D. Rapson - Academia.edu (original) (raw)

Papers by D. Rapson

Blood, 2005

Von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans, results from... more Von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans, results from a deficiency or abnormal functioning of von Willebrand factor (VWF). The most widely accepted estimate of VWD prevalence in the literature is 1%, which is derived from epidemiological studies performed in the USA and Italy. However, both of these studies were based on investigations of healthy, school aged children without overt bleeding symptoms. In contrast, the prevalence of symptomatic VWD has been estimated to be approximately 1 in 10,000 based on patients referred to specialized bleeding clinics. The discrepancy between these prevalence figures has not been explained and requires further investigation. This uncertainty is further complicated by a lack of consensus concerning the frequency of bleeding symptoms in the normal population. VWD can cause a range of symptoms from mild bruising to significant mucocutaneous bleeding. Such symptoms are often presented to primary care physic...

Pediatric Blood & Cancer, 2010

Journal of Parenteral and Enteral Nutrition, 2008

The American Journal of Dermatopathology, 2000

Journal of Thrombosis and Haemostasis, 2007

Journal of Thrombosis and Haemostasis, 2003

Journal of Thrombosis and Haemostasis, 2007

Background/methods: In order to better characterize the genotype-phenotype correlation in type 2M... more Background/methods: In order to better characterize the genotype-phenotype correlation in type 2M von Willebrand disease (VWD), we sequenced the coding region for the mature subunit of the von Willebrand factor (VWF) gene (exons 18-52, including exon/intron boundaries) in 16 index cases originally submitted to the Canadian Type 1 VWD Study as type 1 VWD, but reclassified as type 2M VWD on the basis of phenotype (excessive mucocutaneous bleeding and von Willebrand factor: antigen (VWF:Ag) and/or von Willebrand factor: ristocetin cofactor (VWF:RCo) between 0.05 and 0.50 IU mL -1 on at least two occasions and RCo/Ag ratio < 0.6 and no loss of high molecular weight multimers). Available family members (16 affected, 23 unaffected and six unknown) were sequenced for identified mutations. Results: We identified eight different missense mutations (R854Q, T1054M, R1315C, R1374C, R1374H, L1382P, S2179F, and T2647M) within these 16 families. We were significantly more likely to identify a VWF mutation in cases with RCo/Ag ratios < 0.50 (P < 0.05, chisquared test). Importantly, every index case with an RCo/Ag ratio < 0.40 (4/4 index cases) had a mutation identified within the A1 domain, in contrast to 1/12 cases with an RCo/Ag ratio > 0.40. Difficulties with the standardization of the VWF:RCo may be responsible for the heterogeneity in cases with RCo/Ag ratios between 0.40 and 0.60. Conclusions: The genotypephenotype correlation for cases with RCo/Ag ratios < 0.40 is clear. On the basis of our results, the phenotypic definition of type 2M VWD may need to be more stringent, and should be the subject of an international standardization initiative.

Journal of Thrombosis and Haemostasis, 2004

Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Wil... more Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Willebrand factor multimers. J Thromb Haemost 2004; 2: 1135-42. Summary. Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF) associated with an absence of highmolecular-weight multimers. In this study, sequence analysis of the VWF gene from a Type 2A VWD patient showed a novel, heterozygous T fi A transversion at nucleotide 4510, resulting in the non-conservative substitution of L1503Q in the mature VWF subunit. This substitution, which was not found in 55 unrelated normal individuals, was reproduced by in vitro site directed mutagenesis of a full-length VWF cDNA and was subsequently expressed in COS-7 cells. The corresponding recombinant mutant VWF protein was partially retained in COS-7 cells yet the full spectrum of multimers was observed, suggesting that the absence of the highest molecular weight multimers results from increased proteolysis. The recombinant mutant VWF protein was digested with the ADAMTS13 protease from VWF-depleted plasma and the aberrant VWF multimer pattern was observed. These results suggest that the L1503Q substitution induces a conformational change in the VWF protein, which increases the protein's susceptibility to proteolysis. A three-dimensional model of the A2 domain demonstrates that the L1503Q mutation and the physiological proteolytic cleavage site for ADAMTS13 (Y 1605 -M 1606 ) are localized close together in two adjacent parallel b-sheets. The mutation L1503Q does not significantly disrupt the conformation of the protein; thus the subtle loss of multimers in this patient may be due to altered interactions with the ADAMTS13 protease.

Journal of Thrombosis and Haemostasis, 2010

Journal of Thrombosis and Haemostasis, 2007

P. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and t... more P. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease. J Thromb Haemost 2008; 6: 90-6.

Journal of Thrombosis and Haemostasis, 2008

Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand d... more Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 6: 2062-6. 3 >> type 2 >> type 1 VWD (ANOVA P < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (SpearmanÕs )0.411, P < 0.001). Conclusions: The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD.

Clinical and Laboratory Haematology, 2006

Von Willebrand disease (VWD) is an inherited bleeding disorder that may be associated with signif... more Von Willebrand disease (VWD) is an inherited bleeding disorder that may be associated with significant morbidity, but is often a diagnostic challenge. While an appropriate clinical bleeding history suggests the condition, current laboratory screening investigations lack the sensitivity and specificity to confirm the diagnosis in many cases. Recently, much work has gone into characterizing the genetic mutations associated with the various subtypes of VWD. We report a case in which the diagnosis of VWD type 2B was made via genetic testing, illustrating its value as a useful diagnostic tool.

Critical Care, 2010

Although our understanding of the pathophysiology of sepsis and of subsequently derived therapeut... more Although our understanding of the pathophysiology of sepsis and of subsequently derived therapeutic approaches has advanced signifi cantly in the past, mortality of sepsis still remains unacceptably high. To improve this dilemma, diagnostic laboratory tests are urgently required that

Blood, 2007

In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of... more In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of type 1 von Willebrand disease (VWD), a large multicenter Canadian study was undertaken. We present data from the sequence analysis of the VWF gene in 123 type 1 VWD index cases and their families. We have identified putative mutations within the VWF gene in 63% (n = 78) of index cases, leaving 37% (n = 45) with no identified changes. These changes comprise 50 different putative mutations: 31 (62%) missense mutations, 8 (16%) changes involving the VWF transcriptional regulatory region, 5 (10%) small deletions/insertions, 5 (10%) splicing consensus sequence mutations, and 1 nonsense mutation. Twenty-one of the index cases had more than one putative VWF mutation identified. We were somewhat more likely to identify putative mutations in cases with lower VWF levels, and the contribution of other factors, such as ABO blood group, seems more important in milder cases. Taken as a whole, our dat...

Journal of Thrombosis and Haemostasis, 2008

Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand d... more Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 6: 2062-6. 3 >> type 2 >> type 1 VWD (ANOVA P < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (SpearmanÕs )0.411, P < 0.001). Conclusions: The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD.

Pediatric Blood & Cancer, 2010

Blood, 2005

Von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans, results from... more Von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans, results from a deficiency or abnormal functioning of von Willebrand factor (VWF). The most widely accepted estimate of VWD prevalence in the literature is 1%, which is derived from epidemiological studies performed in the USA and Italy. However, both of these studies were based on investigations of healthy, school aged children without overt bleeding symptoms. In contrast, the prevalence of symptomatic VWD has been estimated to be approximately 1 in 10,000 based on patients referred to specialized bleeding clinics. The discrepancy between these prevalence figures has not been explained and requires further investigation. This uncertainty is further complicated by a lack of consensus concerning the frequency of bleeding symptoms in the normal population. VWD can cause a range of symptoms from mild bruising to significant mucocutaneous bleeding. Such symptoms are often presented to primary care physic...

Pediatric Blood & Cancer, 2010

Journal of Parenteral and Enteral Nutrition, 2008

The American Journal of Dermatopathology, 2000

Journal of Thrombosis and Haemostasis, 2007

Journal of Thrombosis and Haemostasis, 2003

Journal of Thrombosis and Haemostasis, 2007

Background/methods: In order to better characterize the genotype-phenotype correlation in type 2M... more Background/methods: In order to better characterize the genotype-phenotype correlation in type 2M von Willebrand disease (VWD), we sequenced the coding region for the mature subunit of the von Willebrand factor (VWF) gene (exons 18-52, including exon/intron boundaries) in 16 index cases originally submitted to the Canadian Type 1 VWD Study as type 1 VWD, but reclassified as type 2M VWD on the basis of phenotype (excessive mucocutaneous bleeding and von Willebrand factor: antigen (VWF:Ag) and/or von Willebrand factor: ristocetin cofactor (VWF:RCo) between 0.05 and 0.50 IU mL -1 on at least two occasions and RCo/Ag ratio < 0.6 and no loss of high molecular weight multimers). Available family members (16 affected, 23 unaffected and six unknown) were sequenced for identified mutations. Results: We identified eight different missense mutations (R854Q, T1054M, R1315C, R1374C, R1374H, L1382P, S2179F, and T2647M) within these 16 families. We were significantly more likely to identify a VWF mutation in cases with RCo/Ag ratios < 0.50 (P < 0.05, chisquared test). Importantly, every index case with an RCo/Ag ratio < 0.40 (4/4 index cases) had a mutation identified within the A1 domain, in contrast to 1/12 cases with an RCo/Ag ratio > 0.40. Difficulties with the standardization of the VWF:RCo may be responsible for the heterogeneity in cases with RCo/Ag ratios between 0.40 and 0.60. Conclusions: The genotypephenotype correlation for cases with RCo/Ag ratios < 0.40 is clear. On the basis of our results, the phenotypic definition of type 2M VWD may need to be more stringent, and should be the subject of an international standardization initiative.

Journal of Thrombosis and Haemostasis, 2004

Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Wil... more Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Willebrand factor multimers. J Thromb Haemost 2004; 2: 1135-42. Summary. Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF) associated with an absence of highmolecular-weight multimers. In this study, sequence analysis of the VWF gene from a Type 2A VWD patient showed a novel, heterozygous T fi A transversion at nucleotide 4510, resulting in the non-conservative substitution of L1503Q in the mature VWF subunit. This substitution, which was not found in 55 unrelated normal individuals, was reproduced by in vitro site directed mutagenesis of a full-length VWF cDNA and was subsequently expressed in COS-7 cells. The corresponding recombinant mutant VWF protein was partially retained in COS-7 cells yet the full spectrum of multimers was observed, suggesting that the absence of the highest molecular weight multimers results from increased proteolysis. The recombinant mutant VWF protein was digested with the ADAMTS13 protease from VWF-depleted plasma and the aberrant VWF multimer pattern was observed. These results suggest that the L1503Q substitution induces a conformational change in the VWF protein, which increases the protein's susceptibility to proteolysis. A three-dimensional model of the A2 domain demonstrates that the L1503Q mutation and the physiological proteolytic cleavage site for ADAMTS13 (Y 1605 -M 1606 ) are localized close together in two adjacent parallel b-sheets. The mutation L1503Q does not significantly disrupt the conformation of the protein; thus the subtle loss of multimers in this patient may be due to altered interactions with the ADAMTS13 protease.

Journal of Thrombosis and Haemostasis, 2010

Journal of Thrombosis and Haemostasis, 2007

P. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and t... more P. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease. J Thromb Haemost 2008; 6: 90-6.

Journal of Thrombosis and Haemostasis, 2008

Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand d... more Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 6: 2062-6. 3 >> type 2 >> type 1 VWD (ANOVA P < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (SpearmanÕs )0.411, P < 0.001). Conclusions: The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD.

Clinical and Laboratory Haematology, 2006

Von Willebrand disease (VWD) is an inherited bleeding disorder that may be associated with signif... more Von Willebrand disease (VWD) is an inherited bleeding disorder that may be associated with significant morbidity, but is often a diagnostic challenge. While an appropriate clinical bleeding history suggests the condition, current laboratory screening investigations lack the sensitivity and specificity to confirm the diagnosis in many cases. Recently, much work has gone into characterizing the genetic mutations associated with the various subtypes of VWD. We report a case in which the diagnosis of VWD type 2B was made via genetic testing, illustrating its value as a useful diagnostic tool.

Critical Care, 2010

Although our understanding of the pathophysiology of sepsis and of subsequently derived therapeut... more Although our understanding of the pathophysiology of sepsis and of subsequently derived therapeutic approaches has advanced signifi cantly in the past, mortality of sepsis still remains unacceptably high. To improve this dilemma, diagnostic laboratory tests are urgently required that

Blood, 2007

In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of... more In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of type 1 von Willebrand disease (VWD), a large multicenter Canadian study was undertaken. We present data from the sequence analysis of the VWF gene in 123 type 1 VWD index cases and their families. We have identified putative mutations within the VWF gene in 63% (n = 78) of index cases, leaving 37% (n = 45) with no identified changes. These changes comprise 50 different putative mutations: 31 (62%) missense mutations, 8 (16%) changes involving the VWF transcriptional regulatory region, 5 (10%) small deletions/insertions, 5 (10%) splicing consensus sequence mutations, and 1 nonsense mutation. Twenty-one of the index cases had more than one putative VWF mutation identified. We were somewhat more likely to identify putative mutations in cases with lower VWF levels, and the contribution of other factors, such as ABO blood group, seems more important in milder cases. Taken as a whole, our dat...

Journal of Thrombosis and Haemostasis, 2008

Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand d... more Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 6: 2062-6. 3 >> type 2 >> type 1 VWD (ANOVA P < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (SpearmanÕs )0.411, P < 0.001). Conclusions: The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD.

Pediatric Blood & Cancer, 2010