Leukemia & Lymphoma
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia Mona Lisa Alattar, Maria Ciccone, Mahmoud R. Gaballa, Candida Vitale, Xavier C. Badoux, George Manoukian, Michael J. Keating, Michael H. Kroll & Alessandra Ferrajoli To cite this article: Mona Lisa Alattar, Maria Ciccone, Mahmoud R. Gaballa, Candida Vitale, Xavier C. Badoux, George Manoukian, Michael J. Keating, Michael H. Kroll & Alessandra Ferrajoli (2015): Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia, Leukemia & Lymphoma To link to this article: http://dx.doi.org/10.3109/10428194.2015.1037757
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Accepted author version posted online: 29 Apr 2015. Published online: 26 May 2015. Submit your article to this journal
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Date: 12 November 2015, At: 01:24
Leukemia & Lymphoma, 2015; Early Online: 1–3 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1037757
LETTER TO THE EDITOR
Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia Mona Lisa Alattar1*, Maria Ciccone1*, Mahmoud R. Gaballa2*, Candida Vitale1*, Xavier C. Badoux1, George Manoukian3, Michael J. Keating1, Michael H. Kroll3 & Alessandra Ferrajoli1
Downloaded by [University of Wisconsin Oshkosh] at 01:24 12 November 2015
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2Department of Cancer
Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA and 3Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
Acquired von Willebrand Syndrome (AVWS) is a bleeding disorder characterized by a non-inherited low activity of von Willebrand factor (VWF), occurring in patients with no prior medical or family history of bleeding disorders [1,2]. Although the real prevalence of AVWS is not completely addressed, patients with hematological malignancies account for the majority of cases in adults [3]. Different mechanisms have been proposed to explain the pathophysiology of AVWS [4]. The diagnostic work-up for AVWS includes platelet count, coagulation parameters, factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag) level, VWF ristocetin co-factor activity (VWF:RCo), and VWF high molecular weight multimers (VWF:MM) quantification. An international registry has been created for epidemiologic purposes and to collect information on the diseases that are associated with AVWS, in order to better define the pathogenesis, prognosis and optimal treatment of this rare disorder [5]. Here we describe three cases of AVWS occurring in patients with chronic lymphocytic leukemia (CLL), who presented with anemia and mucocutaneous bleeding. The characteristics of the three patients at the time of AVWS diagnosis are listed in Table I. The laboratory work-up assessed to confirm AVWS diagnosis and the clinical history are presented in Table II. This study was approved by the Human Subjects Institutional Review Board at the University of Texas MD Anderson Cancer Center (UTMDACC). Case 1 was a white female diagnosed with CLL at age 77. Her past medical history was significant for hypothyroidism and minor surgeries without history of bleeding. The first symptoms of AVWS developed 3 years after the diagnosis of CLL, and consisted of recurrent oral mucosal bleeding. Of note, the symptom onset approximately coincided with initiation of aspirin treatment. Investigation at that time revealed prolonged activated partial thromboplastin time (aPTT; 43.2 sec), normal prothrombin time (PT), 30% VWF:Ag, ⬍ 12% VWF:RCo, and 24% FVIII:C. Multimer study
showed decreased VWF:MM. Mucosal bleeding temporarily resolved with discontinuation of aspirin, and subsequent recurrences of the symptom were treated with aminocaproic acid mouth rinses. One year later, the patient underwent an elective abdominal hernia surgical repair, received human plasma-derived VWF (HP-VWF/FVIII) concentrate prior to surgery and had an uneventful perioperative course. Nine months later her CLL progressed and frontline treatment with lenalidomide and rituximab was started. After two cycles of therapy, the patient developed a severe gastrointestinal (GI) bleeding and treatment was held. An upper GI endoscopy revealed a duodenal polyp (negative for malignancy) and two small superficial gastric ulcers which were cauterized, but no evidence of angiodysplasia. Due to persistent melena and drop in hemoglobin (Hb) values, a Tag red cell study was done and showed active bleeding within the proximal small bowel. A second endoscopic exam revealed active bleeding from superficial vessels of the distal gastric body, which was controlled with endoclip positioning. Laboratory parameters showed Hb 7.5 g/dL, aPTT 43 sec, 53% VWF:Ag, ⬍ 12% VWF:RCo, 24% FVIII:C, decreased platelet aggregation to ristocetin, and factor VIII inhibitor level was less than 0.05 Bethesda Units. VWF replacement therapy was implemented. Ten days after receiving daily HP-VWF/FVIII replacement, she achieved 223% VWF:Ag, 170% VWF:RCo, 54% FVIII:C, and resolution of the GI bleeding. In the following months the clinical picture was complicated by the development of autoimmune hemolytic anemia with warm antibodies. Treatment with rituximab and methylprednisolone was started, and once the hemolysis resolved was followed by 5 cycles of reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR). A complete remission was achieved with normalized hemostatic parameters and no recurrences of bleeding for 3 years. At the time of this report, more than 5 years after the diagnosis of AVWS, the patient is alive and has not had any further episodes of bleeding or alterations of
*These four authors contributed equally to this report. Correspondence: Alessandra Ferrajoli, MD, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, PO Box 301402, Houston, TX 77030-1402, USA. Tel: Th 1 713 792 2063. Fax: Th 1 713 794 4297. E-mail: [email protected] Received 14 March 2015; revised 26 March 2015; accepted 28 March 2015
1
2 M. L. Alattar et al. Table I. Clinical characteristics of CLL at the time of AVWS diagnosis. Characteristic
Case 1
Case 2
Case 3
Age Gender Rai stage (0-4) FISH IGVH status ZAP70 CD38 DAT test
80 F 2 ⫹ 12, 13qUM (VH1-69) Positive Positive Positive (antiIgG and -C3)§ Hypothyroidism
66 M 1 ⫹ 12, 13q-, 17pUM (VH2-05) NA Positive Negative
65 M 1 11q-, ⫹ 12 UM (VH1-69) Positive Positive Negative
Downloaded by [University of Wisconsin Oshkosh] at 01:24 12 November 2015
Comorbidities
Hypertension
Melanoma, cardiac ischemic disease
FISH, fluorescence in situ hybridization; IGVH, Immunoglobulin variable region of heavy chain; M, mutated; UM, unmutated; DAT, direct antiglobulin test; NA, not available. §DAT test was positive at the time of CLL progression, after the first diagnosis of AVWS.
the coagulation parameters. She has undergone additional treatment with ofatumumab because of recurrent CLL. Case 2 was a 66-year-old African-American male who was otherwise healthy when he experienced severe melena. The initial workup was unrevealing, but the origin of the bleeding was located at the junction of the second and third portion of the duodenum. He underwent several endoscopic procedures, including cauterization, sclerotherapy, and banding. No evidence of angiodysplasia was detected endoscopically. Ultimately, he developed bulky lymphadenopathy, and a histologic diagnosis of CLL/small lymphocytic lymphoma was done. He was started on treatment at an outside facility with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, and because of persistent GI bleeding, was referred to MD Anderson Cancer Center for surgery. At the time of transfer he required resection of the third and fourth portions of duodenum, cholecystectomy, appendectomy, and intestinal reconstruction with a retrocolic side-to-side duodeno-jejunostomy. The pathology assessment excluded lymphoma localization or significant abnormalities on duodenum and jejunum, but revealed Richter’s transformation (large-cell lymphoma histology) on mesenteric lymphonodes, leading to the transitioning to a different chemotherapy regimen (hyper-fractionated cyclophosphamide, vincristine, and cytarabine, plus rituximab)
under the care of his local oncologist. He presented again at our institution approximately 6 months later for hematemesis and severe anemia. An upper endoscopy revealed a bleeding lesion at the efferent limb of the duodeno-jejunostomy, which was cauterized, with no benefit on the bleeding. A lower endoscopy resulted negative. The bleeding was finally controlled with further endoscopic sclerotherapy. Four years later, he presented again at MD Anderson Cancer Center with active CLL, without any evidence of Richter’s transformation, to discuss salvage treatment options. He received six cycles of therapy with oxaliplatin, fludarabine, cytarabine, and rituximab and achieved a complete remission. A few months after completing treatment, he again experienced GI bleeding. The bleeding initially responded to embolization of the gastroduodenal artery, but then recurred. A complete work-up was done and showed normal platelet aggregation to ristocetin, aPTT 47 sec, 29% VWF:Ag, 20% VWF:RCo, and 19% FVIII:C. The diagnosis of AVWS was made and replacement therapy with HP-VWF/FVIII concentrate was initiated, with a correction of the coagulation parameters (270% VWF:Ag, 164% VWF:RCo, and 160% FVIII:C after 1 day of treatment) and control of the bleeding. In the 4 following years, the patient underwent multiple treatment for disease recurrence (lenalidomide and rituximab; bendamustine and rituximab; ibrutinib; ofatumumab, cyclofosfamide and vincristine) and had many lengthy hospitalizations for GI bleeding despite VWF/FVIII replacement. He died with progressive disease approximately 9 years after the initial diagnosis. Case 3 was a 60-year-old white man diagnosed with CLL. He was treated with six cycles of FCR achieving a complete remission lasting more than 3 years. Unfortunately, 4 years after the CLL diagnosis, he was found to have stage III malignant melanoma of his left forearm, metastatic to left axillary lymph nodes. He was treated surgically and after the excision had prolonged bleeding at the surgical site. At that time, aPTT was 44 sec, PT was normal, VWF:Ag was ⬍ 19%, VWF:RCo 12%, FVIII:C 14%, and VWF:MM were decreased. He was therefore diagnosed with moderate-to-severe type 2A AVWS. Initial treatment with DDAVP was moderately effective and administration of HP-VWF/FVIII concentrate was needed to manage the post-operative bleeding and for prophylaxis before the subsequent invasive procedures required for local
Table II. Laboratory assessment at time of AVWS diagnosis and clinical history of bleeding disorder. AVWS characteristics VWF:Ag, % VWF:RCo, % VWF:RCo/Ag ratio* FVIII:C, % VWF:MM Plts (⫻ 103/μL) Hb (g/dL) FVIII inhibitor Bleeding prior to CLL diagnosis Family history of bleeding Outcome AVWS treatment
Case 1
Case 2
Case 3
30 ⬍ 12 ⬍ 0.4 24 Decreased 149 10.6 Negative None
29 20 0.68 19 NA 101 10.4 Not tested None
19 ⬍ 12 ⬍ 0.6 14 Decreased 190 11 Not tested None
Absent Patient deceased with active CLL Treatment of underlying disease and replacement therapy
Absent Patient deceased with metastatic melanoma and active CLL Treatment of underlying disease and replacement therapy
Absent AVWS bleeding resolved Treatment of underlying disease and replacement therapy
VWF:Ag, VWF antigen level; VWF:RCo, VWF ristocetin co-factor activity; FVIII:C, factor VIII coagulant activity; VWF:MM, VWF high molecular weight multimers; Plts, platelets; Hb, hemoglobin; NA, not available. *Normal VWF:RCo/Ag ratio is approximately 1.0 while in AVWS it can drop to values less than 0.6–0.7.
Downloaded by [University of Wisconsin Oshkosh] at 01:24 12 November 2015
AVWS in CLL recurrence of melanoma. Three years later he received salvage treatment for CLL with a combination of sapecitabine, cyclophosphamide, and rituximab according to a clinical study for patients with 11q deletion. However, shortly after initiation of therapy, he had two hospital admissions because of GI bleeding. At that time VWF:Ag was 22%, VWF:RCo ⬍ 12%, and FVIII:C 7%. He received HP-VWF/FVIII concentrate with resolution of the symptom and normalization of coagulation parameters. After five cycles a PET/CT scan revealed multiple diffuse areas of active disease, involving also the lungs and the liver. Due to a suspicion of secondary melanoma localizations, a CT-guided transthoracic biopsy of a pulmonary nodule was performed following adequate prophylaxis with HP-VWF/FVIII concentrate. Unfortunately, the procedure was complicated by fatal hemoptysis. The histological evaluation of the lung nodule was consistent with metastatic melanoma. Although lymphoproliferative disorders account for almost one-half of all AVWS cases, the exact prevalence of this syndrome is not known. The pathogenetic mechanisms responsible for AVWS are very heterogeneous, including the formation of autoantibodies, the absorption of VWF on the malignant cell surface, and a shear stress-induced loss of VWF:MM [6]. The diagnosis of AVWS in the three patients we described was suggested by the combination of bleeding, abnormalities of VWF activity, and absence of any episodes of bleeding prior to the diagnosis of CLL or of any family history of bleeding disorders. Although the factor VIII inhibitor was tested only in Case 1, and Case 2 lacks VWF:MM dosage, the presence of an AVWS-associated condition (e.g. CLL, hypothyroidism, solid tumor) in combination with reduced VWF:Ag and normal VWF:RCo/Ag ratio (Case 2), or in combination with reduced VWF:RCo/Ag ratio and reduced/absent VWF:MM (Cases 1 and 3) strongly supported the diagnosis of AVWS in our series, as has been previously described [1]. In contrast with acquired hemophilia, inhibitory antibodies have failed to be detected accurately by specific laboratory tests in AVWS [7]. Interestingly, all cases diagnosed at our institution had unmutated IGVH, trisomy 12 and CD38 positivity. Although the limited number of cases does not allow us to draw any definitive conclusions, our report suggests that the risk of AVWS could be associated with specific biological markers in CLL, as has already been highlighted for the risk of AIHA [8]. In two of the three cases, AVWS was diagnosed early in the course of CLL disease. However, in Case 3 the diagnosis of AVWS was almost concomitant with the occurrence of stage III melanoma, suggesting that this condition may have contributed to the onset of AVWS. Our patients’ presentation emphasizes the fact that AVWS occurs unpredictably
3
during the course of lymphoproliferative diseases. In all three patients, AVWS occurred after the diagnosis of CLL, however one published case of AVWS developed 10 months before the diagnosis of small lymphocytic lymphoma [9]. In individuals with B-cell lymphomas or multiple myeloma treated with chemotherapy (with or without rituximab), remission of AVWS can be achieved in up to 70% of patients [3]. Therefore, addressing the underlying disease is a mainstay of treatment in these patients [3,4]. The strong association between successful management of AVWS and the ability to control the underlying CLL is further supported by the outcome of our three cases. The patient who did not experience recurrence of bleeding was the one with better response to CLL treatment. In contrast, the recurrent bleeding in Case 2 and Case 3 is likely attributable to uncontrolled malignant disease(s) (in association with progressive melanoma in Case 3), stressing the importance of treating the underlying CLL in patients with bleeding complications associated with AVWS. Finally, the patients with AVWS diagnosed at our institution developed anemia due to significant bleeding, highlighting the need to include AVWS in the differential diagnosis of bleeding episodes in patients with CLL. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Federici AB, Rand JH, Bucciarelli P, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000;84:345–349. [2] Tiede A . Diagnosis and treatment of acquired von Willebrand syndrome. Thromb Res 2012;130(Suppl. 2): S2–6. [3] Tiede A , Rand JH, Budde U, et al. How I treat the acquired von Willebrand syndrome. Blood 2011;117:6777–6785. [4] Callaghan MU, Wong TE, Federici AB. Treatment of acquired von Willebrand syndrome in childhood. Blood 2013;122:2019–2022. [5] Federici AB, Budde U, Rand JH. Acquired von Willebrand syndrome 2004: International Registry–diagnosis and management from online to bedside. Hamostaseologie 2004;24:50–55. [6] Federici AB, Budde U, Castaman G, et al. Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update. Sem Thromb Hemost 2013;39:191–201. [7] Tiede A , Priesack J, Werwitzke S, et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008;6:569–576. [8] Maura F, Visco C, Falisi E, et al. B-cell receptor configuration and adverse cytogenetics are associated with autoimmune hemolytic anemia in chronic lymphocytic leukemia. Am J Hematol 2013;88: 32–36. [9] Slattery W, Rausch D, Saba N. Refractory acquired von Willebrand disease despite successful treatment of the associated lymphoma. Mayo Clinic Proc 2002;77:1391.
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia Mona Lisa Alattar, Maria Ciccone, Mahmoud R. Gaballa, Candida Vitale, Xavier C. Badoux, George Manoukian, Michael J. Keating, Michael H. Kroll & Alessandra Ferrajoli To cite this article: Mona Lisa Alattar, Maria Ciccone, Mahmoud R. Gaballa, Candida Vitale, Xavier C. Badoux, George Manoukian, Michael J. Keating, Michael H. Kroll & Alessandra Ferrajoli (2015): Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia, Leukemia & Lymphoma To link to this article: http://dx.doi.org/10.3109/10428194.2015.1037757
View supplementary material
Accepted author version posted online: 29 Apr 2015. Published online: 26 May 2015. Submit your article to this journal
Article views: 26
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [University of Wisconsin Oshkosh]
Date: 12 November 2015, At: 01:24
Leukemia & Lymphoma, 2015; Early Online: 1–3 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1037757
LETTER TO THE EDITOR
Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia Mona Lisa Alattar1*, Maria Ciccone1*, Mahmoud R. Gaballa2*, Candida Vitale1*, Xavier C. Badoux1, George Manoukian3, Michael J. Keating1, Michael H. Kroll3 & Alessandra Ferrajoli1
Downloaded by [University of Wisconsin Oshkosh] at 01:24 12 November 2015
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 2Department of Cancer
Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA and 3Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
Acquired von Willebrand Syndrome (AVWS) is a bleeding disorder characterized by a non-inherited low activity of von Willebrand factor (VWF), occurring in patients with no prior medical or family history of bleeding disorders [1,2]. Although the real prevalence of AVWS is not completely addressed, patients with hematological malignancies account for the majority of cases in adults [3]. Different mechanisms have been proposed to explain the pathophysiology of AVWS [4]. The diagnostic work-up for AVWS includes platelet count, coagulation parameters, factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag) level, VWF ristocetin co-factor activity (VWF:RCo), and VWF high molecular weight multimers (VWF:MM) quantification. An international registry has been created for epidemiologic purposes and to collect information on the diseases that are associated with AVWS, in order to better define the pathogenesis, prognosis and optimal treatment of this rare disorder [5]. Here we describe three cases of AVWS occurring in patients with chronic lymphocytic leukemia (CLL), who presented with anemia and mucocutaneous bleeding. The characteristics of the three patients at the time of AVWS diagnosis are listed in Table I. The laboratory work-up assessed to confirm AVWS diagnosis and the clinical history are presented in Table II. This study was approved by the Human Subjects Institutional Review Board at the University of Texas MD Anderson Cancer Center (UTMDACC). Case 1 was a white female diagnosed with CLL at age 77. Her past medical history was significant for hypothyroidism and minor surgeries without history of bleeding. The first symptoms of AVWS developed 3 years after the diagnosis of CLL, and consisted of recurrent oral mucosal bleeding. Of note, the symptom onset approximately coincided with initiation of aspirin treatment. Investigation at that time revealed prolonged activated partial thromboplastin time (aPTT; 43.2 sec), normal prothrombin time (PT), 30% VWF:Ag, ⬍ 12% VWF:RCo, and 24% FVIII:C. Multimer study
showed decreased VWF:MM. Mucosal bleeding temporarily resolved with discontinuation of aspirin, and subsequent recurrences of the symptom were treated with aminocaproic acid mouth rinses. One year later, the patient underwent an elective abdominal hernia surgical repair, received human plasma-derived VWF (HP-VWF/FVIII) concentrate prior to surgery and had an uneventful perioperative course. Nine months later her CLL progressed and frontline treatment with lenalidomide and rituximab was started. After two cycles of therapy, the patient developed a severe gastrointestinal (GI) bleeding and treatment was held. An upper GI endoscopy revealed a duodenal polyp (negative for malignancy) and two small superficial gastric ulcers which were cauterized, but no evidence of angiodysplasia. Due to persistent melena and drop in hemoglobin (Hb) values, a Tag red cell study was done and showed active bleeding within the proximal small bowel. A second endoscopic exam revealed active bleeding from superficial vessels of the distal gastric body, which was controlled with endoclip positioning. Laboratory parameters showed Hb 7.5 g/dL, aPTT 43 sec, 53% VWF:Ag, ⬍ 12% VWF:RCo, 24% FVIII:C, decreased platelet aggregation to ristocetin, and factor VIII inhibitor level was less than 0.05 Bethesda Units. VWF replacement therapy was implemented. Ten days after receiving daily HP-VWF/FVIII replacement, she achieved 223% VWF:Ag, 170% VWF:RCo, 54% FVIII:C, and resolution of the GI bleeding. In the following months the clinical picture was complicated by the development of autoimmune hemolytic anemia with warm antibodies. Treatment with rituximab and methylprednisolone was started, and once the hemolysis resolved was followed by 5 cycles of reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR). A complete remission was achieved with normalized hemostatic parameters and no recurrences of bleeding for 3 years. At the time of this report, more than 5 years after the diagnosis of AVWS, the patient is alive and has not had any further episodes of bleeding or alterations of
*These four authors contributed equally to this report. Correspondence: Alessandra Ferrajoli, MD, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, PO Box 301402, Houston, TX 77030-1402, USA. Tel: Th 1 713 792 2063. Fax: Th 1 713 794 4297. E-mail: [email protected] Received 14 March 2015; revised 26 March 2015; accepted 28 March 2015
1
2 M. L. Alattar et al. Table I. Clinical characteristics of CLL at the time of AVWS diagnosis. Characteristic
Case 1
Case 2
Case 3
Age Gender Rai stage (0-4) FISH IGVH status ZAP70 CD38 DAT test
80 F 2 ⫹ 12, 13qUM (VH1-69) Positive Positive Positive (antiIgG and -C3)§ Hypothyroidism
66 M 1 ⫹ 12, 13q-, 17pUM (VH2-05) NA Positive Negative
65 M 1 11q-, ⫹ 12 UM (VH1-69) Positive Positive Negative
Downloaded by [University of Wisconsin Oshkosh] at 01:24 12 November 2015
Comorbidities
Hypertension
Melanoma, cardiac ischemic disease
FISH, fluorescence in situ hybridization; IGVH, Immunoglobulin variable region of heavy chain; M, mutated; UM, unmutated; DAT, direct antiglobulin test; NA, not available. §DAT test was positive at the time of CLL progression, after the first diagnosis of AVWS.
the coagulation parameters. She has undergone additional treatment with ofatumumab because of recurrent CLL. Case 2 was a 66-year-old African-American male who was otherwise healthy when he experienced severe melena. The initial workup was unrevealing, but the origin of the bleeding was located at the junction of the second and third portion of the duodenum. He underwent several endoscopic procedures, including cauterization, sclerotherapy, and banding. No evidence of angiodysplasia was detected endoscopically. Ultimately, he developed bulky lymphadenopathy, and a histologic diagnosis of CLL/small lymphocytic lymphoma was done. He was started on treatment at an outside facility with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, and because of persistent GI bleeding, was referred to MD Anderson Cancer Center for surgery. At the time of transfer he required resection of the third and fourth portions of duodenum, cholecystectomy, appendectomy, and intestinal reconstruction with a retrocolic side-to-side duodeno-jejunostomy. The pathology assessment excluded lymphoma localization or significant abnormalities on duodenum and jejunum, but revealed Richter’s transformation (large-cell lymphoma histology) on mesenteric lymphonodes, leading to the transitioning to a different chemotherapy regimen (hyper-fractionated cyclophosphamide, vincristine, and cytarabine, plus rituximab)
under the care of his local oncologist. He presented again at our institution approximately 6 months later for hematemesis and severe anemia. An upper endoscopy revealed a bleeding lesion at the efferent limb of the duodeno-jejunostomy, which was cauterized, with no benefit on the bleeding. A lower endoscopy resulted negative. The bleeding was finally controlled with further endoscopic sclerotherapy. Four years later, he presented again at MD Anderson Cancer Center with active CLL, without any evidence of Richter’s transformation, to discuss salvage treatment options. He received six cycles of therapy with oxaliplatin, fludarabine, cytarabine, and rituximab and achieved a complete remission. A few months after completing treatment, he again experienced GI bleeding. The bleeding initially responded to embolization of the gastroduodenal artery, but then recurred. A complete work-up was done and showed normal platelet aggregation to ristocetin, aPTT 47 sec, 29% VWF:Ag, 20% VWF:RCo, and 19% FVIII:C. The diagnosis of AVWS was made and replacement therapy with HP-VWF/FVIII concentrate was initiated, with a correction of the coagulation parameters (270% VWF:Ag, 164% VWF:RCo, and 160% FVIII:C after 1 day of treatment) and control of the bleeding. In the 4 following years, the patient underwent multiple treatment for disease recurrence (lenalidomide and rituximab; bendamustine and rituximab; ibrutinib; ofatumumab, cyclofosfamide and vincristine) and had many lengthy hospitalizations for GI bleeding despite VWF/FVIII replacement. He died with progressive disease approximately 9 years after the initial diagnosis. Case 3 was a 60-year-old white man diagnosed with CLL. He was treated with six cycles of FCR achieving a complete remission lasting more than 3 years. Unfortunately, 4 years after the CLL diagnosis, he was found to have stage III malignant melanoma of his left forearm, metastatic to left axillary lymph nodes. He was treated surgically and after the excision had prolonged bleeding at the surgical site. At that time, aPTT was 44 sec, PT was normal, VWF:Ag was ⬍ 19%, VWF:RCo 12%, FVIII:C 14%, and VWF:MM were decreased. He was therefore diagnosed with moderate-to-severe type 2A AVWS. Initial treatment with DDAVP was moderately effective and administration of HP-VWF/FVIII concentrate was needed to manage the post-operative bleeding and for prophylaxis before the subsequent invasive procedures required for local
Table II. Laboratory assessment at time of AVWS diagnosis and clinical history of bleeding disorder. AVWS characteristics VWF:Ag, % VWF:RCo, % VWF:RCo/Ag ratio* FVIII:C, % VWF:MM Plts (⫻ 103/μL) Hb (g/dL) FVIII inhibitor Bleeding prior to CLL diagnosis Family history of bleeding Outcome AVWS treatment
Case 1
Case 2
Case 3
30 ⬍ 12 ⬍ 0.4 24 Decreased 149 10.6 Negative None
29 20 0.68 19 NA 101 10.4 Not tested None
19 ⬍ 12 ⬍ 0.6 14 Decreased 190 11 Not tested None
Absent Patient deceased with active CLL Treatment of underlying disease and replacement therapy
Absent Patient deceased with metastatic melanoma and active CLL Treatment of underlying disease and replacement therapy
Absent AVWS bleeding resolved Treatment of underlying disease and replacement therapy
VWF:Ag, VWF antigen level; VWF:RCo, VWF ristocetin co-factor activity; FVIII:C, factor VIII coagulant activity; VWF:MM, VWF high molecular weight multimers; Plts, platelets; Hb, hemoglobin; NA, not available. *Normal VWF:RCo/Ag ratio is approximately 1.0 while in AVWS it can drop to values less than 0.6–0.7.
Downloaded by [University of Wisconsin Oshkosh] at 01:24 12 November 2015
AVWS in CLL recurrence of melanoma. Three years later he received salvage treatment for CLL with a combination of sapecitabine, cyclophosphamide, and rituximab according to a clinical study for patients with 11q deletion. However, shortly after initiation of therapy, he had two hospital admissions because of GI bleeding. At that time VWF:Ag was 22%, VWF:RCo ⬍ 12%, and FVIII:C 7%. He received HP-VWF/FVIII concentrate with resolution of the symptom and normalization of coagulation parameters. After five cycles a PET/CT scan revealed multiple diffuse areas of active disease, involving also the lungs and the liver. Due to a suspicion of secondary melanoma localizations, a CT-guided transthoracic biopsy of a pulmonary nodule was performed following adequate prophylaxis with HP-VWF/FVIII concentrate. Unfortunately, the procedure was complicated by fatal hemoptysis. The histological evaluation of the lung nodule was consistent with metastatic melanoma. Although lymphoproliferative disorders account for almost one-half of all AVWS cases, the exact prevalence of this syndrome is not known. The pathogenetic mechanisms responsible for AVWS are very heterogeneous, including the formation of autoantibodies, the absorption of VWF on the malignant cell surface, and a shear stress-induced loss of VWF:MM [6]. The diagnosis of AVWS in the three patients we described was suggested by the combination of bleeding, abnormalities of VWF activity, and absence of any episodes of bleeding prior to the diagnosis of CLL or of any family history of bleeding disorders. Although the factor VIII inhibitor was tested only in Case 1, and Case 2 lacks VWF:MM dosage, the presence of an AVWS-associated condition (e.g. CLL, hypothyroidism, solid tumor) in combination with reduced VWF:Ag and normal VWF:RCo/Ag ratio (Case 2), or in combination with reduced VWF:RCo/Ag ratio and reduced/absent VWF:MM (Cases 1 and 3) strongly supported the diagnosis of AVWS in our series, as has been previously described [1]. In contrast with acquired hemophilia, inhibitory antibodies have failed to be detected accurately by specific laboratory tests in AVWS [7]. Interestingly, all cases diagnosed at our institution had unmutated IGVH, trisomy 12 and CD38 positivity. Although the limited number of cases does not allow us to draw any definitive conclusions, our report suggests that the risk of AVWS could be associated with specific biological markers in CLL, as has already been highlighted for the risk of AIHA [8]. In two of the three cases, AVWS was diagnosed early in the course of CLL disease. However, in Case 3 the diagnosis of AVWS was almost concomitant with the occurrence of stage III melanoma, suggesting that this condition may have contributed to the onset of AVWS. Our patients’ presentation emphasizes the fact that AVWS occurs unpredictably
3
during the course of lymphoproliferative diseases. In all three patients, AVWS occurred after the diagnosis of CLL, however one published case of AVWS developed 10 months before the diagnosis of small lymphocytic lymphoma [9]. In individuals with B-cell lymphomas or multiple myeloma treated with chemotherapy (with or without rituximab), remission of AVWS can be achieved in up to 70% of patients [3]. Therefore, addressing the underlying disease is a mainstay of treatment in these patients [3,4]. The strong association between successful management of AVWS and the ability to control the underlying CLL is further supported by the outcome of our three cases. The patient who did not experience recurrence of bleeding was the one with better response to CLL treatment. In contrast, the recurrent bleeding in Case 2 and Case 3 is likely attributable to uncontrolled malignant disease(s) (in association with progressive melanoma in Case 3), stressing the importance of treating the underlying CLL in patients with bleeding complications associated with AVWS. Finally, the patients with AVWS diagnosed at our institution developed anemia due to significant bleeding, highlighting the need to include AVWS in the differential diagnosis of bleeding episodes in patients with CLL. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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