Specific genetic defects should be suspected when a thrombotic event has any of the following characteristics:1-3
- Spontaneous with no predisposing condition, such as prolonged immobilization or surgery
- Patient suffers from more than one thrombotic event
- Patient has a positive family history of thrombosis
- Patient is <50 years old
- Thrombosis occurs at an unusual site (eg, mesenteric or cerebral brain)
Three general categories of test methodology are useful in the assessment of congenital thrombotic conditions:
- Genetic tests for specific mutations
- Clotting-based measurements for specific factor activity levels
- Immunoassays to measure the concentration of specific antigens
Genetic conditions associated with thrombophilia are listed below in order of their relative frequency of occurrence.1,2,4
Table 1. Genetic Conditions Associated With Thrombosis
Genetic Condition
|
Methodology
|
Test Number
|
5While factor VIII elevation is associated with a number of acquired conditions, some individuals appear to have congenitally elevated factor VIII levels that are associated with increased risk of thrombosis.1
|
Methylenetetrahydrofolate reductase (MTHFR) gene mutation
|
Screen: Homocysteine level
|
706994
|
Factor V Leiden mutation
|
Screen: Activated protein C resistance
|
117762
|
Confirmation: Genetic testing
|
511154
|
Prothrombin 20210
|
Genetic testing only
|
511162
|
Increased factor VIII5
|
Factor VIII activity
|
086264
|
Protein S deficiency
|
Protein S (activity, total/free antigen profile)
|
117754
|
Protein C deficiency
|
Protein C (activity and antigen profile)
|
080465
|
Antithrombin deficiency
|
Antithrombin (activity and antigen profile)
|
015594
|
Dysfibrinogenemia
|
Fibrinogen activity
|
001610
|
Fibrinogen antigen
|
117052
|
Genetic testing is useful for the diagnosis or confirmation of MTHFR, factor V Leiden, and the prothrombin 20210 mutations. Regardless of clinical status, genetic testing can be definitive because the patient's DNA remains constant. Antigen and activity levels must be measured to diagnose the other congenital thrombotic conditions. It is important to understand, however, that the results of activity and antigen level tests can be affected by the clinical state of the patient. In many clinical circumstances, such as those listed below, tests for activity or antigen levels may produce misleading results.2,4
Table 2. Clinical Conditions That Affect Tests for Congenital Thrombotic Risk
Clinical Condition
|
Effect
|
Heparin therapy or contamination
|
Decreases antithrombin
|
Warfarin therapy/vitamin K deficiency
|
Decreases protein C and protein S
|
Recent thrombosis or surgery
|
Decreases antithrombin, protein C, protein S; Increases homocysteine
|
DIC, liver disease, sepsis, L-asparaginase therapy
|
Decreases antithrombin, protein C, protein S
|
Kidney disease/nephrotic syndrome
|
Decreases antithrombin and protein S
|
Acute phase reaction, inflammation, infection
|
Decreases protein S; Increases factor VIII
|
Pregnancy or postpartum period
|
Decreases protein S and APCR; Increases homocysteine
|
Oral contraceptives or estrogen replacement
|
Decreases antithrombin and protein S
|
Lupus anticoagulants (LA)
|
Decreases APCR, protein S, and factor VIII
|
Vitamin B12, folate, or B6 deficiency
Treatment with methotrexate, phenytoin, or theophylline; Hypothyroidism, malignancy, menopause
|
Increases homocysteine
|
References
1. Adcock DM. Laboratory evaluation of venous thrombosis risk. Clin Hemost Rev.2003; 17(12):1,2,5,6,8.
2. Marques MB. Testing for genetic predisposition to venous thrombosis. MLO Med Lab Obs. 2002; 34(1):8-13. PubMed 11828956
3. Marlar RA, Adcock DM. The multifactorial threshold model of thrombotic risk. Clin Hemost Rev. 2003; 17(6):1,2,4-6.
4. Triplett DA. Thrombophilia. In McClatchey KD, ed. Clinical Laboratory Medicine.2nd ed. Baltimore, Md: Lippincott Williams and Wilkins; 2002:1033-1049.
5. Brandt JT. Overview of hemostasis. In McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Baltimore, Md: Lippincott Williams and Wilkins; 2002:987-1009.