- Email: [email protected]
15. Acquired C1-inhibitor deficiency with IgA-kappa neutralizing antibody
A6
Abstracts/Netherlands
Journal
Noordijk ‘, P.W. Weijermans ‘, W.B.J. Gerrits ‘, P.J. Seelen 2, Ph.M. Kluin 5, P.F.H. Franck ‘, H. Kruijff ‘, J.C. Kluin-Nelemans 6. ’ Department of Internal Medicine, University Hospital, Leiden; ’ Paraprotein Task Force of the Comprehensive Cancer Centre West, Leiden; 3 Depaninent of Medical Statistics, University of Leiden; 4 Department of Clinical Oncology, University Hospital, Leiden; 5 Department of Pathology, University Hospital, Leiden; ’ Department of Hematology, University Hospital, L&den, Netherlands. To determine the incidence of different paraproteinaemias and the course of action followed by the physician, and to monitor the progression of different paraproteinaemias, a population-based registry was set up by the CCCW (The Netherlands). Included were all patients newly diagnosed with a paraprotein and/or MM in 1991, 1992, and 1993. Patients could be entered by clinical chemists in the case of paraproteinaemia and pathologists, internists, and haematologists in the case of MM. Information on presenting symptoms and signs, patient characteristics, results of laboratory, X-ray, and bone marrow examinations, diagnosis concerning the paraprotein, co-morbidity, and therapy were collected from the patients’ hospital records and entered into a database. Follow-up frequency was once yearly. In addition, a serum sample at first diagnosis was collected and stored centrally at - 70°C. A total of 1832 applications was received, of which 82% were from clinical chemists and 18% from other sources. About 17% of the applications were discarded because they did not meet the inclusion criteria, mainly because a paraprotein had already been found before 1991. To date, 1389 patients have been included in the registry. MM constituted 17%; other haematological malignancies 11%; paraproteins accompanying solid tumours, auto-immune disorders or infections occurred in 16%; monoclonal gammopathy of undetermined significance (MGUSl in 22%; in 3% uncertain diagnosis, while no diagnosis at all was made in 31%, mostly because no action was taken by the physician. From the second quarter of 1992 onward, the latter percentage decreased. The incidence of paraproteinaemia in the CCCW region in 1992 was 31/100000 inhabitants, and 189/100000 for ages 70 and above. The incidence of MM was 4.3/100000, which was comparable to the 4.0 for females, and 4.6 for males reported by the Netherlands Cancer Registry in 1991, Conclusion: The Paraprotein Registry is a unique project because of its multi-disciplinary approach, and its close cooperation with clinical chemists. Apart from being a descriptive registry, this project may also have had a favourable influence on hospital policy concerning the detection and follow-up of patients with a paraproteinaemia. This work was supported by the Praeventiefonds, grant no. 2821620.
14. Incidence of deep-vein thrombosis and pulmonary embolism during hospitaIisatIon in a department of Internal medicine. B. Schuurman, M. Den Heijer, A.M. Nijs, S.J. Graafsma. Department of Internal Medicine, Mariaziekenhuis, Tilburg, Netherlands. Introduction: Hospitalisation is a well-known risk factor for thromboembolic complications. Most studies on the incidence of thrombosis focus on surgical patients. In the present study we
of Medicine
50 (1997)
Al-A44
studied the incidence of thromboembolic complications in a general internal department. Methods: In a retrospective study we collected data of all-patients admitted to the Department of Internal Medicine of the Mariahospital in the last 2 years for deep vein thrombosis (DVT) (ICD-code 453.8) or pulmonary embolism (PE) (ICD-code 415.1). We calculated incidence rates of thromboembolic events occurring during admission. Furthermore, we calculated incidence rates of patients primarily admitted for the same indications. Results: During the last 2 years the incidence rate of DVT during admission (DVT-D) was 0.4%, whereas 0.3% developed PE during admission (PE-D). In contrast, 2.6% of all internal patients were primarily admitted for DVT and 0.9% for PE. Surprisingly, all patients with DVT-D (n = 11) had a malignancy (100%). For PE-D patients this percentage was 50% (n = 3 out of 6 with PE-D). Incidence for DVT-D among cancer patients was 3.5% for DVT-D and 1.2% for PE-D (overall: 4.7%). The malignancies in the DVT-D group were: pancreatic carcinoma (n = 3). colorectal carcinoma (n = 21, large cell anaplastic lung carcinoma (n = 11, adenocarcinoma of unknown origin (n = 11, mammacarcinoma (n = l), cerebral non-Hodgkin lymphoma (n = l), intra-abdominal soft tissue sarcoma (n = 1) and Hodgkin’s disease (n = 1). Malignancies in the PE-D group were metastatic manunacarcinoma (n = 11, metastatic prostatic carcinoma (n = 1) and metastatic teratoma (n = 1). Overall, 82.35% (14/17) of thromboembolic complications during admission were related to malignancy. In comparison, among 31 patients admitted primarily for DVT during the last year only 6 were related to malignancy (19.35%), whereas 2 patients with PE out of 8 had a malignancy (25%). Conclusions: Our data indicate that a high percentage of internal patients developing DVT-D or PE-D (82.35%) have a malignancy. This may be explained by the combination of hospitalisation and malignancy, which are both established risk factors for thrombosis. Further study is warranted to investigate whether prophylaxis of thrombotic events in these patients is feasible.
15. Acquired Cl-inhibitor deficiency with &A-kappa neutralizing antibody. D.J. van Spronsen ‘, S.J. Hoomtje i, A.J. Hannema 2, C.E. Hack 2. ’ Department of Internal Medicine, Catharina Hospital, Eindhoven; 2 Central Laboratory for the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, Netherlands. A 58-year-old man was seen with complaints of recurrent edema for several years. His medical history consisted of a totally resected malignant hypemephroma at age of 51 years and recurrent abdominal pain. Many potential causes of abdominal pain, including intlammatory bowel disease were excluded by laboratory testing and barium enemas. Additionally, he had complaints of recurrent non-itching edema of the tongue, face, feet and scrotum, and bouts of abdominal pain with nausea which lasted for several days. None of his family members ever suffered from angio-edema. Physical examination was completely normal, as were routine haematology and biochemistry results. The Cl inhibitor (ClINH) level appeared to be markedly decreased ( < 0.05; normal 0.76-1.33 U/ml), as were Clq (5; normal 81-128 U/ml)
Abstracts
/Netherlands
Journal
and C4 (0.02; normal 0.15-0.45 U/ml). Since acquired angioedema is associated with B-cell abnormalities, an additional search was performed. Levels of immunoglobulins, routine electrophoresis, immune-complex level and cryoblobulins were all normal. However, with immunofixation an IgA-kappa paraprotein could be detected. A high titer of IgA-kappa neutralizing antibody against C 1INH was found. Though routine histologic examination of bone marrow biopsy was normal, immuno-phenotyping showed evidence for an monoclonal population of IgA-kappa-positive plasma cells. Estimations of ClINH levels were normal in fustdegree relatives. Treatment was started with danazol 200 mg, thrice a day. Until 10 months of follow-up the condition of our patient has been stable, without recurrence of attacks. Conclusions: This patient suffered from ‘acquired angioedema’ because of low levels Clq and C4, the late onset of symptoms, and the absence of disease in the first-degree relatives. The Cl inhibitor deficiency resulted from a high titer of IgA-kappa antibody that inactivates Cl-inhibitor, produced by a monoclonal population of plasma cells (monoclonal gammopathy of undetermined significance).
16. Hlgb prevalence of penicillin-resistant viridans streptococci in patients selected for intensive chemotherapy. 0. Visser * , D.J. Richel *, M.R. Schaafsma * and M.G.R. Hendrix #. * Department of Haematology, Medisch Spectrum Twente, Enschede; # Regional Laboratory of Public Health, Enschede, Netherlands. Despite penicillin prophylaxis, recently several episodes of often fatal bacteraemia caused by penicillin-resistant viridans streptococci (VS) have been described in patients undergoing intensive chemotherapy. Therefore a surveillance culture should include a method for detecting penicillin-resistant VS. The purpose of the present study was to investigate the prevalence of penicillin-resistant VS in our haematology department. We evaluated 59 patients (14 acute myeloid leukaemia, 9 non-Hodgkin lymphoma, 9 multiple myeloma, 19 breast cancer, 8 miscellaneous) for tbe presence of penicillin-resistant VS (MIC > 2.0 u/d. Results: 36% (21/59) of the patients were demonstrated to be colonized with penicillin-resistant VS. Further antibiotic resistance analysis revealed two different patterns of resistance: one pattern showing isolated penicillin resistance, but susceptibility to other beta-lactams; another pattern demonstrating resistance to all betalactams. In some patients, VS with both patterns could be isolated simultaneously, while others showed only one pattern. No betalactamase production was observed in any of the isolates. Therefore beta-lactam resistance might be explained by alterations in penicillin binding proteins (PBP). All isolates were susceptible to glycopeptides (MIC teicoplanin < 2 pg/ml, MIC vancomycin < 2 pg/ml), and no high-level aminoglycoside resistance (MIC > 500 kg/ml) was observed. Conclusion: From these data it might be concluded that 36% of patients selected for intensive chemotherapy are colonized by penicillin-resistant VS. Considering the high percentage of betalactam-resistant VS, a prophylactic regimen including a glycopeptide is mandatory in this subgroup of patients.
of Medicine
50 (1997)
Al -A44
Al
17. The development of inhibitmy a&bodies agniast factor A. A.J. Vlot, S. VIII in a patient with moderate Wittebol. Department of Internal Medicine, Eemland Hospital, Amersfoort,
Netherlands.
In patients with hemophilia A, a serious complication is the induction of antibodies to factor VIII @VIII). This occurs in 8-20% of patients with almost exclusively the severe form of hemophilia A. We describe a 68-year-old patient with the moderate form of hemophilia A with FVIII:C and von Willebmnd factor levels of 36 and 160%, respectively. In 1989 he underwent an elective operative excision with replacement with a graft for an aortic aneurysm. To correct the factor deficiency during surgery and during the postoperative course, he received an intermediate, purified, heat-treated FVIII concentrate. Therapeutic levels of FVIII were obtained and the postoperative course was uneventful. No antibodies against factor VIII were detectable. In July 1996 he underwent prostatectomy for which he received a monoclonally purified FVIII concentrate. The total amount of FVIII received was 5 1700 units in 24 exposure days. Five months later re-admission followed for evaluation of generalised ecchymoses. At referral, his AP7T was prolonged by 80 s and FVIII was < 1%. Antibodies to FVIII were demonstrated by the Bethesda assay (inhibitor titer 15 BU/ml). The patient was treated with activated prothrombinase complex concentrates. The present therapy consists of FVIII/vWF concentrates to induce immune tolerance, as described by Mauser-Bunschoten et al. (Blood 1995;86:983-988). Conclusion: Our patient with moderate hemophilia A probably developed an inhibitor cross-reacting with endogenous FVIII. Whether this is caused by the monoclonally purified FVIII or by other substancespresent in the coagulation factor product remains to be investigated. 18. Factor VIIa is elevated by factor V L&en. W. Waale ‘, R. van Oerle ‘, L. van Pampus I, T. Lindhout ‘, H. Phulippou 3, D.A. Lane 3, K. Hamuly& ‘. ’ Department of Haematology, University Hospital, Maastricht; 2 Department Maastricht University, Maastricht, Netherlands; Haematology, Charing Cross and Westminster London, UK.
of Biochemistry, 3 Department qf Medical School,
Background: It is well known that heterozygous carriers of the Fv L&den mutation have an increased risk for venous thromboembolic complications. Novel laboratory methods are available that might be useful in the elucidation of the mechanism responsible for the hypercoagulable state of Fv Leiden carriers. Methods: In this study we measured the levels of FVIIa, protbrombin fragment 1.2 (Fl + 2) and the tbrombin potential (ETP) in the following groups: (A) heterozygous FV Leiden carriers with proven venous thromboembolism in the past; (B) asymptomatic first-degree family members heterozygous for the FV Leiden mutation; (C) first-degree non-carrier family members; and (D) heterozygous FV Leiden carriers, currently using oral anticoagulants. Groups A, B and C did not use oral anticoagulants. FVIIa levels were measured with a novel assay that utilises a sequence-specific, capture antibody (Philippou et al., Blood, in press) directed to factor VIIa combined with a functional factor VIIa assay. The ETP was measured according to Hemker et al. (Thromb Haemost, 1993:70:617-624). F1+2 levels were mea-
Abstracts/Netherlands
Journal
Noordijk ‘, P.W. Weijermans ‘, W.B.J. Gerrits ‘, P.J. Seelen 2, Ph.M. Kluin 5, P.F.H. Franck ‘, H. Kruijff ‘, J.C. Kluin-Nelemans 6. ’ Department of Internal Medicine, University Hospital, Leiden; ’ Paraprotein Task Force of the Comprehensive Cancer Centre West, Leiden; 3 Depaninent of Medical Statistics, University of Leiden; 4 Department of Clinical Oncology, University Hospital, Leiden; 5 Department of Pathology, University Hospital, Leiden; ’ Department of Hematology, University Hospital, L&den, Netherlands. To determine the incidence of different paraproteinaemias and the course of action followed by the physician, and to monitor the progression of different paraproteinaemias, a population-based registry was set up by the CCCW (The Netherlands). Included were all patients newly diagnosed with a paraprotein and/or MM in 1991, 1992, and 1993. Patients could be entered by clinical chemists in the case of paraproteinaemia and pathologists, internists, and haematologists in the case of MM. Information on presenting symptoms and signs, patient characteristics, results of laboratory, X-ray, and bone marrow examinations, diagnosis concerning the paraprotein, co-morbidity, and therapy were collected from the patients’ hospital records and entered into a database. Follow-up frequency was once yearly. In addition, a serum sample at first diagnosis was collected and stored centrally at - 70°C. A total of 1832 applications was received, of which 82% were from clinical chemists and 18% from other sources. About 17% of the applications were discarded because they did not meet the inclusion criteria, mainly because a paraprotein had already been found before 1991. To date, 1389 patients have been included in the registry. MM constituted 17%; other haematological malignancies 11%; paraproteins accompanying solid tumours, auto-immune disorders or infections occurred in 16%; monoclonal gammopathy of undetermined significance (MGUSl in 22%; in 3% uncertain diagnosis, while no diagnosis at all was made in 31%, mostly because no action was taken by the physician. From the second quarter of 1992 onward, the latter percentage decreased. The incidence of paraproteinaemia in the CCCW region in 1992 was 31/100000 inhabitants, and 189/100000 for ages 70 and above. The incidence of MM was 4.3/100000, which was comparable to the 4.0 for females, and 4.6 for males reported by the Netherlands Cancer Registry in 1991, Conclusion: The Paraprotein Registry is a unique project because of its multi-disciplinary approach, and its close cooperation with clinical chemists. Apart from being a descriptive registry, this project may also have had a favourable influence on hospital policy concerning the detection and follow-up of patients with a paraproteinaemia. This work was supported by the Praeventiefonds, grant no. 2821620.
14. Incidence of deep-vein thrombosis and pulmonary embolism during hospitaIisatIon in a department of Internal medicine. B. Schuurman, M. Den Heijer, A.M. Nijs, S.J. Graafsma. Department of Internal Medicine, Mariaziekenhuis, Tilburg, Netherlands. Introduction: Hospitalisation is a well-known risk factor for thromboembolic complications. Most studies on the incidence of thrombosis focus on surgical patients. In the present study we
of Medicine
50 (1997)
Al-A44
studied the incidence of thromboembolic complications in a general internal department. Methods: In a retrospective study we collected data of all-patients admitted to the Department of Internal Medicine of the Mariahospital in the last 2 years for deep vein thrombosis (DVT) (ICD-code 453.8) or pulmonary embolism (PE) (ICD-code 415.1). We calculated incidence rates of thromboembolic events occurring during admission. Furthermore, we calculated incidence rates of patients primarily admitted for the same indications. Results: During the last 2 years the incidence rate of DVT during admission (DVT-D) was 0.4%, whereas 0.3% developed PE during admission (PE-D). In contrast, 2.6% of all internal patients were primarily admitted for DVT and 0.9% for PE. Surprisingly, all patients with DVT-D (n = 11) had a malignancy (100%). For PE-D patients this percentage was 50% (n = 3 out of 6 with PE-D). Incidence for DVT-D among cancer patients was 3.5% for DVT-D and 1.2% for PE-D (overall: 4.7%). The malignancies in the DVT-D group were: pancreatic carcinoma (n = 3). colorectal carcinoma (n = 21, large cell anaplastic lung carcinoma (n = 11, adenocarcinoma of unknown origin (n = 11, mammacarcinoma (n = l), cerebral non-Hodgkin lymphoma (n = l), intra-abdominal soft tissue sarcoma (n = 1) and Hodgkin’s disease (n = 1). Malignancies in the PE-D group were metastatic manunacarcinoma (n = 11, metastatic prostatic carcinoma (n = 1) and metastatic teratoma (n = 1). Overall, 82.35% (14/17) of thromboembolic complications during admission were related to malignancy. In comparison, among 31 patients admitted primarily for DVT during the last year only 6 were related to malignancy (19.35%), whereas 2 patients with PE out of 8 had a malignancy (25%). Conclusions: Our data indicate that a high percentage of internal patients developing DVT-D or PE-D (82.35%) have a malignancy. This may be explained by the combination of hospitalisation and malignancy, which are both established risk factors for thrombosis. Further study is warranted to investigate whether prophylaxis of thrombotic events in these patients is feasible.
15. Acquired Cl-inhibitor deficiency with &A-kappa neutralizing antibody. D.J. van Spronsen ‘, S.J. Hoomtje i, A.J. Hannema 2, C.E. Hack 2. ’ Department of Internal Medicine, Catharina Hospital, Eindhoven; 2 Central Laboratory for the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, Netherlands. A 58-year-old man was seen with complaints of recurrent edema for several years. His medical history consisted of a totally resected malignant hypemephroma at age of 51 years and recurrent abdominal pain. Many potential causes of abdominal pain, including intlammatory bowel disease were excluded by laboratory testing and barium enemas. Additionally, he had complaints of recurrent non-itching edema of the tongue, face, feet and scrotum, and bouts of abdominal pain with nausea which lasted for several days. None of his family members ever suffered from angio-edema. Physical examination was completely normal, as were routine haematology and biochemistry results. The Cl inhibitor (ClINH) level appeared to be markedly decreased ( < 0.05; normal 0.76-1.33 U/ml), as were Clq (5; normal 81-128 U/ml)
Abstracts
/Netherlands
Journal
and C4 (0.02; normal 0.15-0.45 U/ml). Since acquired angioedema is associated with B-cell abnormalities, an additional search was performed. Levels of immunoglobulins, routine electrophoresis, immune-complex level and cryoblobulins were all normal. However, with immunofixation an IgA-kappa paraprotein could be detected. A high titer of IgA-kappa neutralizing antibody against C 1INH was found. Though routine histologic examination of bone marrow biopsy was normal, immuno-phenotyping showed evidence for an monoclonal population of IgA-kappa-positive plasma cells. Estimations of ClINH levels were normal in fustdegree relatives. Treatment was started with danazol 200 mg, thrice a day. Until 10 months of follow-up the condition of our patient has been stable, without recurrence of attacks. Conclusions: This patient suffered from ‘acquired angioedema’ because of low levels Clq and C4, the late onset of symptoms, and the absence of disease in the first-degree relatives. The Cl inhibitor deficiency resulted from a high titer of IgA-kappa antibody that inactivates Cl-inhibitor, produced by a monoclonal population of plasma cells (monoclonal gammopathy of undetermined significance).
16. Hlgb prevalence of penicillin-resistant viridans streptococci in patients selected for intensive chemotherapy. 0. Visser * , D.J. Richel *, M.R. Schaafsma * and M.G.R. Hendrix #. * Department of Haematology, Medisch Spectrum Twente, Enschede; # Regional Laboratory of Public Health, Enschede, Netherlands. Despite penicillin prophylaxis, recently several episodes of often fatal bacteraemia caused by penicillin-resistant viridans streptococci (VS) have been described in patients undergoing intensive chemotherapy. Therefore a surveillance culture should include a method for detecting penicillin-resistant VS. The purpose of the present study was to investigate the prevalence of penicillin-resistant VS in our haematology department. We evaluated 59 patients (14 acute myeloid leukaemia, 9 non-Hodgkin lymphoma, 9 multiple myeloma, 19 breast cancer, 8 miscellaneous) for tbe presence of penicillin-resistant VS (MIC > 2.0 u/d. Results: 36% (21/59) of the patients were demonstrated to be colonized with penicillin-resistant VS. Further antibiotic resistance analysis revealed two different patterns of resistance: one pattern showing isolated penicillin resistance, but susceptibility to other beta-lactams; another pattern demonstrating resistance to all betalactams. In some patients, VS with both patterns could be isolated simultaneously, while others showed only one pattern. No betalactamase production was observed in any of the isolates. Therefore beta-lactam resistance might be explained by alterations in penicillin binding proteins (PBP). All isolates were susceptible to glycopeptides (MIC teicoplanin < 2 pg/ml, MIC vancomycin < 2 pg/ml), and no high-level aminoglycoside resistance (MIC > 500 kg/ml) was observed. Conclusion: From these data it might be concluded that 36% of patients selected for intensive chemotherapy are colonized by penicillin-resistant VS. Considering the high percentage of betalactam-resistant VS, a prophylactic regimen including a glycopeptide is mandatory in this subgroup of patients.
of Medicine
50 (1997)
Al -A44
Al
17. The development of inhibitmy a&bodies agniast factor A. A.J. Vlot, S. VIII in a patient with moderate Wittebol. Department of Internal Medicine, Eemland Hospital, Amersfoort,
Netherlands.
In patients with hemophilia A, a serious complication is the induction of antibodies to factor VIII @VIII). This occurs in 8-20% of patients with almost exclusively the severe form of hemophilia A. We describe a 68-year-old patient with the moderate form of hemophilia A with FVIII:C and von Willebmnd factor levels of 36 and 160%, respectively. In 1989 he underwent an elective operative excision with replacement with a graft for an aortic aneurysm. To correct the factor deficiency during surgery and during the postoperative course, he received an intermediate, purified, heat-treated FVIII concentrate. Therapeutic levels of FVIII were obtained and the postoperative course was uneventful. No antibodies against factor VIII were detectable. In July 1996 he underwent prostatectomy for which he received a monoclonally purified FVIII concentrate. The total amount of FVIII received was 5 1700 units in 24 exposure days. Five months later re-admission followed for evaluation of generalised ecchymoses. At referral, his AP7T was prolonged by 80 s and FVIII was < 1%. Antibodies to FVIII were demonstrated by the Bethesda assay (inhibitor titer 15 BU/ml). The patient was treated with activated prothrombinase complex concentrates. The present therapy consists of FVIII/vWF concentrates to induce immune tolerance, as described by Mauser-Bunschoten et al. (Blood 1995;86:983-988). Conclusion: Our patient with moderate hemophilia A probably developed an inhibitor cross-reacting with endogenous FVIII. Whether this is caused by the monoclonally purified FVIII or by other substancespresent in the coagulation factor product remains to be investigated. 18. Factor VIIa is elevated by factor V L&en. W. Waale ‘, R. van Oerle ‘, L. van Pampus I, T. Lindhout ‘, H. Phulippou 3, D.A. Lane 3, K. Hamuly& ‘. ’ Department of Haematology, University Hospital, Maastricht; 2 Department Maastricht University, Maastricht, Netherlands; Haematology, Charing Cross and Westminster London, UK.
of Biochemistry, 3 Department qf Medical School,
Background: It is well known that heterozygous carriers of the Fv L&den mutation have an increased risk for venous thromboembolic complications. Novel laboratory methods are available that might be useful in the elucidation of the mechanism responsible for the hypercoagulable state of Fv Leiden carriers. Methods: In this study we measured the levels of FVIIa, protbrombin fragment 1.2 (Fl + 2) and the tbrombin potential (ETP) in the following groups: (A) heterozygous FV Leiden carriers with proven venous thromboembolism in the past; (B) asymptomatic first-degree family members heterozygous for the FV Leiden mutation; (C) first-degree non-carrier family members; and (D) heterozygous FV Leiden carriers, currently using oral anticoagulants. Groups A, B and C did not use oral anticoagulants. FVIIa levels were measured with a novel assay that utilises a sequence-specific, capture antibody (Philippou et al., Blood, in press) directed to factor VIIa combined with a functional factor VIIa assay. The ETP was measured according to Hemker et al. (Thromb Haemost, 1993:70:617-624). F1+2 levels were mea-