Master the nuances of the hypercoagulable work-up! Our expert discussant, Dr. Jean Connors, leads us through when to send testing for thrombophilia and how to interpret the results.
Claim free CME for this episode at curbsiders.vcuhealth.org!
In a person with a venous thrombotic event, Dr. Connors recommends obtaining the following history:
Does the person have a personal history of thrombosis in the past? What was the situation surrounding this previous incident?
Does the person have a family history of thrombosis? What was the situation surrounding the family member’s thrombosis (e.g. provoking factors)? At what age did family members develop the thrombosis? According to Dr. Connors, we usually are most interested in first-degree relatives (Connors, 2017); thrombotic events in second-degree relatives are less concerning. Additionally, we are primarily interested in clots that occurred in family members when they were under the age of 50 (since risk of thrombosis rises dramatically over the age of 60 (Silverstein et al, 1998); younger individuals have a higher threshold to clot development, which can be lowered with inherited thrombophilias.)
Potential factors that may have provoked the present thrombotic event: Dr. Connors said she is careful to take a thorough history to identify potential provoking factors, which can be categorized as weak, moderate, or strong. Various factors often act synergistically in promoting clot formation. Provoking factors that Dr. Connors highlights include:
For patients with clear strong provoking factors (e.g. cancer, high-risk surgery), there is no need to conduct thrombophilia testing, according to Dr. Connors (Connors, 2017). However, for patients with unprovoked thrombosis, or a provoking factor but a strong, suspicious family history (such as the patient in our case from Kashlak), thrombophilia testing can be considered. Other special situations where testing for inherited thrombophilias is warranted is in the case of thrombosis in unusual locations such as the splanchnic circulation or cerebral sinuses (in the case of splanchnic thrombosis, it is also important to rule out myeloproliferative disorders) (Connors, 2017).
Dr. Connors stresses that when considering testing for inherited / acquired forms of thrombophilia, it is important to ask yourself: why are you testing, and what are you going to do with the results?
Dr. Connors emphasizes that a patient’s thrombophilia status will generally not change their personal anticoagulation management. Rather, all patients with a thrombotic event will receive an acute course of anticoagulation. The decision to continue the anticoagulation after the acute period is dependent on whether the clot is provoked or unprovoked, according to most major guidelines (ASH guidelines, 2020). In patients with an identifiable transient provoking factor, anticoagulation can generally be discontinued after 3-6 months, and prophylaxis given in future high-risk situations. However, in patients with unprovoked “out of the blue” clots, anticoagulation should generally be continued indefinitely. This is because the risk of recurrence in a patient with an unprovoked clot is high (10% per year in the first two years) (Prandoni et al, 2007.) However, the recent European Society of Cardiology recommendations on pulmonary embolism recommend not considering the unprovoked vs provoked nature of a VTE and instead considering indefinite continuation of anticoagulation in any patient who experiences a pulmonary embolism (ESC guidelines, 2019), though Dr. Connors believes that this goes a bit too far, as PE in the setting of major provoking factors such as surgery or trauma have an extremely low likelihood of recurrence (Baglin et al, 2003; Iorio et al, 2010) and thus she does not think indefinite anticoagulation is warranted in those settings.
Regardless, the results of thrombophilia testing do not play a role in anticoagulation management for that individual. However, other factors may influence whether thrombophilia test results may be useful and influence the decision to test. One important factor is whether the patient has female family members of childbearing age contemplating starting OCPs or pregnancy, for which knowledge of the presence of an inherited thrombophilia may be valuable (Connors, 2017). For instance, in a middle-aged man with an unprovoked clot, the primary motivation for thrombophilia testing may be the fact that he has an 18-year-old daughter contemplating OCP initiation, rather than because the results will influence treatment decisions for the man himself.
Thrombophilia test results can also be beneficial since a label of inherited thrombophilia in a patient’s chart may cause providers to be more careful about perioperative prophylaxis prior to future surgical procedures. Additionally, knowledge of the presence of an inherited thrombophilia can be helpful for patients who are wondering why a clot occurred. Of course, Dr. Connors emphasizes that just because thrombophilia testing is negative doesn’t mean that a patient is not at risk, and thus should not provide a false sense of security; some patients with a strong family history VTE at young ages may be negative on standard thrombophilia panels, but have still been shown to be at increased risk of thrombosis (Bezemer et al, 2009.)
Regarding future anticoagulation prophylaxis at times of increased risk for patients with a history of provoked clots (which does not depend on thrombophilia status, as discussed above): Dr. Connors recommends use of anticoagulation prophylaxis during future episodes of prolonged air travel (expert opinion; no guidelines due to lack of data.) She usually uses prophylactic dose rivaroxaban 10 mg (one dose) or apixaban 2.5 mg q12 hours (two doses), depending on the length of the trip. Of note, if the patient is going to be on a long bus or car ride after the flight, this needs to be taken into account as well! With regards to prophylaxis during future pregnancy: if a patient has had a prior estrogen-provoked clot, Dr. Connors will definitely recommend prophylactic anticoagulation during pregnancy. If the patient’s prior clot was not estrogen-provoked, use of anticoagulation prophylaxis during pregnancy is more controversial, and shared decision-making involving a discussion with the patient about the pros / cons is warranted. During pregnancy, direct oral anticoagulants (DOACs) are contraindicated as they can cross the placenta, so enoxaparin injections are used for prophylaxis.
What to order
The five core tests that Dr. Connors orders when testing for inherited thrombophilia are: prothrombin gene mutation, factor V Leiden mutation, protein C, protein S, and antithrombin (Connors, 2017). The prothrombin gene mutation is detected by PCR, and factor V Leiden can be detected by PCR or activated protein C resistance testing followed by confirmatory PCR. Inherited deficiencies in protein C, protein S, and antithrombin (which can involve abnormalities in quantity or function) are detected by activity assays. Notably, protein S circulates in a free form and a form bound to C4B binding protein; inflammation can cause levels of C4B binding protein to increase, and thus levels of free protein S detected by the assay can be artificially low in the setting of inflammation, infection, and hospitalization. Antithrombin can also be lowered if a patient is on heparin. PCR testing for prothrombin gene mutation or factor V Leiden is always reliable.
Testing for antiphospholipid syndrome should also be added to the panel in certain situations, as detailed more below.
When to test
According to Dr. Connors, thrombophilia testing should not be performed in the acute setting due to the impact of inflammation on particular test results, although the results of PCR based testing are not affected. Additionally, thrombophilia testing should not be performed while a patient is on anticoagulation, due to the impact of certain anticoagulants on test results. Most of the time, there is no reason to interrupt a patient’s acute 3-6 month anticoagulation course to conduct thrombophilia testing, as the results of testing will not change acute management (with the exception of cases where there is a high suspicion for antiphospholipid syndrome); thus, Dr. Connors recommends waiting 3-6 months until they have completed the acute anticoagulation course before testing. DOACs should be stopped for at least 2 days (if not longer) before testing.
Diagnosing antiphospholipid syndrome
Clinical criteria for antiphospholipid syndrome (by the Sapporo criteria) include the presence of at least one of the following (Miyakis et al, 2006):
including recurrent unexplained miscarriages, unexplained fetal loss beyond 10 weeks, or premature birth before 34 weeks due to eclampsia, pre-eclampsia, or placental insufficiency.
In addition to meeting clinical criteria, patients must also have positive laboratory findings, which involves at least one positive laboratory test on two occasions at least 12 weeks apart (Miyakis et al, 2006). The three laboratory tests used for antiphospholipid syndrome diagnosis are:
Importantly, to make a diagnosis of antiphospholipid syndrome, at least one laboratory test must be positive around the time the event occurred as well as persistently positive at least 12 weeks later. The terms triple positive, double positive, and single positive refer to the number of positive laboratory tests out of the three core laboratory tests (anti-cardiolipin IgG and IgM, anti-beta 2 glycoprotein IgG and IgM, and lupus anticoagulant clot-based assay.)
Treating antiphospholipid syndrome
In antiphospholipid syndrome characterized by venous or arterial thrombotic events, warfarin is the treatment of choice. The TRAPs trial randomized patients with triple positive antiphospholipid syndrome randomized to rivaroxaban vs warfarin, and found that those on rivaroxaban had an increased risk of thrombosis (Pengo et al, 2018). A recent meta-analysis suggests that even single and double positive patients with antiphospholipid syndrome have an increased risk of clot recurrence on a DOAC compared to warfarin (Khairani et al, 2023).
With regards to obstetric antiphospholipid syndrome, data is not robust, but use of prophylactic dose enoxaparin plus aspirin 81mg can improve the live birth rate.
Finally, patients with rheumatologic conditions like lupus often have high titers of antiphospholipid antibodies. However, if they have not experienced a clot, anticoagulation is not indicated.
Listeners will develop an approach to determining which patients to test for inherited / acquired forms of thrombophilia and how to interpret results.
After listening to this episode listeners will…
Dr. Connors reports that she has consulted for Bristol-Meyer Squibb, Pfizer, and Janssen. The Curbsiders report no relevant financial disclosures.
Gandhi MM, Taranto N, Connors J, Williams PN, Watto MF. “#391 Hypercoagulable Work-up with Dr. Jean Connors”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast April 24, 2023.
Got feedback? Suggest a Curbsiders topic. Recommend a guest. Tell us what you think.
We love hearing from you.
Yes, you can now join our exclusive community of core faculty at Kashlak Memorial Hospital along with all the perks:
Close this notice to consent.