr 2004;2(4):547-50. [Medline]. [Full Text].

  23. Bounameaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No. J Thromb Haemost. Apr 2004;2(4):551-4. [Medline]. [Full Text].

  24. Cho L, Kottke-Marchant K, Lincoff AM, et al. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations. Am J Cardiol. May 1 2003;91(9):1110-3. [Medline].

  25. Welsby IJ, McDonnell E, El-Moalem H, Stafford-Smith M, Toffaletti JG. Activated clotting time systems vary in precision and bias and are not interchangeable when following heparin management protocols during cardiopulmonary bypass. J Clin Monit Comput. Jul 2002;17(5):287-92. [Medline].

  26. Chang LC, Lee HF, Yang Z, Yang VC. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (I): preparation and characterization. AAPS PharmSci. 2001;3(3):E17. [Medline].

  27. Schick BP, Maslow D, Moshinski A, San Antonio JD. Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo. Blood. Feb 15 2004;103(4):1356-63. [Medline]. [Full Text].

  28. Welsby IJ, Stafford-Smith M. Monitoring direct thrombin inhibitors: time for standardization. Anesthesiology. Oct 2004;101(4):1048-9. [Medline].

  29. Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation. Aug 31 2004;110(9 suppl 1):I19-26. [Medline]. [Full Text].

  30. Hafner G, Roser M, Nauck M. Methods for the monitoring of direct thrombin inhibitors. Semin Thromb Hemost. Oct 2002;28(5):425-30. [Medline].

  31. Malherbe S, Tsui BC, Stobart K, Koller J. Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anesthesiology. Feb 2004;100(2):443-5. [Medline].

  32. Powner DJ, Hartwell EA, Hoots WK. Counteracting the effects of anticoagulants and antiplatelet agents during neurosurgical emergencies. Neurosurgery. Nov 2005;57(5):823-31; discussion 823-31. [Medline].

[ CLOSE WINDOW ]

Keywords

hypercoagulability, hereditary thrombophilia, thrombosis, DVT, pulmonary embolism, vein thrombosis, venous thrombosis, deep venous thrombosis, hypercoagulable state, emboli, embolism, hemostasis disorder, anticoagulant therapy, heparin, antithrombin agents, hereditary thrombophilia, lupus anticoagulants, blood coagulation disorder, acquired hypercoagulability, thromboembolic disease, blood clots

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Coauthor(s)

Barbara P Schick, PhD, Professor, Department of Medicine, Cardeza Foundation; Professor, Department of Biochemistry and Molecular Pharmacology, Professor, Department of Biochemistry and Molecular Biology, Jefferson Medical College of Thomas Jefferson University
Disclosure: Nothing to disclose.

Medical Editor

Pradyumna D Phatak, MBBS, MD,, Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute
Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.