A Unique Case of Type 3 Von Willebrand Disease

Abstract

Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder worldwide. Genetic mutations in the von Willebrand gene may result in either quantitative (Types 1 and 3 vWD) or qualitative defects (Type 2 vWD) of von Willebrand Factor (vWF). Type 3 is the rarest and most severe form of vWD, resulting in a virtual absence of vWF. Type 3 vWD follows autosomal recessive inheritance and is most often reported in patients who are homozygous for the same gene mutation. We report a patient with type 3 vWD who inherited two different mutations, one from each parent, resulting in compound heterozygosity. Case: Our patient, now a 2 year old female, initially presented with prolonged bleeding lasting approximately 5 hours at the injection site of her 2 month immunizations. Labs on initial presentation showed a normal WBC count, hemoglobin, hematocrit, and platelet count, with normal levels of Factor IX, XI, and XII activity. PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. Von Willebrand panel showed markedly decreased Factor VIII (2%), vWF antigen (6%), and vWF activity (8%). VWF multimers were absent, consistent with a diagnosis of type 3 vWD. VWF gene sequence analysis showed two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Her parents, both 27 years old and with no history of abnormal bleeding, are non-consanguineous. Analysis of parents for vWD revealed that mother is heterozygous for the c2345delC variant and the patient's father is heterozygous for the deletion within exon 6 of the VWF gene. The patient's older sibling who is now 4 years old developed unusual petechiae and bruising after an altercation at school, his testing was positive for only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations. Our patient has subsequently suffered recurrent episodes of bruising, gingival bleeding, and poor tissue healing and currently requires replacement therapy (prophylaxis) with Humate-P three times each week and additionally as needed. Discussion: Type 3 vWD is quite rare, with a prevalence ranging from 0.1-5.3 per million. Our case is especially interesting due to the unique inheritance pattern resulting in our patient's type 3 vWD phenotype. Type 3 vWD cases are often described in patients homozygous for a mutation in the VWF gene, frequently as a result of consanguinity. Our patient inherited a unique variant from each parent, resulting in heterozygous expression of two defective VWF alleles (compound heterozygosity). Our patient's maternally inherited defect c2435delC in exon 18 is the variant found in the original vWD family described by Dr. Erik von Willebrand in 1926. Less is understood about the paternally inherited defect of a deletion in exon 6 of VWF. In our patient's family, because each parent is heterozygous for a mutation in the VWF gene, future children have a 75% chance of inheriting at least one mutation, and a 25% chance of inheriting both mutations, leading to Type 3 vWD. Type 3 vWD patients have impaired endogenous synthesis of functional vWF, thus therapies such as desmopressin, used in other types of vWD to stimulate secretion of endogenous vWF, are ineffective. Instead, first-line treatment in Type 3 is replacement therapy with Humate-P as needed during bleeding episodes and/or as prophylaxis. Humate P is VWF/FVIII concentrate obtained from pooled human plasma from many carefully screened plasma donors and contains the clotting proteins VWF and FVIII. Humate-P has a VWF:FVIII ratio of approximately 2.4:1. Complications of therapy include the rare development of anti-vWF alloantibodies, which most often occurs in patients with partial or complete VWF gene deletions. Our patient has received aminocaproic acid for minimal bleeding episodes and due to her severe intensity of disease and age of increased risk of injuries had received plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies yet, but is at high risk. The rWVF (recombinant von Willebrand factor) offers new perspective in treatment of vWD more so with type 3 disease. It is a homogenous protein synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line, retains its intact multimer pattern because it is never exposed to proteases(ADAMTS13) which can degrade it. The rVWF is currently in phase 3 clinical trials Disclosures No relevant conflicts of interest to declare.

Genetic Alterations, DNA Methylation, Alloantibodies and Phenotypic Heterogeneity in Type III von Willebrand Disease

“…Type III vWD is considered the most severe form of von Willebrand Disease. Studies conducted in different regions of the world have shown different mutations [ 8 , 9 , 10 , 11 ]. Scarce data is available regarding the Pakistani Population.…”

“…The gene of VWF is located on chromosome 12p having 52 exons encoding a protein of 2813 amino acids [ 7 ]. Worldwide studies have revealed that mutations are spread throughout the entire span of genes and few studies have reported that mutations in certain sites are more prevalent in a particular population [ 8 , 9 , 10 , 11 ]. In addition to the inherited form, several other forms of the disease have been reported, including autoantibodies against VWF and conditions that may cause rapid degradation and clearance of VWF and adsorption of VWF on malignant cells.…”

Novel gene mutation causing type 3 Von Willebrand disease: a case report and review of literature

“…More recently, even compound heterozygous inheritance has been identified. 5 Epidemiological data predominantly from western literature estimates a prevalence of 0.1-5 per million. 6 Trasi et al postulated that type 3 patients are more numerous in India owing to a high rate of consanguineous marriages in certain communities and an underdiagnosis of milder variants.…”

von Willebrand disease: A guide for the internist

“…Due to their lack of VWF, these patients have low factor VIII levels because factor VIII is not being stabilized in plasma by VWF. 19 Type 2: Defective VWF variants In contrast to patients with type 1, type 1C, or type 3 VWD, those with type 2 have normal levels of VWF. However, their VWF has a qualitative defect and does not function as it should.…”