AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 to choose 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. (See articles on Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy for greater detail.) Therefore, only essential points are emphasized below. (In the following lists, * indicates tests that should be done in most evaluations.)
• • Thrombosis – d-Dimer*
  • Lupus anticoagulant^{1, 2}: 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 (ISCT), or both.
  • • Screening tests: aPTT, dilute Russell viper venom time (RVVT), mixing studies*
    • Confirmatory studies: Demonstrations of phospholipid dependence*
    • Cardiolipin antibody: Immunoglobulin G (IgG) and immunoglobulin M (IgM)* 
  • Activated protein C (APC) resistance and factor V Leiden  
  • • Functional studies for APC resistance should be done since 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 since some cases of ATIII deficiency may be associated with normal antigen levels.
  • • Functional assay: Chromogenic heparin cofactor assay*
    • Antigenic 
  • Protein C deficiency: Functional studies should always be performed since some cases of protein C deficiency may be associated with normal antigen levels.
  • • Functional assay: Amidolytic*
    • Antigen 
  • Protein S deficiency: The 3 tests should be performed since there are variants with low total but normal free protein S, with low normal total but low free protein S, and with 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 ATIII functional activity should not be done while the patient is on heparin, LMWH, or Coumadin.
    • Testing for protein C or S functional activity should not be done while the patient is on Coumadin since they are vitamin K–dependent proteins.
    • Testing for APC resistance should be deferred when patients are on anticoagulant therapy since 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 since the detection of the anticoagulant is based on coagulation assays.  
  • ATIII, 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^{3, 4}.
• • 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 were 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 anticoagulation and consideration of long-term anticoagulation after a single event in patients with antiphospholipid syndromes. There are conflicting reports on the optimal International Normalized Ratio (INR) level in patients with lupus anticoagulants who are on Coumadin. 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 mutation.
    • 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The goal of this article is not to review the management of venous thrombosis and pulmonary embolism; therapy for these conditions is reviewed in other articles. (See articles on Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy for greater detail.)

Coumadin, heparin, and LMWH have been used to manage venous thrombosis and pulmonary embolism. Antithrombin agents may become another option for managing venous thrombosis and pulmonary embolism.

One goal of this article is to review the effectiveness of monitoring and managing bleeding due to LMWH and antithrombin agents. Several aspects of commonly used anticoagulants are listed in Table 2.

Table 2. Aspects of Commonly Used Anticoagulants

*Fresh frozen plasma (FFP) can be used to reverse acute bleeding in patients with high INRs due to Coumadin overdose. r-VIIa and prothrombin complex concentrates also have been used in these patients, but the risk of thrombosis due to these agents is being evaluated^{5, 6}.

Monitoring of low molecular weight heparins

In general, LMWHs are administered without routine laboratory monitoring since 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 is not a measure of the coagulation status of the patient.

In actuality, monitoring of LMWH is complicated by several factors⁷. The formulations available for clinical use vary in their composition and relative amounts of anti-IIa and, and anti-Xa activity. The optimal anti-Xa levels vary amongst these preparations. Thus, the physician must understand the characteristics of the LMWH being prescribed⁸. 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 optimum timing of monitoring or determination of desired target levels⁹.

Standardization of the assay from different providers and in different laboratories is not yet ideal¹⁰. While high doses of LMWH are considered to present greater risk of bleeding, there has not been a correlation of anti-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 indicate that routine monitoring is unnecessary for most patients. However, subgroups such as overweight and underweight patients, children, patients with reduced creatinine clearance, and patients undergoing prolonged therapy (eg, cancer patients and pregnant women, especially in the third trimester) should be monitored to be sure that no excess heparin accumulates in the blood.

Monitoring antithrombin agents

The Ecarin clotting time, activated clotting time, 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. Unfortunately, the Ecarin clotting time is not available at most medical centers.

Reversal of anticoagulation

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

Protamine can reverse no more than 60% of the anti-FXa activity of LMWH and has had very limited efficacy in controlling bleeding in clinical use. Reversal agents such as low molecular weight protamines¹¹ and cationic concatameric peptides¹² are under investigation but are not yet in clinical use.

Fondaparinux (Arixtra, Sanofi-Aventis Corp.) is the pentasaccharide that binds to ATIII. 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 no longer is 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 since it is thought that these agents are almost 100% available and thus their effects are predictable. This recommendation is in part due to the lack of reliability or unavailability of these test for monitoring LMWH and antithrombin agents. For example, FXa levels are not reliable for determining whether the level of anticoagulation is sufficient to prevent thrombosis and 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 since some of the LMWH and antithrombin agents have a long half life¹³. 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 diagnosis and management of thrombophilias and hypercoagulable disorders. Equally important is that the lab evaluations for thrombophilia be carried out in labs with extensive experience with these tests.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

See Medical Care.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 two hereditary thrombophilias or with a thrombophilia and an acquired hypercoagulable disorder. Prophylactic therapy should be considered in these circumstances.

Complications

See Mortality/Morbidity.

Prognosis

Prognosis is probably worse in patients with ATIII deficiency and lupus anticoagulants than in those without these factors.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The question of when to test a patient for thrombophilia could become a medicolegal pitfall. For example, should every woman be tested prior to starting 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Rand JH, Senzel L. Antiphospholipid antibodies and the antiphospholipid syndrome. In: Colman RW, Marder VJ, Clowes AW, et al, eds. Hemostasis and Thrombosis. 5^th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006:1621-36.
2. Ortel TL. Thrombosis and the antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2005;462-8. [Medline].
3. Cushman M. Inherited risk factors for venous thrombosis. Hematology Am Soc Hematol Educ Program. 2005;452-7. [Medline].
4. Aiach M, Emmerrich J. Thrombophilia genetics. In: Colman RW, Marder VJ, Clowes AW, et al. Hemostasis and Thrombosis. 5^th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2006:779-93.
5. Hanley JP. Warfarin reversal. J Clin Pathol. Nov 2004;57(11):1132-9. [Medline].
6. 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].
7. 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].
8. Harenberg J. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? Yes. J Thromb Haemost. Apr 2004;2(4):547-50. [Medline].
9. 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].
10. 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].
11. 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].
12. 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].
13. Weitz JI. New anticoagulants for treatment of venous thromboembolism. Circulation. Aug 31 2004;110(9 Suppl 1):I19-26. [Medline].
14. 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].
15. Colman-Brochu S. Deep vein thrombosis in pregnancy. MCN Am J Matern Child Nurs. May-Jun 2004;29(3):186-92. [Medline].
16. Hafner G, Roser M, Nauck M. Methods for the monitoring of direct thrombin inhibitors. Semin Thromb Hemost. Oct 2002;28(5):425-30. [Medline].
17. 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].
18. 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].
19. 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].
20. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. Apr 3 1999;353(9159):1167-73. [Medline].
21. 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].
22. Triplett DA. Antiphospholipid antibodies. Clin Adv Hematol Oncol. Dec 2003;1(12):726-30. [Medline].
23. 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].
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Article Last Updated: Apr 30, 2007