In late 2019, coronavirus disease 2019 (COVID-19) began to spread throughout Wuhan, China. The severity of the virus ranged from asymptomatic cases to very severe symptoms and even death. By March of 2020, COVID-19 had spread throughout the world leading to government-mandated lockdowns, and the World Health Organization (WHO) implementing various public health measures to mitigate the spread of the virus [1–3]. COVID-19 has been associated with systemic inflammation, thrombosis, and neurological symptoms likely due to a diminished alternative renin-angiotensin (RAS) pathway [4]. The role of microvascular dysfunction is also emerging and warrants further investigation. To date, there are no widely available, effective therapeutics for COVID-19 [5].

In this review, we explore how the COVID-19 virus and the intensive care unit (ICU) treatment of severe COVID can contribute to subarachnoid hemorrhage (SAH). SAH is a devastating condition with substantial morbidity and mortality. SAH leads to severe vasospasm, triggered cerebral ischemia, brain edema, and blood-brain barrier disruption. This can result in increased intracranial pressure, decreased cerebral perfusion pressure, and finally apoptotic neurodegeneration of the brain [6] (Figure 1).

SAH is a severe medical emergency characterized by the presence of blood in the subarachnoid space, brain parenchyma, and occasionally ventricles [7–9]. Nontraumatic SAH is most often caused by a ruptured aneurysm, called an aneurysmal SAH (aSAH). This condition is associated with high rates of death due to initial blood loss, severe rise in intracranial pressure, the potential for aneurysmal rebleeding, and delayed cerebral ischemia [6, 8, 10]. In fact, up to 30% of patients suffering from aSAH develop delayed cerebral ischemia, which can lead to stroke or permanent brain damage [8]. Those most at risk for aSAH are women over 65 years, smokers, alcohol abusers, patients with hyperlipidemia, diabetics, and patients with heart disease. However, the leading cause of aSAH is hypertension [11, 12].

In patients who suffer from SAH, there is a drastic elevation in norepinephrine, pointing to an increase in sympathetic activity [13]. The hyperactivity typically stems from the medulla oblongata and the hypothalamus in response to increased intracranial pressure [12]. Heightened sympathetic tone contributes to elevations in blood pressure, cardiac dysfunction, neurogenic pulmonary edema, and the development of a systemic inflammatory response syndrome [8, 11, 13].

Cerebral aneurysms are caused by a disruption of the normal laminar flow in cranial blood vessels [14]. As laminar blood flow turns turbulent, there is increased mechanical force on the blood vessel wall leading to endothelial cell stretching. This shift to turbulent flow can be caused by atherosclerotic plaques obstructing the blood flow, blood vessel stenosis, and hypertension [15].

Infection with COVID-19 has been shown to lead to hypertension and acute ischemic events [16, 17]. ACE2 is a receptor for the COVID-19 spike protein. When patients are infected with COVID-19, the virus binds to ACE2 leaving less ACE2 available to bind angiotensin (1–7) [4]. This ACE2/angiotensin (1–7) interaction is known as the alternative RAS pathway. This pathway has been shown to have anti-inflammatory effects and reduce sympathetic tone through the release of NO, vasodilation, diuresis, and reduced ROS [4, 18]. Due to diminished alternative RAS activity, the ACE-angiotensin 2 pathway (classical RAS pathway) dominates. The classical RAS pathway leads to inflammation, vasoconstriction, water retention, and increased ROS. As a result, patients infected with COVID-19 are displaying diminished alternative RAS pathway and are at an increased risk for developing cerebral atherosclerotic plaques and blood vessel stenosis. This could cause turbulence in the cerebral blood vessels leading to the development of an aneurysm. Patients with occult aneurysms prior to COVID-19 infection are at an increased risk for aneurysmal rupture due to the hypertensive and ischemic effects of COVID-19.

Additionally, COVID-19 induced endothelial damage causes an increased expression of tissue factors leading to activation of the clotting cascade [19]. This phenomenon leads to elevated levels of D-dimer, fibrinogen degradation products, and bradykinin [20]. Clots that become lodged in the brain can lead to stroke; however, partial occlusion of a vessel can lead to turbulent flow and subsequent aneurysm or aneurysmal rupture.

The increased inflammation present in COVID-19 patients, from the mechanisms described above, can lead to increased permeability of the blood-brain barrier [21]. Breakdown of the blood-brain barrier can disrupt the matrix metalloproteinase-9 (MMP-9) [22]. Elevations in MMP-9 can lead to the dysregulated breakdown of arterial collagen. Thus, elevated MMP-9 and inflammatory cytokines in COVID-19 infection can lead to arterial instability and subsequent aSAH [23, 24].

Cranial vasospasm, or delayed narrowing of cerebral arteries, is a condition that appears in 70% of SAH patients 4–15 days after SAH [25–28]. This condition is severe and typically leads to death or permanent disability due to delayed cerebral ischemia and stroke. One possible explanation for post-SAH cerebral vasospasm is subarachnoid hemolysis leading to the accumulation of hemoglobin, oxyhemoglobin, methemoglobin, oxygen-free radicals, and inflammatory molecules [27]. Additionally, post-SAH neutrophil activation increases the levels of ROS in the brain leading to vasospasm [25]. aSAH patients with active COVID-19 infection and consequent vasoconstriction are at increased risk for vessel occlusion and vasospasm. Microvascular dysfunction may be a key contributor to this process as recently outlined by Kanat [2, 3].

Vaccination against COVID-19 has become a critical initiative in controlling the COVID-19 pandemic. However, there have been some cases of patients suffering from vaccine-induced thrombotic thrombocytopenia (VITT) following vaccination with ChAdOx1 nCov-19 (AstraZeneca) or Ad26.COV2.S (Johnson&Johnson) COVID-19 vaccines [42–45]. To date, this condition has not been described with the novel messenger RNA (mRNA) vaccines such as those from Moderna and Pfizer. VITT is described as concurrent thrombosis in the presence of thrombocytopenia. Interestingly, thrombotic events typically occur in the cerebral vessels and venous sinuses which can lead to hemorrhage.

Platelet factor 4 (PF4) is a positively charged chemokine that is released when platelets are activated [46]. In the well-described disease, heparin-induced thrombocytopenia (HIT), PF4 binds negatively charged heparin in the patients’ serum [47]. This forms very large PF4-heparin complexes that have antigenic characteristics [46]. As a result, immunoglobulin G (IgG) autoantibodies against this complex can be formed which directly induces platelet activation and promotes crosslinking of platelet FcγRIIA receptors [48]. The pathogenesis of VITT is very similar to HIT.

Patients suffering from VITT have increased levels of anti-PF4 autoantibodies, similar to those of HIT. Likely, the negatively charged components of the vaccines such as the adenovirus glycoprotein, adjuvant components, and/or adenovirus DNA are able to bind PF4 similar to heparin [42, 49]. Autoantibodies against PF4 lead to thrombocytopenia and thrombosis [44]. These PF4-anionic complexes can also directly bind to endothelium causing the release of von Willebrand factor and increased expression of leukocyte adhesion molecules [46]. Thus, the spike protein interaction with the endothelium is not to blame for the rare adverse vaccination events.

The systemic effects of the COVID-19 virus may contribute to the development of cerebral aneurysms and subsequent aSAH. This is due to the inflammation, increased cytokines, vasoconstriction, ischemia, and blood hyper-viscosity caused by COVID-19. Some other viruses can cause similar findings, which will be a topic of further review. A key limitation for this current paper is that most studies to date are single case reports. This limits more extensive analysis and overall conclusions. As further retrospective data emerges from cohort studies, the role of a systematic review and meta-analysis is apparent. Further studies should be done to see if COVID-19 is a causative agent of SAH. Additionally, different treatment options for COVID-19 should be explored to reduce the systemic wide inflammation and ischemia. Possible treatments that can be explored are antiplatelet treatments, prophylactic heparin, Janus kinase (JAK) inhibitors, and Bruton’s tyrosine kinase (BTK) inhibitors. These treatments could possibly reduce ischemic events and vasoconstriction; however, administration of blood thinners and antiplatelet regiments could also increase the risk of severe bleed if aneurysmal rupture occurs so should be administered cautiously.