Contributions
Abstract: PB1813
Type: Publication Only
Background
VonWillebrand 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), which plays a major role in hemostasis. 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.
Aims
We report a case with type 3 vWD inheriting two different mutations, one from each parent, resulting in compound heterozygosity.
Methods
Array Comparative Genomic Hybridization (aCGH)/Duplication analysis was performed on our patient sample. Family was tested by PCR amplification and bi-directional DNA sequence analysis of requested exons.
Results
Our patient presented with a normal CBC and normal levels of Factor IX, XI, and XII activity. Her PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. A 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 was sent to the Blood Center of Wisconsin and demonstrated two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Subsequent analysis revealed that the patient’s 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 inherited only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations.
Conclusion
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 most 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). 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. 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 is 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. Adjuvant treatment with fibrinolytic agents has been attempted in some patients, and platelet transfusions have been administered in patients with excessive bleeding despite first-line treatment, with some success. 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 plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies, but is at high risk.
Session topic: 34. Bleeding disorders (congenital and acquired)
Keyword(s): Von Willebrand factor (vWF), Von Willebrand's disease
Abstract: PB1813
Type: Publication Only
Background
VonWillebrand 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), which plays a major role in hemostasis. 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.
Aims
We report a case with type 3 vWD inheriting two different mutations, one from each parent, resulting in compound heterozygosity.
Methods
Array Comparative Genomic Hybridization (aCGH)/Duplication analysis was performed on our patient sample. Family was tested by PCR amplification and bi-directional DNA sequence analysis of requested exons.
Results
Our patient presented with a normal CBC and normal levels of Factor IX, XI, and XII activity. Her PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. A 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 was sent to the Blood Center of Wisconsin and demonstrated two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Subsequent analysis revealed that the patient’s 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 inherited only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations.
Conclusion
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 most 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). 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. 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 is 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. Adjuvant treatment with fibrinolytic agents has been attempted in some patients, and platelet transfusions have been administered in patients with excessive bleeding despite first-line treatment, with some success. 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 plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies, but is at high risk.
Session topic: 34. Bleeding disorders (congenital and acquired)
Keyword(s): Von Willebrand factor (vWF), Von Willebrand's disease