Shakespeare is to English literature what von Willebrand disease (vWD) is to hematology: ubiquitous and oft-quoted, but well understood by relatively few. Shakespeare is likely the most assigned author for English-speaking countries’ school reading assignments. vWD, meanwhile, is the most common bleeding disorder. Everybody knows a little Shakespeare, even if they haven’t read it, and we hematologists all have a passing familiarity with vWD, even if we can’t remember the difference between 2B and 2M two days after the boards. Then there are those among us who deal with vWD daily. While everyone knows this article’s title is a play on Hamlet’s famous soliloquy, most haven’t actually read it (raise your hand if you fall into this category… it’s okay, this is a judgement-free space). Outside of the bleeding disorders community, vWD, especially the perennially less-than-straightforward cases of type 2 vWD, tends to create a good deal of diagnostic uncertainty, perplexing general hematologists and patients alike.
Even if your practice is not primarily nonmalignant hematology, you’ll have patients with a bleeding phenotype. From a purely statistical standpoint, you will more often than not be considering vWD in your diagnosis. How do you currently work these patients up? Most newly (or yet-to-be) diagnosed patients with vWD who come referred to me have had “the basics” done: von Willebrand factor (vWF) antigen and activity measurements (more on these assays to come) and multimers.
Earlier this year, Dr. Paula James co-authored the ASH ISTH NHF WFH 2021 Guidelines on the Diagnosis of von Willebrand Disease, guidelines which suggest genetic testing for distinguishing between some of the type 2 variants. These guidelines recommend the use of an algorithm that ultimately advocates genetic testing to distinguish between type 2A and type 2B vWD and suggest a role for vWF genetic testing to confirm type 2N. Specifically, these guidelines suggest genetic testing instead of low-dose ristocetin-induced platelet agglutination based on evidence that diagnostic accuracy can be limited with this assay. But is this recommendation useful if a laboratory has experience with the relevant assays and avoids pitfalls of some of the more variable assays?
I regularly hand my fellows, residents, and students in clinic a fantastic review by Drs. Luciano Baronciani and Flora Peyvandi that relies completely on biochemical assays rather than genetic testing. It’s a great teaching paper that helps trainees think through the structure of vWF and how that affects laboratory assays and clinical findings. Diagnosing vWD type 2A via biochemical assays is an elegant and rewarding process, but distinguishing some of these is difficult, because ultimately, vWF assays are notoriously variable between laboratories as has been described in detail by Dr. Emmanuel Favaloro and colleagues’ September 2021 review on the topic . Also, depending on your location, some assays needed for a biochemical diagnosis may not be easily obtainable. For example, ristocetin cofactor (RCo) assays are routinely done in many private laboratories, rather than a collagen-binding or platelet GPIbα assay, which may mean additional steps are required for a diagnosis. To address this, Dr. Favaloro presented the aforementioned excellent review that combines an algorithmic approach to diagnosis based on biochemical assays, while integrating limitations and the differential utility of different assays.
In the age of easy genetic diagnosis, are biochemical assays an academic exercise? Indeed, by the admission of one of our panelists, type 2B vWD can be an “elusive” diagnosis,1 but distinguishing type 2 von Willebrand subtypes via “traditional” assays has generous supporting literature for clinicians. Where should laboratories focus financial resources? Given that many centers may not have certain biochemical or genetic assays available in-house, should the best decision be the one that is most cost-effective or time-sensitive for the setting? In my own clinical practice, I do use genetic testing but tend to use it on a “case by case” basis. Balancing the ease of genetic testing are the complexities of genotype and phenotype relationships we learn through test results and the growing knowledge of the disorder itself.2,3 Despite these complexities, modern sequencing technology is easy and affordable enough to make it attractive as a first-line tool.4
So, in our main card event for vWD diagnosis, who will come out on top? Is it a fight? Are there two roads to the same destination of equal value? I think the real “winners” in a for-and-against discussion like this are the clinicians treating vWD. The more we move toward a standardized, accepted group of tests, whether they be biochemical, genetic, or both, the better we can diagnose and treat our patients with this most common of bleeding disorders.
At this year’s meeting, Dr. James will chair the Education Spotlight session “Genetic Testing for von Willebrand Disease” (with live Q&A taking place virtually and in-person on Monday, December 13, at 10:30 a.m. Eastern time [ET]. Additionally, the Special Education Session on ASH Clinical Practice Guidelines on von Willebrand Disease will provide updates on these guidelines and the guideline development process, also on Monday, at 4:30 p.m. ET in-person and virtually.
To return to Shakespeare, I for one am happy to have experts working toward a more reliable, standardized method to help patients meet their own “outrageous fortune” of being diagnosed with a bleeding disorder.
- Favaloro EJ. Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin? Semin Thromb Hemost. 2008;34(1):113-127.
- Swystun LL, James P. Using genetic diagnostics in hemophilia and von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2015;2015:152-159.
- Maas DPMSM, Atiq F, Blijlevens NMA, et al. Von Willebrand disease type 2M: correlation between genotype and phenotype. J Thromb Haemost. 2021; Doi: 10.1111/jth.15586.
- Batlle J, Pérez-Rodríguez A, Corrales I, et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm. Thromb Haemost. 2016;115(1):40-50.
Dr. Ellsworth indicated no relevant conflicts of interest.
