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    • The higher mortality in sickle cell disease compared to the

    2018-10-23

    The higher mortality in sickle cell disease compared to the general population may be due to heighten inflammatory response in sickle cell disease relative to subjects without sickle cell disease. For example recent advances have shown that specific SCR7 and T cells directly influence a cytokine imbalance in dengue that eventually leads to severe disease and vascular damage (Remy, 2014). Additionally, several studies in patients with SCD have shown excessive inflammatory cytokines in both steady-state and during a vaso-occlusive crisis and therefore the existence of ongoing inflammation (Musa et al., 2010). Taken together these observations may indicate an amplified inflammatory response in SCD during a dengue infection resulting in increased morbidity and mortality. Firstly, it may be that subjects with HbSC are more susceptible to fatal dengue due to the increased susceptibility of the red blood cell in HbSC to dehydration based on K+ loss (Hannemann et al., 2011). This leads to a greater propensity for dense cell formation when compared to HSS. These dense cells have an increased intracellular haemoglobin concentration hence higher mean cell haemoglobin concentration (MCHC). The higher MCHC causes both an increase in HB S polymerization and also decreases the time to sickling (Nagel et al., 2003). Perhaps the dengue virus either alters the HbSC RBC rheology by triggering RBC dehydration or affects the endothelial adhesivity resulting in a massive vascular leak syndrome and intravascular dehydration. This in turn would result both in intravascular dehydration and massive sickling. Another possible mechanism which could explain a higher morbidity in HbSC disease is neo-angiogenesis. It has been reported that neo-angiogenesis and retinopathy are more frequent in HbSC patients (Banu et al., 2013). It is possible that blood vessels produced by neo-angiogenesis are more permeable in response to inflammatory cytokines such as High mobility group box 1 (HMGB1) protein which increases vascular permeability of endothelial cells in a dose dependent manner in in-vitro experiments (Ong et al., 2012). The HMGB protein is increased in dengue fever infection and sickle cell vaso-occlusive crises (Xu et al., 2014) and is thought to play an important role in dengue shock syndrome (Ong et al., 2012). This could contribute to a massive vascular leak syndrome, intravascular dehydration and shock.
    Conclusion
    Author Contributions
    Acknowledgements
    Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder associated with inherited or, more commonly, acquired deficiency in the plasma metalloprotease, ADAMTS13 (Levy et al., 2001; Fujikawa et al., 2001). Severe ADAMTS13 deficiency (activity generally <10%) results in insufficient processing of von Willebrand factor (VWF) — a critical mediator of normal platelet tethering. ADAMTS13 deficiency results in the accumulation of the most haemostatically active “ultra-large” forms of VWF in plasma. These UL-VWF multimers can unravel during passage through the microcirculation, which precipitates unwanted platelet aggregation and multi-organ microvascular thrombosis. This accounts for the clinical sequelae of TTP, namely thrombocytopenia and microangiopathic haemolytic anaemia, variably with neurological, cardiac, gastro-intestinal and/or renal involvement. Autoantibodies against ADAMTS13, predominantly immunoglobulin class G (IgG), are present in the majority of acquired TTP patients and cause profound loss of VWF-cleaving function (Hovinga et al., 2010; Ferrari et al., 2007, 2009; Peyvandi et al., 2008). Antibodies that bind the N-terminal domains of ADAMTS13 (herein termed MDTCS) are detected in most patients, although antibodies recognising the C-terminal domains of ADAMTS13 have also been reported (Klaus et al., 2004; Luken et al., 2005, 2006; Soejima et al., 2003; Zheng et al., 2010; Pos et al., 2011). However, epitope mapping studies alone do not identify the antibodies that are inhibitory and/or pathogenic. For example, non-inhibitory IgG antibodies that do not impair ADAMTS13 function in vitro may still be pathogenic and compromise VWF processing in vivo (Scheiflinger et al., 2003). Autoantibodies against different ADAMTS13 domains likely inhibit enzyme function to different extents, and may cause deficiency in vivo via distinct mechanisms.