The vaso-occlusive pain crisis is the hallmark of sickle cell disease (SCD), which affects approximately 100,000 Americans and hundreds of thousands more people around the world. During a pain crisis, small blood vessels become occluded, causing tissue ischemia, severe pain, and potentially irreversible organ damage. SCD itself is caused by abnormal hemoglobin, but the pathophysiology of a vaso-occlusive pain crisis is complex. In addition to red blood cells, endothelial adhesion molecules, leukocytes, and plasma coagulation factors play a role in initiating and propagating SCD vaso-occlusion. Current treatment of SCD pain crisis is limited to supportive care with opioids, anti-inflammatory drugs, intravenous fluids, and rest. These measures palliate pain but do not directly affect vaso-occlusion or ischemia, and SCD patients are often unfairly stigmatized as “drug-seeking.” Interrupting adhesion of RBCs to the endothelium is an attractive target for treating SCD pain crises.
Telen and colleagues identified sevuparin, a synthetic heparinoid with low anticoagulant properties, as a potential therapy for SCD pain crisis. In endothelial cell cultures, sevuparin bound to endothelial adhesion molecules, as well as several plasma coagulation factors, and prevented adhesion of SCD patients’ RBCs. The investigators then used a hybrid system to study microvascular blood flow, in which a “window” was implanted in the dorsal skin fold of mice, allowing in vivo microscopy of the microvasculature. RBCs from SCD patients were infused into these mice along with sevuparin or saline control. Sevuparin treatment reduced microvascular occlusion in these mice, with greater improvement in microvascular blood flow seen with higher sevuparin concentrations.
Although these results are promising, translating an abortive therapy to clinical trials and eventually patient care will present some challenges. First, it is unclear how long after pain crisis onset an abortive therapy can be effective. At some point during a vaso-occlusive episode, irreversible tissue infarction may occur, and pain may continue due to inflammation resulting from tissue death. Initiation of abortive treatment as soon as possible after onset of a pain crisis may be necessary to improve patient outcomes. Second, acute care for pain crisis tends to be fragmented. Advocacy will be needed to ensure that patients have access to centers where a specialized therapy is immediately available. Ultimately, improving care for SCD patients will require both research and public policy advances.
M. J. Telen et al., Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion. Br. J. Haematol. 10.1111/bjh.14303 (2016). [Abstract]
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