eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

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

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
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

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.

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

• 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.

Differential Diagnoses

Other Problems to Be Considered

A number of disorders and conditions are associated with thrombosis, as discussed in other eMedicine articles:

• Paroxysmal nocturnal hemoglobinuria (PNH) 
• Homocysteinemia
• Heparin-induced thrombocytopenia
• Atherosclerosis
• Myeloproliferative disorders including polycythemia vera

• Budd-Chiari syndrome
• Sinus venous thrombosis

Workup

Laboratory Studies

• A number of tests exist for each of the hypercoagulable disorders or thrombophilia. The challenge is first to decide who should be tested, then to recognize that anticoagulation and active thrombosis affect the validity of these tests. Next is choosing the appropriate tests and, finally, to interpret the results carefully.
  
  Details of most of these tests have been reviewed in other articles published in eMedicine; therefore, only essential points are emphasized below. (See Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy for greater detail.)(In the following lists, * indicates tests that should be done in most evaluations.)
  • Thrombosis - D-dimer*
  • Lupus anticoagulant^6,7 : Screening tests are usually performed. However, the criteria for diagnosis are positive confirmatory studies, a moderate to marked cardiolipin antibody level on 2 occasions more than 6 weeks apart (International Society for Cellular Therapy [ISCT]), or both.
    • Screening tests: activated partial thromboplastin time (aPTT), dilute Russell viper venom time (RVVT), mixing studies*
    • Confirmatory studies: Demonstrations of phospholipid dependence*
    • Cardiolipin antibody: Immunoglobulin (Ig) G and IgM*
  • APC resistance and factor V Leiden
    • Functional studies for APC resistance should be done, because some cases are not due to the presence of factor V Leiden.*
    • Genetic tests for factor V Leiden: Polymerase chain reaction (PCR)*
  • Prothrombin G20210A - Genetic tests such as PCR*
  • Antithrombin III deficiency: Functional studies should always be performed, because some cases of antithrombin III deficiency may be associated with normal antigen levels.
    • Functional assay: Chromogenic heparin cofactor assay*
    • Antigenic
  • Protein C deficiency: Functional studies should always be performed, because some cases of protein C deficiency may be associated with normal antigen levels
    • Functional assay: Amidolytic*
    • Antigen
  • Protein S deficiency: The following 3 tests should be performed, because there are variants with low total but normal free protein S, low normal total but low free protein S, and normal total and free but functionally abnormal protein S.
    • Antigen: Free*
    • Antigen: Total*
    • Functional*
• The above tests are affected by a number of conditions, have quite variable results, and are difficult to interpret. Primarily, testing should be performed before patients are placed on anticoagulant therapy. Therefore, the following precautions about deciding if and when to carry out laboratory studies to rule out an underlying thrombophilia are important:
  • Only certain studies can be performed while patients are undergoing anticoagulation therapy.
    • Testing for antithrombin III functional activity should not be done while the patient is on heparin, LMWH, or warfarin.
    • Testing for protein C or S functional activity should not be done while the patient is on warfarin, because they are vitamin K–dependent proteins.
    • Testing for APC resistance should be deferred when patients are on anticoagulant therapy, because the test is a coagulation assay. However, genetic tests of factor V Leiden can be ordered.
    • Testing for lupus anticoagulants would not be possible while the patient is being anticoagulated, because the detection of the anticoagulant is based on coagulation assays.
  • Antithrombin III, protein S, and protein C levels may be increased during acute thromboembolism. Therefore, both protein assays and functional assays of these proteins could be inaccurate during the acute phase of thromboembolic disease.
  • The tests should be performed in laboratories that specialize in testing for thrombophilia.
  • These test results are difficult to interpret and are best interpreted by a physician with considerable experience in this area.
• The decision to initiate a laboratory workup for thrombophilia is complex.^13,14
  • A workup for thrombophilia is usually indicated only in patients with a history of multiple thromboembolic episodes, thromboembolism at a young age (ie, <40 y), family history for thromboembolism, or thrombosis in an unusual site.
  • Idiopathic venous thrombosis is defined as venous thromboembolism without any obvious risk factor. About 50% of patients with idiopathic venous thrombosis have an underlying thrombophilia. Therefore, some studies have recommended that a thrombophilia workup should be done in patients with idiopathic venous thrombosis.
  • The conundrum of whether to order a thrombophilia workup is that the identification of an underlying thrombophilia might not affect therapeutic strategy and morbidity and mortality. If this is the case, then testing for thrombophilia in asymptomatic or symptomatic patients would not be indicated. Anticoagulation for venous thrombosis or prophylactic anticoagulation because of advanced age, immobilization, and other scenarios is initiated regardless of whether an underlying thrombophilia has been identified.
• Some benefits may exist to testing patients for thrombophilia.
  • Some organizations recommend that patients with lupus anticoagulants be treated more aggressively. For example, the American College of Chest Physicians recommends 12 months of anticoagulation and consideration of long-term anticoagulation after a single event in patients with antiphospholipid syndromes.¹⁵ There are conflicting reports on the optimal international normalized ratio (INR) level in patients with lupus anticoagulants who are on warfarin.
    • The severity of the venous thrombosis, the presence of several acquired or hereditary risk factors, as well the risk of bleeding due to anticoagulation should be considered when deciding on the management of individual patients.
    • It follows that the identification of an underlying thrombophilia would be useful information when confronted with decision making in these patients.
  • Patients with more than one risk factor have a greater incidence for venous thrombosis than the sum of the individual risks. For example, in women who both carry a prothrombotic mutation and use oral estrogen, venous thrombosis risk is increased 25-fold, compared with nonusers of estrogen without a mutation.¹⁶
  • Patients who have an identifiable thrombophilic risk factor should be advised to have blood relatives tested so that appropriate precautionary advice can be given when they are placed in an at-risk situation such as surgery or when hormone treatment such as oral contraception is considered.

Treatment

Medical Care

It is important to review the effectiveness of monitoring and managing bleeding due to LMWH and antithrombin agents. Several aspects of commonly used anticoagulants are listed in the table below.

Table 2. Aspects of Commonly Used Anticoagulants

PT = Prothrombin time.

*Fresh frozen plasma (FFP) can be used to reverse acute bleeding in patients with high INRs due to warfarin overdose. Recombinant factor VIIa and prothrombin complex concentrates also have been used in these patients, but the risk of thrombosis due to these agents is being evaluated.^19,20

Monitoring of LMWHs

In general, LMWHs are administered without routine laboratory monitoring, because the dosage effects are fairly consistent. The most common method for monitoring LMWH is a chromogenic assay for anti–factor Xa activity. This assay measures the level of heparin in the blood, but it is not a measure of the coagulation status of the patient.

In actuality, monitoring of LMWH is complicated by several factors.²¹ The formulations available for clinical use vary in their composition and relative amounts of anti–factor IIa and anti–factor Xa activity. The optimal anti–factor Xa levels vary amongst these preparations. Thus, the physician must understand the characteristics of the LMWH being prescribed.²² The peak plasma concentrations are achieved at periods of about 4 hours following subcutaneous administration, and this is the time at which blood is usually obtained for monitoring. However, because of different dosage regimens (once or twice daily) and the possibility of different clearance rates, there is no perfect method for the optimum timing of monitoring or determination of desired target levels.²³

Moreover, standardization of the chromogenic assay for anti–factor Xa activity from different providers and in different laboratories is not yet ideal.¹⁵ Although high doses of LMWH are considered to present a greater risk of bleeding, there has not been a correlation between anti–factor Xa activity levels and actual incidence of bleeding in patients. Likewise, the assay has limited predictive value for predicting antithrombotic efficiency.

Guidelines for monitoring of LMWH were issued by the College of American Pathologists in 1998 and by the Control of Anticoagulation Subcommittee of the International Society for Thrombosis and Hemostasis. Both organizations indicate that routine monitoring is unnecessary for most patients. However, patient subgroups such as overweight and underweight individuals, children, those with reduced creatinine clearance, and persons undergoing prolonged therapy (eg, cancer patients and pregnant women, especially in the third trimester) should be monitored to be ascertain that no excess heparin accumulates in the blood.

Monitoring antithrombin agents

The Ecarin clotting time (ECT),²⁴ activated clotting time,²⁵ and activated factor X tests have been used to monitor antithrombin agents. The Ecarin clotting time is thought to be the most reliable test, but further clinical experience with this assay would be important to establish a more complete track record.²⁴ Unfortunately, the Ecarin clotting time is not available at most medical centers.

Reversal of anticoagulation

A major consideration in the administration of anticoagulants is the reversal of anticoagulation in patients who bleed. All currently available anticoagulants carry similar risks of serious bleeding episodes. Unfractionated heparin is readily reversible with protamine, but protamine carries some risk of hypotensive and anaphylactic reactions. warfarin can be reversed in a short time by the administration of FFP, but reversal with vitamin K can take several hours or days.

Protamine can reverse no more than 60% of the anti–factor Xa activity of LMWH and has had very limited efficacy in controlling bleeding in clinical use. Reversal agents such as low molecular weight protamines²⁶ and cationic concatameric peptides²⁷ are under investigation but are not yet in clinical use.

Fondaparinux (Arixtra, Sanofi-Aventis Corp) is the pentasaccharide that binds to antithrombin III. There is no known reversal agent for this drug. The long half-lives of LMWH and fondaparinux and the possibility of continued release into the circulation from the site of subcutaneous injection after bleeding begins further complicate the reversal process.

Likewise, no reversal agents are available for lepirudin, bivalirudin, and argatroban, or for the oral direct thrombin inhibitors that are currently in clinical trials.

Exanta (ximelagatran) has been withdrawn and is no longer available due to its side effects.

Recombinant factor VIIa has been proposed as a reversal agent for patients who bleed while undergoing anticoagulation, but thus far, there have been no controlled studies to determine its efficacy. Thrombosis may be a significant risk of recombinant factor VIIa therapy.

In summary, experts have proposed that monitoring LMWH and direct thrombin inhibitors is not necessary, because it is thought that these agents are almost 100% available and thus their effects are predictable.²⁸ This recommendation is in part due to the lack of reliability or unavailability of the tests for monitoring LMWH and antithrombin agents. For example, Factor Xa levels are not reliable for determining whether the level of anticoagulation is sufficient to prevent thrombosis, as well as not reliable for predicting the risk for bleeding.

The inadequacy of monitoring tests and the fact that antidotes are not available places patients who bleed at considerable risk, especially because some of the LMWH and antithrombin agents have a long half-life.²⁹ The reversal of bleeding due to LMWH and antithrombin agents, especially if the agent has a long half-life, has been difficult.

Consultations

Consult a hematologist experienced in the diagnosis and management of thrombophilias and hypercoagulable disorders. Equally important is that the laboratory evaluations for thrombophilia are carried out in laboratories with extensive experience with these tests.

Medication

See Medical Care.

Follow-up

Deterrence/Prevention

• If a patient is known to have a lupus anticoagulant or a thrombophilia, it is important to avoid oral contraceptives and hormone replacement therapy. Also, prophylactic anticoagulation should be considered when there is an additional risk for venous thrombosis, such as immobilization and surgery.
• The risk of venous thrombosis is considerably greater in patients with 2 hereditary thrombophilias or with a thrombophilia and an acquired hypercoagulable disorder. Prophylactic therapy should be considered in these circumstances.

Complications

See Mortality/Morbidity.

Prognosis

The prognosis is probably worse in patients with antithrombin III deficiency and lupus anticoagulants than in those without these factors.

Miscellaneous

Medicolegal Pitfalls

• The question of when to test a patient for thrombophilia could become a medicolegal pitfall. For example, should every woman be tested before being started hormone replacement therapy? This is currently not done, but it could be argued that physicians may be liable if a patient is not tested.
• The question of when a patient with a thrombophilia should be on long-term anticoagulation is one of conflicting opinions. Legal issues may arise if a patient with a known thrombophilia develops a venous thrombosis if the patient had not been anticoagulated.
• Legal issues may also be raised if a patient has significant bleeding due to anticoagulation that was initiated without a valid indication.

References

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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

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.

Related eMedicine Topics

• Antiphospholipid Antibody Syndrome and Pregnancy [in the Obstetrics & Gynecology section]
• Antiphospholipid Syndrome [in the Rheumatology section]
• Antithrombin III Deficiency [in the Pediatrics: General Medicine section]
• Deep Venous Thrombosis and Thrombophlebitis [in the Emergency Medicine section]
• Protein C Deficiency
• Protein S Deficiency
• Pulmonary Embolism [in the Pulmonology section]

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• Hypercoagulability and Thromboembolic Risk in Patients With Malignant Disease, Evaluated by Thrombelastograph (TEG®)
• Pharmacokinetics of Low Molecular Weight and Unfractionated Heparin in Pregnancy
• TIPPS: Thrombophilia in Pregnancy Prophylaxis Study

Clinical Guideline

• Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). American College of Chest Physicians - Medical Specialty Society. 2001 Jan (revised 2008 Jun). 43 pages. NGC:006675

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