Acquired von willebrand syndrome in patients with philadelphia-negative myeloproliferative neoplasm

Ik-Chan Song; Sora Kang; Myung-Won Lee; Hyewon Ryu; Hyo-Jin Lee; Hwan-Jung Yun; Deog-Yeon Jo

doi:10.5045/br.2023.2022218

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Blood Res 2023; 58(1):

Published online March 31, 2023

https://doi.org/10.5045/br.2023.2022218

Acquired von willebrand syndrome in patients with philadelphia-negative myeloproliferative neoplasm

Ik-Chan Song, Sora Kang, Myung-Won Lee, Hyewon Ryu, Hyo-Jin Lee, Hwan-Jung Yun, Deog-Yeon Jo

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Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea

Correspondence to : Deog-Yeon Jo, M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
E-mail: deogyeon@cnu.ac.kr

Received: November 7, 2022; Revised: December 27, 2022; Accepted: January 25, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Erratum: Blood Res 2023; 58(2): 124-124

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Background
Acquired von Willebrand syndrome (AVWS) has not been investigated in Korean patients with Philadelphia chromosome-negative myeloproliferative neoplasm.
Methods
This study analyzed the prevalence at diagnosis and clinical features of AVWS in patients with essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic/early primary myelofibrosis (pre-PMF), or overt PMF (PMF) diagnosed between January 2019 and December 2021 at Chungam National University Hospital, Daejeon, Korea. AVWS was defined as below the lower reference limit (56%) of ristocetin cofactor activity (VWF:RCo).
Results
Sixty-four consecutive patients (36 with ET, 17 with PV, 6 with pre-PMF, and 5 with PMF; 30 men and 34 women) with a median age of 67 years (range, 18‒87 yr) were followed for a median of 25.1 months (range, 2.6‒46.4 mo). AVWS was detected in 20 (31.3%) patients at diagnosis and was most frequent in ET patients (41.4%), followed by patients with pre-PMF (33.3%) and PV (17.6%) patients. VWF:RCo was negatively correlated with the platelet count (r=0.937; P=0.002). Only one episode of minor bleeding occurred in a patient with ET and AVWS. Younger age (<50 yr) [odds ratio (OR), 7.08; 95% confidence interval (CI), 1.27‒39.48; P=0.026] and thrombocytosis (>600×10⁹/L) (OR, 13.70; 95% CI, 1.35‒138.17; P=0.026) were independent risk factors for developing AVWS.
Conclusion
AVWS based on VWF:RCo was common in patients with ET and pre-PMF, but less common in patients with PV in the Korean population. Clinically significant bleeding is rare in these patients.

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Keywords: Myeloproliferative neoplasm, Essential thrombocythemia, Polycythemia vera, Primary myelofibrosis, Acquired von Willebrand syndrome

Article

Original Article

Blood Res 2023; 58(1): 42-50

Published online March 31, 2023 https://doi.org/10.5045/br.2023.2022218

Acquired von willebrand syndrome in patients with philadelphia-negative myeloproliferative neoplasm

Ik-Chan Song, Sora Kang, Myung-Won Lee, Hyewon Ryu, Hyo-Jin Lee, Hwan-Jung Yun, Deog-Yeon Jo

Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea

Correspondence to:Deog-Yeon Jo, M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
E-mail: deogyeon@cnu.ac.kr

Received: November 7, 2022; Revised: December 27, 2022; Accepted: January 25, 2023

Erratum: Blood Res 2023; 58(2): 124-124

Abstract

Keywords: Myeloproliferative neoplasm, Essential thrombocythemia, Polycythemia vera, Primary myelofibrosis, Acquired von Willebrand syndrome

Abstract

Fig 1.

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Figure 1.Correlation between von Willebrand factor ristocetin cofactor activity (VWF:RCo) and platelet count.

Blood Research 2023; 58: 42-50https://doi.org/10.5045/br.2023.2022218

Fig 2.

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Figure 2.Representative changes with time in platelet count and von Willebrand factor ristocetin cofactor activity (VWF:RCo) following hydroxyurea treatment in a patient with essential thrombocythemia.

Blood Research 2023; 58: 42-50https://doi.org/10.5045/br.2023.2022218

Fig 3.

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Figure 3.Changes in platelet count after normalization of von Willebrand factor ristocetin cofactor activity following cytoreductive treatment in patients with acquired von Willebrand syndrome.

Blood Research 2023; 58: 42-50https://doi.org/10.5045/br.2023.2022218

Table 1 . Patient characteristics (N=64)..

	ET (N=36)	PV (N=17)	pre-PMF (N=6)	PMF (N=5)
Age (yr), median (range)	65 (18–84)	72 (17–86)	60.5 (34–87)	77 (42–86)
Female, N (%)	20 (55.6)	10 (58.8)	3 (50.0)	1 (20.0)
Palpable splenomegaly, N (%)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Volumetric splenomegaly, N (%)	24 (66.7)	15 (88.2)	6 (100)	5 (100)
Laboratory findings
WBC, ×10⁹/L	10.9±4.7	14.6±4.6^a)	15.9±3.3^a)	12.9±9.0
Monocyte, ×10⁹/L	0.7±0.6	0.6±0.3	0.6±0.3	1.4±1.2^a)
Hemoglobin, g/dL	14.0±1.4	17.9±2.5^a)	12.7±2.5	10.7±1.7^a)
Platelet, ×10⁹/L	870.3±314.0	614.2±381.3^a)	909.5±369.4	868.4±420.8
Platelet, ×10⁹/L, N (%)
450–599	4 (11.1)	2 (11.8)	1 (16.7)	4 (80.0)
600–999	26 (72.2)	6 (35.3)	4 (66.7)	0 (0.0)
1,000–1,449	4 (11.1)	0 (0.0)	0 (0.0)	0 (0.0)
≥1,500	2 (5.6)	2 (11.8)	1 (16.7)	1 (20.0)
LDH, ×UNL	1.3±0.4	1.5±0.4	2.0±0.9^a)	1.9±0.3^a)
Driver gene mutation, N (%)
JAK2V617F	30 (83.3)	17 (100)	4 (66.7)	3 (60.0)
CALR	3 (8.3)	-	1 (16.7)	1 (20.0)
MPL	1 (2.8)	-	0 (0.0)	0 (0.0)
JAK2V617F VAF (%)	26.3±11.1	63.6±19.9^a)	47.6±19.4^a)	50.5±37.0^a)
IPSET, N (%)
Low	9 (25.0)	-	-	-
Intermediate	12 (33.3)	-	-	-
High	15 (41.7)	-	-	-
IPSS, N (%)
Low	-	-	2 (33.3)	1 (20.0)
Intermediate-1	-	-	2 (33.3)	1 (20.0)
Intemediate-2	-	-	1 (16.7)	3 (60.0)
High	-	-	1 (16.7)	0 (0.0)
Comorbidity, N (%)
Hypertension	15 (41.7)	13 (76.5)	1 (16.7)	3 (60.0)
Diabetes mellitus	4 (11.1)	6 (35.3)	1 (16.7)	1 (20.0)
Chronic kidney disease	6 (16.7)	7 (41.2)	2 (33.3)	2 (40.0)
Smoking	7 (19.4)	3 (17.6)	2 (33.3)	1 (20.0)
Dyslipidemia	5 (13.9)	3 (17.6)	1 (16.7)	1 (20.0)
Treatments, N (%)
Cytoreductive treatment
Hydroxyurea	23 (63.9)	17 (88.2)	6 (66.7)	4 (80.0)
Anagrelide	0 (0.0)	0 (0.0)	1 (16.7)	1 (20.0)
Aspirin	33 (91.7)	17 (100)	6 (100)	6 (100)
Thrombosis, N (%)^b)	6 (16.7)	3 (17.6)	3 (33.3)	3 (60.0)
FU (yr), median (range)	1.8 (0.1–3.9)	2.5 (1.1–3.8)	1.3 (0.2–2.9)	2.5 (1.3–3.1)

^a)P<0.05 compared with ET. ^b)Thrombosis occurred before and at the time of diagnosis..

Abbreviations: ET, essential thrombocythemia; FU, follow-up; IPSET, International Prognostic Score for Essential Thrombocythemia; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; pre-PMF, prefibrotic/early myelofibrosis; PV, polycythemia vera; UNL, upper normal limit; VAF, variant allele frequency..

Table 2 . Prevalence of acquired von Willebrand syndrome in patients with myeloproliferative neoplasm (N=64)..

	ET (N=36)	PV (N=17)	pre-PMF (N=6)	PMF (N=5)
VWF:RCo <56%, N (%)	15 (41.7)	3 (17.6)	2 (33.3)	0 (0.0)
VWF:Rco <30%, N (%)	3 (8.3)	3 (17.6)	1 (16.7)	0 (0.0)

Abbreviations: ET, essential thrombocythemia; pre-PMF, prefibrotic/early primary myelofibrosis; PV, polycythemia vera; VWF:Rco, von Willebrand factor ristocetin cofactor activity..

Table 3 . Clinical features of patients with essential thrombocythemia, according to von Willebrand factor ristocetin cofactor activity (N=36)..

	≥56% (N=21)	<56% (N=15)	P^a)	≥30% (N=33)	<30% (N=3)	P^a)
Age (yr), median (range)	65 (40–84)	56 (18–83)	0.035	65 (18–84)	69 (56–72)	0.560
Volumetric splenomegaly, N (%)	13 (61.9)	11 (73.3)	0.473	23 (69.7)	1 (33.3)	0.201
Laboratory findings
WBC, ×10⁹/L	10.5±3.2	11.5±6.4	0.527	11.0±4.8	10.0±2.5	0.718
Monocyte, ×10⁹/L	0.7±0.4	0.7±0.3	0.971	0.7±0.6	0.5±0.1	0.562
Hemoglobin, g/dL	14.0±1.5	13.9±1.5	0.821	14.0±1.2	13.2±0.8	0.406
Platelet, ×10⁹/L	813.7±170.7	949.7±440.0	0.205	837.8±228.8	1,228.3±824.8	0.037
Platelet ≥600×10⁹/L, N (%)	18 (85.7)	14 (93.3)	0.473	29 (87.9)	3 (100)	0.522
Platelet ≥1,000×10⁹/L, N (%)	3 (14.3)	3 (20.0)	0.650	5 (15.2)	1 (33.3)	0.418
Platelet ≥1,500×10⁹/L, N (%)	0 (0.0)	2 (13.2)	0.085	1 (3.0)	1 (33.3)	0.028
LDH, ×UNL	1.4±0.4	1.2±0.3	0.141	1.3±0.4	1.5±0.4	0.488
PT, sec	12.1±1.0	11.5±0.9	0.057	11.9±0.9	11.0±1.6	0.139
aPTT, sec	35.6±3.8	35.8±3.6	0.829	35.9±3.6	32.9±3.7	0.168
Driver gene mutation, N (%)
JAK2V617F	19 (90.5)	12 (80.0)	0.370	29 (87.9)	2 (66.7)	0.309
JAK2V617F VAF >30%	7 (33.3%)	3 (20.0%)	0.379	9 (27.3)	1 (33.3)	0.825
CALR	1 (4.8)	2 (13.3)	0.625	2 (6.1)	1 (33.3)	0.249
Thrombosis, N (%)^b)	4 (19.0)	2 (13.3)	0.650	6 (18.2)	0 (0.0)	0.418
Bleeding, N (%)
Major bleeding	0 (0.0)	0 (0.0)	-	0 (0.0)	0 (0.0)	-
Minor bleeding	0 (0.0)	1 (6.7)	0.230	1 (3.0)	0 (0.0)	0.760
Overall	0 (0.0)	1 (6.7)	0.230	1 (3.0)	0 (0.0)	0.760
Normalization of VWF:RCo after cytoreduction, N (%)^c)	-	11/11 (100)	-	-	-	-
Time to normalization of VWF:RCo (wk), median (range)	-	8 (2–18)	-	-	-	-

^a)Data presented as mean±SD were analyzed using Student t-test for pared samples; data presented as percentages were analyzed using the Chi-square test. ^b)Thrombosis occurred before, at the time of, and after diagnosis. ^c)Platelet counts were 556.5±171.8×10⁹/L at the time of initial normalization of VWF:RCo..

Abbreviations: aPTT, activated partial thromboplastin time; LDH, lactate dehydrogenase; PT, prothrombin time; UNL, upper normal limit; VAF, variant allele frequency; VWF:RCo, von Willabrand factor ristocetin cofactor activity..

Table 4 . Clinical features of patients with polycythemia vera according to von Willebrand factor ristocetin cofactor activity (N=17)..

	≥30% (N=14)	<30% (N=3)	P^a)
Age (yr), median (range)	73.5 (44–86)	61 (55–72)	0.377
Volumetric splenomegaly, N (%)	13 (92.9)	2 (66.7)	0.201
Laboratory findings
WBC, ×10⁹/L	15.2±5.0	16.6±2.7	0.656
Monocyte, ×10⁹/L	00.6±0.2	0.8±0.2	0.075
Hemoglobin, g/dL	17.9±2.6	17.7±2.6	0.879
Platelet, ×10⁹/L	510.0±206.7	1,120.7±671.7	0.009
Platelet >600×10⁹/L, N (%)	5 (35.7)	3 (100)	0.043
Platelet >1,000×10⁹/L, N (%)	1 (7.1)	1 (33.3)	0.201
Platelet >1,500×10⁹/L, N (%)	1 (7.1)	1 (33.3)	0.201
LDH, ×UNL	1.5±0.5	1.6±0.1	0.728
JAK2V617F, N (%)	14 (100)	3 (100)	-
JAK2V617F VAF >50%, N (%)	2 (14.3)	0 (0.0)	0.661
Thrombosis, N (%)^b)	3 (21.4)	0 (0.0)	0.377
Bleeding, N (%)	0 (0.0)	0 (0.0)	-
Normalization of VWF:RCo after cytoreduction, N (%)^c)	-	3 (100)	-

^a)Data presented as mean±SD were analyzed using Student t-test for pared samples; data presented as percentages were analyzed using the Chi-square test. ^b)Thrombosis occurred before, at the time of, and after diagnosis. ^c)Platelet counts were 444.0±194.6×10⁹/L at the time of initial normalization of VWF:RCo..

Abbreviations: LDH, lactate dehydrogenase; UNL, upper normal limit; VAF, variant allele frequency; VWF:RCo; von Willabrand factor, ristocetin cofactor activity..

Table 5 . Logistic regression analysis of the risk factors for developing acquired von Willebrand syndrome at diagnosis in patients with myeloproliferative neoplasm (N=64)..

	Univariate analysis			Multivariate analysis
	OR	95% CI	P	OR	95% CI	P
Age <50 yr	4.29	1.05–17.45	0.042	7.08	1.27–39.48	0.026
Male	0.73	0.73–2.81	0.651	-	-	-
ET	3.29	1.02–10.62	0.047	2.94	0.76–11.36	0.117
IPSET high^a)	0.28	0.05–1.62	0.155	-	-	-
R-IPSET-T high^a)	0.47	0.03–8.60	0.603	-	-	-
WBC >11.0×10⁹/L	0.89	0.23–3.42	0.864	-	-	-
Monocyte >1.0×10⁹/L	0.30	0.03–3.04	0.310	-	-	-
Platelet >600×10⁹/L	8.87	1.07–73.03	0.043	13.70	1.35–138.17	0.026
Platelet >800×10⁹/L	1.23	0.45–3.79	0.631	-	-	-
Platelet >1,000×10⁹/L	1.58	0.39–6.38	0.518	-	-	-
LDH >1.5×UNL	1.25	0.30–5.23	0.760	-	-	-
Serum ferritin	0.99	0.98–1.00	0.201	-	-	-
Positive JAK2V617F	0.90	0.20–4.01	0.884	-	-	-
JAK2V617F VAF >50%	0.67	0.19–2.40	0.535	-	-	-
JAK2V617F VAF >70%	0.43	0.08–2.22	0.314	-	-	-
Positive CALR mutation	1.52	0.23–9.88	0.662	-	-	-
Chronic kidney disease	1.83	0.68–5.83	0.306	-	-	-
Diabetes mellitus	1.23	0.30–4.28	0.863	-	-	-
Hypertension	0.56	0.19–1.63	0.283	-	-	-
Smoking	0.60	0.15–2.47	0.479	-	-	-
Dyslipidemia	0.93	0.22–4.05	0.926	-	-	-
Volumetric splenomegaly	0.77	0.22–2.70	0.684	-	-	-
Thrombosis before or at diagnosis	0.65	0.10–4.14	0.652	-	-	-

^a)Among ET patients..

Abbreviations: CI, confidence interval; ET, essential thrombocythemia; IPSET, International Prognostic Score for Essential Thrombocythemia; LDH, lactate dehydrogenase; OR, odds ratio; R-IPSET-T, revised IPSET-thrombosis; UNL, upper normal limit; VAF, variant allele frequency..