The Hypercoagulable State
Mary Cushman, MD - Medicine Health Care Service
Edwin Bovill, MD - Pathology and Laboratory Medicine
The FAHC Laboratory and Hematology Division of the Medicine Health Care Service announce the development of a new referral system for evaluation of the hypercoagulable state. This process includes the ordering of laboratory evaluation based on two panels of tests, as well as clinical consultation for interpretation of results and patient management advice. We are hopeful that organized delivery of this service, as a joint venture between Laboratory Medicine and Hematology, will maximize the quality and value of care to patients, as well as foster an environment supportive of research endeavors for interested investigators across disciplines.
Background
The hypercoagulable state is defined as the occurrence of unexplained vascular thrombosis. The etiology is better understood in the 1990's compared to a decade ago. Venous thrombosis can be classified into two major types, primary and secondary. Secondary thrombosis is related to several factors, including the post-operative state, pregnancy, oral contraceptive use, stasis, severe illness, and malignancy. The identifiable causes for the primary hypercoagulable state include resistance to activated protein C (or Factor V Leiden), lupus anticoagulant, anticardiolipin antibody, inherited deficiency of protein C, protein S, or antithrombin III (the major natural inhibitors of coagulation), dysfibrinogenemias, and mild homocysteinemia 1.
The most prevalent cause of the primary hypercoagulable state is resistance to activated protein C. This clotting abnormality is due (in over 90% of cases) to slowed inactivation of the factor V molecule by it?s inhibitor, protein C. The cause is a mutation in the factor V gene, Factor V Leiden. In persons affected, this slowed inactivation of factor V can lead to increase in the activity of factor V, causing a shift in the normal homeostatic balance of coagulation which predisposes to pathologic clot formation 2. Factor V Leiden is found in 3-8% of the healthy population. It is found in 20-60% of patients with unexplained deep vein thrombosis 3-7. In the general population, the risk of venous thrombosis in carriers of the mutation is 3 to 7-fold increased, compared to non-carriers. Oral contraceptives increase the risk of venous thrombosis by 35-fold in women who are carriers of the mutation 8.
Testing for resistance to activated protein C may be done by two methods: (1) activated protein C ratio (APC ratio), a clotting assay based upon the aPTT test; or (2) DNA analysis for the Leiden mutation. Generally it is recommended that the APC ratio be used for patients who are not being anticoagulated while the DNA assay is used for patients on warfarin or heparin.
The other disorders related to the hypercoagulable state are less common than resistance to activated protein C (15-25% of patients). In about 40% of patients with unexplained venous thrombosis, no diagnosis can be made with presently available methods. Many disorders remain to be defined!
Patients appropriate for work up for the hypercoagulable state include those with unexplained, recurrent, and/or familial venous thrombosis. Selected patients with premature atherosclerosis or atherosclerosis without typical risk factors may also be appropriate for evaluation.
New Thrombosis Lab Panels
We recommend that NO EVALUATION be undertaken in a patient who is acutely ill, unless it is expected that results will change initial management. Results for several of the assays are affected by illness, especially by acute thrombosis. This often results in misdiagnosis, referrals, and repeat testing. Optimally, testing should be performed AFTER the patient has completed their prescribed course of oral anticoagulation.
In addition to a thrombosis panel for patients who are not anticoagulated, we offer a panel for patients who cannot be discontinued from warfarin, since it is not always appropriate to do this. This panel excludes assays which are affected by warfarin. All patients will present to the laboratory after an overnight fast (NPO after midnight), unless there is a medical contraindication. Following are the assays included in each panel, and the disorders that each assay identifies:
|
Thrombosis Panel / Warfarin |
Thrombosis Panel / No Warfarin |
Disorder Identified |
|
Prothrombin Time |
Prothrombin Time |
Lupus inhibitor |
|
aPTT |
aPTT |
Lupus inhibitor |
|
Dilute Russell Vipor Venom Time |
Dilute Russell Vipor Venom Time |
Lupus inhibitor |
|
Anticardiolipin Antibody |
Anticardiolipin Antibody |
Anticardiolipin Antibody |
|
Thrombin Time |
Thrombin Time |
Dysfibrinogenemia |
|
Antithrombin III Level |
Antithrombin III Level |
Antithrombin III deficiency |
|
Factor V Leiden DNA Analysis |
APC Ratio |
Resistance to activated protein C |
|
Fasting homocysteine |
Fasting homocysteine |
Mild hyperhomocysteinemia |
|
Protein C Activity |
Protein C Deficiency - type I or II | |
|
Protein S Activity |
Protein S Deficiency - type I or II |
Complete Clinicopathological Consultation
To promote useful interpretation of the above testing, we encourage primary providers to concurrently schedule patients for evaluation in Hematology Clinic at FAHC. Outpatient services for these referrals will be organized so that patient results are available to the hematologist at the time of consultation. Therefore most patients will be seen by the hematologist only once, maximizing efficiency of the care. Complete written reports will be sent to the referring physician in timely fashion, including results of laboratory testing and clinical management recommendations.
This care process can be arranged by consulting Dr. Mary Cushman through Provider Access (656-2480, 1-800-639-2480). Based on this telephone consultation, if it is determined that a patient should be evaluated, arrangements will be made directly with the patient for timely testing and clinic visit for discussion of results. If evaluation without clinical hematology consultation is desired, a provider may order the thrombosis panels as listed above. The primary provider will be responsible to ensure that the patient is aware of their appointment time at the laboratory, is fasting at the time of blood collection, and that the laboratory is aware of the anticoagulation status.
References
- Schafer A. Hypercoagulable states: molecular genetics to clinical practice. Lancet 1994; 344:1739-42.
- Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor V-R506Q. J Biol Chem 1995; 270:4053-7.
- Koster T, Rosendaal F, de Ronde H, Briet E, Vandenbroucke J, Bertina R. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342:1503-6.
- Griffin J, Evatt B, Wideman C, Fernandez J. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82:1989-93.
- Svensson P, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330:517-22.
- Cushman M, Bhushan F, Bovill E, Tracy R. Plasma resistance to activated protein C in venous and arterial thrombosis. Thromb Haemostas 1994; 72:647.
- Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene encoding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332:912-7.
- Vandenbroucke J, Koster T, Briet E, Reitsma P, Bertina R, Rosendaal F. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344:1453-7.
A Publication of the Department of Pathology and Laboratory Medicine
