Our data suggest that RBCT is associated with an increased risk of TE in SAH patients. This relationship was independent of age, sex, injury severity, and admission hemoglobin. Secondary analysis, including length of stay, did not change the significance or magnitude of the effect. There was a dose-dependent effect of transfusion; the risk of TE increased by over 50 % per unit transfused when controlling for univariate associations. Accounting for these associations, the attributable risk of transfusion on thrombosis was 22.0 %, which was greater than the effect of Fisher group, a widely accepted predictor of DCI and stroke after SAH, on cerebral infarction (17.8 %).
Studies in non-SAH patients corroborate the association between RBCT and thrombotic complications [16–18]. RBCT was identified as an independent risk factor for the development of DVT in a two studies of trauma patients [17, 18]. In a nationwide database study of over 500,000 cancer patients, RBCT was significantly and independently associated with the development of VTE with an odds ratio of 1.6 [95 % CI (1.53, 1.67) p < 0.001) . Arterial TE were also more prevalent among patients who were transfused [5.2 vs 3.0 % (p < 0.001)] .
SAH patients may be prone to a transient hypercoagulable state mediated by tissue factor release and catalyzed by the inflammatory cascade. The brain has the body’s highest concentrations of tissue factor, much of it localized in the adventitia of cerebral arteries and perivascular astrocytes . Stein and colleagues proposed that after aneurysm rupture, exposure of the adventitial surface of cerebral vessels to subarachnoid blood may incite local disseminated intravascular coagulation (DIC) . Subarachnoid blood also activates endothelial cells of larger vessels, creating a local hypercoagulable milieu which may further contribute to a transient hypercoagulable state .
The presence of coagulopathy after SAH is supported by numerous studies demonstrating activation of both the coagulation and fibrinolytic systems in peripheral blood samples of SAH patients [22–24]. Activation of the coagulation system manifests as increased plasma thrombin-antithrombin (TAT) complexes, whereas activation of the fibrinolytic system is characterized by a documented increase in plasma D-dimer levels [13, 15, 29]. Both TAT and D-dimer levels have been shown to correlate with severity of illness in SAH patients [13, 15, 24].
Other possible mechanisms may explain the association between transfusion and thrombosis. RBCT augments blood viscosity which results in turbulent flow and increased platelet interactions, putatively culminating in thrombosis . Furthermore, endothelial NO causes vasodilatation, increased blood flow, reduced blood pressure, and inhibition of platelet adhesion/aggregation; therefore, alterations in blood flow and platelet function due to a lack of NO may result in thrombosis . One study of over 400 SAH patients concluded that NO may mediate the association between RBCT and angiographically confirmed vasospasm . Therefore, RBCT employed to minimize DCI may unwittingly predispose to it.
Storage-related changes have also been implicated in the development of thrombosis after RBCT. Prolonged storage of RBCs was associated with an increased risk of DVT in a cohort of trauma patients . Free iron, found in high concentrations in stored blood, has been associated with oxidative stress via formation of free radicals. This type of damage has been associated with cardiovascular disease. Free hemoglobin can also bind and inactivate nitric oxide (NO), which may lead to vasoconstriction . Anucleoid membrane vesicles, or microparticles, increase in concentration with storage duration. Microparticles have been implicated in post-transfusion thrombosis via plasma-mediated thrombin generation . However, despite these plausible mechanisms, age of blood was not identified as a risk factor for the development of TE in our study. The conflicting data may be due in part to the effect of leukoreduction, as white blood cells have been implicated as the primary cause of deleterious storage-related changes [30, 31].
At the time of this study, the institutional SAH protocol called for maintenance of hemoglobin concentration above 10 g/dL. Such a liberal threshold may not be warranted as it may promote thrombosis via augmented blood viscosity, amplified turbulent flow, and increased platelet interactions, as previously mentioned. However, the optimal transfusion threshold for patients with SAH remains unclear . Therefore, we propose that clinical equipoise remains regarding transfusion thresholds for those patients at risk for cerebral ischemia; current recommendations advocate for maintaining hemoglobin levels between 8 and 10 g/dL .
This study’s findings are both robust and noteworthy. The effect of transfusion on TE was found to be dose-dependent and it persisted in multivariable analysis after controlling for several potential confounders. Furthermore, the magnitude of the association is large. In subgroup analysis, the adjusted odds ratios of RBCT on VTE and cerebral infarction risk remained significant [2.4 [95 % CI (1.0, 5.4) p = 0.04] and OR 2.2 95 % CI (1.1–4.1); p = 0.01] despite fewer outcomes. The effect of RBCT was also independent of other blood product administration.
Our study has some significant limitations, chief among them are the definition and determination of TE. The definition of cerebral infarction after SAH as a thrombotic event implies a thromboembolic etiology, although it may result from arterial vasospasm. However, the mechanisms of DCI and the etiology of cerebral infarction after SAH remain unclear. Therefore, we believe that it was reasonable to consider cerebral infarction a TE given our working hypothesis and the aforementioned evidence that SAH is associated with a hypercoagulable state. Moreover, the association persisted in subgroup analysis of VTE, suggesting that the mechanism is plausible. Second, surveillance Doppler ultrasounds were performed twice weekly, a protocol designed to protect neurologically injured patients from the consequences of VTE. However, this protocol may have lead to an ascertainment bias. Moreover, the observed rate of DVT was almost double the previously published rates; however, this may reflect the local surveillance policy or the increased acuity of illness at our institution, a dedicated hospital for vascular neurosurgery . Although this may limit the generalizability of the results, it does not mitigate the observed association between RBCT and thrombosis. Third, diagnostic testing for other TE was limited to that clinically indicated by the treating physician. Therefore, investigation of non-DVT TE was only undertaken when deemed clinically indicated and subclinical TE may have gone unrecognized.
Confounders may also limit generalizability of this study. Due to its retrospective design, the study may be confounded by unmeasured parameters and, therefore, cannot confirm causality. Anemia, a marker of disease severity, may confound by intention as anemic patients warrant transfusion. However, rates of premorbid anemia, defined by admission hemoglobin concentration, were not significantly different among those patients with and without TE. Similarly, although surgical intervention significantly affected likelihood of transfusion, in multivariable analysis, it had no effect on thrombosis risk. Injury severity as assessed in this study may not adequately account for the greater burden of comorbidities, systemic complications, or severe immobility, which may contribute to thrombosis risk in ICU patients. However, the effect of transfusion on TE persisted in multivariable analysis when accounting for both Hunt and Hess grade and length of stay, established surrogates for severity of illness.