Sickle cell disease is characterised by chronic haemolytic anaemia, painful vaso-occlusive episodes, progressive organ damage, and early mortality.1, 2, 3, 4 Vaso-occlusive crises are the main reason for the hospitalisation of these patients. On average, patients have 2·5 vaso-occlusive crises per year, of which 1·5 led to hospitalisation.5 In particular, young adults aged 18–30 years appear to have the highest health-care utilisation due to vaso-occlusive crises and are at risk for complications like acute chest syndrome, one of the most important causes of early mortality in adult patients with sickle cell disease.6 There is currently no approved therapy for acute vaso-occlusive crisis besides pain management. Pain treatment is often already initiated at home by use of pain relief (eg, non-steroidal anti-inflammatory drugs and oral opioids), rest, and rehydration; however, hospitalisation for intravenous opioids, intravenous fluids, oxygen, and sometimes antibiotics and transfusion, are frequently needed.7 The scarcity of specific treatments for sickle cell disease,8, 9, 10 frequent pain, risk of opioid dependency, disease confinement to socioeconomically challenged groups, and the difficulty to maintain school and work activities due to sickle cell disease all contribute to the overall disease burden and reduced quality of life for patients.11, 12, 13
Research in context
Evidence before this study
We searched for clinical trials published from inception to Dec 1, 2020, using the search terms “sickle cell disease” combined with either “adhesion” or “heparin”. We identified 46 clinical trials. Abstracts were reviewed to identify all phase 2 and 3 trials studying anti-adhesive therapy directed at selectins or using heparins in sickle cell disease. This review resulted in two relevant clinical studies before the initiation of our trial and one relevant clinical study after initiation of our trial. In one randomised controlled clinical trial done in 2007, treatment with low molecular weight heparin (tinzaparin) significantly reduced the duration of vaso-occlusive crisis in comparison with placebo in patients with sickle cell disease admitted to hospital with vaso-occlusive crisis. In 2015, a small randomised phase 2 study showed that the pan-selectin inhibitor (GMI-1070 [rivipansel]) had no effect on the duration of a vaso-occlusive crisis, but significantly reduced opioid use in patients with sickle cell disease admitted with a vaso-occlusive crisis as compared with patients in the placebo group. In another randomised clinical study done in 2017, preventive P-selectin inhibition with a neutralising monoclonal antibody reduced the incidence of vaso-occlusive crisis by 45% but has not been studied in patients with sickle cell disease admitted with a vaso-occlusive crisis.
Added value of this study
This study showed that anti-adhesive therapy aimed primarily at P-selectin is not able to change the duration or the severity of pain in patients with sickle cell disease. This finding suggests that different from preventive strategies, P-selectin inhibition is not able to change the clinical course of patients with sickle cell disease and with an already manifest vaso-occlusive crisis.
Implications of all the available evidence
An implication of this important finding is that the role of anti-adhesive strategies as a single drug in general might need to be limited to the prevention and not to the treatment of vaso-occlusive crises. The findings also show that a non-anticoagulant heparinoid might not be beneficial in the vaso-occlusive crisis setting. Whether anti-adhesive strategies could be useful in addition to other drugs that modify other aspects of sickle cell pathophysiology, should be subject of future studies. Another goal in future studies could be to administer anti-selectins or non-anticoagulant heparinoid drugs very early in the course of a vaso-occlusive crisis to prevent the crisis developing further.
Vaso-occlusion in sickle cell disease is a complex phenomenon, involving increased adhesion of erythrocytes and leukocytes to activated endothelial cells, which results in vascular obstruction.14, 15 Anti-adhesive P-selectin or pan-selectin inhibition has prevented vaso-occlusion in several animal models16, 17, 18, 19 and published data from a randomised controlled clinical trial8 showed that P-selectin inhibition is effective in preventing vaso-occlusive crisis. In a clinical trial published in 2007,20 full anticoagulant therapy using tinzaparin (175 IU/kg) reduced vaso-occlusive crisis duration and time of severe pain in patients with sickle cell disease hospitalised for vaso-occlusive crisis.20 In addition to their anticoagulant properties, heparinoids are also potent multimodal effectors of blood rheology with activities on adhesive, inflammatory, and immune-related components.16, 21 The anticoagulant properties, however, limit the therapeutic use of heparinoids due to the risk of bleeding. We hypothesised that a heparinoid with markedly attenuated anticoagulant activity, but retaining its broad anti-adhesive properties, could be effective in treating vaso-occlusive crises in patients with sickle cell disease who are hospitalised. Sevuparin is a novel short heparinoid modified to be non-anticoagulant by the elimination of the anti-thrombin binding domain resulting in abrogated anti-factor II and anti-factor X activities.22 Sevuparin retains some degree of isolated residual activated partial thromboplastin time (aPTT) activity, which is likely attributable to heparin cofactor II activity.22 Although its anticoagulant properties are markedly attenuated, sevuparin maintains the anti-adhesive, anti-aggregate, and anti-inflammatory properties of heparin as shown by its activities on P-selectin, L-selectin, thrombospondin, von Willebrand factor, and fibronectin.23, 24
The primary objective of the present study was to assess whether sevuparin could shorten the time to vaso-occlusive crisis resolution in patients with sickle cell disease who were hospitalised compared with placebo, and to evaluate the effect of sevuparin on the mean change in pain intensity, duration of severest pain, and cumulative dose of parental opioids. This study investigated the assumed benefit of non-adhesive treatment to shorten the duration of vaso-occlusive crisis strategies in general and specifically if a non-anticoagulant heparinoid would be beneficial in that setting.