The Finnish physician Erik Adolf von Willebrand (1870-1949) practiced a variety of sub-specialistic and specialistic fields of medicine – from internal medicine, physical therapy, and balneology to the understanding of metabolic disorders, such as diabetes. His greatest contribution, however, was done in the field of hematology and coagulation and resulted with a disease and a factor named after him. What exactly is von Willebrand factor and how was it discovered?
Helsinki, April 1924. A five-year-old girl Hjordis Sundblom, accompanied by her parents, was brought to the clinic of Erik von Willebrand because of a history of severe recurrent mucosal hemorrhages.
A checkup confirmed that she was healthy, lucid and had a satisfactory nutritional status. In addition, there were no signs of abnormalities other than small, scattered hematomas. Blood analysis confirmed the presence of mild anemia (Hb 108 g/L) and mild thrombocytopenia (140×109/L). Blood cell count was normal, as were the coagulation time and clot retraction. Using the Duke method, which is commonly used to determine the time required to stop earlobe bleeding, an unexpectedly long bleeding time of two hours was noted. The result of a test performed with a tourniquet (a test used to determine a patient’s susceptibility to bleeding, i.e. an assay to determine the fragility of the capillary walls) was very positive.
Initially, von Willebrand thought that the cause of Hjordis’ disorder was a dysfunction of her platelets, associated with defunct capillary walls. The hereditary characteristics of this disease – in addition to Hjordis’ deceased older sisters and the fact that her parents had informed von Willebrand of the occurrence of the same symptoms in their male and female cousins – prompted him to investigate more thoroughly.
Von Willebrand published a first paper on the mysterious disease
In February of 1926, nearly two years after first encountering Hjordis’ case, von Willebrand published a first paper on the newly discovered disease. He characterized the disease and distinguished it from ‘’actual’’ hemophilia and purpuric trombopathy.
He examined and described 66 individuals who belonged to the the two blood-related families, one of whom Hjordis’ herself was a member. Of those 66 individuals spanning four generations, as many as 23 exhibited symptoms belonging to the disease under study. The analysis confirmed the existence of autosomal dominant inheritance and the existence of recessive type of this illness was confirmed later on.
The same symptoms were found in Hjordis’ closer cousins, with whom Hjordis shared the same maternal grandmother who died during childbirth due to constant bleeding. The same symptoms were not found in the three of Hjordis’ ten siblings.
Owing to the thorough work and efforts in researching the disorder conducted on the family from Foglo, on the island of Aland – by the end of 1930s and the beginning of 1940s this disease was named after the researcher – von Willebrand disease.
Von Willebrand factor
In 1953, three laboratories spotted the absence of the factor VIII (FVIII) in certain patients suffering from von Willebrand disease. In 1972, scientists Owen and Wagner concluded that the antihemophilic globulin consisted of FVIII and a larger multimeric glycoprotein, later named von Willebrand factor. Von Willebrand factor (denoted later as VWF) is crucial in shielding the factor VIII from a rapid proteolytic inactivation, for transporting said factor through blood circulation, and for platelet clot formation and hemostasis by binding platelets to the exposed subendothelium. VWF plays a key role in the pathogenesis of von Willebrand disease – the absence of this particular plasmatic protein leads to the severe form of the disease, whereas the milder, autosomally inherited types are characterized by the abnormal VWF or with the lack of VWF (decreased concentration).
The first line of treatment for von Willebrand disease type 1 is desmopressin – a synthetic analogue of vasopressin that stimulates the synthesis of VWF, whereas the transfusion of FVIII and VWF concentrates is applied in the cases where desmopressin therapy fails. Antifibrinolytics are also administered before and/or after surgery in order to slow down the degradation of blood clots, as well as contraceptives that reduce menstrual bleeding – estrogen leads to increased levels of the factor VIII and VWF.
The outcome of Hjordis’ disease
Following the diagnosis, Hjordis had several life-threatening hemorrhages from the nose and lips, bleedings after a tooth removal and joint bleeding. Hjordis Sundblom died at the age of fourteen due to persistent bleeding during her fourth menstrual period.
Translated by Dominik Šutalo
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