Which side of the balance determines the frequency of vaso-occlusive crises in children with sickle cell anemia: Blood viscosity or microvascular dysfunction?

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Abstract

Vascular resistance and tissue perfusion may be both affected by impaired vascular function and increased blood viscosity. Little is known about the effects of vascular function on the occurrence of painful vaso-occlusive crises (VOC) in children with sickle cell anemia (SCA). The aim of the present study was to determine which side of the balance (blood viscosity or vascular function) is the most deleterious in SCA and increases the risk for frequent hospitalized VOC. Microvascular function, microcirculatory oxygenation and blood viscosity were determined in a group of 22 SCA children/adolescents at steady state and a group of 13 healthy children/adolescents. Univariate analyses demonstrated blunted microvascular reactivity during local thermal heating test and decreased microcirculatory oxygenation in SCA children compared to controls. Multivariate analysis revealed that increased blood viscosity and decreased microcirculatory oxygenation were independent risk factors of frequent VOC in SCA. In contrast, the level of microvascular dysfunction does not predict VOC rate. In conclusion, increased blood viscosity is usually well supported in healthy individuals where vascular function is not impaired. However, in the context of SCA, microvascular function is impaired and any increase of blood viscosity or decrease in microcirculatory oxygenation would increase the risks for frequent VOC.

Introduction

Vaso-occlusive crises (VOC) are the most frequent complications occurring in patients with sickle cell anemia (SCA). Each painful VOC may last for several days [1] and is caused by the physical entrapment of the rigid and adherent sickle red blood cells (RBC) into the microcirculation [2]. However, the identification of biomarkers and/or physiological factors to predict the occurrence of frequent VOC in SCA patients still remains an important challenge for physicians.

Previous studies demonstrated that SCA patients with the highest hematocrit or blood viscosity are frequently exposed to hospitalized VOC [1], [3], [4], [5]. However, although blood hyper-viscosity could trigger VOC, not all the SCA patients with high blood viscosity develop VOC [6]. It is now well admitted that preserved vascular function may limit the deleterious effects of increased blood viscosity on the cardiovascular system and tissue oxygenation in the general population [7]. SCA patients are characterized by macro- [8], [9] and micro-vascular [10] dysfunction, as well as decreased microcirculatory oxygenation level [11]. Basal blood flow is higher in SCA than in healthy subjects but NO-dependent vasodilation is reduced in the former population [8], [9], [10], [12], [13]. The role of vascular/endothelial dysfunction in pulmonary hypertension is somewhat well established in SCA [3] but its role in painful VOC is poorly described. Whether the level of vascular dysfunction in SCA patients may help to identify those at the highest risk to develop frequent hospitalized VOC is currently unknown.

The aim of the present study was to determine which side of the balance (blood viscosity or vascular function) is the most deleterious in SCA and increases the risk for frequent hospitalized VOC. Blood viscosity, microvascular function and microcirculatory oxygenation were determined in a group of SCA children/adolescents regularly followed at the Sickle Cell Centre of Pointe-à-Pitre (Guadeloupe).

Section snippets

Patients and participants

Twenty-two SCA (i.e., HbSS) children/adolescents at steady-state [4] were included in this study (age: 15.2 ± 2.3 y; height: 1.62 ± 0.12 m; weight: 50.1 ± 13.9 kg). Four patients were under hydroxyurea treatment for more than 6 months (dose ~ 20 mg/kg per day). Charts were retrospectively reviewed by three physicians to recognize all VOC episodes in SCA from birth to the time of the study, based on previous described criteria [4], [14]. The rate of VOC [4] was calculated for each patient. Thirteen healthy

Results

The inclusion or exclusion of the 4 patients under hydroxyurea did not affect the results. Results below include all the patients.

Discussion

This study is the first one to investigate both blood viscosity and microvascular function in the same time in a group of SCA children/adolescents. Our results confirmed that microvascular reactivity is blunted in SCA compared to healthy children. However, the level of microvascular dysfunction (Peak or Plateau %CVCBL) does not predict the occurrence of frequent VOC. Instead, increased blood viscosity seems to be an independent risk factor of frequent VOC. In addition, our findings also support

Conclusion

Our study demonstrated that although SCA children/adolescents have impaired microvascular reactivity, not only increased blood viscosity but also reduced microvascular oxygenation are the most important factors in promoting frequent vaso-occlusive crises in this population.

Acknowledgments

XV, MDHD, MR, SAJ and PC designed the study. KC, BM, SJ, SAJ and PC designed the data collection instruments, and coordinated and supervised data collection. KC, BM, SJ, LDD, MP, BT, VT, SAJ and PC carried out the study. KC and PC conducted the statistical analyses. KC, MR and PC drafted the initial manuscript. All authors reviewed and revised the manuscript, approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

KC, BK, SJ and XW were funded by the

References (38)

  • M.T. Gladwin et al.

    Pulmonary complications of sickle cell disease

    N. Engl. J. Med.

    (2008)
  • Y. Lamarre et al.

    Hemorheological risk factors of acute chest syndrome and painful vaso-occlusive crisis in children with sickle cell disease

    Haematologica

    (2012)
  • D. Nebor et al.

    Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

    Haematologica

    (2011)
  • P. Connes et al.

    Haemolysis and abnormal haemorheology in sickle cell anaemia

    Br. J. Haematol.

    (2014)
  • M.J. Simmonds et al.

    Nitric oxide, vasodilation and the red blood cell

    Biorheology

    (2014)
  • A. Blum et al.

    Endothelial function in patients with sickle cell anemia during and after sickle cell crises

    J. Thromb. Thrombolysis

    (2005)
  • P.L. Tharaux et al.

    Cutaneous microvascular blood flow and reactivity in patients with homozygous sickle cell anaemia

    Eur. J. Haematol.

    (2002)
  • X. Waltz et al.

    Hemorheological alterations, decreased cerebral microvascular oxygenation and cerebral vasomotion compensation in sickle cell patients

    Am. J. Hematol.

    (2012)
  • M. de Montalembert et al.

    Endothelial-dependent vasodilation is impaired in children with sickle cell disease

    Haematologica

    (2007)
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