Von Willebrand Disease: History and Discovery

In 1926 the Finnish physician Erik Adolf von Willebrand described a hereditary bleeding tendency in a large family from the remote island of Föglö in the Åland archipelago, in the Baltic Sea. His index patient was a five-year-old girl named Hjördis, several of whose relatives had bled to death. Von Willebrand recognised that the disorder was not classic hemophilia: it struck girls and boys alike, the bleeding came chiefly from the mucous membranes — nosebleeds, bleeding gums, heavy menstrual loss — rather than from the joints, and the bleeding-time test was strikingly prolonged. He called it hereditary pseudohemophilia. The protein at fault, von Willebrand factor, would not be identified for almost half a century. Today the condition that bears his name is recognised as the most common inherited bleeding disorder in the world.

Table of Contents

  1. The Åland Islands and the Family from Föglö
  2. Hjördis and the 1926 Description
  3. Why It Was Not Hemophilia
  4. “Hereditary Pseudohemophilia” and von Willebrand’s Hypothesis
  5. From Pseudohemophilia to an Eponym
  6. The Factor VIII Connection: Nilsson and the 1950s
  7. Identifying von Willebrand Factor in the 1970s
  8. Desmopressin, Concentrates, and Modern Care
  9. Legacy: The Most Common Inherited Bleeding Disorder
  10. Research Papers and References
  11. Connections

The Åland Islands and the Family from Föglö

The story of von Willebrand disease begins not in a great teaching hospital but in a scatter of small islands. The Åland Islands are an archipelago in the northern Baltic Sea, lying between Sweden and Finland at the mouth of the Gulf of Bothnia; they are Swedish-speaking and, then as now, sparsely populated. On one of those islands, Föglö, lived an extended family in which a tendency to bleed had been passed down for at least three generations. Because the island communities were small and comparatively isolated, the same families intermarried over time, and an inherited trait could persist and concentrate in a way that made its pattern unusually easy to read across a pedigree — an accident of geography that would prove scientifically priceless.

The bleeding in this family was not a minor inconvenience. According to von Willebrand’s own account and the historical literature that has since re-examined it, several relatives had bled to death; deaths from uncontrollable bleeding were recorded across the generations, and a striking feature was that the fatal bleeders included women and girls. In an era before blood transfusion was routine, before clotting factors could be measured, and before any specific treatment existed, a severe bleeding disorder of this kind was genuinely life-threatening, particularly around childbirth, menstruation, tooth extraction, and childhood injuries.

It was this family — large, well-documented, and visibly affected on both the male and the female side — that came to the attention of Erik Adolf von Willebrand and gave him the natural experiment from which a new disease would be defined.

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Hjördis and the 1926 Description

Erik Adolf von Willebrand (1 February 1870 – 12 September 1949) was a Finnish physician who spent his career in Helsinki, associated with the University of Helsinki and the city’s Deaconess Hospital. In April 1924 a five-year-old girl from Föglö named Hjördis (Hjördis Sundblom in the historical record) was brought to his attention because of her bleeding tendency. She was one of a large sibling group, and several of her brothers and sisters had already died of bleeding. Rather than treating her case in isolation, von Willebrand did something that defined the work: he reconstructed the entire family pedigree.

Working from Helsinki — with the help of a local schoolteacher on the islands, since he did not travel to Föglö himself — he mapped the bleeding tendency through three previous generations and across both sides of Hjördis’s family. He examined dozens of relatives. In the cohort he analysed, roughly sixteen of thirty-five women and seven of thirty-one men were affected to some degree, and the known deaths from bleeding were predominantly among the women. He published these findings in 1926, in Swedish, under the title “Hereditär pseudohemofili” (Hereditary Pseudohemophilia) in Finska Läkaresällskapets Handlingar, the proceedings of the Finnish Medical Society. The paper was later translated into German and, much later, into English, carrying the observation out of a regional Swedish-language journal and into the international hematology literature.

What made the 1926 paper a landmark was not a single dramatic experiment but the careful synthesis of clinical observation and family genetics. Von Willebrand had taken a cluster of bleeding deaths on a Baltic island and shown that they represented a single, heritable, internally consistent disorder with a recognisable pattern — one that did not fit the bleeding disease medicine already knew.

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Why It Was Not Hemophilia

By the 1920s, classic hemophilia was a recognised entity with well-known features: it affected boys and men almost exclusively, was transmitted through unaffected female carriers in the now-familiar X-linked recessive pattern, and produced deep bleeding into joints and muscles. The bleeding tendency in the Föglö family broke that mould in several ways at once, and von Willebrand catalogued the differences carefully.

First, the disorder affected both sexes — indeed women and girls appeared to be affected at least as often as men, and they made up the fatal cases. From this von Willebrand inferred that the inheritance was dominant rather than recessive, and clearly not the sex-linked pattern of hemophilia. (In modern terms most forms of von Willebrand disease are inherited in an autosomal manner, the common type 1 typically as an autosomal dominant trait; the precise genetics are more layered than a single rule, but von Willebrand’s core insight — that this was not the X-linked disease of hemophilia — was correct.) Second, the character of the bleeding was different: instead of the deep joint and muscle bleeds of hemophilia, these patients bled from the mucous membranes — recurrent nosebleeds, bleeding from the gums, bleeding after minor cuts and tooth extraction, and, in girls and women, heavy and sometimes dangerous menstrual bleeding.

Third, the laboratory picture differed. The clotting time — the test that is characteristically prolonged in hemophilia — was essentially normal in these patients, yet the bleeding time (the time a small standardised skin wound takes to stop bleeding) was markedly prolonged. The platelet count was normal or only slightly reduced. This combination — normal clotting time but grossly abnormal bleeding time — pointed away from the coagulation defect of hemophilia and toward a problem in the earliest, platelet-and-vessel phase of stopping a bleed. It is precisely the signature that, decades later, would be explained by deficiency of von Willebrand factor.

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“Hereditary Pseudohemophilia” and von Willebrand’s Hypothesis

The name von Willebrand chose — hereditary pseudohemophilia — captured exactly what he had found: an inherited bleeding disease that resembled hemophilia (the “pseudo”) but was demonstrably a different illness. The label was descriptive and deliberately cautious; he was naming a clinical syndrome, not claiming to know its cause.

As for the cause, von Willebrand offered a hypothesis, and it is important to mark it as such. He did not — and with the tools of 1926 could not — identify the missing protein that we now know is responsible. Instead he proposed a dual defect: that the disorder arose from a combination of abnormal platelet function and a defect in the walls of the small blood vessels (the capillaries), acting together to impair the first plug that normally seals a wound. In his own framing the pathogenesis reflected a co-operation between disturbed thrombocyte (platelet) function and a general lesion of the capillary walls. This was an intelligent inference from a prolonged bleeding time with normal clotting — but it was a model, not a molecule, and it would later be superseded by the discovery of a specific plasma protein deficiency.

That distinction — between von Willebrand’s accurate clinical and genetic description in 1926 and the much later molecular discovery of the responsible factor — is the central thread of this disease’s history. Von Willebrand defined and delimited the illness; others, working decades afterward, found the cause.

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From Pseudohemophilia to an Eponym

The disease did not acquire von Willebrand’s name immediately, and along the way it picked up several other labels. In the early 1930s von Willebrand collaborated with the German hematologist Rudolf Jürgens; together they studied the disorder further and, around 1933, re-described it under the name constitutional thrombopathy, emphasising the platelet-function component of von Willebrand’s original dual-defect idea. For a time the combined eponym von Willebrand–Jürgens syndrome was also used.

Over the following years the simpler eponym took hold. The historical literature places the general adoption of the name von Willebrand disease between roughly the late 1930s and the early 1940s, as the condition became recognised internationally and as the limitations of the earlier descriptive names became apparent. The shift to an eponym was fitting: no single mechanistic name could yet capture the disorder, because its mechanism was still unknown, but the family of patients von Willebrand had so carefully documented gave the disease a clear and stable identity.

It is worth noting that von Willebrand died in 1949, before the protein that bears his name was isolated. He defined the disease and lived to see it named after him, but not to see it explained.

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The Factor VIII Connection: Nilsson and the 1950s

The first decisive step toward the modern understanding came in the 1950s, and again it came from Scandinavia. The Swedish physician Inga Marie Nilsson and her colleagues in Malmö studied patients with von Willebrand’s disorder and made a pivotal observation: their plasma was deficient in a factor related to the antihemophilic activity — what we now call Factor VIII — and, crucially, their bleeding and their prolonged bleeding time could be corrected by infusing a fraction of normal plasma. Importantly, that corrective fraction worked even when it had been prepared from the plasma of patients with classic hemophilia, which told the investigators that the substance missing in von Willebrand disease was not the same as the substance missing in hemophilia A, even though the two were related.

This was a profound clue. It tied von Willebrand’s mucosal-bleeding, prolonged-bleeding-time disorder to the coagulation system in a specific, measurable way, and it hinted that there were really two distinct entities bound up in the Factor VIII story: the clotting factor itself, and some companion substance, lacking in von Willebrand disease, on which normal hemostasis also depended. Nilsson’s work in the 1950s reframed the disease from a purely descriptive syndrome into a defined plasma-factor deficiency — and set the stage for the discovery of the protein in the 1970s. (Decades later, Nilsson would also write an authoritative commentary revisiting von Willebrand’s original 1926 paper, helping bring his Swedish-language work to a modern audience.)

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Identifying von Willebrand Factor in the 1970s

The missing piece — the molecule itself — was characterised in the 1970s. During that decade investigators succeeded in purifying the relevant protein and showing, with the immunological and gel-electrophoresis methods then becoming available, that the “Factor VIII” activity measured in plasma actually comprised two physically distinct components: the coagulation factor responsible for hemophilia A, and a separate, very large multimeric protein that is deficient or defective in von Willebrand disease. That second protein was named von Willebrand factor (VWF). A frequently cited example of this work is the 1975 study by Gralnick and colleagues in the journal Blood, which identified and characterised the von Willebrand protein and showed it to be reduced or abnormal in patients with the disease.

With the protein in hand, the disease finally made mechanistic sense, and von Willebrand’s old clinical observations clicked into place. Von Willebrand factor turns out to do two jobs. First, it is the molecular “glue” that lets platelets stick to the wall of an injured blood vessel and to one another, especially under the high shear forces of small arteries — which is exactly why a deficiency produces a prolonged bleeding time and mucosal-surface bleeding while the deeper coagulation cascade is intact. Second, VWF acts as the carrier protein for Factor VIII in the circulation, binding it and protecting it from premature breakdown; when VWF is low, Factor VIII levels fall too, which is why severe von Willebrand disease can look partly hemophilia-like in the laboratory and why the two disorders were entangled for so long.

The picture sharpened further in later decades — the human VWF gene was cloned in the mid-1980s and a modern classification into types 1, 2, and 3 was developed — but the conceptual breakthrough that explained von Willebrand’s 1926 family was the 1970s recognition of VWF as a protein in its own right, distinct from Factor VIII.

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Desmopressin, Concentrates, and Modern Care

For most of the disease’s history there was no specific treatment; care meant local measures, avoidance of injury, and — once it became available — transfusion of plasma or plasma fractions to replace the missing factor. Two developments transformed everyday management.

The first was desmopressin (DDAVP), a synthetic analogue of the natural hormone vasopressin, which came into use for bleeding disorders from the late 1970s (a foundational clinical report appeared in 1977). Desmopressin does not contain von Willebrand factor; instead it triggers the body’s own cells lining the blood vessels to release stored VWF (and Factor VIII) into the bloodstream, raising their levels several-fold for a number of hours. For patients with milder, type 1 disease this is often enough to cover dental work, minor surgery, and many bleeds — without any blood product — which made it an inexpensive, convenient, and widely used first-line option. (It does not help everyone: patients whose VWF is structurally abnormal or essentially absent need a different approach.)

The second development was the availability of von Willebrand factor concentrates — purified products, derived from plasma or made by recombinant technology, that supply functional VWF (often together with Factor VIII) directly. These are used when desmopressin is unsuitable or insufficient: in the more severe forms of the disease, for major surgery, and for serious bleeding. Together, desmopressin and VWF concentrates mean that a disorder which once killed children and women on a Baltic island is now, for the great majority of patients, a manageable condition compatible with a normal life.

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Legacy: The Most Common Inherited Bleeding Disorder

One of the most striking facts about von Willebrand disease is how common it turned out to be. Far from a rare curiosity confined to one island family, it is now recognised as the most common inherited bleeding disorder in humans. Because many people have only a mild form — easy bruising, frequent nosebleeds, heavy menstrual periods, or excessive bleeding after surgery or childbirth — a great many cases historically went unrecognised or were dismissed as “just bruising easily,” and milder disease still often goes undiagnosed. Von Willebrand had, in effect, identified a widespread human condition by studying its severe, concentrated expression in a single isolated kindred.

That recognition carries a quietly important public-health message, especially for girls and women: heavy menstrual bleeding, bleeding that is hard to stop after dental or surgical procedures, and frequent nosebleeds can be signs of an inherited bleeding disorder that is treatable once identified. The female predominance among the fatal bleeders in von Willebrand’s original family was not a coincidence — it reflected the toll that mucosal and menstrual bleeding can take in a condition that was, for them, untreated.

The arc of this history is a model of how a disease comes to be understood. A careful physician on the edge of the Baltic took a cluster of bleeding deaths in one family, recognised that it was something new, described its clinical and genetic features accurately, and named it honestly as a hemophilia-like but distinct disorder — proposing a mechanism only as a hypothesis, knowing he could not prove it. Decades later, others traced the disorder to a deficiency of Factor VIII–related activity, then isolated the responsible protein and named it for him. The result is that an inherited bleeding disorder, once a death sentence for some, is today common, diagnosable, and treatable — a direct line from Hjördis of Föglö to the modern hematology clinic.

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Research Papers and References

The references below combine peer-reviewed reviews and historical commentaries on von Willebrand disease with curated PubMed topic-search links into the historical and clinical literature. Von Willebrand’s original 1926 paper (“Hereditär pseudohemofili,” Finska Läkaresällskapets Handlingar) is named in the article as a historical primary source. Direct DOI and PMID links are given only where the identity of the source is established; broader themes are linked as PubMed searches. Each external link opens at the cited publisher or at PubMed (National Library of Medicine) in a new tab.

  1. Nilsson IM. Commentary to Erik von Willebrand’s original paper from 1926 ‘Hereditär pseudohemofili’. Haemophilia. 1999;5(3):220–221. — doi:10.1046/j.1365-2516.1999.0320a.x · PMID 10444292
  2. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annual Review of Biochemistry. 1998;67:395–424. — doi:10.1146/annurev.biochem.67.1.395 · PMID 9759493
  3. Gralnick HR, Coller BS, et al. Studies of the human factor VIII/von Willebrand’s factor protein. II. Identification and characterization of the von Willebrand protein. Blood. 1975;46(3):417–430. — PMID 1080062
  4. Historical perspective on von Willebrand disease — PubMed: von Willebrand disease history, Åland Islands
  5. What can historical literature on von Willebrand disease teach us? — PubMed: historical literature on von Willebrand disease
  6. Erik von Willebrand — the physician and his landmark contribution — PubMed: Erik von Willebrand, landmark contribution
  7. Inga Marie Nilsson and the Factor VIII / von Willebrand factor connection (1950s) — PubMed: Nilsson, von Willebrand disease and Factor VIII
  8. von Willebrand factor as the carrier of Factor VIII — PubMed: von Willebrand factor as Factor VIII carrier
  9. Cloning of the human VWF gene and molecular genetics — PubMed: VWF gene cloning and molecular genetics
  10. Classification of von Willebrand disease (types 1, 2, 3) — PubMed: classification of von Willebrand disease
  11. Desmopressin (DDAVP) in von Willebrand disease — PubMed: desmopressin (DDAVP) in von Willebrand disease
  12. von Willebrand factor concentrates and replacement therapy — PubMed: VWF concentrates and replacement therapy
  13. von Willebrand disease as the most common inherited bleeding disorder — epidemiology — PubMed: epidemiology of von Willebrand disease
  14. von Willebrand disease, heavy menstrual bleeding, and women — PubMed: von Willebrand disease and heavy menstrual bleeding

External Authoritative Resources

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Connections

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