Blood Cells, Molecules and Diseases 52 (2014) 205–207
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Acquired von Willebrand syndrome in patients with Gaucher disease Mirjana Mitrovic a,⁎, Ivo Elezovic a,b, Predrag Miljic a,b, Nada Suvajdzic a,b a b
Clinic of Hematology CCS, Koste Todorovica 2, Belgrade, Serbia Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, Serbia
a r t i c l e
i n f o
Article history: Submitted 27 July 2013 Revised 5 October 2013 Available online 22 November 2013 (Communicated by A. Zimran, M.D., 26 October 2013 ) Keywords: Gaucher disease Bleeding Acquired von Willebrand syndrome Enzyme replacement therapy
a b s t r a c t Although various coagulation abnormalities occur in patients with Gaucher disease (GD), von Willebrand factor (vWF) deficiency has rarely been reported. A retrospective review of six treatment naïve cases with GD and concomitant vWF deficiency over a 12-year-period in a single center is presented. All patients had a personal history of prior hemorrhages. Based on both reduced level of vWF antigen (vWF:Ag, range 14–56%) and ristocetin cofactor activity (vWF:RCo, range 12–53%), with a vWF:RCo/Ag ratio N0.7, the diagnosis of type 1 von Willebrand disease was made in all six cases. During enzyme replacement therapy (ERT) of a 2-year duration all patients normalized their vWF:Ag levels. Based on the positive ERT effect on vWF:Ag levels, vWF deficiency was assumed to be acquired. It should be noted that beside vWF deficiency four patients with GD exhibited mild thrombocytopenia (range 81–131 × 109/L) and three had additional hemostatic defects (reduced collagen platelet aggregation, FV, FXI and FXII deficiencies). © 2013 Elsevier Inc. All rights reserved.
Introduction
Patients and methods
Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder characterized by structural or functional defects of von Willebrand factor (vWF). It is secondary to lymphoproliferative, myeloproliferative, other neoplastic, autoimmune or cardio-vascular disorders, hypothyreosis, uremia or other miscellaneous conditions [1,2]. Pathogenetic mechanisms include autoantibodies against vWF, selective or non-selective absorption, mechanical destruction, increased proteolysis and decreased synthesis or secretion of vWF [1,2]. Clinical and laboratory findings are similar to congenital von Willebrand disease (vWD) [1,2]. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AvWS. Some treatments of the underlying medical condition may result in remission of AvWS [1,2]. In Gaucher disease (GD) bleeding, ranging from mild to life threatening, is a frequent manifestation. A broad spectrum of hemostatic abnormalities such as: thrombocytopenia, platelet dysfunction, reduced level of clotting factors together with increased markers of coagulation and fibrinolytic system activation have been described in GD [3–8]. These abnormalities are partially explained by low-grade intravascular coagulation triggered by macrophage-driven cytokines [3,9]. However, vWF deficiency has rarely been reported in GD and there are no data regarding the effects of enzyme replacement therapy (ERT) [6,10]. Addressing this issue we present six patients with GD and concomitant vWF deficiency and the effect of ERT for 2 years on the vWF level in five of them.
Six patients with GD and concomitant vWF deficiency were analyzed between 2000 and 2012 in the Clinic of Hematology. GD was diagnosed by determining β-glucocerebrosidase activity in peripheral blood leukocytes and confirmed via genotyping. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and factor (F) VIII were measured on an ACL-Automated Coagulation Laboratory (IL, Italy). vWF: Antigen (vWF:Ag) was assayed by ELISA and ristocetin cofactor activity (vWF:RCo) using an immunoturbidimetric vWF activity assay. vWF:Ag had been assessed repeatedly two to three times before therapy initiation in a 6 month interval and on the ERT beginning day. In the measuring moment patients did not have signs of bleeding, inflammation, pregnancy and recent surgery. Closure time was measured in four patients with a platelet function analyzer (PFA-100®, Dade Behring, Germany) using either a collagen-ADP or collagen-epinephrine cartridge. Ristocetin induced platelet aggregation (RIPA) was determined in citrated platelet-rich plasma by the Born method on a whole-blood aggregometer (Model 560, Chrono-Log Corporation, USA) with ristocetin (1.25 mg/ml). Three patients were tested for response to subcutaneously injected desmopresine (DDAVP) at 0.3 μg/kg body weight. The vWF:Ag level was measured 60 min after DDAVP application. Five patients were treated with imiglucerase (30–60 U/kg i.v. every 2 weeks). Hemostatic parameters were assessed after 6, 12 and 24 months of therapy (ERT 6, 12, 24). Results
⁎ Corresponding author at: Clinic of Hematology CCS, Koste Todorovica 2, 11000 Belgrade, Serbia. Fax: +381 633065112. E-mail address: [email protected] (M. Mitrovic). 1079-9796/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcmd.2013.11.001
All of the patients were compound heterozygotes for N370S (1226G). Symptoms of GD were mild in three (patients Nos. 1, 3 and.
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M. Mitrovic et al. / Blood Cells, Molecules and Diseases 52 (2014) 205–207
Table 1 Specific characteristics of Gaucher disease. Patient No.
Age (years)
Sex
Mutations
Chitotriosidase⁎ (nmol/ml/h)
Splenectomy
Spleen volume (x normal)
GauSSI-I12
Zimran severity score 13
ERT
1 2 3 4 5 6
13 30 18 24 22 54
M M M F M F
L444R/N370/S N370S/? N370S/? N370S/? L444R/N370S N370S/?
3079 7068 12,748 6588 20,667 3640
No Yes No Yes No No
10 – 18 – 33 5
11 11 12 10 16 15
10 mild 11 intermediate 10 mild 13 intermediate 14 intermediate 9 mild
Yes Yes Yes Yes Yes No
M — male, F — female, GauSSI-I — Gaucher Disease Severity Score Index-Type I, ERT — enzyme replacement therapy. ⁎ Control levels in our population: 6–162 nmol/mL/h.
6) and of intermediate severity in three cases (Nos. 2, 4 and 5). Splenectomy was performed in two cases. The GD specific characteristics are presented in Table 1. All six patients had a personal history of prior hemorrhages and a negative family history for bleeding. In two patients (Nos. 5 and 6) bleeding was severe. Two patients (Nos.1 and 5) had blood type O (Table 2). The results of baseline (before ERT) coagulation tests are presented in Table 2. Prolonged aPTT and PFA-100 values were evident in 4/6 and 3/4 patients, respectively. All six patients had reduced levels of vWF:Ag and vWF:RCo, with vWF:RCo/Ag ratio N0.7. The response to DDAVP infusion was registered in each of the three treated patients with increase in vWF:Ag. vWF/FVIII concentrate (Haemate-P®, Aventis, USA) at 40 units/kg was administered only to patient No. 6 due to a post neurosurgery bleeding. Complete control of bleeding was achieved. Levels of vWF at 5, 30 and 60 min after vWF/ FVIII concentrate administration were 90%, 88% and 84%, respectively. Though, vWF multimer analysis, vWF collagen and FVIII binding assays were not performed. Three patients (Nos. 1, 2 and 6) had additional hemostatic defects (low FV, reduced platelet aggregation on collagen, deficiencies of both FXI and XII; Table 2). It should be noted that serum protein electropherograms, serum immunoglobulin levels, antinuclear antibodies, thyroid hormone levels and cardiac ultrasounds were inside normal ranges
in all patients. During ERT, vWF:Ag levels normalized in all patients: two after 6 months, one after 12 months and the remaining two after 24 months (Table 3). vWF:Ag levels normalization were followed by bleeding cessation in all patients (Table 3). Discussion It is well known that various coagulation abnormalities ranging from subclinical laboratory findings to life threatening bleeding occur in patients with GD [3–7]. However, vWF deficiency has been reported in two cases, only [6,10]. Addressing this issue we report an additional six treatment-naïve patients with GD and concomitant type 1 vWD (vWF:RCo/Ag ratio N0.7). In determining the type of VWD, we adhered to the guidelines of the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report [1]. As the laboratory checks performed during ERT showed normalization of vWF:Ag levels in all five treated patients, a diagnosis of AvWD was made. The pathogenesis of GD associated AvWS is unclear. Based on the DDAVP response, normal half-life of administered vWF, immunological tests, serum protein electrophoresis and cardiac ultrasounds selective or non-selective absorption, both mechanical destruction and increased
Table 2 Baseline coagulation abnormalities. DDAVP test vWF:Ag (%)
Additional hemostatic abnormalities
0.60–1 0.45 0.40
65 53
97 169
0.8 0.9 0.75
ND ND ND
FV deficiency –Reduced platelet aggregation on collagen –FXI, FXII deficiency No No No
170
0.85
80
Patient No.
Bleeding (localization)
Blood type
Plt (x109/L)
PT (%)
aPTT (s)
vWF:Ag (%)
vWF:RoC (%)
FVIII (%)
PFA-100 ADP CT (s)
EPI CT (s)
Normal 1 2
0 A
150–400 89 324
75–125 65 65
25–35 37.1 40.1
60–150 21 14
60–150 25 12
50–150 49 35
N: 71–118 s ND 134
N: 85–165 s
Mucocutaneous Epistaxis
Epistaxis Mucocutaneous Epistaxis, iliopsoas hematoma Post-neurosurgery
A AB 0
131 228 81
69 111 65
32.6 28.9 35.5
42 35 49
38 33 53
67 70 90
113 121 ND
A
124
88
39.4
56
49
54
122
3 4 5 6
173
RIPA %
Reduced platelet aggregation on collagen
Table 3 Effect of enzyme replacement therapy on von Willebrand factor (vWF) levels. Patient No. 1
Patient No. 2
Patient No. 3
vWF:Ag (%)
Bleeding
vWF:Ag (%)
Bleeding
vWF:Ag (%)
ERT 0
21
Mucocutaneous
14
Epistaxis
42
ERT 6 ERT 12 ERT 24
70 65 66
No No No
28 28 84
Epistaxis No No
56 56 112
Patient No. 4
Patient No. 5
Bleeding
vWF:Ag (%)
Bleeding
vWF:Ag (%)
Bleeding
Epistaxis
35
Mucocutaneous
49
No No No
70 98 84
No No No
49 70 84
Epistaxis iliopsoas hematoma No No No
ERT 0, 6, 12, 24 — parameters at start of enzyme replacement therapy and after 6, 12 and 24 months.
M. Mitrovic et al. / Blood Cells, Molecules and Diseases 52 (2014) 205–207
proteolysis of vWF can be excluded as a cause of AvWS [1,10]. However, in GD abnormal storage of sphingolipids in megakaryocytes and endothelium might be responsible for the impaired vWF production or secretion [10]. Conclusion In conclusion, our experience shows that acquired vWF deficiency might contribute to the bleeding tendency in patients with GD. Therefore, coagulation assays including vWF:Ag and vWF:RCo could be useful when these patients are referred to the hematologist for bleeding or surgical procedures, particularly if aPTT and PFA-100 closure time are prolonged [11]. In addition, mixing studies, multimer analysis and detection of broad spectrum of vWF binding antibodies by ELISA may provide useful information in some patients. If bleeding occurs or if a patient with GD and AvWS is subjected to an invasive procedure, treatment with DDAVP or vWF/FVIII concentrate could be helpful. In some non-urgent cases ERT might improve the patient's coagulation profile prior to surgery [11]. Conflict of interests The authors declare no conflict of interests. Acknowledgments We thank Ana Ivkovic, Senior Librarian, Institute for Oncology and Radiology of Serbia, who deserves special mention for arranging the relevant articles.
207
References [1] W.L. Nicholas, M.B. Hulitin, A.H. James, et al., von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA), Haemophilia, 14, 2008, pp. 171–232. [2] A. Tiede, J.H. Rand, U. Budde, A. Ganser, A.B. Federici, How I treat the acquired von Willebrand syndrome, Blood 117 (25) (2011) 6777–6785. [3] C.E.M. Hollak, M. Levi, F. Berneds, J.M. Aerts, M.H. van Oers, Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy, Br. J. Haematol. 96 (1997) 470–476. [4] M. Mitrovic, D. Antic, I. Elezovic, D. Janic, P. Miljic, Z. Sumarac, et al., Haemostatic abnormalities in treatment-naïve patients with Type 1 Gaucher's disease, Platelets 2 (2012) 143–149. [5] M. Mitrovic, Z. Sumarac, D. Antic, A. Bogdanovic, I. Elezovic, et al., Markers of coagulation activation and enhanced fibrinolysis in Gaucher type 1 patient: effects of enzyme replacement therapy, Blood Cells Mol. Dis. 49 (1) (2012) 58–59. [6] H.H. Billett, S. Rizvi, A. Sawitski, Coagulation abnormalities in patients with Gaucher's disease: effect of therapy, Am. J. Hematol. 51 (1996) 234–236. [7] G. Spectre, B. Roth, G. Ronen, D. Rosengarten, D. Elstein, A. Zimran, et al., Platelet adhesion defect in type I Gaucher disease is associated with a risk of mucosal bleeding, Br. J. Haematol. 153 (2011) 372–378. [8] M.J. Simchen, R. Oz, B. Shenkman, A. Zimran, D. Elstein, G. Kenet, Impaired platelet function and peripartum bleeding in women with Gaucher disease, Thromb. Haemost. 105 (2011) 509–514. [9] M. Jmoudiak, A.H. Futerman, Gaucher disease: pathological mechanisms and modern management, Br. J. Haematol. 129 (2005) 178–188. [10] B. Tavil, Y. Isık Balcı, C. Karacan, M. Sahin, A. Kara, Acquired von Willebrand disease in Turkish boy with Gaucher disease, Pediatr. Hematol. Oncol. 24 (2007) 317–319. [11] D. Hughes, M.D. Cappellini, M. Berger, J. Van Droogenbroeck, M. de Fost, D. Janic, T. Marinakis, H. Rosenbaum, J. Villarubia, E. Zhukovskaya, C. Hollak, Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease, Br. J. Haematol. 138 (6) (2007) 676–686. [12] A. Zimran, G. Altarescu, B. Rundensky, A. Abrahamov, D. Elstein, Survey of hematological aspects of Gaucher disease, Hematology 10 (2) (2005) 151–156. [13] M. Di Rocco, F. Giona, F. Carubbi, S. Linari, F. Minichilli, R.O. Brady, G. Mariani, M.D. Cappellini, A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease, Haematologica 93 (8) (2008) 1211–1218.
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Acquired von Willebrand syndrome in patients with Gaucher disease Mirjana Mitrovic a,⁎, Ivo Elezovic a,b, Predrag Miljic a,b, Nada Suvajdzic a,b a b
Clinic of Hematology CCS, Koste Todorovica 2, Belgrade, Serbia Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, Serbia
a r t i c l e
i n f o
Article history: Submitted 27 July 2013 Revised 5 October 2013 Available online 22 November 2013 (Communicated by A. Zimran, M.D., 26 October 2013 ) Keywords: Gaucher disease Bleeding Acquired von Willebrand syndrome Enzyme replacement therapy
a b s t r a c t Although various coagulation abnormalities occur in patients with Gaucher disease (GD), von Willebrand factor (vWF) deficiency has rarely been reported. A retrospective review of six treatment naïve cases with GD and concomitant vWF deficiency over a 12-year-period in a single center is presented. All patients had a personal history of prior hemorrhages. Based on both reduced level of vWF antigen (vWF:Ag, range 14–56%) and ristocetin cofactor activity (vWF:RCo, range 12–53%), with a vWF:RCo/Ag ratio N0.7, the diagnosis of type 1 von Willebrand disease was made in all six cases. During enzyme replacement therapy (ERT) of a 2-year duration all patients normalized their vWF:Ag levels. Based on the positive ERT effect on vWF:Ag levels, vWF deficiency was assumed to be acquired. It should be noted that beside vWF deficiency four patients with GD exhibited mild thrombocytopenia (range 81–131 × 109/L) and three had additional hemostatic defects (reduced collagen platelet aggregation, FV, FXI and FXII deficiencies). © 2013 Elsevier Inc. All rights reserved.
Introduction
Patients and methods
Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder characterized by structural or functional defects of von Willebrand factor (vWF). It is secondary to lymphoproliferative, myeloproliferative, other neoplastic, autoimmune or cardio-vascular disorders, hypothyreosis, uremia or other miscellaneous conditions [1,2]. Pathogenetic mechanisms include autoantibodies against vWF, selective or non-selective absorption, mechanical destruction, increased proteolysis and decreased synthesis or secretion of vWF [1,2]. Clinical and laboratory findings are similar to congenital von Willebrand disease (vWD) [1,2]. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AvWS. Some treatments of the underlying medical condition may result in remission of AvWS [1,2]. In Gaucher disease (GD) bleeding, ranging from mild to life threatening, is a frequent manifestation. A broad spectrum of hemostatic abnormalities such as: thrombocytopenia, platelet dysfunction, reduced level of clotting factors together with increased markers of coagulation and fibrinolytic system activation have been described in GD [3–8]. These abnormalities are partially explained by low-grade intravascular coagulation triggered by macrophage-driven cytokines [3,9]. However, vWF deficiency has rarely been reported in GD and there are no data regarding the effects of enzyme replacement therapy (ERT) [6,10]. Addressing this issue we present six patients with GD and concomitant vWF deficiency and the effect of ERT for 2 years on the vWF level in five of them.
Six patients with GD and concomitant vWF deficiency were analyzed between 2000 and 2012 in the Clinic of Hematology. GD was diagnosed by determining β-glucocerebrosidase activity in peripheral blood leukocytes and confirmed via genotyping. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and factor (F) VIII were measured on an ACL-Automated Coagulation Laboratory (IL, Italy). vWF: Antigen (vWF:Ag) was assayed by ELISA and ristocetin cofactor activity (vWF:RCo) using an immunoturbidimetric vWF activity assay. vWF:Ag had been assessed repeatedly two to three times before therapy initiation in a 6 month interval and on the ERT beginning day. In the measuring moment patients did not have signs of bleeding, inflammation, pregnancy and recent surgery. Closure time was measured in four patients with a platelet function analyzer (PFA-100®, Dade Behring, Germany) using either a collagen-ADP or collagen-epinephrine cartridge. Ristocetin induced platelet aggregation (RIPA) was determined in citrated platelet-rich plasma by the Born method on a whole-blood aggregometer (Model 560, Chrono-Log Corporation, USA) with ristocetin (1.25 mg/ml). Three patients were tested for response to subcutaneously injected desmopresine (DDAVP) at 0.3 μg/kg body weight. The vWF:Ag level was measured 60 min after DDAVP application. Five patients were treated with imiglucerase (30–60 U/kg i.v. every 2 weeks). Hemostatic parameters were assessed after 6, 12 and 24 months of therapy (ERT 6, 12, 24). Results
⁎ Corresponding author at: Clinic of Hematology CCS, Koste Todorovica 2, 11000 Belgrade, Serbia. Fax: +381 633065112. E-mail address: [email protected] (M. Mitrovic). 1079-9796/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcmd.2013.11.001
All of the patients were compound heterozygotes for N370S (1226G). Symptoms of GD were mild in three (patients Nos. 1, 3 and.
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M. Mitrovic et al. / Blood Cells, Molecules and Diseases 52 (2014) 205–207
Table 1 Specific characteristics of Gaucher disease. Patient No.
Age (years)
Sex
Mutations
Chitotriosidase⁎ (nmol/ml/h)
Splenectomy
Spleen volume (x normal)
GauSSI-I12
Zimran severity score 13
ERT
1 2 3 4 5 6
13 30 18 24 22 54
M M M F M F
L444R/N370/S N370S/? N370S/? N370S/? L444R/N370S N370S/?
3079 7068 12,748 6588 20,667 3640
No Yes No Yes No No
10 – 18 – 33 5
11 11 12 10 16 15
10 mild 11 intermediate 10 mild 13 intermediate 14 intermediate 9 mild
Yes Yes Yes Yes Yes No
M — male, F — female, GauSSI-I — Gaucher Disease Severity Score Index-Type I, ERT — enzyme replacement therapy. ⁎ Control levels in our population: 6–162 nmol/mL/h.
6) and of intermediate severity in three cases (Nos. 2, 4 and 5). Splenectomy was performed in two cases. The GD specific characteristics are presented in Table 1. All six patients had a personal history of prior hemorrhages and a negative family history for bleeding. In two patients (Nos. 5 and 6) bleeding was severe. Two patients (Nos.1 and 5) had blood type O (Table 2). The results of baseline (before ERT) coagulation tests are presented in Table 2. Prolonged aPTT and PFA-100 values were evident in 4/6 and 3/4 patients, respectively. All six patients had reduced levels of vWF:Ag and vWF:RCo, with vWF:RCo/Ag ratio N0.7. The response to DDAVP infusion was registered in each of the three treated patients with increase in vWF:Ag. vWF/FVIII concentrate (Haemate-P®, Aventis, USA) at 40 units/kg was administered only to patient No. 6 due to a post neurosurgery bleeding. Complete control of bleeding was achieved. Levels of vWF at 5, 30 and 60 min after vWF/ FVIII concentrate administration were 90%, 88% and 84%, respectively. Though, vWF multimer analysis, vWF collagen and FVIII binding assays were not performed. Three patients (Nos. 1, 2 and 6) had additional hemostatic defects (low FV, reduced platelet aggregation on collagen, deficiencies of both FXI and XII; Table 2). It should be noted that serum protein electropherograms, serum immunoglobulin levels, antinuclear antibodies, thyroid hormone levels and cardiac ultrasounds were inside normal ranges
in all patients. During ERT, vWF:Ag levels normalized in all patients: two after 6 months, one after 12 months and the remaining two after 24 months (Table 3). vWF:Ag levels normalization were followed by bleeding cessation in all patients (Table 3). Discussion It is well known that various coagulation abnormalities ranging from subclinical laboratory findings to life threatening bleeding occur in patients with GD [3–7]. However, vWF deficiency has been reported in two cases, only [6,10]. Addressing this issue we report an additional six treatment-naïve patients with GD and concomitant type 1 vWD (vWF:RCo/Ag ratio N0.7). In determining the type of VWD, we adhered to the guidelines of the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report [1]. As the laboratory checks performed during ERT showed normalization of vWF:Ag levels in all five treated patients, a diagnosis of AvWD was made. The pathogenesis of GD associated AvWS is unclear. Based on the DDAVP response, normal half-life of administered vWF, immunological tests, serum protein electrophoresis and cardiac ultrasounds selective or non-selective absorption, both mechanical destruction and increased
Table 2 Baseline coagulation abnormalities. DDAVP test vWF:Ag (%)
Additional hemostatic abnormalities
0.60–1 0.45 0.40
65 53
97 169
0.8 0.9 0.75
ND ND ND
FV deficiency –Reduced platelet aggregation on collagen –FXI, FXII deficiency No No No
170
0.85
80
Patient No.
Bleeding (localization)
Blood type
Plt (x109/L)
PT (%)
aPTT (s)
vWF:Ag (%)
vWF:RoC (%)
FVIII (%)
PFA-100 ADP CT (s)
EPI CT (s)
Normal 1 2
0 A
150–400 89 324
75–125 65 65
25–35 37.1 40.1
60–150 21 14
60–150 25 12
50–150 49 35
N: 71–118 s ND 134
N: 85–165 s
Mucocutaneous Epistaxis
Epistaxis Mucocutaneous Epistaxis, iliopsoas hematoma Post-neurosurgery
A AB 0
131 228 81
69 111 65
32.6 28.9 35.5
42 35 49
38 33 53
67 70 90
113 121 ND
A
124
88
39.4
56
49
54
122
3 4 5 6
173
RIPA %
Reduced platelet aggregation on collagen
Table 3 Effect of enzyme replacement therapy on von Willebrand factor (vWF) levels. Patient No. 1
Patient No. 2
Patient No. 3
vWF:Ag (%)
Bleeding
vWF:Ag (%)
Bleeding
vWF:Ag (%)
ERT 0
21
Mucocutaneous
14
Epistaxis
42
ERT 6 ERT 12 ERT 24
70 65 66
No No No
28 28 84
Epistaxis No No
56 56 112
Patient No. 4
Patient No. 5
Bleeding
vWF:Ag (%)
Bleeding
vWF:Ag (%)
Bleeding
Epistaxis
35
Mucocutaneous
49
No No No
70 98 84
No No No
49 70 84
Epistaxis iliopsoas hematoma No No No
ERT 0, 6, 12, 24 — parameters at start of enzyme replacement therapy and after 6, 12 and 24 months.
M. Mitrovic et al. / Blood Cells, Molecules and Diseases 52 (2014) 205–207
proteolysis of vWF can be excluded as a cause of AvWS [1,10]. However, in GD abnormal storage of sphingolipids in megakaryocytes and endothelium might be responsible for the impaired vWF production or secretion [10]. Conclusion In conclusion, our experience shows that acquired vWF deficiency might contribute to the bleeding tendency in patients with GD. Therefore, coagulation assays including vWF:Ag and vWF:RCo could be useful when these patients are referred to the hematologist for bleeding or surgical procedures, particularly if aPTT and PFA-100 closure time are prolonged [11]. In addition, mixing studies, multimer analysis and detection of broad spectrum of vWF binding antibodies by ELISA may provide useful information in some patients. If bleeding occurs or if a patient with GD and AvWS is subjected to an invasive procedure, treatment with DDAVP or vWF/FVIII concentrate could be helpful. In some non-urgent cases ERT might improve the patient's coagulation profile prior to surgery [11]. Conflict of interests The authors declare no conflict of interests. Acknowledgments We thank Ana Ivkovic, Senior Librarian, Institute for Oncology and Radiology of Serbia, who deserves special mention for arranging the relevant articles.
207
References [1] W.L. Nicholas, M.B. Hulitin, A.H. James, et al., von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA), Haemophilia, 14, 2008, pp. 171–232. [2] A. Tiede, J.H. Rand, U. Budde, A. Ganser, A.B. Federici, How I treat the acquired von Willebrand syndrome, Blood 117 (25) (2011) 6777–6785. [3] C.E.M. Hollak, M. Levi, F. Berneds, J.M. Aerts, M.H. van Oers, Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy, Br. J. Haematol. 96 (1997) 470–476. [4] M. Mitrovic, D. Antic, I. Elezovic, D. Janic, P. Miljic, Z. Sumarac, et al., Haemostatic abnormalities in treatment-naïve patients with Type 1 Gaucher's disease, Platelets 2 (2012) 143–149. [5] M. Mitrovic, Z. Sumarac, D. Antic, A. Bogdanovic, I. Elezovic, et al., Markers of coagulation activation and enhanced fibrinolysis in Gaucher type 1 patient: effects of enzyme replacement therapy, Blood Cells Mol. Dis. 49 (1) (2012) 58–59. [6] H.H. Billett, S. Rizvi, A. Sawitski, Coagulation abnormalities in patients with Gaucher's disease: effect of therapy, Am. J. Hematol. 51 (1996) 234–236. [7] G. Spectre, B. Roth, G. Ronen, D. Rosengarten, D. Elstein, A. Zimran, et al., Platelet adhesion defect in type I Gaucher disease is associated with a risk of mucosal bleeding, Br. J. Haematol. 153 (2011) 372–378. [8] M.J. Simchen, R. Oz, B. Shenkman, A. Zimran, D. Elstein, G. Kenet, Impaired platelet function and peripartum bleeding in women with Gaucher disease, Thromb. Haemost. 105 (2011) 509–514. [9] M. Jmoudiak, A.H. Futerman, Gaucher disease: pathological mechanisms and modern management, Br. J. Haematol. 129 (2005) 178–188. [10] B. Tavil, Y. Isık Balcı, C. Karacan, M. Sahin, A. Kara, Acquired von Willebrand disease in Turkish boy with Gaucher disease, Pediatr. Hematol. Oncol. 24 (2007) 317–319. [11] D. Hughes, M.D. Cappellini, M. Berger, J. Van Droogenbroeck, M. de Fost, D. Janic, T. Marinakis, H. Rosenbaum, J. Villarubia, E. Zhukovskaya, C. Hollak, Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease, Br. J. Haematol. 138 (6) (2007) 676–686. [12] A. Zimran, G. Altarescu, B. Rundensky, A. Abrahamov, D. Elstein, Survey of hematological aspects of Gaucher disease, Hematology 10 (2) (2005) 151–156. [13] M. Di Rocco, F. Giona, F. Carubbi, S. Linari, F. Minichilli, R.O. Brady, G. Mariani, M.D. Cappellini, A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease, Haematologica 93 (8) (2008) 1211–1218.
