Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease

Abstract

Pharmacologic efforts to improve outcomes following aneurysmal subarachnoid hemorrhage (aSAH) remain disappointing, likely owing to the complex nature of post-hemorrhage brain injury. Previous work suggests that heparin, due to the multimodal nature of its actions, reduces the incidence of clinical vasospasm and delayed cerebral ischemia that accompany the disease. This narrative review examines how heparin may mitigate the non-vasospastic pathological aspects of aSAH, particularly those related to neuroinflammation. Following a brief review of early brain injury in aSAH and heparin's general pharmacology, we discuss potential mechanistic roles of heparin therapy in treating post-aSAH inflammatory injury. These roles include reducing ischemia-reperfusion injury, preventing leukocyte extravasation, modulating phagocyte activation, countering oxidative stress, and correcting blood-brain barrier dysfunction. Following a discussion of evidence to support these mechanistic roles, we provide a brief discussion of potential complications of heparin usage in aSAH. Our review suggests that heparin's use in aSAH is not only safe, but effectively addresses a number of pathologies initiated by aSAH.

Keywords: brain injury; edema; enoxaparin; heparin; inflammation; subarachnoid hemorrhage.

Figure 1

Summary of heparin chemical derivatives. Chemical modification of unfractionated heparin modulates its pharmacology. Although all derivatives discussed demonstrate reduced anticoagulant activity, chemical modification also affects heparin’s other pharmacologic properties in a regiospecific manner. 2,3-O-desulfated heparin demonstrates nearly retained selecting and RAGE inhibition; 6-O-desulfated heparin, despite numerous sulfated residues, fails to bind selectins and does not demonstrate significant anti-inflammatory effects in vivo. Although less well studied in inflammation, N-acetyl heparin does demonstrate evidence of efficacy in ischemia-reperfusion (I/R) injury despite reduced anticoagulant activity. Finally, glycol split heparin retains the ability to inhibit proteases such as elastase despite reduced anti-coagulant activity.

Figure 2

Summary of heparin’s modes of action. Several confluent processes combine to injure the brain including extravasation of circulating cells into the brain parenchyma, activation of microglia, production of harmful molecules and cytokines by activated phagocytes, and blood-brain barrier breakdown with subsequent vasogenic edema formation. Heparin antagonizes these processes, with heparin’s mechanisms of action indicated in the white boxes.