Original Clinical ScienceçGeneral
Von Willebrand Factor Deficiency Corrected by Lung Transplantation Rafael Forés, MD,1 Ana Lario, MD,1 Santiago Gil, MD, PhD,1 Jose-Luis Campo-Cañaveral, MD,2 David Gomez-De-Antonio, MD,2 Rosalia Laporta, MD,3 Monica Martin, MD,4 Grace Anze, MD,1 Nieves Dorado, MD,1 Jose-Luis Bueno, MD,1 and Rafael Cabrera, MD, PhD1 Background. In experimental models with von Willebrand disease pigs, plasma von Willebrand factor (vWF) was significantly increased after lung transplantation because lung endothelial cells strongly express vWF. However, these findings have not been confirmed in human beings. Methods. A 26-year-old man with mild vWF deficiency (FvW:antigen 39 IU/dL; FvW:ristocetin cofactor activity 44 IU/dL; factor VIII 99%; normal multimeric plasma vWF pattern) was referred to our institution and underwent bilateral lung transplantation for cystic fibrosis. The patient received factor VIII/vWF concentrate both during and after surgery without any relevant bleeding events. At hospital discharge, he was taking immunosuppression with oral tacrolimus, prednisone, and mycophenolate mofetil, which has continued until the present day (22 months after the procedure). Results. Plasma vWF level increased during the postoperative days, presumably due to endothelial injuries and the infusion of vWF concentrate. Laboratory tests at 5, 11, 14, and 22 months after lung transplantation demonstrated sustained normalization of all parameters. Conclusions. To our knowledge, this is the first reported case of von Willebrand deficiency corrected through lung transplantation.
(Transplantation 2015;99: 2663–2664)
V
on Willebrand disease (vWD) is the most common inherited bleeding disorder. The disease results from a qualitative or quantitative deficiency in von Willebrand factor (vWF), a multimeric glycoprotein synthesized by endothelial cells (ECs) and megakaryocytes, whose main functions are platelet adhesion to connective tissues and subendothelium, platelet aggregation as well as protecting factor VIII (FVIII) from proteolytic degradation in plasma. Most cases are transmitted as an autosomal dominant trait. Von Willebrand disease is classified into 3 categories: type 1, the most common (70%80% of all cases), which includes partial quantitative deficiency with a normal quantitative multimeric profile; type 2 with qualitative defects, divided into 4 secondary categories: 2A (10%20%), 2B (5%), 2M and 2N; and type 3 with undetectable levels of vWF, a rare disease with an estimated incidence of one per million. The diagnosis of vWD is based on coagulation studies, such as PFA100-closure time, vWF:antigen (Ag), vWF: ristocetin cofactor activity (RCo), FVIII, and vWF multimer
Received 27 December 2014. Revision received 6 March 2015. Accepted 7 March 2015. 1 Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 2 Department of Thoracic Surgery, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 3
Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
4
Department of Hematology, Hospital Universitario La Paz, Madrid, Spain.
The authors declare no funding or conflicts of interest. Correspondence: Rafael Forés, Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9912-2663 DOI: 10.1097/TP.0000000000000768
Transplantation
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December 2015
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Volume 99
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Number 12
profile.1,2 In the diagnosis of type 1, there is no generalized consensus regarding the type and number of vWF variables that should be considered,3 and some institutions have proposed the term “low vWF” for cases with modestly low vWF levels (eg, 30 to 50 IU/dL). In experimental models with vWD pigs, plasma vWF was significantly increased after lung transplantation4 because lungs are very rich in ECs that strongly express vWF. However, it has not been possible to extrapolate these results to human organ transplantation. We report a case of human lung transplantation which resulted in the full correction of mild vWF deficiency. METHODS A 26-year-old man, with mild bleeding episodes (epistaxis) and family history of bleeding disorder (mother with menorrhagia), was diagnosed with type 1 vWD (FvW:Ag, 39 IU/dL; FvW:RCo, 44 IU/dL; FVIII 99%) in November 2012. The patient was referred to our institution for lung transplantation as a result of cystic fibrosis. The vWF deficiency was confirmed by low levels of vWF and a normal multimeric plasma vWF pattern (SDS-agarose gel electrophoresis). Bilateral lung transplantation was performed in April 2013, the donor being a 53-year-old woman who had died from a subarachnoid hemorrhage. The mechanical ventilation time was 48 hours and PaO2/FiO2 was 358. Ischemic times were 315 minutes (right lung) and 435 minutes (left lung). Ex vivo lung perfusion was performed with the Organ Care System (preservation time 120 minutes). The FVIII/vWF concentrate (Haemate-P) was administered both during and after surgery without any relevant bleeding events. The patient developed primary lung graft dysfunction grade 2 although he was extubated on the second postoperative day with good oxygenation. However, he developed progressive lung infiltrates with respiratory www.transplantjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
2663
2664
Transplantation
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December 2015
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Volume 99
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Number 12
www.transplantjournal.com
TABLE 1.
Evolution of laboratory tests
At diagnosis Month −5 Day 0 (surgery) Day +2a Month +1a Month +5 Month +11 Month +14 Month + 22
APTT (s) (29.2-40.0)
FVIII (%) (60‐150)
FvW:Ag (IU/dL) (50‐160)
FvW:RCo (IU/dL) (55‐140)
99 85 69 169 227 122 97 95 123
39 48 74 203 206 101 111 85 96
44
46.6 43.3 40.9 38.7 36.9 40.9 40.0 41.0
PFA100 COL/EPI (s) (94‐193)
158 Not detected 157 151 89 85 73 84
125 167 174 103
a Treatment with FVIII/vWF concentrate (Haemate-P®). APTT indicates activated partial thromboplastin time (Diagnostica Stago, France); FVIII:C, Factor VIII procoagulant activity (Diagnostica Stago, France); immunoturbidimetric method (Liatest VWF:Ag, Diagnostica Stago, France). VWF:RCo, ristocetin cofactor activity, Immunoturbidimetric method (Siemens, Marburg, Germany). PFA100: closure time (PFA100, Siemens, Marburg, Germany).
failure, and extracorporeal membrane oxygenation was administered for 10 days. Bronchoscopy and bronchoalveolar lavage showed neither alveolar hemorrhage nor infection. He was treated with corticosteroids and plasmapheresis with a good response. There were no data of posttransplant thrombotic microangiopathy. At hospital discharge in June 2013, he was taking immunosuppression with oral tacrolimus, prednisone, and mycophenolate mofetil, which has continued until the present day (22 months after the procedure). RESULTS Plasma vWF levels increased during the postoperative days, presumably due to endothelial injuries and infusion of vWF concentrate. Laboratory tests performed 5, 11, 14, and 22 months after lung transplantation demonstrated sustained normalization of all parameters. The vWF multimer analyses before and after surgery showed that all ranges were present. Table 1 presents the evolution of laboratory data over time (activated partial thromboplastin time, FVIII, FvW:Ag, FvW:RCo, and PFA100-closure time). CONCLUSIONS There are reported cases of liver transplantation that lead to the cure of hemophilia5,6; however, there have been no reported successes of this procedure in vWD.7 One case, published by Schulman et al,8 showed that a liver transplantation resulted in a slight production of vWF due to the graft; nevertheless, it did not correct the disorder. Brouland et al4 reported that pigs with type 3 vWD who were submitted to lung transplantation demonstrated ECs that were morphologically and functionally intact, in addition, their vWF plasma levels were partially corrected which indicated that the EC cells were viable after transplantation. However, they concluded that these data could not be extrapolated to human lung transplantation in which phenomena such as graft rejection or immunosuppressive therapy could be toxic to ECs and may affect vWF synthesis. Our patient had a mild vWF deficiency with mild bleeding symptoms and a family history of bleeding disorder. He was initially diagnosed with type 1 vWD but subsequently reclassified as low vWF, although there is some overlap between the 2 categories.9
This case is additionally surprising in that patients with pulmonary affectation by cystic fibrosis usually have higher levels of vWF.10 In the case reported here, lung transplantation led to increased plasma vWF levels which were produced by normal lung ECs and resulted in the defect being corrected. It could be speculated that the transplanted lung endothelium is responsible for the production of approximately 30% of the vWF (experimental left pneumonectomy in pigs induced a 14% decrease of plasma vWF level4) and that basal plasma vWF levels probably depend on the mass of secretory ECs. The toxic effect of immunosuppressive drugs on the vascular tree does not seem to be relevant. To our knowledge, this is the first reported case of von Willebrand deficiency corrected through lung transplantation. ACKNOWLEDGMENTS The authors thank Martin Hadley-Adams for assisting with the English language. REFERENCES 1. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood. 2013;122:3735–3740. 2. Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4:2103–2114. 3. Quiroga T, Goycoolea M, Belmont S, et al. Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease. J Thromb Haemost. 2014;12:1238–1243. 4. Brouland JP, Egan T, Jacqueline R, et al. In vivo regulation of von Willebrand factor synthesis: von Willebrand factor production in endothelial cells after lung transplantation between normal pigs and von Willebrand factor-deficient pigs. Arterioscler Thromb Vasc Biol. 1999;19:3055–3062. 5. Wawrzynowicz-Syczewska M, Czupryńska M, Bander D, et al. Orthotopic liver transplantation for HCV-related liver cirrhosis in patients with hemophilia A: one procedure and two benefits. Pol Arch Med Wewn. 2014;124:338–339. 6. Lerut JP, Laterre PF, Lavenne-Pardonge E, et al. Liver transplantation and haemophilia A. J Hepatol. 1995;22:583–585. 7. Mannucci PM, Federici A, Cattaneo M, et al. Liver transplantation in severe von Willebrand disease. Lancet. 1991;337:1105. 8. Schulman S, Ericzon BG, Eleborg L. Modification of von Willebrand disease after liver transplantation. Thromb Haemost. 2001;86:1588–1589. 9. Sadler JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology Am Soc Hematol Educ Program. 2009:106–112. 10. Romano M, Collura M, Lapichino L, et al. Endothelial perturbation in cystic fibrosis. Thromb Haemost. 2001;86:1363–1367.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Von Willebrand Factor Deficiency Corrected by Lung Transplantation Rafael Forés, MD,1 Ana Lario, MD,1 Santiago Gil, MD, PhD,1 Jose-Luis Campo-Cañaveral, MD,2 David Gomez-De-Antonio, MD,2 Rosalia Laporta, MD,3 Monica Martin, MD,4 Grace Anze, MD,1 Nieves Dorado, MD,1 Jose-Luis Bueno, MD,1 and Rafael Cabrera, MD, PhD1 Background. In experimental models with von Willebrand disease pigs, plasma von Willebrand factor (vWF) was significantly increased after lung transplantation because lung endothelial cells strongly express vWF. However, these findings have not been confirmed in human beings. Methods. A 26-year-old man with mild vWF deficiency (FvW:antigen 39 IU/dL; FvW:ristocetin cofactor activity 44 IU/dL; factor VIII 99%; normal multimeric plasma vWF pattern) was referred to our institution and underwent bilateral lung transplantation for cystic fibrosis. The patient received factor VIII/vWF concentrate both during and after surgery without any relevant bleeding events. At hospital discharge, he was taking immunosuppression with oral tacrolimus, prednisone, and mycophenolate mofetil, which has continued until the present day (22 months after the procedure). Results. Plasma vWF level increased during the postoperative days, presumably due to endothelial injuries and the infusion of vWF concentrate. Laboratory tests at 5, 11, 14, and 22 months after lung transplantation demonstrated sustained normalization of all parameters. Conclusions. To our knowledge, this is the first reported case of von Willebrand deficiency corrected through lung transplantation.
(Transplantation 2015;99: 2663–2664)
V
on Willebrand disease (vWD) is the most common inherited bleeding disorder. The disease results from a qualitative or quantitative deficiency in von Willebrand factor (vWF), a multimeric glycoprotein synthesized by endothelial cells (ECs) and megakaryocytes, whose main functions are platelet adhesion to connective tissues and subendothelium, platelet aggregation as well as protecting factor VIII (FVIII) from proteolytic degradation in plasma. Most cases are transmitted as an autosomal dominant trait. Von Willebrand disease is classified into 3 categories: type 1, the most common (70%80% of all cases), which includes partial quantitative deficiency with a normal quantitative multimeric profile; type 2 with qualitative defects, divided into 4 secondary categories: 2A (10%20%), 2B (5%), 2M and 2N; and type 3 with undetectable levels of vWF, a rare disease with an estimated incidence of one per million. The diagnosis of vWD is based on coagulation studies, such as PFA100-closure time, vWF:antigen (Ag), vWF: ristocetin cofactor activity (RCo), FVIII, and vWF multimer
Received 27 December 2014. Revision received 6 March 2015. Accepted 7 March 2015. 1 Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 2 Department of Thoracic Surgery, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 3
Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
4
Department of Hematology, Hospital Universitario La Paz, Madrid, Spain.
The authors declare no funding or conflicts of interest. Correspondence: Rafael Forés, Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain. ([email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9912-2663 DOI: 10.1097/TP.0000000000000768
Transplantation
■
December 2015
■
Volume 99
■
Number 12
profile.1,2 In the diagnosis of type 1, there is no generalized consensus regarding the type and number of vWF variables that should be considered,3 and some institutions have proposed the term “low vWF” for cases with modestly low vWF levels (eg, 30 to 50 IU/dL). In experimental models with vWD pigs, plasma vWF was significantly increased after lung transplantation4 because lungs are very rich in ECs that strongly express vWF. However, it has not been possible to extrapolate these results to human organ transplantation. We report a case of human lung transplantation which resulted in the full correction of mild vWF deficiency. METHODS A 26-year-old man, with mild bleeding episodes (epistaxis) and family history of bleeding disorder (mother with menorrhagia), was diagnosed with type 1 vWD (FvW:Ag, 39 IU/dL; FvW:RCo, 44 IU/dL; FVIII 99%) in November 2012. The patient was referred to our institution for lung transplantation as a result of cystic fibrosis. The vWF deficiency was confirmed by low levels of vWF and a normal multimeric plasma vWF pattern (SDS-agarose gel electrophoresis). Bilateral lung transplantation was performed in April 2013, the donor being a 53-year-old woman who had died from a subarachnoid hemorrhage. The mechanical ventilation time was 48 hours and PaO2/FiO2 was 358. Ischemic times were 315 minutes (right lung) and 435 minutes (left lung). Ex vivo lung perfusion was performed with the Organ Care System (preservation time 120 minutes). The FVIII/vWF concentrate (Haemate-P) was administered both during and after surgery without any relevant bleeding events. The patient developed primary lung graft dysfunction grade 2 although he was extubated on the second postoperative day with good oxygenation. However, he developed progressive lung infiltrates with respiratory www.transplantjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
2663
2664
Transplantation
■
December 2015
■
Volume 99
■
Number 12
www.transplantjournal.com
TABLE 1.
Evolution of laboratory tests
At diagnosis Month −5 Day 0 (surgery) Day +2a Month +1a Month +5 Month +11 Month +14 Month + 22
APTT (s) (29.2-40.0)
FVIII (%) (60‐150)
FvW:Ag (IU/dL) (50‐160)
FvW:RCo (IU/dL) (55‐140)
99 85 69 169 227 122 97 95 123
39 48 74 203 206 101 111 85 96
44
46.6 43.3 40.9 38.7 36.9 40.9 40.0 41.0
PFA100 COL/EPI (s) (94‐193)
158 Not detected 157 151 89 85 73 84
125 167 174 103
a Treatment with FVIII/vWF concentrate (Haemate-P®). APTT indicates activated partial thromboplastin time (Diagnostica Stago, France); FVIII:C, Factor VIII procoagulant activity (Diagnostica Stago, France); immunoturbidimetric method (Liatest VWF:Ag, Diagnostica Stago, France). VWF:RCo, ristocetin cofactor activity, Immunoturbidimetric method (Siemens, Marburg, Germany). PFA100: closure time (PFA100, Siemens, Marburg, Germany).
failure, and extracorporeal membrane oxygenation was administered for 10 days. Bronchoscopy and bronchoalveolar lavage showed neither alveolar hemorrhage nor infection. He was treated with corticosteroids and plasmapheresis with a good response. There were no data of posttransplant thrombotic microangiopathy. At hospital discharge in June 2013, he was taking immunosuppression with oral tacrolimus, prednisone, and mycophenolate mofetil, which has continued until the present day (22 months after the procedure). RESULTS Plasma vWF levels increased during the postoperative days, presumably due to endothelial injuries and infusion of vWF concentrate. Laboratory tests performed 5, 11, 14, and 22 months after lung transplantation demonstrated sustained normalization of all parameters. The vWF multimer analyses before and after surgery showed that all ranges were present. Table 1 presents the evolution of laboratory data over time (activated partial thromboplastin time, FVIII, FvW:Ag, FvW:RCo, and PFA100-closure time). CONCLUSIONS There are reported cases of liver transplantation that lead to the cure of hemophilia5,6; however, there have been no reported successes of this procedure in vWD.7 One case, published by Schulman et al,8 showed that a liver transplantation resulted in a slight production of vWF due to the graft; nevertheless, it did not correct the disorder. Brouland et al4 reported that pigs with type 3 vWD who were submitted to lung transplantation demonstrated ECs that were morphologically and functionally intact, in addition, their vWF plasma levels were partially corrected which indicated that the EC cells were viable after transplantation. However, they concluded that these data could not be extrapolated to human lung transplantation in which phenomena such as graft rejection or immunosuppressive therapy could be toxic to ECs and may affect vWF synthesis. Our patient had a mild vWF deficiency with mild bleeding symptoms and a family history of bleeding disorder. He was initially diagnosed with type 1 vWD but subsequently reclassified as low vWF, although there is some overlap between the 2 categories.9
This case is additionally surprising in that patients with pulmonary affectation by cystic fibrosis usually have higher levels of vWF.10 In the case reported here, lung transplantation led to increased plasma vWF levels which were produced by normal lung ECs and resulted in the defect being corrected. It could be speculated that the transplanted lung endothelium is responsible for the production of approximately 30% of the vWF (experimental left pneumonectomy in pigs induced a 14% decrease of plasma vWF level4) and that basal plasma vWF levels probably depend on the mass of secretory ECs. The toxic effect of immunosuppressive drugs on the vascular tree does not seem to be relevant. To our knowledge, this is the first reported case of von Willebrand deficiency corrected through lung transplantation. ACKNOWLEDGMENTS The authors thank Martin Hadley-Adams for assisting with the English language. REFERENCES 1. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood. 2013;122:3735–3740. 2. Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4:2103–2114. 3. Quiroga T, Goycoolea M, Belmont S, et al. Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease. J Thromb Haemost. 2014;12:1238–1243. 4. Brouland JP, Egan T, Jacqueline R, et al. In vivo regulation of von Willebrand factor synthesis: von Willebrand factor production in endothelial cells after lung transplantation between normal pigs and von Willebrand factor-deficient pigs. Arterioscler Thromb Vasc Biol. 1999;19:3055–3062. 5. Wawrzynowicz-Syczewska M, Czupryńska M, Bander D, et al. Orthotopic liver transplantation for HCV-related liver cirrhosis in patients with hemophilia A: one procedure and two benefits. Pol Arch Med Wewn. 2014;124:338–339. 6. Lerut JP, Laterre PF, Lavenne-Pardonge E, et al. Liver transplantation and haemophilia A. J Hepatol. 1995;22:583–585. 7. Mannucci PM, Federici A, Cattaneo M, et al. Liver transplantation in severe von Willebrand disease. Lancet. 1991;337:1105. 8. Schulman S, Ericzon BG, Eleborg L. Modification of von Willebrand disease after liver transplantation. Thromb Haemost. 2001;86:1588–1589. 9. Sadler JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology Am Soc Hematol Educ Program. 2009:106–112. 10. Romano M, Collura M, Lapichino L, et al. Endothelial perturbation in cystic fibrosis. Thromb Haemost. 2001;86:1363–1367.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
![A monomeric von Willebrand factor fragment, Leu-504--Lys-728, inhibits von Willebrand factor interaction with glycoprotein Ib-IX [corrected].](/assets/img/hold.png)
