Episode 132: VTE Series- Approach to Hypercoagulable/Thrombophilia Testing
This week, we talk all about hypercoagulable testing - a very common referral in outpatient hematology. Who do we consider testing on? Who should we encourage not to test? We discuss this and more here.
Caveat: Recommendations regarding hypercoagulable testing are just that - guidelines. We do not recommend being overly dogmatic, however it is important to understand the pros and cons of testing prior to recommending testing. The discussion represented here is how we at TFOC approach these situations and these conversations.
Before testing, always ask yourself, how does it change management?
If unprovoked VTE, indefinite anticoagulation is highly recommended
If provoked, how does testing impact duration of A/C?
When is hypercoagulable testing considered?
Patients with with minimally provoked VTE who want to know if their family members are at risk
In patients with VTE in unusual locations:
Concurrent or simultaneous arterial and venous thromboembolism; consider in the differential:
Antiphospholipid antibody syndrome
Heparin induced thrombocytopenia (
Behcet’s syndrome (if you are thinking about this be sure to involve your Rheum colleagues)
Dural venous sinus thrombosis; consider in the differential:
MPN (JAK2 V617F positive MPN)
Paroxysmal nocturnal hemoglobinuria (PNH)
Visceral thrombosis (portal vein or splenic vein thrombosis) in the absence of provoking risk factors; consider in the differential:
MPN (JAK2 V617F positive MPN)
Paroxysmal nocturnal hemoglobinuria (PNH)
Thrombosis in a very young patient. Consider:
Antiphospholipid antibody syndrome
Antithrombin deficiency
Obstetrics colleagues often order testing for patients with recurrent pregnancy losses
What are some of the more borderline indications where testing can be considered?
Essentially, situations where positive testing may push a recommendation for more indefinite anticoagulation instead of finite course:
Patients with minimally provoked VTE (for example, VTE after a long flight or outpatient surgical procedure) or recurrent provoked VTE who are reluctant to remain on indefinite anticoagulation
Patients who have a higher risk of bleeding
If patient wants to choose limited course of anticoagulation and understands the risks of recurrent thrombosis, do not push for additional testing
Consider in young patients with a strong family history of thrombosis
If they are found to have a low risk thrombophilia, we know from their family history that there is something about their family’s genes that sets them up for a higher risk of VTE.
What are the main inherited thrombophilias we consider for testing?
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin G20210A mutation (PT gene mutation for short)
ATIII deficiency is by far the highest risk condition.
Average age at first VTE is 14 years of age
Testing involves sending an antithrombin III activity level, which we know will be reduced in patients who are on anticoagulation, particularly with heparin or lovenox.
Levels can also be falsely low for patients with acute thrombosis as well
Patients who do have this condition can be treated with anticoagulation (enoxaparin seems to work pretty well, but some patients may need antithrombin replacement for it to be maximally effective) or even injections of recombinant antithrombin
Note: acquired ATIII deficiency in patients on asparaginase is something to consider!
Protein C and S deficiency
Diagnosis can be tricky here as well!
Remember that production of both protein C and S is suppressed by warfarin (so be weary of this diagnosis when a patient has a history of “protein C and S deficiency”)
These factors also both change in pregnancy
Protein S levels decline by up to 50% from baseline, so any patient diagnosed with deficiency during pregnancy also needs to have repeat testing at least 6 weeks postpartum.
Acute illness like a severe infection can also deplete protein C and S levels
How to test:
Protein C activity level
Protein S activity
Being on non-warfarin anticoagulant can impact the activity assay so consider Protein S antigen level in these situations
Protein S antigen
FYI: Activated protein C resistance is a screen for FVL (this is NOT the correct test!)
Treatment implications: For patients with Protein C deficiency increased risk of warfarin skin necrosis so generally warfarin is avoided; if it is needed, then ensure that the patient is started on a low dose and kept them on their bridging anticoagulant until they have had at least 2 consecutive INRs in the goal range.
Factor V Leiden and Prothrombin Gene Mutation:
Common in the heterozygous state
Low risk mutations overall
Factor V Leiden and the PT gene mutation are both very common in the heterozygous state, and are considered low risk mutations. They are higher risk with compound heterozygosity (heterozygous for both PT and factor V mutations), pseudohomozygosity (one mutated gene copy, and one loss-of-function gene copy), and true homozygosity, but in all this is a lower risk situation with fewer implications for therapy.
This includes patients with a history of recurrent pregnancy losses.
Unfortunately the evidence suggests there is not a significant decrease in risk of pregnancy loss if we use prophylactic anticoagulation for patients with these lower risk mutations.
Patients who have a history of thrombosis during pregnancy should generally be put on prophylactic AC for pregnancy and for 6 wk postpartum
What are other acquired thrombophilias to consider?
JAK2 V617F
PNH
Antiphospholipid antibody syndrome
IBD
Hypercoagulability of malignancy
Nephrotic syndrome
Remember that those anticoagulant proteins C and S are smaller and more readily filtered through a leaky glomerulus than the factors of the coagulation cascade. These patients will often present with renal vein thrombosis.
Things we typically do not test for include:
PAI-1 mutations
MTHFR mutations and homocysteine levels
Elevated factor VIII levels
What is the role of searching for a malignancy in a patient with an unprovoked VTE?
While malignancy is a risk factor, we recommend age-appropriate cancer screenings
“Fishing” for cancers is not appropriate in the absence of symptoms
ASH Thrombophilia guidelines: https://ashpublications.org/bloodadvances/article/7/22/7101/495845/American-Society-of-Hematology-2023-guidelines-for
The crew behind the magic:
Show outline: Daniel Hausrath
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
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