eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders
Hypercoagulability: Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
Updated: Apr 30, 2007
Introduction
Background
Venous thrombosis and pulmonary embolism are associated with significant morbidity and mortality. The most common predisposing conditions for venous thrombosis and pulmonary embolism are such risk factors as the following:- Advanced age
- Immobilization
- Inflammation
- Pregnancy
- Oral contraception
- 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. Lupus anticoagulants are acquired risk factors for venous as well as arterial thrombosis. Thrombophilias are listed in Table 1 in Frequency. Several thrombophilic conditions have been reviewed in other eMedicine articles. (See articles on Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy.)
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.
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 towards thrombosis are listed above (see 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 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. 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.
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. Factor V Leiden is the most common basis for APC resistance, and its neutralization is impaired even if the protein 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 venous thrombosis.
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.
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 in patients with venous thrombosis. The risk for thrombosis is also shown.
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 Thrombosis
Open table in new window
Table
| Condition | Prevalence in General Population, % | Prevalence in Persons With Venous Thrombosis, % | Increased Risk for Thrombosis |
| Factor V Leiden | 5-15 | 20 | 3.8 |
| Prothrombin 20210A | 1-6 | 2 | 3.0 |
| Protein C | 0.2 | 3 | 25-50 |
| Protein S | Unknown | 1-2 | 10-15 |
| Antithrombin III | 0.02 | 1 | 10 |
| Condition | Prevalence in General Population, % | Prevalence in Persons With Venous Thrombosis, % | Increased Risk for Thrombosis |
| Factor V Leiden | 5-15 | 20 | 3.8 |
| Prothrombin 20210A | 1-6 | 2 | 3.0 |
| Protein C | 0.2 | 3 | 25-50 |
| Protein S | Unknown | 1-2 | 10-15 |
| Antithrombin III | 0.02 | 1 | 10 |
Mortality/Morbidity
Morbidity and mortality in patients with hypercoagulable states and thrombophilia are primarily due to venous thrombosis and pulmonary embolism. While the incidence of factor V Leiden and prothrombin 20210A is significantly greater than that of protein C, protein S, and ATIII deficiencies, the risk of venous thrombosis in the case of the latter three is greater than in the former two abnormalities, as shown in Table 1 in Frequency.
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.
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 may have 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 thrombosis).
- 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 Coumadin-induced skin necrosis when placed on Coumadin since 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 are also associated with other autoimmune diseases. Lupus anticoagulants may occur in patients taking phenothiazines, phenytoin, Dilantin, 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.
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References
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.
Ortel TL. Thrombosis and the antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2005;462-8. [Medline].
Cushman M. Inherited risk factors for venous thrombosis. Hematology Am Soc Hematol Educ Program. 2005;452-7. [Medline].
Aiach M, Emmerrich J. Thrombophilia genetics. In: Colman RW, Marder VJ, Clowes AW, et al. Hemostasis and Thrombosis. 5th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006:779-93.
Hanley JP. Warfarin reversal. J Clin Pathol. Nov 2004;57(11):1132-9. [Medline].
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].
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].
Harenberg J. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? Yes. J Thromb Haemost. Apr 2004;2(4):547-50. [Medline].
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].
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].
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].
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].
Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation. Aug 31 2004;110(9 Suppl 1):I19-26. [Medline].
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].
Colman-Brochu S. Deep vein thrombosis in pregnancy. MCN Am J Matern Child Nurs. May-Jun 2004;29(3):186-92. [Medline].
Hafner G, Roser M, Nauck M. Methods for the monitoring of direct thrombin inhibitors. Semin Thromb Hemost. Oct 2002;28(5):425-30. [Medline].
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].
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].
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].
Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. Apr 3 1999;353(9159):1167-73. [Medline].
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].
Triplett DA. Antiphospholipid antibodies. Clin Adv Hematol Oncol. Dec 2003;1(12):726-30. [Medline].
Welsby IJ, McDonnell E, El-Moalem H, et al. 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].
Welsby IJ, Stafford-Smith M. Monitoring direct thrombin inhibitors: time for standardization. Anesthesiology. Oct 2004;101(4):1048-9. [Medline].
Further Reading
Keywords
venous thrombosis, deep venous thrombosis, DVT, pulmonary embolism, emboli, embolism, anticoagulant therapy, heparin, antithrombin agents, hereditary thrombophilia, lupus anticoagulants, blood coagulation disorder, acquired hypercoagulability
