Original Article
Diagnosis of von Willebrand disease in Argentina: a single institution experience
Abstract
Background: von Willebrand disease (VWD) is the most common autosomal bleeding disorder, mostly inherited as dominant trait. VWD is due to deficiency/abnormality of von Willebrand factor (VWF). The true prevalence of VWD is unknown, but estimated as 0.1% to 1% of the general population.
Methods: The bleeding score (BS) was used to evaluate the bleeding status of patients presenting at our institution. Laboratory analyses include: VWF:Ag, VWF:RCo, VWF:CB, multimeric pattern, VWF propeptide, Desmopressin challenge test. Genotypic analysis comprises the study of specific exons of VWF, depending on the suspected variant.
Results: We describe the main characteristics of our VWD population, including phenotypic and genotypic methods used to achieve the diagnosis. From our 2,482 patients registered, quantitative variants account for 83.2% of cases, and qualitative, 16.8% of cases. Platelet-type VWD (PT-VWD) was diagnosed in two patients and acquired von Willebrand syndrome (AVWS) in six. From quantitative variants, relative frequencies are: possible type 1, 78.7%; type 1, 14.9%; type 1S, 1.5%; type 1C, 0.4%; type 3, 1.6%. From qualitative variants: 2M, 21.9%; 2B, 10.3%; 2A, 8.4%; 2N, 3.4%; patients currently without complete diagnosis: 56%. Family history of bleeding: 64.7% of cases. Type 3, 2A and 2B VWD showed the highest major bleeding (MB) frequency. Genotypic diagnosis was reached in eight type 1C, 72 type 2M, 38 type 2B, 30 type 2A, 14 type 2N, and two PT-VWD patients. Five de novo mutations were identified among 52 families (9.61%): two mutations were associated with type 2B VWD (p.V1316M and p.S1310F), one mutation associated with type 1C (Vicenza) (p.R1205H) described in combination with p.R924Q, one deletion associated to type 1 VWD according to the ISTH VWF database (p.Pro1648fs*45) in combination with p.R1426C resulting in a 2M phenotype and one mutation related to type 2A VWD (p.Y1542D). Six patients are under prophylactic treatment due to their severe bleeding: four are type 3 VWD, one type 2M VWD, and one, the patient with p.Pro1648fs*45 and p.R1426C.
Conclusions: The wide heterogeneity of clinical symptoms and laboratory data from possible type 1 VWD implies a risk for bleeding that becomes crucial in challenging situations. In our population, type 2M was found to be more frequent than the type 2A variant. DDAVP (1-deamino-8-D-arginine vasopressin) challenge test, VWF propeptide/antigen ratio and genotypic studies are useful tools for discriminating cases representing difficult diagnoses such as type 2M versus type 1C VWD. Elevated propeptide ratio, the detection of antiphospholipid antibodies, platelet-associated antibodies or anti-VWF immunoglobulins and negative genotypic screening is useful to discriminate inherited VWD from AVWS. Genotypic testing assisted discrimination between types 2B versus platelet-type-VWD and type 2N VWD versus mild hemophilia A.
Methods: The bleeding score (BS) was used to evaluate the bleeding status of patients presenting at our institution. Laboratory analyses include: VWF:Ag, VWF:RCo, VWF:CB, multimeric pattern, VWF propeptide, Desmopressin challenge test. Genotypic analysis comprises the study of specific exons of VWF, depending on the suspected variant.
Results: We describe the main characteristics of our VWD population, including phenotypic and genotypic methods used to achieve the diagnosis. From our 2,482 patients registered, quantitative variants account for 83.2% of cases, and qualitative, 16.8% of cases. Platelet-type VWD (PT-VWD) was diagnosed in two patients and acquired von Willebrand syndrome (AVWS) in six. From quantitative variants, relative frequencies are: possible type 1, 78.7%; type 1, 14.9%; type 1S, 1.5%; type 1C, 0.4%; type 3, 1.6%. From qualitative variants: 2M, 21.9%; 2B, 10.3%; 2A, 8.4%; 2N, 3.4%; patients currently without complete diagnosis: 56%. Family history of bleeding: 64.7% of cases. Type 3, 2A and 2B VWD showed the highest major bleeding (MB) frequency. Genotypic diagnosis was reached in eight type 1C, 72 type 2M, 38 type 2B, 30 type 2A, 14 type 2N, and two PT-VWD patients. Five de novo mutations were identified among 52 families (9.61%): two mutations were associated with type 2B VWD (p.V1316M and p.S1310F), one mutation associated with type 1C (Vicenza) (p.R1205H) described in combination with p.R924Q, one deletion associated to type 1 VWD according to the ISTH VWF database (p.Pro1648fs*45) in combination with p.R1426C resulting in a 2M phenotype and one mutation related to type 2A VWD (p.Y1542D). Six patients are under prophylactic treatment due to their severe bleeding: four are type 3 VWD, one type 2M VWD, and one, the patient with p.Pro1648fs*45 and p.R1426C.
Conclusions: The wide heterogeneity of clinical symptoms and laboratory data from possible type 1 VWD implies a risk for bleeding that becomes crucial in challenging situations. In our population, type 2M was found to be more frequent than the type 2A variant. DDAVP (1-deamino-8-D-arginine vasopressin) challenge test, VWF propeptide/antigen ratio and genotypic studies are useful tools for discriminating cases representing difficult diagnoses such as type 2M versus type 1C VWD. Elevated propeptide ratio, the detection of antiphospholipid antibodies, platelet-associated antibodies or anti-VWF immunoglobulins and negative genotypic screening is useful to discriminate inherited VWD from AVWS. Genotypic testing assisted discrimination between types 2B versus platelet-type-VWD and type 2N VWD versus mild hemophilia A.
