A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease

Am J Hematol. 2012 May;87(5):536-9. doi: 10.1002/ajh.23147. Epub 2012 Apr 10.

Abstract

Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acute Pain / etiology
  • Acute Pain / physiopathology
  • Acute Pain / prevention & control
  • Administration, Oral
  • Adult
  • Anemia, Sickle Cell / drug therapy*
  • Anemia, Sickle Cell / pathology
  • Anemia, Sickle Cell / physiopathology
  • Arterial Occlusive Diseases / etiology
  • Arterial Occlusive Diseases / physiopathology
  • Arterial Occlusive Diseases / prevention & control
  • Blood Flow Velocity / drug effects*
  • Double-Blind Method
  • Early Termination of Clinical Trials / economics
  • Endothelial Cells / drug effects*
  • Humans
  • Microcirculation / drug effects*
  • P-Selectin / antagonists & inhibitors*
  • Pentosan Sulfuric Polyester / administration & dosage
  • Pentosan Sulfuric Polyester / pharmacology
  • Pentosan Sulfuric Polyester / therapeutic use*
  • Vascular Cell Adhesion Molecule-1 / blood

Substances

  • P-Selectin
  • Vascular Cell Adhesion Molecule-1
  • Pentosan Sulfuric Polyester