Thrombophilia laboratory findings
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]
Overview
Laboratory findings consistent with the diagnosis of inherited thrombophilias vary based on the etiology of the thrombus.[1]
Laboratory Findings
Initial assessment
- Aim: Determining whether a blood clot classifies as provoked (most common) vs. unprovoked, and whether it is the first episode vs. subsequent are critical aspects of the initial evaluation that can guide further workup and treatment.
- The initial assessment involves a carefully taken clinical history and physical examination in addition to performing appropriate laboratory, imaging and other relevant investigations.
- Depending on the initial assessment and the clinical management decisions to be addressed, laboratory testing for heritable thrombophilia can be considered.
- NICE guidelines:
- Provoked VTE: The most recent guidelines recommend against offering inherited thrombophilia testing to patients presenting with a provoked VTE in any clinical setting.
- Unprovoked VTE: Testing should not be considered unless a first degree relative with a history of VTE exists.
- The NICE guidelines in accordance with the American Society of Hematology’s Choosing Wisely recommendations also recommend against routinely offering thrombophilia testing to asymptomatic first-degree relatives of patients with a history of VTE or known inherited thrombophilia as there is no evidence to support thromboprophylaxis in this setting.
- Hospitalized patients:
- Its been recommended that the clinicians should avoid ordering thrombophilia testing for hospitalized patients with unprovoked VTE because of the following:
- Many thrombophilia tests are inaccurate in the setting of acute VTE and/or anticoagulation
- Results of testing often do not influence management
- Testing is not cost-effective
- A positive test result may lead to unnecessary patient anxiety
- Testing may result in inappropriately prolonged anticoagulation courses or unnecessary involvement of inpatient consultants.
- Its been recommended that the clinicians should avoid ordering thrombophilia testing for hospitalized patients with unprovoked VTE because of the following:
- Individualized approach: Depending on the underlying inherited condition and expression of the genetic abnormality, the relative risk of VTE in patients with inherited thrombophilia is 3- to 20-fold greater than that of the general population which further states that testing for inherited thrombophilia might be clinically useful. However, the testing process may divert attention away from the management of more prevalent and potentially modifiable risk factors such as immobility, oral contraceptive use, or malignancy which are also associated with recurrent VTE. However, the evidence for doing so is very limited. Hence, testing should only be considered using an individualized approach in the outpatient setting with appropriate genetic counseling.
Indications for thrombohilia screening and testing
- Indiscriminate application of laboratory investigations is clinically inappropriate, wastage of scarce resources, creates unnecessary anxiety and can be misleading as diagnostic uncertainty is frequent.
- Hence, its been advisable to take hematologists consult on the selection of patients for testing as the testing of unselected patients is inappropriate and should be avoided.
Table 1: Thrombophilia testing may be indicated in the following scenarios:
| Indications for Thrombophilia testing |
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Common thrombophilia tests
- An interpretation of thrombophilia test results is difficult and fraught with pitfalls which can occasionally lead to underdiagnosis and frequently to overdiagnosis of defects. Hence, it is strongly recommended that thrombophilia testing is supervised by and results are interpreted by an experienced clinician who is aware of all relevant factors that may influence individual test results in each individual.
- Additionally, the tests will not find abnormalities in all patients with VTE and a strong family history which reflects the likelihood that some heritable states are yet to be identified especially in the non-Caucasian population. Therefore, a negative set of investigations does not exclude an inherited prothrombotic tendency and a referral to a thrombosis specialist should be made in the doubtful cases.
- Table 2: Diagnostic workup for thrombophilia testing
| Diagnostic tests |
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- Following tests are not indicated commonly:
- MTHFR (methylenetetrahydrofolate reductase) genetic test
- Factor VIII level
- tPA (tissue plasminogen activator) blood levels
- PAI-1 (plasminogen activator inhibitor type 1) blood levels
- Genetic tests
Factors affecting the accuracy of the tests
- Table 3: List of factors affecting the accuracy of thrombophilia test results
| Factors |
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When to collect samples for thrombophilia testing
- As the management of an acute thrombotic event never gets influenced by the finding of a thrombophilic abnormality. Hence, there is little point in striving to obtain samples for tests for heritable thrombophilia when the patient presents with an acute thrombotic event.
- Timing of testing:
- Testing should be done approximately four weeks following the completion of a course of anticoagulation.
- Vitamin K antagonists: Testing sample should be taken 2 weeks after their cessation
- Low molecular weight heparins: Tests should be performed 24 hours after stopping them as these produce a false positive lupus anticoagulant test.
- Testing should be delayed for approximately six months in acute thrombosis events which can affect levels of coagulation factors or once the acute phase of the thrombosis has resolved.
- Antiphospholipid antibody testing is recommended to be repeated 12 weeks apart.
- Testing should be done approximately four weeks following the completion of a course of anticoagulation.
- PCR-based tests for FV Leiden and the prothrombin 20210A allele mutation can be done in patients presenting in an acute phase and/or being on anticoagulants as these are genetic tests.
- Sample collection:
- All samples should be taken in sodium citrate/blue vacutainers filling them to the line to ensure the correct dilution is attained.
- Local policies for anticardiolipin tests vary and may require a clot-activated sample with red top vacutainer or without gel for serum separation/gold top vacutainer.
- Hence, the timing and sample collection are important to accurately evaluate for the thrombophilic states given the variability of test results under the guidance of a hematologist consultant. [2][3]
Emergency room assessment and screening
- Modified Wells' criteria: It is applied to the patients presenting to the emergency department with signs and symptoms suggestive of possible venous thrombosis to help guide further diagnostic studies. For patients with high Wells score, a serum D-dimer should be checked.
- D-dimer: It is a fibrin degradation product that is present in the blood after fibrinolysis.
- Positive: Its elevation is very sensitive though less specific to detect venous thrombosis; however, it could be elevated in patients with underlying malignancy, post-surgical patients and pregnant females.
- Negative: A negative D-dimer result helps to rule out a clot and avoid unnecessary imaging studies or anticoagulation initiation.
- However, when there is a high pretest probability for PE or DVT, imaging studies should be completed immediately without regard to D-dimer levels.
- Pulmonary embolism: The recommended imaging studies are CT angiography and ventilation/perfusion imaging (V/Q scan). The V/Q scan is sometimes preferred over CTPA to avoid radiation exposure or intravenous contrast in those with underlying renal impairment. However, not all facilities have V/Q scanning capabilities or expertise at interpreting the results, so CTPA is often used.
- Deep venous thrombosis: As often, pulmonary emboli result from fragmentation of preexisting thrombosis as a DVT in an extremity. Hence, compression sonography (Duplex US) of lower and/or upper extremities is also often performed to evaluate for concurrent DVT.
References
- ↑ Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis". N Engl J Med. 344 (16): 1222–31. doi:10.1056/NEJM200104193441607. PMID 11309638.
- ↑ Cohoon KP, Heit JA (2014). "Inherited and secondary thrombophilia". Circulation. 129 (2): 254–7. doi:10.1161/CIRCULATIONAHA.113.001943. PMC 3979345. PMID 24421360.
- ↑ Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M; et al. (2016). "Guidance for the evaluation and treatment of hereditary and acquired thrombophilia". J Thromb Thrombolysis. 41 (1): 154–64. doi:10.1007/s11239-015-1316-1. PMC 4715840. PMID 26780744.