Newborn boy’s unusual bleeding leads to rare von Willebrand diagnosis
Report points to value of genetic testing in complex bleeding cases
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A newborn boy with unusual bleeding symptoms was diagnosed with a rare form of von Willebrand disease (VWD) linked to two inherited variants in the VWF gene, a U.S. case study reported.
The infant was treated off-label with Hemlibra (emicizumab-kxwh) as preventive therapy, along with antifibrinolytics and von Willebrand factor replacement treatment when needed.
“This case highlights the diagnostic and therapeutic challenges of atypical VWD presentations influenced by novel genetic variants,” the researchers wrote.
The study, “Mucosal Bleeding in a Newborn With Low Factor VIII Activity: An Unusual Combination of Type 2A and Type 2N von Willebrand Disease,” was published in Haemophilia.
Rare VWD case first looked like hemophilia A
In VWD, the body cannot properly form blood clots, leading to abnormally heavy and prolonged bleeding. It is usually caused by inherited changes affecting von Willebrand factor, a clotting protein. Uncommon presentations can bring “diagnostic and therapeutic challenges,” the researchers wrote.
This report describes the case of a newborn boy who had unusual bleeding soon after birth. At birth, he had bruising on his face and bleeding in the whites of his eyes. These were first thought to be caused by the difficult delivery. On his second day of life, he had a circumcision, but bleeding lasted longer than expected, requiring medical treatment to stop.
Because of this, he was referred to a blood specialist. Initial blood tests showed a prolonged activated partial thromboplastin time, meaning his blood was taking longer than normal to clot. He also had very low levels of factor VIII (FVIII), a protein needed for clotting. This raised suspicion for hemophilia A, a genetic bleeding disease caused by changes in the gene encoding FVIII.
Family history added more clues. His mother and maternal grandmother had heavy menstrual bleeding and frequent nosebleeds. His brother also had nosebleeds, and his father had gum bleeding as a child. This suggested a possible inherited bleeding disease. Further testing at two weeks of age showed that FVIII activity levels were still low. However, some of his symptoms, such as eye bleeding and bruising, were not typical for hemophilia A.
That led doctors to test for VWD. His von Willebrand factor (VWF), a protein that helps platelets stick together to form clots and also carries FVIII in the blood, had markedly reduced activity, while VWF protein levels were reduced to a lesser degree. This mismatch suggested VWD type 2, in which the protein is present, but does not function properly.
Genetic testing helped explain overlapping VWD features
More detailed tests at one month of age showed that VWF had a very low ability to support platelet binding and to bind to FVIII, explaining why his FVIII levels were low. Doctors also examined the structure of VWF using a test called multimer analysis, which looks at different sizes of the protein. The pattern was abnormal and did not match typical forms found in VWD, making the diagnosis more complex.
Genetic testing provided an important clue. It revealed two genetic variants in the VWF gene, each inherited from one parent. These variants are currently classified as variants of uncertain significance, but the researchers suspected they affected the protein in different ways, leading to features of both VWD type 2A, marked by abnormal VWF multimer patterns and poor platelet-binding activity, and type 2N, marked by reduced binding to FVIII. Testing of the parents helped confirm that one variant was inherited from each parent.
“Accurate diagnosis of VWD often requires a combination of family history, clinical assessment, specialized laboratory testing, and, in some cases, genetic testing. This process becomes even more challenging when genetic variants of uncertain significance involving the VWF gene are identified but have yet to be previously reported,” the researchers wrote.
Doctors started preventive treatment with Hemlibra, which helps blood clot more effectively by mimicking part of FVIII’s role in the clotting process. Hemlibra is approved to prevent or reduce bleeding in hemophilia A, but not VWD. Still, it “has been shown to be effective in severe VWD,” the researchers wrote. The baby also received antifibrinolytics, which prevent clots from breaking down, and VWF replacement treatment when needed.
“In this case report, we describe a single patient’s clinical [presentation] and molecular and genetic features … of both type 2A and type 2N VWD and highlight the important diagnostic characteristics and management,” the researchers wrote. “These findings underscore the importance of comprehensive clinical, laboratory, and genetic evaluation.”
