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Study Explores Endothelial Mechanisms of Hydroxyurea’s Stroke Prevention in SCA

May 30, 2024

June 2024

Ruth Jessen Hickman, MD

Ruth Jessen Hickman, MD, is a freelance medical and science writer based in Bloomington, Indiana.

 

A study published in Blood Vessels, Thrombosis & Hemostasis suggests potential causative links between the endothelial activator angiopoietin-2 and complications of stroke from sickle cell anemia (SCA), effects that may be partially ameliorated through hydroxyurea treatment.1

The disease-modifying agent hydroxyurea is part of standard-of-care treatment for SCA in the U.S., with guidelines from the National Heart, Lung, and Blood Institute recommending that therapy be initiated as early as 9 months of age, regardless of clinical severity.2 Hydroxyurea induces the production of fetal hemoglobin, which helps inhibit intracellular polymerization of sickle hemoglobin and consequent hemolysis, and also reduces inflammation via myelosuppression of white blood cells and platelets.3 Less is known about potential effects mediated through endothelial activation pathways.

Until recently, it was unclear whether hydroxyurea’s benefits outweigh its potential risks in children with SCA in sub-Saharan Africa, given that close count monitoring may be less feasible and patients face challenges from malaria, other endemic infections, and malnutrition.

In the prospective NOHARM study, researchers compared hydroxyurea to placebo for one year, demonstrating the safety of hydroxyurea for pediatric patients with SCA in Uganda.4 The REACH trial, which studied more than 600 children with SCA in sub-Saharan Africa, further found that hydroxyurea reduced vaso-occlusive events and the need for transfusions while reducing the risks of malaria and other infections.2 Although now approved by the Ugandan Ministry of Health, hydroxyurea is not yet standard of care; it is currently primarily available only for children with repeated complications or for some families able to self-pay.

Observational studies have also shown that hydroxyurea may help prevent devastating complications of stroke in patients with SCA.5 Analyses from NOHARM found that children receiving hydroxyurea had a very low incidence of stroke, as well as decreased stroke risk as indicated by low intracerebral arterial velocities via transcranial Doppler (TCD).6

The current report provides additional analyses from the NOHARM study, investigating 798 plasma samples from 205 children. Andrea L. Conroy, PhD, of Indiana University School of Medicine in Indianapolis, collaborated with Robert O. Opoka, MMDE, MHPE, MPH, MD, and the rest of the research team at Global Health Uganda in Kampala. They further analyzed markers of endothelial activation and explored potential mechanisms of hydroxyurea’s benefits.1

Angiopoietin-2 is an endothelial activator that can function in both angiogenesis and inflammation, attracting white blood cells to an injury site. The researchers found that higher levels of angiopoietin-2 at study enrollment corresponded to patients who had more episodes of dactylitis, vaso-occlusive crises, and acute chest syndrome in their previous medical history.1

Moreover, hydroxyurea doses of 20 mg/day decreased the endothelial activation markers P-selectin, sE-selectin, and angiopoietin-2, and higher levels of the latter two markers were positively associated with higher TCD velocities (and inferred increased stroke risk). Using mediation analyses, they found that increased hemoglobin, increased fetal hemoglobin, and decreased white blood cell count may decrease TCD velocities partly through effects mediated via angiopoietin-2, which may also have other direct effects on the endothelium.1

“We were really trying to better understand the mechanisms of hydroxyurea,” Dr. Conroy said. “Although there have been wonderful studies done previously, a major limitation in North America is that you don’t have that many children, and many start hydroxyurea or transfusion programs early on.” However, Dr. Conroy also noted a limitation of the current study design: Although the data are suggestive, they don’t provide direct mechanistic proof of these potential connections between angiopoietin-2 and hydroxyurea, so follow-up is needed.

Dr. Conroy and colleagues speculate that angiopoietin-2 might potentially be used as a predictive biomarker to stratify high-risk patients, especially in settings where TCD isn’t available. Angiopoietin-2 might also serve as an attractive target for SCA therapies. However, Dr. Conroy noted that such an approach (e.g., via a monoclonal antibody) might have limited impact in resource-limited settings such as the sub-Saharan population.

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Siegert TF, Opoka RO, Nakafeero M, et al. Angiopoietin-2 is associated with sickle cell complications, including stroke risk, and decreases with hydroxyurea therapy. Blood VTH. 2024;1(1):100001.
  2. Tshilolo L, Tomlinson G, Williams TN, et al. Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa. N Engl J Med. 2019;380(2):121-131.
  3. McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 2015;14(11):1749-1758.
  4. Opoka RO, Ndugwa CM, Latham TS, et al. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood. 2017;130(24):2585-2593.
  5. Hasson C, Veling L, Rico J, et al. The role of hydroxyurea to prevent silent stroke in sickle cell disease: systematic review and meta-analysis. Medicine (Baltimore). 2019;98(51):e18225.
  6. Opoka RO, Hume HA, Latham TS, et al. Hydroxyurea to lower transcranial Doppler velocities and prevent primary stroke: the Uganda NOHARM sickle cell anemia cohort. Haematologica. 2020;105(6):e272-e275.

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