Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia

Abstract Abstract 4657 Background Several studies have shown that between 15% to 25% of patients with severe aortic stenosis present bleeding episodes that may be attributed to an acquired von Willebrand syndrome (AVWS). Until now, to our knowledge, no association of AVWS with mitral valve disfunction has been reported. Design and Methods Four patients with mitral valve leak presented acquired abnormalities of von Willebrand factor (VWF) and a bleeding history. Two of them presented severe bleedings requiring blood transfusions. All of them were within an adequate range of oral anticoagulation. Results Prior to surgery, these patients presented an APTT prolonged and in two of them the closure time determined by the platelet function analyzer (PFA-100®) (with COL/ADP and COL/Epi) was prolonged also. Factor VIII procoagulant activity (FVIII:C), VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo) and VWF collagen binding (VWF:CB) were considerably elevated and the VWF multimers in plasma, showed a lower relative proportion of the high molecular weight VWF multimers (HMWM), to some extent similar to type 2A congenital von Willebrand disease (VWD). In two of them, the VWF:RCo/VWF:Ag or VWF: CB/VWF:Ag ratios were less than normal range (>0.7) while in the other two were normal. After surgery, FVIII:C, and VWF properties were extremely increased and the ratios VWF:RCo/VWF:Ag and VWF: CB/VWF:Ag > 0.7. After surgery, FVIII:C, VWF:Ag, VWF:RCo and VWF:CB increased considerably. The ratios were > 0.7. The PFA-100® (COL/ADP and COL/Epi) was corrected in the two patients who had it prolonged. The multimeric VWF profile were also corrected in all of them. Conclusions The present study describes acquired VWF qualitative alterations for the first time in mitral valve leak. When such alterations are important they may be associated or to contribute to a bleeding diathesis. This problem was reported previously in aortic valve stenosis in relationship with a suspected very high shear stress. This situation may be not usually present in mitral valve stenosis, but it seems that it must occur in the presence of mitral valve leak. Consequently, the AVWS should be taken into account in patients with mitral valve leak that present a bleeding diathesis, not explained by an excess of oral anticoagulation. ACKNOWLEDGEMENTS This work was supported by the Fondo de Investigación Sanitaria, F.I.S. Carlos III, Ministerio de Sanidad, Spain (FIS PI# 07/0229), and Consellería de Innovación e Industria, Xunta de Galicia (INCITE08ENA916109ES). Disclosures: No relevant conflicts of interest to declare.

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Reversal of Acquired von Willebrand Disease after Allogeneic Hematopoietic Stem Cell Transplantation in a Patient with High Risk Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.4014.4014 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4014-4014 ◽

Cited By ~ 1

Author(s):

Christian Langer ◽

Martin Griesshammer ◽

Donald Bunjes ◽

Ulrich Budde ◽

Martin Gruenewald ◽

...

Keyword(s):

Stem Cell ◽

Chronic Lymphocytic Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Lymphocytic Leukemia ◽

Hematopoietic Stem ◽

Binet Stage ◽

Von Willebrand

Abstract Acquired von Willebrand (AvWD) disease is a relatively rare bleeding disorder and since the initial description, fewer than 300 cases of AvWD have been reported. The most frequently observed association is with dysproteinemias such as monoclonal gammopathy of undetermined significance (MGUS) and plasma cell proliferative disorders such as Waldenstroem macroglobulinemia and multiple myeloma. Other hematological diseases associated with AvWD have been reported including lymphoproliferative and myeloproliferative disorders. We report the case of a 59 year old male patient with an AvWD associated with a chronic lymphocytic leukemia. In November 2000 this patient was diagnosed with a B cell chronic lymphocytic leukemia (CLL). Because of an initial Binet-Stage A no specific therapy was initiated. In October 2003 the CLL progressed to Binet-Stage B and molecular examinations revealed an unfavorable risk profile with a 11q22.3-q23.1 deletion and an unmutated IgVH gene status. Because of the presence of an HLA-identical brother the patient was enrolled into a pilot study of allogeneic stem cell transplantation following conditioning with fludarabine and cyclophosphamid in patients with high-risk chronic lymphocytic leukemia. Four cycles of fludarabine and cyclophosphamide were given prior to allogeneic stem cell transplantation and induced a partial remission. Since 2000 the patient reported a new clinical bleeding tendency, presenting mainly as frequent epistaxis. Further laboratory investigations showed a prolonged activated partial thromboplastin time (50 sec.) and a reduced plasma von Willebrand factor (vWF) antigen and vWF activity of 6% and 2%, respectively. This was accompanied by a reduced Factor VIII activity of 14% (factor IX-, XI-, XII- activity > 100%, respectively; lupus anticoagulant assay negative; immunofixation negativ). A vWF multimer analysis showed selective decrease in the high-molecular-weight multimers as seen in type II congenital vWD. The reduced intensity conditioning (RIC) regimens consisted the following combination: Fludarabine 30mg/m² /d (=150mg/m² total dose) and Cyclophosphamide 500mg/m² /d (=2500mg/m² total dose) (day -7 through day -3), GVHD prophylaxis with Cyclosporin A (CsA) and mycophenolate mofetil (MMF). A therapeutic trial of desmopressin (DDAVP) was insufficient and therefore a continuous infusion of the factor VIII/vWF concentrate (Haemate® P; Aventis Behring) was administered from the start of conditioning until platelet recovery. Under this regimen no bleeding complication was observed, neither spontaneously nor during intensive procedures. In accordance with previous reports of replacement therapy in AvWD we observed a shortened half-life of the vWF. On day 30 after allogenic hematopoietic stem cell transplantation we observed for the first time a normalization of the activated partial thromboplastin time followed by a gradual increase of the vWF antigen and activity. On day 60 we were able to document the normalization of both the vWF antigen and activity and the vWF multimer analysis. This nomalisation was coincident with the establishment of a complete donor chimerism for the first time. We therefore believe that this case shows a form of AvWD associated with chronic lymphocytic leukemia and its reversal by treatment of the underlying disease by allogeneic hematopoietic stem cell transplantation. Figure Figure

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Acquired von Willebrand’s Syndrome and Acquired Thrombopathy in a Patient with a Chronic Lymphocytic Leukemia

10.1055/s-0039-1689640 ◽

1975 ◽

Author(s):

J. L. Wautier ◽

S. Levy-Toledano ◽

Y. Sultan ◽

E. Bodevin

Keyword(s):

Platelet Aggregation ◽

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Normal Range ◽

Spontaneous Bleeding ◽

History Of ◽

Abnormal Bleeding ◽

Normal Hemostasis ◽

Von Willebrand ◽

Ristocetin Cofactor

The patient was 65 years old when she developped spontaneous bleeding. She did not have a family history of abnormal bleeding and profered clear evidence of normal hemostasis before.Bleeding time, platelet aggregation induced by collagen were abnormal. VIII related antigen, ristocetin cofactor were 10 per cent the normal range while VIII procoagulant activity was 50%.Interaction with rabbit sub endothelium was studied: contact and adhesion were 50% of the normal range and thrombi were absent.Infusion of cryoprecipitate corrected partially von Willebrand abnormalities while platelet aggregation induced by collagen remained unchanged. Velocity of platelet aggregation induced by collagen, VIII related antigen and ristocetin cofactor increased moderately after corticotherapy.The association of an acquired thrombopathy and von Willebrand’s disease in a patient with chronic lymphocytic leukemia lead one to wonder about possible relationship between these diseases in this case.

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Increased SERUM VON Willebrand Levels in Chronic Lymphocytic Leukemia (CLL) Patients Are Related to a Shorter Time to Treatment

Blood ◽

10.1182/blood-2018-99-119520 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5547-5547

Author(s):

Thommais Tryfou ◽

Paraskevi Papaioannou ◽

Panagiotis Repousis ◽

Annita Ioanna Gkioka ◽

Sotirios Sachanas ◽

...

Keyword(s):

Endothelial Cell ◽

Chronic Lymphocytic Leukemia ◽

Von Willebrand Factor ◽

Conflicts Of Interest ◽

Umbilical Vein ◽

Lymphocytic Leukemia ◽

Endothelial Cell Proliferation ◽

Von Willebrand ◽

Willebrand Factor

Abstract CLL is a frequent and usually indolent disease that require only follow-up in about 2/3 of patients while the rest 1/3 of patients are symptomatic, have a worse outcome and need to be treated. The role of angiogenesis in CLL prognosis remains unclear. It has been shown that CLL plasma promotes von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs) [1]. Therefore, we investigated whether serum vWF levels in CLL patients at diagnosis could provide prognostic information. Patients and methods: 33 CLL patients were studied of whom 55%, 32% and 13% were Binet staged A, B and C respectively. 45% never required treatment while 55% required treatment either at the time of diagnosis or during their follow-up. The time to first treatment (TFT) was 34 months. Serum vWF was measured by ELISA (R&D Quantiquine, duo Set) in frozen sera drawn at patients' diagnosis and in 10 healthy individuals (HI). Measurements were performed in duplicate according to the manufacturer's instructions. Statistical analysis was performed by conventional methods, using the SPSS v.22 software. P values below 0,05 were considered statistically significant. Results: Serum vWF levels ranged from 178,5 to 14353,5 pg/ml (median 1028,5) in patients and from 374,6 to 1141,3 pg/ml (median 528,5) in HI, the difference being statistically significant (p< 0,05). Patients with Serum vWF levels above 528,5 pg/ml (median normal value) had a significantly shorter TFT than the others (p=0,01) as shown in figure. Otherwise, serum vWF levels correlated only with hypogammaglobulinemia (p=0,04). Conclusion: Serum vWF levels were increased in CLL patients. Importantly, we showed for the first time, to our knowledge, that higher vWF levels correlated with a shorter TFT, suggesting that increased vWF levels reflect active neoangiogenesis that in turn, contributes to a more aggressive disease behavior. [1] Shahidi M et al, Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB. Blood Coagul Fibrinolysis. 2016 Sep;27(6):711-6. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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