CORRESPONDENCE Association between relative systemic hypertension and otologic disorders in patients with sickle cell-hemoglobin C disorder To the Editor: The definition of systemic hypertension (HTN) is not clearly established in sickle cell patients. Although sickle cell-hemoglobin C (SC) patients have slightly lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) values than the general population [1], they have higher blood pressure values than patients with homozygous sickle cell anemia (SCA) [1]. Recently, in SCA, it was reported that increased blood viscosity could be a risk factor for relative systemic HTN (SBP/DBP > 120/70 mmHg) [2] and that relative systemic hypertension could be a risk factor for several chronic complications in SCA, such as glomerulopathy and pulmonary hypertension [3]. However, these relationships have not been investigated in SC patients. We used the data of 89 SC adult patients (M/F: 40/49; mean age: 38 6 13 years), regularly followed by the Sickle Cell Center of Pointe-a-Pitre (Guadeloupe), to address these issues. The cohort characteristics, including inclusion and exclusion criteria, have been previously reported [4]. While leg ulcers, pulmonary hypertension, priapism, and cerebral vasculopathy were very rare in our cohort, retinopathy (60%), glomerulopathy (40%), osteonecrosis (31%), and otologic disorders (20%) were frequent [4]. Blood pressures (SBP/DBP) were measured for each patient, as recommended [2]. Systemic arterial HTN was defined using the three cutoff values previously proposed for sickle cell patients: (1) HTN1 > 120/70 mmHg [5]; (2) HTN2 > 130/80 mmHg [6]; or (3) HTN3 > 140/90 mmHg [5]. Hematological and hemorheological parameters (blood viscosity, red blood cell deformability, and aggregation) were performed as previously described [4]. Results are reported in the Table I. When using the HTN1 cutoff (i.e., relative systemic HTN), we found a trend for greater hematocrit (P < 0.1) and higher blood viscosity (111%; P < 0.01) in patients with relative systemic HTN than in those without. Blood viscosity was still higher in SC patients with SBP/DBP greater than the HTN2 cutoff values compared to patients with SBP/DBP below this cutoff (111%; P < 0.05). We also noted a trend toward patients with HTN2 being older than patients with SBP/DBP below the HTN2 cutoff values (P < 0.1). Finally, using the HTN3 cutoff, the significant difference in blood viscosity between the two subgroups (i.e., patients with SBP/DBP below vs. above HTN3 cutoff values) did not persist (P 5 0.18). However, we noted a significant correlation between blood viscosity and the severity of HTN (r 5 0.35; P < 0.01). SC patients with HTN3 were older (P < 0.05) and had greater red blood cell aggregates strength than patients with SBP/DBP below HTN3 cutoff (P < 0.05). Whatever the SBP/ DBP cutoff used, HTN was neither associated with glomerulopathy, nor with osteonecrosis or retinopathy. In contrast, we observed an association between otologic disorders and HTN when using the HTN1 cutoff, with 69% of patients with otologic disorders having HTN (P < 0.05). Our findings support the need to closely monitor blood pressure levels in SC patients as the presence of relative systemic hypertension (i.e., SBP/DBP > 120/70 mmHg), which was associated with blood viscosity level, could indicate a risk to develop otologic disorders. SC clinical management should include close monitoring of blood pressure level, particularly when it rises above 120/70 mmHg. 1

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NATHALIE LEMONNE, MARC ROMANA, YANN LAMARRE, MARIE–DOMINIQUE HARDY–DESSOURCES,2,3,4 FRANÇOIS LIONNET,5 XAVIER WALTZ,2,3,4 1 1 VANESSA TARER, DANIELLE MOUGENEL, BENOIˆT TRESSIE`RES,6

MARIE–LAURE LALANNE–MISTRIH,2,3,4,6 MARYSE ETIENNE–JULAN,1,2,3,4 AND PHILIPPE CONNES,2,3,4,7,8,9* 1 Unite Transversale de la Drepanocytose, CHU de Pointe-a-Pitre, Pointe-a-Pitre, Guadeloupe; 2Inserm UMR 1134, H^opital Ricou, CHU de Pointe-a-Pitre, Pointe-a-Pitre, Guadeloupe; 3Universite des Antilles et de la Guyane, Pointe-a-Pitre, Guadeloupe; 4Laboratory of Excellence GR-Ex, (The red cell: from genesis to death), PRES Sorbonne Paris Cite, Paris, France; 5Centre de Reference de la Drepanocytose, H^opital Tenon, AP-HP, Paris, France; 6Centre d’Investigation Clinique Antilles Guyane, Inserm/DGOS CIC 1424, CHU a Pitre, de Pointe-a-Pitre, Pointe-a-Pitre, Guadeloupe; 7Laboratoire ACTES EA3596, Pointe  Guadeloupe; 8Institut Universitaire de France, Paris, France Conflict of interest: Nothing to report *Correspondence to: Philippe Connes, Inserm UMR 1134, H^opital Ricou, CHU de Pointe- aPitre, Pointe-a-Pitre 97157, Guadeloupe. E-mail: [email protected] Received for publication: 17 March 2014; Accepted: 21 March 2014 Published online: 25 March 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.23717

䊏 References 1. Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: Risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997;102:171–177. 2. Lamarre Y, Lalanne-Mistrih ML, Romana M, et al. Male gender, increased blood viscosity, body mass index and triglyceride levels are independently associated with systemic relative hypertension in sickle cell anemia. PLoS One 2013;8:e66004. 3. Gordeuk VR, Sachdev V, Taylor JG, et al. Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. Am J Hematol 2008;83:15–18. 4. Lemonne N, Lamarre Y, Romana M, et al. Impaired blood rheology plays a role in chronic disorders in sickle cell-hemoglobin C disease. Haematologica, in press. 5. Ballas SK, Lieff S, Benjamin LJ, et al. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol 2010;85:6–13. 6. Lionnet F, Hammoudi N, Stojanovic KS, et al. Hemoglobin sickle cell disease complications: A clinical study of 179 cases. Haematologica 2012;97:1136–1141.

ADAMTS-13 content of plasma-derived factor VIII/ von Willebrand factor concentrates To the Editor: We read with interest the article by Peyvandi et al. [1] on the ADAMTS13 content of plasma-derived factor VIII/von Willebrand factor (FVIII/ VWF) concentrates. The authors make reference to published case studies on the use of two FVIII conV centrates in treatment of congenital thrombotic thrombocytopenic purpura (TTP): 8Y V V [2] and Koate -DVI [3]. Use of 8Y in the treatment of congenital TTP has also been described by Lester et al. [4] and is exemplified in national guidelines on the diagnosis and management of TTP and other thrombotic microangiopathies [5]. In the course of their discussion, the authors compare the ADAMTS-13 activity of V V Koate -DVI and 8Y : 9.08 U/mL and 3.5 U/mL, respectively [6]. When these concentrates were utilized in the treatment of congenital TTP, dosing has been described in terms of FVIII administered; 30–35 IU FVIII/kg body weight (b.w.) in the case of V V KOATE -DVI [3] and 15–30 IU FVIII/kg b.w. in the case of 8Y [2]. Based on the reported levels of ADAMTS-13 in these two FVIII concentrates, the authors suggest that V the ADAMTS-13 administered when 8Y was given would have been substantially lower V than that when Koate -DVI was used for treatment. However, there is a four-fold R

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TABLE I. Hematological and Hemorheological Determinants of Systemic Hypertension (HTN) Defined by Three Different CutOff Values (HTN1; HTN2; HTN3) in SC Patients HTN1 (>120/70 mmHg)

Age (years) White blood cells (3109 L) Platelet count (3109 L) Red blood cells (31012 L) Hemoglobin (g/dL) Hematocrit (%) Blood viscosity (cP) RBC deformability (a.u.) RBC aggregation (%) RBC disaggregation threshold (s21)

HTN2 (>130/80 mmHg)

HTN3 (>140/90 mmHg)

HTN12 (n 5 46)

HTN11 (n 5 43)

HTN22 (n 5 62)

HTN21 (n 5 27)

HTN32 (n 5 74)

HTN31 (n 5 15)

38 6 13 7.1 6 2.5 291 6 148 4.3 6 0.6 11.3 6 1.3 30.7 6 3.5 7.05 6 1.10 0.43 6 0.06 48 6 7 297 6 80

38 6 14 7.9 6 3.1 300 6 147 4.5 6 0.7 11.6 6 1.1 31.8 6 2.7a 7.97 6 1.22** 0.43 6 0.07 49 6 11 337 6 155

36 6 13 7.3 6 2.6 300 6 151 4.3 6 0.7 11.4 6 1.3 31.1 6 3.4 7.17 6 1.24 0.43 6 0.06 48 6 7 306 6 102

42 6 14a 7.9 6 3.3 284 6 138 4.5 6 0.6 11.5 6 1.1 31.7 6 2.5 8.00 6 1.14* 0.43 6 0.07 49 6 12 342 6 162

36 6 13 7.3 6 2.5 302 6 154 4.4 6 0.7 11.4 61.2 31.2 6 3.3 7.33 6 1.21 0.43 6 0.07 48 6 8 299 6 103

45 6 14* 8.5 6 3.9 275 6 132 4.4 6 0.5 11.4 6 1.1 31.5 6 2.3 8.03 6 1.19 0.44 60.07 50 6 12 387 6 188*

Means 6 SD. 2 5 absence of HTN and 1 5 presence of HTN. RBC 5 red blood cell. RBC disaggregation threshold reflects the strength of RBC aggregates. Difference between groups (*P < 0.05; **P < 0.01). a Statistical trend (P < 0.1).

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difference between the stated FVIII potency of Koate -DVI (100 IU/mL) and that of 8Y (25 IU/mL). Taking this potency difference into consideration, the ratio of ADAMTS-13 activity to FVIII in the two products is calculated to be similar at 0.09 U ADAMTS-13/ V V IU FVIII (for Koate -DVI) and 0.14 U ADAMTS-13/IU FVIII (for 8Y ). This comparison would indicate that, in fact, the dosing regimens described for the two FVIII concentrates would have resulted in similar levels of ADAMTS-13 being administered (2–4 U ADAMTS-13/kg b.w.). Although both these concentrates contain VWF and FVIII, which could influence the clinical outcome, the similarity of these dosing calculations is consistent with a therapeutic mechanism which is mediated by ADAMTS-13 substitution. We agree that VWF multimer distribution in the concentrates is predominantly attributable to manufacturing process rather than to ADAMTS-13 activity. Furthermore, a higher ratio of ADAMTS-13 to FVIII in the concentrate would be consistent with the treatment of a thrombotic condition such as TTP, where elevation of superfluous procoagulant proteins may be undesirable. R

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SARAH KINGSLAND* AND PETER FELDMAN Research, Development and Medical Department, Bio Products Laboratory Ltd., Hertfordshire, United Kingdom

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American Journal of Hematology, Vol. 89, No. 6, June 2014

*Correspondence to: Sarah Kingsland, Research, Development and Medical Department, Bio Products Laboratory Ltd., Hertfordshire WD6 3BX, United Kingdom. E-mail: [email protected] Received for publication: 28 February 2014; Accepted: 6 March 2014 Published online: 10 March 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.23706

䊏 References 1. Peyvandi F, Mannucci P, Valsecchi C, Pontiggia S, Farina C, Retzios A. ADAMTS13 content in plasma -derived factor VIII/ von Willebrand factor concentrates. Am. J. Hematol 2013;88:895–898. 2. Scully M, Gattens M, Khair K, et al. The use of intermediate purity FVIII concentrate BPL 8Y as prophylaxis and treatment in congenital thrombotic thrombocytopenic purpura. Br J Heamatol 2006;135:101–104. 3. Naik S, Mahoney DH. Successful treatment of congenital TTP with a novel approach using plasma derived FVIII. J Pediatr Heamatol Oncol 2013;35:551–553. 4. Lester W, Williams M, Allford S, et al. Successful treatment of thrombotic thrombocytopenic purpura using the intermediate purity FVIII concentrate 8Y. Br J Heamatol 2002;119:176–179. 5. Scully M, Hunt B, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012;158:323–335. 6. Bolsa H, Kingsland S, Feldman P. Measurement of ADAMTS-13 in a factor VIII concentrate, V 8Y . Haemophilia 2012;18(suppl 3):FP-TH-01.1–2. R

doi:10.1002/ajh.23710