American Journal of Hematology 3 5 1 14-1 17 (1990)
Acquired von Willebrand Disease in Multiple Myeloma Secondary to Absorption of von Willebrand Factor by Plasma Cells C. Richard, M.A. Cuadrado, M. Prieto, J. Batlle, M.F. Lopez Fernandez, M.L. Rodriguez Salazar, C. Bello, M. Recio, T. Santoro, M.T. Gomez Casares, and A. Zubizarreta Department of Hematology, Faculty of Medicine, National Hospital “Marques de Valdecilla,” Santander, Department of Hematology, University Hospital, University of Salamanca, Salamanca, and Department of Hematology, Hospital “General Yague,” Burgos, Spain
A case of acquired von Willebrand disease (AvWD) associated with an IgA lambda multiple myeloma is reported. No form of inhibitor could be detected. SDS-agarose gel electrophoresis patterns of von Willebrand factor (vWF) both in plasma and platelet lysates were normal but a decrease in all-sized multimers with a type IA pattern was seen. After l-deamino-8-D arginine vasopressin (DDAVP) infusion, vWF multimers larger than those seen in the resting state appeared in patient plasma, which were progressively cleared. Indirect immunofluorescence studies with a monoclonal antibody to vWF showed that vWF was selectively absorbed into myelomatous cells. This is the first case of AvWD associated with multiple myeloma resulting from the selective absorption of vWF into abnormal plasma cells. This feature established a new pathophysiological mechanism of AvWD in multiple myeloma and probably in other lymphoproliferative diseases. Key words: acquired von Willebrand disease, multiple myeloma, von Willebrand factor
INTRODUCTION
The syndrome called acquired von Willebrand disease (AvWD) is strikingly similar to the congenital disease characterized by a prolonged bleeding time and low plasma levels of factor VIII-von Willebrand factor (F VIII-vWF) measurements. Von Willebrand factor exists in plasma as a series of multimers. The large multimers are the most hemostatically competent and are decreased in plasma from von Willebrand disease patients [I]. AVWD has been reported with immune system dysfunctions and particularly with lymphoproliferative diseases; an association in benign monoclonal gammopathies and multiple has been [2-81. This last association has been demonstrated and circulating inhibitors to FVIII-vWF are most common feature, although others investigators have failed to demonstrate this [2]. Selective immunoadsorption of vWF to abnormal lymphocyte clones has been reported in Waldenstrom macbut this mechanism has not been roglobulinemia reported in multiple myeloma. i 8 1 7
0 1990 Wiley-Liss, Inc.
This report describes a case of AvWD in an IgA lambda multiple myeloma patient. Indirect immunofluorescence studies with anti-vWF monoclonal antibody demonstrated that a myeloma cell population immunoabsorbed selectively the vWF, leading to low plasma levels. MATERIALS AND METHODS Case Report A 67 year-old was admitted to the hospital because of melena after aspirin ingestion. There was a previous history of epigastralgy and pyrosis. She was diagnosed as having a hiata] hernia in 1983. At admission the physical examination was Laboratory
Received for publication January 19, 1990; accepted April 26, 1990. Address reprint requests to Dr. C. Richard, Servicio de Hematologia, Hospital Nacional “Marquts de Valdecilla,” 39008 Santander, Spain.
Case Report: AvWD in Multiple Myeloma
115
studies showed the following data: hematocrit 26.5 per- plasma or monoclonal-purified IgA with 1 vol of pooled cent, hemoglobin 8.8 g/dl, WBC count 5,600 with 53 normal plasma. Controls were mixtures of ten different percent neutrophils, 44 percent lymphocytes, and 3 per- normal plasmas (1 vol) with phosphate-buffered saline cent monocytes. The platelet count was 180,000 per containing 3% albumin (2 vol). The first incubation was mm3, and the erythrocyte sedimentation rate 74 mm per at 37°C for 1 hr and then at 4°C for an additional 12 hr. hr. After medical treatment bleeding stopped and the The samples were then centrifuged at 2,500g for 20 min, hemoglobin level increased to 11.5 g/dl. The biochemi- and aliquots of the supernatants were assayed for vWF: cal investigation of renal and hepatic function was nor- Ag and vWF:RiCoF [2]. Monoclonal IgA purification. Monoclonal IgA was mal. Immunoelectrophoresis revealed an IgA lambda monoclonal protein (1,500 mg/dl) with an IgG of 507 purified from a 5 ml serum sample by two chromatomg/dl and IgM of 11.9 mg/dl. Iliac crest bone marrow graphic cycles on Sepharose S300 (Pharmacia) followed aspirate showed a 32 percent plasma cell infiltration. by IgG immunoabsorption on IgG-Sepharose 4B of There was not radiographic evidence of bone involve- eluted fractions containing IgA. Purified IgA was devoid ment. The evaluation of hemostatic functions revealed of contamination with IgG or IgM molecules tested by the following data: bleeding time (Ivy) 4 min (n.
Acquired von Willebrand Disease in Multiple Myeloma Secondary to Absorption of von Willebrand Factor by Plasma Cells C. Richard, M.A. Cuadrado, M. Prieto, J. Batlle, M.F. Lopez Fernandez, M.L. Rodriguez Salazar, C. Bello, M. Recio, T. Santoro, M.T. Gomez Casares, and A. Zubizarreta Department of Hematology, Faculty of Medicine, National Hospital “Marques de Valdecilla,” Santander, Department of Hematology, University Hospital, University of Salamanca, Salamanca, and Department of Hematology, Hospital “General Yague,” Burgos, Spain
A case of acquired von Willebrand disease (AvWD) associated with an IgA lambda multiple myeloma is reported. No form of inhibitor could be detected. SDS-agarose gel electrophoresis patterns of von Willebrand factor (vWF) both in plasma and platelet lysates were normal but a decrease in all-sized multimers with a type IA pattern was seen. After l-deamino-8-D arginine vasopressin (DDAVP) infusion, vWF multimers larger than those seen in the resting state appeared in patient plasma, which were progressively cleared. Indirect immunofluorescence studies with a monoclonal antibody to vWF showed that vWF was selectively absorbed into myelomatous cells. This is the first case of AvWD associated with multiple myeloma resulting from the selective absorption of vWF into abnormal plasma cells. This feature established a new pathophysiological mechanism of AvWD in multiple myeloma and probably in other lymphoproliferative diseases. Key words: acquired von Willebrand disease, multiple myeloma, von Willebrand factor
INTRODUCTION
The syndrome called acquired von Willebrand disease (AvWD) is strikingly similar to the congenital disease characterized by a prolonged bleeding time and low plasma levels of factor VIII-von Willebrand factor (F VIII-vWF) measurements. Von Willebrand factor exists in plasma as a series of multimers. The large multimers are the most hemostatically competent and are decreased in plasma from von Willebrand disease patients [I]. AVWD has been reported with immune system dysfunctions and particularly with lymphoproliferative diseases; an association in benign monoclonal gammopathies and multiple has been [2-81. This last association has been demonstrated and circulating inhibitors to FVIII-vWF are most common feature, although others investigators have failed to demonstrate this [2]. Selective immunoadsorption of vWF to abnormal lymphocyte clones has been reported in Waldenstrom macbut this mechanism has not been roglobulinemia reported in multiple myeloma. i 8 1 7
0 1990 Wiley-Liss, Inc.
This report describes a case of AvWD in an IgA lambda multiple myeloma patient. Indirect immunofluorescence studies with anti-vWF monoclonal antibody demonstrated that a myeloma cell population immunoabsorbed selectively the vWF, leading to low plasma levels. MATERIALS AND METHODS Case Report A 67 year-old was admitted to the hospital because of melena after aspirin ingestion. There was a previous history of epigastralgy and pyrosis. She was diagnosed as having a hiata] hernia in 1983. At admission the physical examination was Laboratory
Received for publication January 19, 1990; accepted April 26, 1990. Address reprint requests to Dr. C. Richard, Servicio de Hematologia, Hospital Nacional “Marquts de Valdecilla,” 39008 Santander, Spain.
Case Report: AvWD in Multiple Myeloma
115
studies showed the following data: hematocrit 26.5 per- plasma or monoclonal-purified IgA with 1 vol of pooled cent, hemoglobin 8.8 g/dl, WBC count 5,600 with 53 normal plasma. Controls were mixtures of ten different percent neutrophils, 44 percent lymphocytes, and 3 per- normal plasmas (1 vol) with phosphate-buffered saline cent monocytes. The platelet count was 180,000 per containing 3% albumin (2 vol). The first incubation was mm3, and the erythrocyte sedimentation rate 74 mm per at 37°C for 1 hr and then at 4°C for an additional 12 hr. hr. After medical treatment bleeding stopped and the The samples were then centrifuged at 2,500g for 20 min, hemoglobin level increased to 11.5 g/dl. The biochemi- and aliquots of the supernatants were assayed for vWF: cal investigation of renal and hepatic function was nor- Ag and vWF:RiCoF [2]. Monoclonal IgA purification. Monoclonal IgA was mal. Immunoelectrophoresis revealed an IgA lambda monoclonal protein (1,500 mg/dl) with an IgG of 507 purified from a 5 ml serum sample by two chromatomg/dl and IgM of 11.9 mg/dl. Iliac crest bone marrow graphic cycles on Sepharose S300 (Pharmacia) followed aspirate showed a 32 percent plasma cell infiltration. by IgG immunoabsorption on IgG-Sepharose 4B of There was not radiographic evidence of bone involve- eluted fractions containing IgA. Purified IgA was devoid ment. The evaluation of hemostatic functions revealed of contamination with IgG or IgM molecules tested by the following data: bleeding time (Ivy) 4 min (n.
