Case report 395
Lymphoplasmacytic lymphoma exposed by haemoptysis and acquired von Willebrand syndrome Line Couckea, Ludo Marcelisb, Dries Deerenc, Jo Van Dorped, Kathleen Lambeine and Katrien Devreesea We report on a 36-year-old man who presented to the emergency department with haemoptysis. Computed tomography (CT) of the thorax showed a pulmonary mass paramediastinal in the right upper lobe, with the density of a haematoma. Laboratory data demonstrated an absolute lymphocytosis of 5.900 T 109/l (normal range, 1.150–3.250 T 109/l) and a prolonged activated partial thromboplastin time (APTT) of 47.7 s (normal range, 28.0–39.0 s). A de novo diagnosis of lymphoplasmacytic lymphoma (Waldenstro¨m macroglobulinaemia) was made, complicated by an acquired von Willebrand syndrome (aVWS) as demonstrated by further laboratory investigations. In this case report, we present a case of aVWS with markedly prolonged APTT and haemoptysis that revealed an underlying Waldenstro¨m macroglobulinaemia.
Introduction Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder. The prevalence is estimated to be low, but the actual prevalence in the general population is unknown [1]. aVWS presents as a bleeding disorder usually in adult patients with negative personal or family bleeding history. Bleeding severity varies from absent or mild bleeding tendency to life-threatening haemorrhage. aVWS occurs typically in patients with a clonal haematological malignancy, cardiovascular or immunologic disorders. aVWS is associated with lymphoproliferative disorders in approximately 30% of cases [2]. Both clinical presentation with mucocutaneous bleeding and laboratory findings are similar to inherited von Willebrand disease.
Case report A 36-year-old man presented to the emergency department with haemoptysis. The patient’s family history of bleeding was negative. The patient was not taking any medications that could induce altered blood coagulation. Computed tomography (CT) of the chest exposed a pulmonary mass paramediastinal in the right upper lobe with a diameter of 6.2 cm, with the density of a haematoma. A CT of the abdomen showed retroperitoneal adenopathies situated at the left-sided infrarenal para-aortic lymph nodes and surrounding the common iliac artery. The complete blood count showed a white cell count of 9.040 109/l (normal range, 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Blood Coagul Fibrinolysis 25:395–397 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:395–397 Keywords: acquired von Willebrand syndrome, haemoptysis, non-Hodgkin lymphoma, von Willebrand factor, Waldenstro¨m macroglobulinaemia a Coagulation Laboratory, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, bClinical Laboratory, cClinical Hematology, dDepartment of Pathology, AZ Delta Hospital, Roeselare and e Department of Pathology, Ghent University Hospital, Ghent, Belgium
Correspondence to Line Coucke, MPharm, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital 2P8, De Pintelaan 185, 9000 Ghent, Belgium E-mail: [email protected] Received 24 July 2013 Revised 13 November 2013 Accepted 1 December 2013
3.700–9.500 109/l), platelet count of 174 109/l (normal range, 150–450 109/l) and a haemoglobin concentration of 99 g/l (normal range, 133–167 g/l). Immunophenotyping and protein electrophoresis of the peripheral blood were consistent with lymphoplasmacytic lymphoma (LPL, absolute B lymphocytosis 1.552/ml, kappa light chainþ, CD5, CD10), with an IgM monoclonal gammopathy and IgM concentration of 62 g/l (normal range, 0.4–2.3 g/l). Bone marrow aspiration was unsuccessful because of a dry tap, the bone marrow biopsy was diffusely infiltrated with LPL. There were no clinical signs of hyperviscosity syndrome (no skin bleeds, no headache, dizziness, blurred vision or vertigo) and fundoscopic examination was normal. The patient’s serum tested negative for the presence of cryoglobulins. Further investigation for coagulation abnormalities to determine the cause of the lung bleeding revealed a prolonged activated partial thromboplastin time (APTT) of 47.7 s (normal range, 28.0–39.0 s) and normal prothrombin time (PT) of 14.1 s (11.6–19.2 s). Functional analysis of blood platelets measuring the closure time by platelet function analysis (PFA) was inconclusive because of low haematocrit 32.3% (normal range 39.0– 50.0%) [3]. The nature of APTT prolongation was studied by mixing the patient’s plasma with normal pooled plasma (NPP) and this supported a deficiency rather than the presence of an inhibitor. Results for von Willebrand factor (VWF) antigen (VWF:Ag) 15% (normal range, 50–160%), ristocetin cofactor activity (VWF:RCo) DOI:10.1097/MBC.0000000000000052
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
396 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 4
Fig. 1
Course of laboratory test results during hospitalization and treatment (x-axis). For the activated partial thromboplastin time (APTT), normal results preceding the diagnosis by 3 years are shown in grey. Both the APTT (s; solid line) and the IgM concentration in serum (g/l; dotted line) were prolonged at diagnosis, plotted on the primary y-axis. The bars represent additional test results on the secondary y-axis for FVIII (%), VWF antigen (%) and VWF ristocetin cofactor activity (%): all are decreased at diagnosis. At the bottom of the figure, below the x-axis, each R-CHOP administration is shown. After three R-CHOP administrations, FVIII increased from 14 to 46%. Six and 12 months after the initial diagnosis, all coagulation test results remain within the normal range and the IgM concentration is decreasing slowly. R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and methylprednisolone; VWF, von Willebrand factor; VWS, von Willebrand syndrome.
9% (normal range, 50–160%), collagen-binding capacity (VWF:CB) 19% (normal range, 60–130%) and VWF activity (VWF:Act, latex immunoturbidimetric assay) 20% (normal range, 50–150%) were all decreased. Coagulation factor VIII (FVIII:C) activity was 17% (normal range, 60–150%). No FVIII:C inhibitor was present. Quantitative analysis of VWF propeptide yielded a normal result (60.6%; normal value 60–140%), gel electrophoresis of VWF multimers was qualitatively normal. Additional immunohistochemical staining of the bone marrow biopsy showed no aberrant expression of CD42b on lymphoplasmacytic cells.
Discussion In the reported case, patient’s history and laboratory tests were in favour of aVWS associated with LPL. The patient’s presenting feature upon admission was haemoptysis. Thorax imaging showed an opaque mass with the density of blood that could explain the patient’s symptoms. Biochemical tests, flow cytometry and pathology tests on peripheral blood and bone marrow were all concordant with the diagnosis of Waldenstro¨m
macroglobulinaemia. The patient had only one adverse prognostic factor at diagnosis: the haemoglobin concentration of 99 g/l. This corresponds to the low-risk category by the International Prognostic Scoring System for Waldestro¨m’s Macroglobulinaemia (ISSWM) [4]. According to the aVWS registry and the literature, 2– 4% of aVWS cases are LPL patients [2]. A recent study by Hivert et al. [5] assessed VWF antigen and VWF:RCo in 72 consecutive patients with Waldenstro¨m macroglobulinaemia. A total of 13% of the patients met the diagnostic criteria of aVWS. Antibodies to VWF are known to be involved in the pathogenesis, especially if the aVWS coincides with a lymphoproliferative or myeloproliferative disorder. However, even if these inhibitory antibodies are responsible for the acquired bleeding disorder, the current laboratory techniques fail to detect all anti-VWF antibodies. Only in a minority of patients, approximately 10%, will an antibody be detected [2]. The detection of VWF inhibitors could alter the therapeutic approach: patients with IgG autoantibodies may benefit from intravenous immunoglobulin infusions, immunosuppressants or plasmapheresis. Additional tests to ascertain the pathogenic
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acquired von Willebrand syndrome Coucke et al. 397
mechanism in the described case could not indicate a neutralizing VWF inhibitor: VWF activity measured by latex turbidimetry normalized after mixing the index plasma with NPP (61%; normal range, 50–150%). An ELISA assay with recombinant VWF could not demonstrate the presence of an inhibitor. The VWF propeptide level was normal, indicating normal VWF synthesis. A described mechanism for decreased VWF is adsorption to the malignant cells [6]. Case reports of lymphoma accompanied by aVWS have demonstrated increased expression of CD42b on the malignant cell surface, which account for platelet-binding properties and consequently VWF binding [7]. However, CD42b staining of lymphoplasmacytic cells on the bone marrow biopsy of this patient was negative. Hyperviscosity syndrome is a complication of aVWS in 10–30% of cases [8]. In this patient, no clinical signs were present, and fundoscopy was normal. Thus, no plasmapheresis was necessary. In general, the treatment options for aVWS are predominantly focused on treating the underlying disorder, but in light of prevention and treatment of bleeding episodes, treatment with desmopressin, VWF/ FVIII concentrate, plasmapheresis or intravenous immunoglobulin in cases with monoclonal IgG production is reported successful in the literature [9]. Treatment for LPL was initiated with rituximab, cyclophosphamide, doxorubicin, vincristine and methylprednisolone (R-CHOP), resulting in rapid normalization of APTT, VWF:Ag, VWF:RCo and FVIII:C levels (Fig. 1), slow decrease of plasma IgM values and resolution of the pulmonary mass.
Conclusion
In this case report, we illustrated that the diagnosis of aVWS relies on clinical suspicion and a careful bleeding history. A correct diagnosis needs further laboratory testing and is necessary for an optimal management.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3
4
5
6
7
8 9
Kumar S, Pruthi RK, Nichols WL. Estimation of prevalence and natural history of acquired von Willebrand disease. Haemophilia 2000; 6:212–221. Budde U, Federici AB, Rand JH. Pathophysiology, epidemiology, diagnosis, and treatment of acquired von Willebrand syndrome. In: Federici AB, Lee CA, Berntorp EE, Lillicrap D, Montgomery RR, editors. Von Willebrand disease basic and clinical aspects, 1st ed. Chichester: Wiley-Blackwell; 2011. pp. 214–230. Harrison P, Robison MS, Mackie IJ, Joseph J, McDonald SJ, Liesner R, et al. Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coagul Fibrinolysis 1999; 10:25–31. Morel P, Duhamel A, Gobbi P, Dimopoulos M, Dhodapkar M, McCoy J, et al. International Prognostic Scoring System for Waldenstro¨m Macroglobulinemia. Blood 2009; 113:4163–4170. Hivert B, Caron C, Petit S, Charpy C, Fankam-Siaka C, Lecocq S, et al. Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenstro¨m macroglobulinemia. Blood 2012; 120:3214–3221. Michiels JJ, Budde U, van der Planken M, van Vliet HHDM, Schroyens W, Berneman Z. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol 2001; 14:401–436. Tefferi A, Hanson CA, Kurtin PJ, Katzmann JA, Dalton RJ, Nichols WL. Acquired von Willebrand’s disease due to aberrant expression of platelet glycoprotein 1b by marginal zone lymphoma cells. Br J Haematol 1997; 96:850–853. Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood 2012; 119:2205–2208. Tiede A, Rand J, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome? Blood 2011; 117:6777–6785.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lymphoplasmacytic lymphoma exposed by haemoptysis and acquired von Willebrand syndrome Line Couckea, Ludo Marcelisb, Dries Deerenc, Jo Van Dorped, Kathleen Lambeine and Katrien Devreesea We report on a 36-year-old man who presented to the emergency department with haemoptysis. Computed tomography (CT) of the thorax showed a pulmonary mass paramediastinal in the right upper lobe, with the density of a haematoma. Laboratory data demonstrated an absolute lymphocytosis of 5.900 T 109/l (normal range, 1.150–3.250 T 109/l) and a prolonged activated partial thromboplastin time (APTT) of 47.7 s (normal range, 28.0–39.0 s). A de novo diagnosis of lymphoplasmacytic lymphoma (Waldenstro¨m macroglobulinaemia) was made, complicated by an acquired von Willebrand syndrome (aVWS) as demonstrated by further laboratory investigations. In this case report, we present a case of aVWS with markedly prolonged APTT and haemoptysis that revealed an underlying Waldenstro¨m macroglobulinaemia.
Introduction Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder. The prevalence is estimated to be low, but the actual prevalence in the general population is unknown [1]. aVWS presents as a bleeding disorder usually in adult patients with negative personal or family bleeding history. Bleeding severity varies from absent or mild bleeding tendency to life-threatening haemorrhage. aVWS occurs typically in patients with a clonal haematological malignancy, cardiovascular or immunologic disorders. aVWS is associated with lymphoproliferative disorders in approximately 30% of cases [2]. Both clinical presentation with mucocutaneous bleeding and laboratory findings are similar to inherited von Willebrand disease.
Case report A 36-year-old man presented to the emergency department with haemoptysis. The patient’s family history of bleeding was negative. The patient was not taking any medications that could induce altered blood coagulation. Computed tomography (CT) of the chest exposed a pulmonary mass paramediastinal in the right upper lobe with a diameter of 6.2 cm, with the density of a haematoma. A CT of the abdomen showed retroperitoneal adenopathies situated at the left-sided infrarenal para-aortic lymph nodes and surrounding the common iliac artery. The complete blood count showed a white cell count of 9.040 109/l (normal range, 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Blood Coagul Fibrinolysis 25:395–397 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:395–397 Keywords: acquired von Willebrand syndrome, haemoptysis, non-Hodgkin lymphoma, von Willebrand factor, Waldenstro¨m macroglobulinaemia a Coagulation Laboratory, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, bClinical Laboratory, cClinical Hematology, dDepartment of Pathology, AZ Delta Hospital, Roeselare and e Department of Pathology, Ghent University Hospital, Ghent, Belgium
Correspondence to Line Coucke, MPharm, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital 2P8, De Pintelaan 185, 9000 Ghent, Belgium E-mail: [email protected] Received 24 July 2013 Revised 13 November 2013 Accepted 1 December 2013
3.700–9.500 109/l), platelet count of 174 109/l (normal range, 150–450 109/l) and a haemoglobin concentration of 99 g/l (normal range, 133–167 g/l). Immunophenotyping and protein electrophoresis of the peripheral blood were consistent with lymphoplasmacytic lymphoma (LPL, absolute B lymphocytosis 1.552/ml, kappa light chainþ, CD5, CD10), with an IgM monoclonal gammopathy and IgM concentration of 62 g/l (normal range, 0.4–2.3 g/l). Bone marrow aspiration was unsuccessful because of a dry tap, the bone marrow biopsy was diffusely infiltrated with LPL. There were no clinical signs of hyperviscosity syndrome (no skin bleeds, no headache, dizziness, blurred vision or vertigo) and fundoscopic examination was normal. The patient’s serum tested negative for the presence of cryoglobulins. Further investigation for coagulation abnormalities to determine the cause of the lung bleeding revealed a prolonged activated partial thromboplastin time (APTT) of 47.7 s (normal range, 28.0–39.0 s) and normal prothrombin time (PT) of 14.1 s (11.6–19.2 s). Functional analysis of blood platelets measuring the closure time by platelet function analysis (PFA) was inconclusive because of low haematocrit 32.3% (normal range 39.0– 50.0%) [3]. The nature of APTT prolongation was studied by mixing the patient’s plasma with normal pooled plasma (NPP) and this supported a deficiency rather than the presence of an inhibitor. Results for von Willebrand factor (VWF) antigen (VWF:Ag) 15% (normal range, 50–160%), ristocetin cofactor activity (VWF:RCo) DOI:10.1097/MBC.0000000000000052
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
396 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 4
Fig. 1
Course of laboratory test results during hospitalization and treatment (x-axis). For the activated partial thromboplastin time (APTT), normal results preceding the diagnosis by 3 years are shown in grey. Both the APTT (s; solid line) and the IgM concentration in serum (g/l; dotted line) were prolonged at diagnosis, plotted on the primary y-axis. The bars represent additional test results on the secondary y-axis for FVIII (%), VWF antigen (%) and VWF ristocetin cofactor activity (%): all are decreased at diagnosis. At the bottom of the figure, below the x-axis, each R-CHOP administration is shown. After three R-CHOP administrations, FVIII increased from 14 to 46%. Six and 12 months after the initial diagnosis, all coagulation test results remain within the normal range and the IgM concentration is decreasing slowly. R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and methylprednisolone; VWF, von Willebrand factor; VWS, von Willebrand syndrome.
9% (normal range, 50–160%), collagen-binding capacity (VWF:CB) 19% (normal range, 60–130%) and VWF activity (VWF:Act, latex immunoturbidimetric assay) 20% (normal range, 50–150%) were all decreased. Coagulation factor VIII (FVIII:C) activity was 17% (normal range, 60–150%). No FVIII:C inhibitor was present. Quantitative analysis of VWF propeptide yielded a normal result (60.6%; normal value 60–140%), gel electrophoresis of VWF multimers was qualitatively normal. Additional immunohistochemical staining of the bone marrow biopsy showed no aberrant expression of CD42b on lymphoplasmacytic cells.
Discussion In the reported case, patient’s history and laboratory tests were in favour of aVWS associated with LPL. The patient’s presenting feature upon admission was haemoptysis. Thorax imaging showed an opaque mass with the density of blood that could explain the patient’s symptoms. Biochemical tests, flow cytometry and pathology tests on peripheral blood and bone marrow were all concordant with the diagnosis of Waldenstro¨m
macroglobulinaemia. The patient had only one adverse prognostic factor at diagnosis: the haemoglobin concentration of 99 g/l. This corresponds to the low-risk category by the International Prognostic Scoring System for Waldestro¨m’s Macroglobulinaemia (ISSWM) [4]. According to the aVWS registry and the literature, 2– 4% of aVWS cases are LPL patients [2]. A recent study by Hivert et al. [5] assessed VWF antigen and VWF:RCo in 72 consecutive patients with Waldenstro¨m macroglobulinaemia. A total of 13% of the patients met the diagnostic criteria of aVWS. Antibodies to VWF are known to be involved in the pathogenesis, especially if the aVWS coincides with a lymphoproliferative or myeloproliferative disorder. However, even if these inhibitory antibodies are responsible for the acquired bleeding disorder, the current laboratory techniques fail to detect all anti-VWF antibodies. Only in a minority of patients, approximately 10%, will an antibody be detected [2]. The detection of VWF inhibitors could alter the therapeutic approach: patients with IgG autoantibodies may benefit from intravenous immunoglobulin infusions, immunosuppressants or plasmapheresis. Additional tests to ascertain the pathogenic
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acquired von Willebrand syndrome Coucke et al. 397
mechanism in the described case could not indicate a neutralizing VWF inhibitor: VWF activity measured by latex turbidimetry normalized after mixing the index plasma with NPP (61%; normal range, 50–150%). An ELISA assay with recombinant VWF could not demonstrate the presence of an inhibitor. The VWF propeptide level was normal, indicating normal VWF synthesis. A described mechanism for decreased VWF is adsorption to the malignant cells [6]. Case reports of lymphoma accompanied by aVWS have demonstrated increased expression of CD42b on the malignant cell surface, which account for platelet-binding properties and consequently VWF binding [7]. However, CD42b staining of lymphoplasmacytic cells on the bone marrow biopsy of this patient was negative. Hyperviscosity syndrome is a complication of aVWS in 10–30% of cases [8]. In this patient, no clinical signs were present, and fundoscopy was normal. Thus, no plasmapheresis was necessary. In general, the treatment options for aVWS are predominantly focused on treating the underlying disorder, but in light of prevention and treatment of bleeding episodes, treatment with desmopressin, VWF/ FVIII concentrate, plasmapheresis or intravenous immunoglobulin in cases with monoclonal IgG production is reported successful in the literature [9]. Treatment for LPL was initiated with rituximab, cyclophosphamide, doxorubicin, vincristine and methylprednisolone (R-CHOP), resulting in rapid normalization of APTT, VWF:Ag, VWF:RCo and FVIII:C levels (Fig. 1), slow decrease of plasma IgM values and resolution of the pulmonary mass.
Conclusion
In this case report, we illustrated that the diagnosis of aVWS relies on clinical suspicion and a careful bleeding history. A correct diagnosis needs further laboratory testing and is necessary for an optimal management.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 2
3
4
5
6
7
8 9
Kumar S, Pruthi RK, Nichols WL. Estimation of prevalence and natural history of acquired von Willebrand disease. Haemophilia 2000; 6:212–221. Budde U, Federici AB, Rand JH. Pathophysiology, epidemiology, diagnosis, and treatment of acquired von Willebrand syndrome. In: Federici AB, Lee CA, Berntorp EE, Lillicrap D, Montgomery RR, editors. Von Willebrand disease basic and clinical aspects, 1st ed. Chichester: Wiley-Blackwell; 2011. pp. 214–230. Harrison P, Robison MS, Mackie IJ, Joseph J, McDonald SJ, Liesner R, et al. Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coagul Fibrinolysis 1999; 10:25–31. Morel P, Duhamel A, Gobbi P, Dimopoulos M, Dhodapkar M, McCoy J, et al. International Prognostic Scoring System for Waldenstro¨m Macroglobulinemia. Blood 2009; 113:4163–4170. Hivert B, Caron C, Petit S, Charpy C, Fankam-Siaka C, Lecocq S, et al. Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenstro¨m macroglobulinemia. Blood 2012; 120:3214–3221. Michiels JJ, Budde U, van der Planken M, van Vliet HHDM, Schroyens W, Berneman Z. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol 2001; 14:401–436. Tefferi A, Hanson CA, Kurtin PJ, Katzmann JA, Dalton RJ, Nichols WL. Acquired von Willebrand’s disease due to aberrant expression of platelet glycoprotein 1b by marginal zone lymphoma cells. Br J Haematol 1997; 96:850–853. Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood 2012; 119:2205–2208. Tiede A, Rand J, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome? Blood 2011; 117:6777–6785.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
