Haptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage

Abstract

Cerebral vasospasm (CV) and the resulting delayed cerebral ischemia (DCI) significantly contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Free hemoglobin (Hb) within the subarachnoid space has been implicated in the pathogenesis of CV. Haptoglobin (Hp) binds free pro-oxidant Hb, thereby modulating its harmful effects. Humans can be of three Hp phenotypes: Hp1-1, Hp2-1, or Hp2-2. In several disease states, the Hp2-2 protein has been associated with reduced ability to protect against toxic free Hb. We hypothesized that individuals with the Hp2-2 phenotype would have more CV, DCI, mortality, and worse functional outcomes after aSAH. In a sample of 74 aSAH patients, Hp2-2 phenotype was significantly associated with increased focal moderate (P = 0.014) and severe (P = 0.008) CV and more global CV (P = 0.014) after controlling for covariates. Strong trends toward increased mortality (P = 0.079) and worse functional outcomes were seen for the Hp2-2 patients with modified Rankin scale at 6 wk (P = 0.076) and at 1 y (P = 0.051) and with Glasgow Outcome Scale Extended at discharge (P = 0.091) and at 1 y (P = 0.055). In conclusion, Hp2-2 phenotype is an independent risk factor for the development of both focal and global CV and also predicts poor functional outcomes and mortality after aSAH. Hp phenotyping may serve as a clinically useful tool in the critical care management of aSAH patients by allowing for early prediction of those patients who require increased vigilance due to their inherent genetic risk for the development of CV and resulting DCI and poor outcomes.

Planar Functionalized Surfaces for Direct Immunoaffinity Desorption/Ionization Mass Spectrometry

“…Haptoglobin (Hp) 5 plays an important role in scavenging of hemoglobin, which induces oxidative stress and tissue damage. Monomeric Hp consists of ␣ and ␤ subunits.…”

“…Prior to the introduction of modern DNA-based approaches, haptoglobin phenotyping was used for paternity exclusion. Currently, haptoglobin phenotyping serves as a clinically relevant biomarker to predict complications in patients with diabetes mellitus (3)(4)(5). To determine Hp phenotype, several biochemical and molecular biological methods have been introduced (6 -8 ).…”

Precision medicine of aneurysmal subarachnoid hemorrhage, vasospasm and delayed cerebral ischemia

“…Patient with Hp 2-2 phenotype were associated with higher rates of CV when compared with Hp 1-1 [80]. Furthermore, Leclerc et al found that patients with the Hp 2-2 phenotype were significantly more likely to have moderate, severe, or global CV, trended toward poorer outcomes as measured by mRS and GOS, and had increased incidence of mortality [81]. Several novel therapies have been effective in preventing vasospasm in mice with Hp 2-2 phenotype, including glutamate receptor antagonists [82], systemic L-citrulline [83], glutathione peroxidase mimetic [84], and controlled nitric oxide delivery [85].…”

Leukocyte expression of heme oxygenase-1 [hmox1] varies inversely with severity of tricuspid regurgitation in acute pulmonary embolism

“…[14] These data suggest that the cognate ability of haptoglobin to sequester hemoglobin, and thus limit its vasoconstrictive effect, provides a protective effect—a finding already observed in humans with sepsis and subarachnoid hemorrhage. [15,16] Similarly, inducible heme oxygenase-1 ( hmox -1) converts free heme from a potent vasoconstrictor, oxidant and inflammatory molecule into the vasodilator carbon monoxide and the antioxidant biliverdin, possibly explaining elevations in carboxyhemoglobin concentrations observed in nonsmoking patients with PE. [17] Experimentally increased expression of heme oxygenase-1 improves, and decreased expression worsens right heart injury in experimental models of pulmonary hypertension.…”