LETTERS TO THE EDITORS
FVIII:C levels. Evaluation of bleeding symptoms is an essential aspect of the study. The BAT used is not validated for evaluating bleeding tendency among haemophilia carriers, which may be a limitation of the study. The BAT has, however, been used in several publications to rate and compare the severity and frequency of bleeding symptoms among individuals with a certain diagnosis [10]. Another limitation of the study may be the lack of use of CTI. However, there are reports suggesting that CTI addition is only beneficial for thrombin generation triggered with TF concentrations below 0.5 pM [5,11]. We speculate that carriers might lack the ability to mobilize FVIII from depots in situations that challenge the haemostatic system, such as trauma and surgery. In this study, blood was not sampled during such situations, which might have contributed to the outcome. Inter-individual variations in other clotting factor levels, platelet function, fibrinolytic activity or endothelial vessel wall components might also contribute to variation in clinical pheno-
References 1 Plug I, Mauser-Bunschoten EP, BrockerVriends AH et al. Bleeding in carriers of hemophilia. Blood 2006; 108: 52–6. 2 Olsson A, Hellgren M, Berntorp E, Ljung R, Baghaei F. Clotting factor level is not a good predictor of bleeding in carriers of haemophilia A and B. Blood Coagul Fibrinolysis 2014; 25: 471–5. 3 Dargaud Y, Beguin S, Lienhart A et al. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost 2005; 93: 475–80. 4 van Veen JJ, Gatt A, Bowyer AE, Cooper PC, Kitchen S, Makris M. Calibrated automated thrombin generation and modified thromboelastometry in haemophilia A. Thromb Res 2009; 123: 895–901.
e113
type among carriers and explain the difficulty in demonstrating that TGA is a useful tool in this setting. In conclusion, the TGA results did not differ between carriers of haemophilia A with and without bleeding tendency. Our results suggest that TGA may not be a suitable test to predict bleeding risk among carriers of moderate and severe haemophilia A.
Authorship contribution A Olsson performed the research, designed the research study, analysed data and wrote the article. M Hellgren and M Holmstr€ om analysed data and critically reviewed the paper. E Berntorp and F Baghaei designed the study, analysed data and critically reviewed the paper.
Disclosures This research was supported by grants from Bayer Healthcare (AO) and grants from Lund University/Region Sk ane (EB).
5 Santagostino E, Mancuso ME, Tripodi A et al. Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile. J Thromb Haemost 2010; 8: 737–43. 6 Bowman M, Mundell G, Grabell J et al. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 6: 2062–6. 7 Hemker HC, Giesen P, Al Dieri R et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4–15. 8 Trossaert M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay
to assess the bleeding phenotype. J Thromb Haemost 2008; 6: 486–93. 9 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17: 41–4. 10 Rodeghiero F, Tosetto A, Abshire T et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8: 2063–5. 11 Spronk HM, Dielis AW, Panova-Noeva M et al. Monitoring thrombin generation: is addition of corn trypsin inhibitor needed? Thromb Haemost 2009; 101: 1156–62.
Is it congenital or acquired von Willebrands disease? M . A . S A I F , * J . T H A C H I L , * R . B R O W N , * B . W . B I G G E R , † R . F . W Y N N , † M . N A S H * and C. R. HAY* *Department of Haematology; and †Department of Paediatric Haematology Manchester Royal Infirmary, Manchester, UK
Correspondence: Jecko Thachil, Department of Haematology, Manchester Royal Infirmary, Oxford Road, M13 9WL Manchester, UK. Tel.: 0044 161 276 4812; fax: 0044 161 276 8085; e-mail: [email protected] Accepted after revision 19 October 2014 DOI: 10.1111/hae.12588 © 2014 John Wiley & Sons Ltd
Acquired von Willebrand disease (VWD) is a rare bleeding disorder which usually presents late in life with no significant previous or family history of bleeding. It is frequently unrecognized or is misdiagnosed as inherited VWD. Although late onset presentation with bleeding and negative family history should prompt the suspicion of this condition, type 1 VWD Haemophilia (2015), 21, e70--e121
e114
LETTERS TO THE EDITORS
can be asymptomatic for decades and may lack family history because of low penetrance. Also inherited and acquired VWD could be present coincidentally. Very often, the diagnosis of acquired VWD is suspected in the setting of bleeding which develops in conditions like autoimmune diseases, myeloproliferative disorders or severe aortic stenosis [1]. This report describes the difficulty in making the diagnosis of acquired VWD in the absence of well-recognized associations. A 91-year-old lady presented with haemoglobin of 40 g L1 and a history of melaena. She had a previously established diagnosis of type 2A VWD, following diagnostic work up for extensive bleeding after tooth extraction, when she was 71 years. This included prolonged bleeding time (>15 min), reduced VWF:Rco (14 IU dL1) and VWF:Ag (41 IU dL1) and absence of high molecular weight multimers. She had an excellent clinical and laboratory response to the VW replacement product, Haemate-P at the time. Prior to her initial presentation with gum bleeding, she had significant haemostatic challenges in the form
Table 1. Response to Haemate-P previous to and during the last admission. Factor VIII 41
Baseline at diagnosis
Response to Haemate-P 1000 IU twice daily (after diagnosis) Day 1 Pre dose levels 47 Post dose levels 58 Day 7 Pre dose levels 67 Post dose levels 104 Day 8 Pre dose levels 89 Post dose levels 149 Pharmacokinetic study (last admission) Pre dose (Haemate-P 2000 IU) 70 Post dose 30 min 105 1h 105 2h 98 4h 92 6h 92
(a)
VWF:RCo 6
13 58 39 132 67 158 1 : 512 dilution) to von Willebrand factor (VWF) in the patient plasma. The absorbance values from negative control (normal plasma from O Rhesus positive individual) and plasma with human IgG anti-IDUA antibodies is also shown in the figure confirming the specificity of the assay to VWF. (b) Shows no difference in absorbance between negative control, patient plasma and plasma with human IgG anti-IDUA antibodies.
Haemophilia (2015), 21, e70--e121
© 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
recognized candidate VWF mutation, while multiplex ligation-dependent probe amplification assay also did not identify any VWD-specific gene mutation. Unfortunately, the renal function continued to deteriorate despite supportive measures and patient died due to acute renal failure. This manuscript describes an unusual presentation of VWD where a patient presenting late in life with a history of bleeding is diagnosed with type 2A VWD based on the excellent clinical response to VWF replacement therapy. Although acquired VWD is more common in this context an excellent recovery to Haemate-P is uncommon in this condition. However, subsequent presentation and development of suspected inhibitors to Haemate-P, previously unreported for this subtype, lead to a re-evaluation of the initial diagnosis. The development of inhibitors is reported in response to a large number of recombinant human proteins [2]. A number of factors such as impurities, aggregation of particles, dose, route and frequency of treatment and presence of residual protein (sometimes referred to as cross reactive immunologic material or CRIM) are considered to influence the development of inhibitors [2,3]. Absence of CRIM, results in a higher incidence of alloimmune response [4] compared to those patients who have had some residual functional or dysfunctional protein which the immune system becomes tolerant to. The presence of IgG antibodies to VWF in our patient, confirms the presence of inhibitory immune response to replaced Haemate-P. However, it is extremely unlikely that a patient with-type 2A VWD, with approximately 10% baseline VWF:RiCo could have developed an alloimmune response. Also, the absence of a causative
References 1 Rinder MR, Richard RE, Rinder HM. Acquired von Willebrand’s disease: a concise review. Am J Hematol 1997; 54: 139–45. 2 Porter S. Human immune response to recombinant human proteins. J Pharm Sci 2001; 90: 1–11. 3 Richards SM. Immunologic considerations for enzyme replacement therapy in the treat-
© 2014 John Wiley & Sons Ltd
e115
VWF gene mutation, makes a diagnosis of inherited type 2A VWD very unlikely [5]. It can, therefore, be concluded that the acquired VWD was responsible for a phenotype resembling inherited type 2A VWD in this patient despite adequate recovery of VWF:RCo post Haemate-P infusion. It is possible that the low-titre auto-immune antibodies in patient plasma at presentation were overcome by the high dose of Haemate-P and failed to inhibit the infused product in vivo, resulting in satisfactory VWF:RCo recovery. A similar phenomenon has been reported in enzyme replacement therapy (ERT)-treated patients with Mucopolysaccharidosis where very low-titre antibodies in some patients did not show any functional inhibition of replaced therapy in contrast to those patients who developed a high-titre immune response to ERT [6]. In this context, quantification of antibody by a sensitive immune assay such as ELISA could have confirmed the diagnosis of acquired VWD at presentation. Based on our report, it could be argued that patients suspected to have VWD later in life should have thorough investigation to include genetic testing, family studies and if appropriate, a sensitive immune assay to exclude the presence of an antibody to VWF, to exclude acquired VWD.
Funding None.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
ment of lysosomal storage disorders. Clin Appl Immunol Rev 2002; 2: 241–53. 4 Kishnani PS, Goldenberg PC, DeArmey SL et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab 2010; 99: 26–33. 5 Gadisseur A, Hermans C, Berneman Z et al. Laboratory diagnosis and molecular
classification of von Willebrand disease. Acta Haematol 2009; 121: 71–84. 6 Saif MA, Bigger BW, Brookes KE et al. Hematopoietic stem cell transplantation ameliorates the high incidence of neutralizing allo-antibodies observed in MPSIHurler after pharmacological enzyme replacement therapy. Haematologica 2012; 97: 1320–8.
Haemophilia (2015), 21, e70--e121
Copyright of Haemophilia is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
FVIII:C levels. Evaluation of bleeding symptoms is an essential aspect of the study. The BAT used is not validated for evaluating bleeding tendency among haemophilia carriers, which may be a limitation of the study. The BAT has, however, been used in several publications to rate and compare the severity and frequency of bleeding symptoms among individuals with a certain diagnosis [10]. Another limitation of the study may be the lack of use of CTI. However, there are reports suggesting that CTI addition is only beneficial for thrombin generation triggered with TF concentrations below 0.5 pM [5,11]. We speculate that carriers might lack the ability to mobilize FVIII from depots in situations that challenge the haemostatic system, such as trauma and surgery. In this study, blood was not sampled during such situations, which might have contributed to the outcome. Inter-individual variations in other clotting factor levels, platelet function, fibrinolytic activity or endothelial vessel wall components might also contribute to variation in clinical pheno-
References 1 Plug I, Mauser-Bunschoten EP, BrockerVriends AH et al. Bleeding in carriers of hemophilia. Blood 2006; 108: 52–6. 2 Olsson A, Hellgren M, Berntorp E, Ljung R, Baghaei F. Clotting factor level is not a good predictor of bleeding in carriers of haemophilia A and B. Blood Coagul Fibrinolysis 2014; 25: 471–5. 3 Dargaud Y, Beguin S, Lienhart A et al. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost 2005; 93: 475–80. 4 van Veen JJ, Gatt A, Bowyer AE, Cooper PC, Kitchen S, Makris M. Calibrated automated thrombin generation and modified thromboelastometry in haemophilia A. Thromb Res 2009; 123: 895–901.
e113
type among carriers and explain the difficulty in demonstrating that TGA is a useful tool in this setting. In conclusion, the TGA results did not differ between carriers of haemophilia A with and without bleeding tendency. Our results suggest that TGA may not be a suitable test to predict bleeding risk among carriers of moderate and severe haemophilia A.
Authorship contribution A Olsson performed the research, designed the research study, analysed data and wrote the article. M Hellgren and M Holmstr€ om analysed data and critically reviewed the paper. E Berntorp and F Baghaei designed the study, analysed data and critically reviewed the paper.
Disclosures This research was supported by grants from Bayer Healthcare (AO) and grants from Lund University/Region Sk ane (EB).
5 Santagostino E, Mancuso ME, Tripodi A et al. Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile. J Thromb Haemost 2010; 8: 737–43. 6 Bowman M, Mundell G, Grabell J et al. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost 2008; 6: 2062–6. 7 Hemker HC, Giesen P, Al Dieri R et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4–15. 8 Trossaert M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay
to assess the bleeding phenotype. J Thromb Haemost 2008; 6: 486–93. 9 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17: 41–4. 10 Rodeghiero F, Tosetto A, Abshire T et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8: 2063–5. 11 Spronk HM, Dielis AW, Panova-Noeva M et al. Monitoring thrombin generation: is addition of corn trypsin inhibitor needed? Thromb Haemost 2009; 101: 1156–62.
Is it congenital or acquired von Willebrands disease? M . A . S A I F , * J . T H A C H I L , * R . B R O W N , * B . W . B I G G E R , † R . F . W Y N N , † M . N A S H * and C. R. HAY* *Department of Haematology; and †Department of Paediatric Haematology Manchester Royal Infirmary, Manchester, UK
Correspondence: Jecko Thachil, Department of Haematology, Manchester Royal Infirmary, Oxford Road, M13 9WL Manchester, UK. Tel.: 0044 161 276 4812; fax: 0044 161 276 8085; e-mail: [email protected] Accepted after revision 19 October 2014 DOI: 10.1111/hae.12588 © 2014 John Wiley & Sons Ltd
Acquired von Willebrand disease (VWD) is a rare bleeding disorder which usually presents late in life with no significant previous or family history of bleeding. It is frequently unrecognized or is misdiagnosed as inherited VWD. Although late onset presentation with bleeding and negative family history should prompt the suspicion of this condition, type 1 VWD Haemophilia (2015), 21, e70--e121
e114
LETTERS TO THE EDITORS
can be asymptomatic for decades and may lack family history because of low penetrance. Also inherited and acquired VWD could be present coincidentally. Very often, the diagnosis of acquired VWD is suspected in the setting of bleeding which develops in conditions like autoimmune diseases, myeloproliferative disorders or severe aortic stenosis [1]. This report describes the difficulty in making the diagnosis of acquired VWD in the absence of well-recognized associations. A 91-year-old lady presented with haemoglobin of 40 g L1 and a history of melaena. She had a previously established diagnosis of type 2A VWD, following diagnostic work up for extensive bleeding after tooth extraction, when she was 71 years. This included prolonged bleeding time (>15 min), reduced VWF:Rco (14 IU dL1) and VWF:Ag (41 IU dL1) and absence of high molecular weight multimers. She had an excellent clinical and laboratory response to the VW replacement product, Haemate-P at the time. Prior to her initial presentation with gum bleeding, she had significant haemostatic challenges in the form
Table 1. Response to Haemate-P previous to and during the last admission. Factor VIII 41
Baseline at diagnosis
Response to Haemate-P 1000 IU twice daily (after diagnosis) Day 1 Pre dose levels 47 Post dose levels 58 Day 7 Pre dose levels 67 Post dose levels 104 Day 8 Pre dose levels 89 Post dose levels 149 Pharmacokinetic study (last admission) Pre dose (Haemate-P 2000 IU) 70 Post dose 30 min 105 1h 105 2h 98 4h 92 6h 92
(a)
VWF:RCo 6
13 58 39 132 67 158 1 : 512 dilution) to von Willebrand factor (VWF) in the patient plasma. The absorbance values from negative control (normal plasma from O Rhesus positive individual) and plasma with human IgG anti-IDUA antibodies is also shown in the figure confirming the specificity of the assay to VWF. (b) Shows no difference in absorbance between negative control, patient plasma and plasma with human IgG anti-IDUA antibodies.
Haemophilia (2015), 21, e70--e121
© 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
recognized candidate VWF mutation, while multiplex ligation-dependent probe amplification assay also did not identify any VWD-specific gene mutation. Unfortunately, the renal function continued to deteriorate despite supportive measures and patient died due to acute renal failure. This manuscript describes an unusual presentation of VWD where a patient presenting late in life with a history of bleeding is diagnosed with type 2A VWD based on the excellent clinical response to VWF replacement therapy. Although acquired VWD is more common in this context an excellent recovery to Haemate-P is uncommon in this condition. However, subsequent presentation and development of suspected inhibitors to Haemate-P, previously unreported for this subtype, lead to a re-evaluation of the initial diagnosis. The development of inhibitors is reported in response to a large number of recombinant human proteins [2]. A number of factors such as impurities, aggregation of particles, dose, route and frequency of treatment and presence of residual protein (sometimes referred to as cross reactive immunologic material or CRIM) are considered to influence the development of inhibitors [2,3]. Absence of CRIM, results in a higher incidence of alloimmune response [4] compared to those patients who have had some residual functional or dysfunctional protein which the immune system becomes tolerant to. The presence of IgG antibodies to VWF in our patient, confirms the presence of inhibitory immune response to replaced Haemate-P. However, it is extremely unlikely that a patient with-type 2A VWD, with approximately 10% baseline VWF:RiCo could have developed an alloimmune response. Also, the absence of a causative
References 1 Rinder MR, Richard RE, Rinder HM. Acquired von Willebrand’s disease: a concise review. Am J Hematol 1997; 54: 139–45. 2 Porter S. Human immune response to recombinant human proteins. J Pharm Sci 2001; 90: 1–11. 3 Richards SM. Immunologic considerations for enzyme replacement therapy in the treat-
© 2014 John Wiley & Sons Ltd
e115
VWF gene mutation, makes a diagnosis of inherited type 2A VWD very unlikely [5]. It can, therefore, be concluded that the acquired VWD was responsible for a phenotype resembling inherited type 2A VWD in this patient despite adequate recovery of VWF:RCo post Haemate-P infusion. It is possible that the low-titre auto-immune antibodies in patient plasma at presentation were overcome by the high dose of Haemate-P and failed to inhibit the infused product in vivo, resulting in satisfactory VWF:RCo recovery. A similar phenomenon has been reported in enzyme replacement therapy (ERT)-treated patients with Mucopolysaccharidosis where very low-titre antibodies in some patients did not show any functional inhibition of replaced therapy in contrast to those patients who developed a high-titre immune response to ERT [6]. In this context, quantification of antibody by a sensitive immune assay such as ELISA could have confirmed the diagnosis of acquired VWD at presentation. Based on our report, it could be argued that patients suspected to have VWD later in life should have thorough investigation to include genetic testing, family studies and if appropriate, a sensitive immune assay to exclude the presence of an antibody to VWF, to exclude acquired VWD.
Funding None.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
ment of lysosomal storage disorders. Clin Appl Immunol Rev 2002; 2: 241–53. 4 Kishnani PS, Goldenberg PC, DeArmey SL et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab 2010; 99: 26–33. 5 Gadisseur A, Hermans C, Berneman Z et al. Laboratory diagnosis and molecular
classification of von Willebrand disease. Acta Haematol 2009; 121: 71–84. 6 Saif MA, Bigger BW, Brookes KE et al. Hematopoietic stem cell transplantation ameliorates the high incidence of neutralizing allo-antibodies observed in MPSIHurler after pharmacological enzyme replacement therapy. Haematologica 2012; 97: 1320–8.
Haemophilia (2015), 21, e70--e121
Copyright of Haemophilia is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
