A Leiden Wild Card

In our August 2019 issue, Leslie J. Raffini, MD, responded to a colleague seeking advice on managing large venous thromboembolisms (VTEs) in two teenaged siblings, one with homozygous factor V Leiden (FVL). Readers who responded to the question were divided as to whether the siblings had an inherited thrombophilic condition. Here, two groups of hematologists wrote to ASH Clinical News about the difficulties of interpreting the clinical significance of “wild type FVL.”


The August 2019 “You Make the Call” question reported on a 19-year old woman with VTE and FVL, which, “along with her history of unprovoked proximal VTE and pulmonary embolism is worrisome for a high risk of recurrence.” In my view, this case warrants further comment.

First, in a 19-year-old woman, I would want to know explicitly whether she has been using oral or other hormonal contraceptives. Even though the definition of unprovoked VTE with regard to hormone use is not always homogeneous, oral contraceptive use should be considered a provoking risk factor and hence would strongly influence my decision to stop or to continue anticoagulant therapy.1,2

Second, is the woman really homozygous for FVL? The report states “wild type factor V Leiden,” which is a confusing expression. Doesn’t it mean that the patient has wild-type factor V – that is, no alleles with the point mutation (F5 G1691A) that results in a single amino acid change (arginine506 to glutamine) at one of the activated protein C cleavage sites?

Third, if the woman is homozygous for FVL, does this indeed represent a risk factor for recurrent VTE? Interestingly, two discordant (at first sight) studies have been published. The first, a meta-analysis of data from six randomized controlled trials and two prospective cohort studies showed a pooled odds ratio for recurrence of 2.65 (95% CI 1.18-5.79).3 The second, a case-control study design within a large family study, in which the risk for recurrent VTE in homozygous FVL carriers was compared with their relatives without inherited thrombophilia, found an odds ratio for recurrent VTE of 1.2 (95% CI 0.5-2.6).4

How can this discrepancy be explained? The 95% confidence intervals of the point estimates in each study overlap and, although no statistical heterogeneity was found in the meta-analysis, the point estimates of the odds ratios for VTE recurrence in the indivi-dual studies ranged from 0.64 to 15.33.5,6 Also, although the effect of homozygosity of FVL on risk of recurrent VTE was assessed in each study, differences in study design, population, and study size also may contribute to the apparent different results. For instance, the highest odds ratio (of 15.33) was derived from a study that included two homozygous individuals only and showed great statistical uncertainty (95% CI 0.85-276.51). Studying the effect of homozygous FVL in thrombophilic families may lead to comparing a known thrombophilia (homozygous FVL) with another, yet-unknown strong thrombophilia. If one would add the data from the family study into the meta-analysis and omit patients who had recurrent VTE while on anticoagulant treatment, the pooled odds ratio would drop to 2.22 (95% CI 1.17-4.22).

Now, would this influence my decision to continue anticoagulant treatment? According to current guidelines, I would advise both siblings with unprovoked VTE to continue anticoagulant treatment, provided they tolerate this well. In counseling, the presence of homozygous FVL would be an additional argument favoring this advice.2

Saskia Middeldorp, MD
Amsterdam University Medical Center
Amsterdam, The Netherlands

References

  1. Middeldorp S, Iorio A. Oral contraceptive use is a provoking factor for venous thromboembolism. BMJ. 2017;357:j2073.
  2. Bistervels IM, Scheres LJJ, Hamulyák EN, Middeldorp S. Sex matters: Practice 5P’s when treating young women with venous thromboembolism. J Thromb Haemost. 2019;17:1417-29.
  3. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301:2472-85.
  4. Lijfering WM, Middeldorp S, Veeger NJGM, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121:1706-12.
  5. Christiansen SC, Cannegieter SC, Koster T, et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293:2352-61.
  6. Høibraaten E, Mowinckel MC, De Ronde H, et al. Hormone replacement therapy and acquired resistance to activated protein C: Results of a randomized, double-blind, placebo-controlled trial. Br J Haematol. 2001;115:415-20.
  7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52.

In the August 2019 “You Make the Call” clinical dilemma, the 19-year-old woman was said to have “wild type factor V Leiden [FVL].” While the discussant interpreted this term as indicating that the patient is homozygous for FVL, this conclusion cannot be drawn based on the terminology used in the presentation. The statement may well be inaccurate.

“Wild type FVL” is not a scientifically or clinically accurate term. In genetics, the term “wild type” is used for the presence of the typical/normal gene, i.e., the absence of a genetic variant or mutation. Thus, we wonder whether the laboratory FVL test report of the 19-year-old really meant “wild type factor V,” which would indicate that the patient does not have FVL. Alternatively, the report should have read “homozygous FVL,” “homozygous R506G (Arg506Gln) FVL mutation,” or “two alleles with the FVL mutation” if the mutation was present. “Wild type FVL” has no meaning and should not be used.

Obviously, laboratories need to use correct, clear terminology when communicating laboratory tests. Similarly, clinicians need to be careful when interpreting laboratory test reports and using them for clinical decision making.

In respect to FVL, a clinician who interprets a “normal factor V activity” result as indicating absence of FVL is basing the assessment on the wrong test ordered and is misinterpreting the meaning of the result.1 Similarly, in the current case, the genetic test report terminology may well have led to misinterpretation of the result, with potential consequences for clinical management. In addition, paternity may be questioned if FVL results of offspring and parents do not match up.

Stephan Moll, MD
University of North Carolina School of Medicine
Chapel Hill, NC

Ming Y. Lim, MD
University of Utah
Salt Lake City, UT

Reference

Houghton DE, Sud S, Moll S, Rollins-Raval MA. Perils in the thrombophilia workup: Frequency and circumstances of erroneously ordered factor V activity tests for thrombophilia. Vasc Med. 2017;22:527-8.


Dr. Raffini’s response:

I would like to acknowledge my error in misinterpreting the term “wild type” in this interesting case of siblings. I am well aware that this term refers to the normal genotype, not homozygous factor V Leiden and am sorry to have generated so much confusion. I am appreciative of my colleagues that recognized my error and highlighted the importance of not misinterpreting genetic test results!

Dr. Middeldorp also brings up the interesting and conflicting data regarding whether homozygosity for the factor V Leiden mutation contributes to the risk of recurrent VTE. Her comments and explanations for why findings have differed are very helpful.

I stand by my original treatment recommendations, for both siblings. In the end, this perhaps highlights the limited utility of thrombophilia testing – although it is still common practice in young patients with unprovoked VTE.

Leslie Raffini, MD
Children’s Hospital of Philadelphia
Philadelphia, PA

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