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According to the World Health Organization, almost 5 million people have died from COVID-19, with >245 million confirmed cases.1 A number of vascular and thromboembolic complications of COVID-19 were noted early in the pandemic,2 and this was soon followed by observations suggesting a heightened risk of stroke and other cerebrovascular complications.3 Comparative meta-analytic studies have since been undertaken to confirm that infection with SARS-CoV-2 increases the risk of ischemic stroke relative to noninfected contemporary or historical controls,4 as well as relative historical controls infected with influenza.5 In addition to ischemic stroke, hemorrhagic stroke,6 cerebral venous sinus thrombosis (CVST),7 and posterior reversible encephalopathy syndrome8 have all been reported as possible complications.
Vaccines against SARS-CoV-2 are a milestone in the fight against COVID-19. Response to this global crisis, with devastating health, social, and economic impact, was extraordinary, and thanks to cooperation between companies and governments, within a year, several vaccines against SARS-CoV-2 have shown impressive efficacy in randomized clinical trials that have translated into real-world observations. Unfortunately, extremely rare cases of thrombocytopenia and thromboembolic complications have been reported following administration of the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca) and the Ad26.COV2-S vaccine (Janssen), which has contributed to vaccine hesitancy among the public. The situation, however, is highly nuanced, as the risk of thromboembolic complications from infection with SARS-CoV-2 alone is significant. This is of special relevance to stroke and cerebrovascular complications given the significant morbidity associated with intracranial thromboses and hemorrhage.
In what follows, we review the evidence surrounding stroke and cerebrovascular complications of both SARS-CoV-2 infection and SARS-CoV-2 vaccination. In so doing, we review thromboinflammation and the proposed pathophysiology of stroke as a complication of COVID-19, and vaccine-induced immune thrombotic thrombocytopenia (VITT), its typical clinical presentation, and the cases that have presented with stroke and cerebrovascular complications. We conclude by identifying the main pathophysiologic abnormalities common to the two conditions and compare the risk of stroke related to infection and vaccination.
Early reports of neurological complications of SARS-CoV-2 infection emerged in the pre-peer review literature in March 2020. By April 2020, the first retrospective observational reports from Wuhan were published finding neurological symptoms in as many as 36.4% of the admitted patients, specifically citing both ischemic and hemorrhagic stroke as complications of SARS-CoV-2.3 In this section, we discuss the risk of ischemic stroke and other cerebrovascular disorders, as well as putative pathophysiology for stroke in patients with COVID-19.
Oxley at al9 soon reported a series of relatively young patients (<50 years old) presenting with large vessel occlusion ischemic strokes during the first peak in New York City, all of whom tested positive for SARS-CoV-2. As time would tell, the risk of such presentations was not as great as was initially feared. In fact, initial retrospective incidence rates varied considerably; Li et al10 reported ischemic strokes in as many as 4.6% of their Wuhan inpatient cohort (n=219), whereas Yaghi et al11 found that only 0.9% of their patients admitted in New York had stroke diagnosed during their admission (n=3556). Cohorts in Italy,12 France,13 Germany,14 Philadelphia,15 and other New York hospital systems5,16 fell within this range. To date, the largest multinational studies17–19 and meta-analytic4 estimates of risk among hospitalized patients are shown to be between 0.5% and 1.3%. However, there are important caveats to these estimates, most notably that the majority of strokes did not present with typical clinically evident focal neurological deficits. Rather, the events were detected on neuroimaging during hospital admission,5,17,20 leading many to dispute the true incidence given that not all patients undergo neuroimaging.21 From our personal experience in New York, this was especially true during the peak periods of COVID-19, social distancing, and airborne isolation rules. Risk has been shown to vary with clinical severity of COVID-19.4,10,14,22 Consistent with this hypothesis, studies that include mild disease (managed in the outpatient setting) have yielded lower estimates of risk.23,24 In terms of relative risk, patients requiring hospitalization for COVID-19 have a 3- to 4-fold greater risk of stroke compared with noninfected hospitalized historical or contemporary control cohorts.4,5,11,25 Compared with patients with influenza requiring hospitalization, COVID-19 patients have a 7- to 8-fold greater risk of stroke, although the CIs of these estimates are wide and overlap significantly with the risk estimates when compared with historical controls.5 Patients with COVID-19 at the highest risk of ischemic stroke appear to be those with a history of ischemic stroke,26 possibly a history of diabetes4 and other traditional stroke risk factors,27 and higher serum d-dimer levels.28,29
Outcomes in strokes occurring in patients with COVID-19 also appear worse, in terms of initial stroke severity (compared with historical controls),30 functional outcome at discharge (compared with contemporary and historical controls),30,31 discharge destination (compared with historical controls),32 and inpatient mortality (compared with both contemporary and historical controls).4,30–33
With regard to etiologic classification, patients with COVID-19–associated ischemic strokes have been shown to present with more embolic-appearing findings on neuroimaging. Specifically, multiple case series have been published, highlighting an increased rate of strokes with large vessel occlusions.9,16,17,31,34–37 The majority of these strokes were classified as cryptogenic or embolic stroke of undetermined source.38 Consistent with this, the risk of specifically cryptogenic strokes has been found to be disproportionately increased in patients with COVID compared with control cohorts.4,5,11,16 Many of these patients were also found to have other systemic evidence of thromboembolic disease39,40 and visceral infarction—a phenomenon that is known to be associated with cardioembolic and cryptogenic strokes.41
The mechanism leading to cerebrovascular complications in the setting of SARS-CoV-2 is likely multifactorial. First, patients with COVID-19, especially those with severe disease, frequently have comorbid factors that increase their baseline risk of thromboembolism. These include dehydration, immobilization, chronic cardiovascular risk factors, or prior atherosclerotic diseases (ie, coronary artery disease, cerebrovascular disease, and chronic kidney disease), as well as inherited thrombophilia.42 Patients with severe COVID-19 requiring intensive care unit (ICU) admission have been shown to have significantly higher rates of arterial or venous thromboembolic events,43 presumably due to a combination of factors discussed herein. Interestingly, studies comparing the rates of ischemic stroke between critically ill COVID-19 patients and other acute respiratory distress syndrome patients have not detected a significant difference, suggesting acute respiratory distress syndrome or critical illness itself likely confers some risk for stroke.44
However, more causal mechanisms have also been proposed given that SARS-CoV-2 both increases the risk of cardiac pathology and impacts all 3 factors comprising Virchow triad (endothelial injury, stasis, and hypercoagulable state), ultimately promoting thrombosis.
Regarding cardiac complications, SARS-CoV-2 has been shown to increase the risk of developing atrial fibrillation,45 which is a well-established risk factor for ischemic stroke.46 In addition, myocardial infarction,47 myocarditis,48 and Takotsubo cardiomyopathy48 have been reported in hospitalized patients with COVID-19, all of which predispose to the formation of left ventricular thrombi and subsequent cardiac embolism.49 Additionally, bacterial superinfection is common in patients with severe COVID-19,50 which increases the risk of bacteremia and infective endocarditis; both of which increase the risk of ischemic stroke.51
In addition, vascular injury is a recognized hallmark of COVID-19. The precise pathophysiology of this remains unclear, but both ACE2 (angiotensin-converting enzyme 2)-dependent and independent processes have been implicated, with some suggesting direct platelet activation via the SP (spike protein) itself.52,53 Within the pulmonary circulation, postmortem analysis has found severe endothelial injury, disrupted cell membranes, with diffuse vascular thrombosis and occlusion of alveolar capillaries.54 Within the cerebral microvasculature specifically, combined imaging and histopathologic assessments have revealed thinning of the basal lamina of the endothelial cells, capillary congestion with fibrinogen leakage, and perivascular inflammation associated with macrophage infiltrates and CD3+ and CD8+ T cells.55 This mild-to-moderate, nonspecific inflammation without clear evidence of vasculitis is a consistent finding in autopsy studies. In contrast to the pulmonary pathology, however, cerebral histopathology has only rarely revealed frank vascular occlusion55,56 or florid cerebrovascular inflammation as seen in the pulmonary microcirculation.57,58 Despite this, these studies have frequently noted mild-to-moderate hypoxic-ischemic injury and microhemorrhages, as well as a stroke phenotype involving multiple small infarcts, including in the corpus callosum, presumed to be a manifestation of microvascular occlusion secondary to thromboinflammation. There are reports of SARS-CoV-2–like particles being found in the brain and endothelium using ultrastructural analysis of tissue from SARS-CoV-2–infected patients with neurological symptoms59; however, diagnosis is challenging due to similar appearing normal cellular structures.60
Consequent to this vascular endothelial inflammation,61 whether systemically or in the cerebral microcirculation, patients with COVID-19 can demonstrate a coagulopathy with an increased risk of in situ thrombosis.62 Specifically, endothelial release of proinflammatory cytokines (the so-called cytokine storm) has been shown to be associated with a hypercoagulable state as evidenced by deranged levels of VWF (von Willebrand factor), D-dimer, fibrinogen, and factor VIII.63 Specifically, small case series of patients with severe COVID-19 have shown exaggerated interleukin-mediated release of VWF, and suppression of the function of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), promoting thrombosis via a thrombotic microangiopathy-like process.64,65 This increases the risk of both arterial and venous thrombosis with or without paradoxical embolism to the cerebral circulation.
Studies evaluating the risk of hemorrhagic stroke, which includes intracerebral, subdural, and subarachnoid hemorrhage, have been more limited. The largest studies to date suggest the prevalence among hospitalized patients is rare (as low as 0.2%) and was more likely to occur in older patients and those receiving therapeutic anticoagulation.6 Those hospitalized with ICH and COVID-19 had worse outcomes than those with COVID-19 alone. Studies with more granular hospital course data have suggested that hemorrhages tend to occur during the hospitalization, and the mechanism of these hemorrhages tends to be related to coagulopathy or supratherapeutic anticoagulation, as opposed to primary causes of intracerebral hemorrhages.66
In a self-controlled case series including 29.1 million people in the United Kingdom comparing rates of thrombotic complications of COVID-19 and vaccinations for COVID-19, testing positive for SARS-CoV-2 was associated with an increased risk of CVST.67 While the point estimate of this risk was high, the CIs were broad, suggesting significant uncertainty of the precise risk. In a meta-analysis of 67 845 patients, the pooled rate of CVST was 0.03%.4 Case series7,68 and reviews have highlighted relatively few (<50) CVST cases reported in the literature to date and suggest it is a relatively rare complication of COVID-19 that is not associated to severe disease as with ischemic stroke. Almost 90% of the reported cases have occurred in women and are mostly found in the transverse sinus. Clinical presentations, however, are subtle, and authors recommend that high suspicion is maintained when encountering patients with COVID-19, headache, and focal neurological deficits.
Posterior reversible encephalopathy syndrome is another relatively rare neurovascular complication that has been linked to hospitalized patients with COVID-19. Almost all the data on this phenomenon are at the level of case series with relatively few cases reported in the literature in total (<50).69 Cases have mostly presented with prolonged or otherwise unexplained encephalopathy and poor level of consciousness, with some complicated by seizures or a focal neurological deficit.8 Most have been in the setting of critically ill patients who have traditional risk factors for posterior reversible encephalopathy syndrome (acute kidney injury and uncontrolled hypertension), and it remains unclear whether the rate of posterior reversible encephalopathy syndrome in patients with COVID-19 is any greater than in patients with other critical illness or multiorgan failure.
To date, the European Medicines Agency has approved 5 vaccines:70 (1) Comirnaty (BNT 162b2 mRNA vaccine) by Pfizer BionTech; (2) Ad26.COV2.S adenovirus vaccine by Johnson & Johnson/Janssen; (3) Spikevax (mRNA-1273 vaccine) by Moderna; (4) Vaxzevria (ChAdOx1 nCoV-19 vaccine) by Oxford-AstraZeneca, and more recently, (5) Nuvaxovid (NVX-CoV2373) by Novovax. The Food and Drug Administration similarly approved these excluding Vaxzevria and Nuvaxovid.71 Both the European Medicines Agency (EudraVigilance) and the Food and Drug Administration are monitoring the safety of authorized COVID-19 vaccines. This enables the detection of any side effects that may emerge during the mass vaccination. At the time of writing, a total of 6 838 727 352 vaccine doses have been administered worldwide.1 Although most of the reported vaccine-related side effects are mild and transient, concerns progressively emerged about post-Vaxzevria embolic and thrombotic events associated with thrombocytopenia (thrombosis with thrombocytopenia syndrome [TTS], renamed VITT). On April 14, 2021, the European Medicines Agency’s Safety Committee (Pharmacovigilance Risk Assessment Committee) concluded that a causal relationship between Vaxzevria vaccination and rare cases of venous thrombosis in unusual sites (ie, CVST and splanchnic vein thrombosis) and less frequently arterial thrombosis was plausible. As of July 31, 2021, 1503 cases of suspected TTS with Vaxzevria out of about 592 million administered doses were globally reported.70
With a much lower incidence, TTS has also been described after Janssen vaccination. In the United States, by July 8, 2021, 38 TTS confirmed cases occurring within 15 days after vaccination were reported to the Vaccine Adverse Event Reporting System, four of which resulted in death. The overall calculated rate was 3.0 TTS cases per million administered doses, with a higher reporting rate of 8.8 TTS cases per million administered doses among women aged 30 to 49 years.72,73 Nevertheless, a population-level risk-benefit analysis has shown a large population benefit of Janssen vaccination as compared with rare occurrence of TTS.72 In Europe, as of June 27, 2021, 21 cases over about 7 million administered doses were spontaneously reported to EudraVigilance, four of which were fatal.70 Though further case ascertainment is required to confirm TTS in these reported cases, the relationship between the administration of DNA vaccines and TTS has now been established. In fact, according to the Bradford-Hill criteria, which are the accepted criteria for assessing causality of an association, the link between the ChAdOx1 nCoV-19 vaccine and TTS has recently been demonstrated.74 However, the precise estimate of this association is not known, since the incidence rates vary from 0.5 to 25 per 100 000 vaccinated individuals, depending on the different countries.74 Nevertheless, benefits of adenoviral vector vaccines, clearly demonstrated in randomized controlled trials,75,76 still outweigh the risks of these rare thrombotic events, especially in subjects >30 years.77 Interestingly, Hippisley-Cox et al67 found an increased risk of ischemic stroke after 15 to 21 days from BNT162b2 mRNA vaccination (Pfizer BionTech), and after a positive SARS-CoV-2 test, but not after ChAdOx1 nCov-19 vaccination (Oxford-AstraZeneca). The same authors found an increased risk of thrombocytopenia after ChAdOx1 nCov-19 vaccination, and of CVST after ChAdOx1 nCoV-19 vaccination (at 8–14 days), after BNT162b2 mRNA vaccination (at 15–21 days), and after a positive SARS-CoV-2 test.67 More data on these adverse events from BNT162b2 mRNA vaccination are needed.
All the approved vaccines are based on the full-length homotrimeric SARS-CoV-2 SP. SP plays a key role in viral infection and pathogenesis, since it mediates the entrance of the virus into the host cells via the binding with ACE2. SP, which is located on the viral envelope, comprises 3 S1/S2 heterodimers: S1 harbors the N-terminal domain and the receptor-binding domain.78–80 Interestingly, the SP ectodomain consists of a head where receptor-binding domains are located and a stalk with 3 flexible hinges connecting SP to the viral membrane. This high degree of conformational freedom of SP on the viral surface may interfere with antibody access to the stalk, add strength to the virus, and facilitate the binding of the SP with the host receptor.81
In December 2020, Wajnberg et al82 found that most of the infected individuals with mild-to-moderate COVID-19 had developed a robust IgG antibody response against the viral SP. These authors also showed that titers were long-lasting (several months) and that anti-SP binding titers significantly correlated with neutralization of SARS-CoV-2.82 All these data confirmed the SP as the main target of vaccine development.78
The three vaccines approved by the United States and 4 of the 5 approved by the European Union (EU) are DNA or mRNA vaccines encoding the SARS-CoV-2 SP. In DNA vaccines (Janssen and Oxford-AstraZeneca), the genetic materials need to pass through the nucleus to create mRNA with subsequent transcription of the protein in the cytoplasm.83 In mRNA vaccines (Pfizer and Moderna), the nuclear step is missing, making the process even simpler.84 Pfizer and Moderna vaccines consist of a lipid-enclosed nucleoside-modified mRNA encoding a different mutated SP, whereas the AstraZeneca and Janssen vaccines utilize a chimpanzee nonreplicating adenovirus and a type 26 nonreplicating recombinant adenovirus vector, respectively. Moreover, the AstraZeneca vaccine has the complete coding sequence of SP plus a sequence of a tissue-type plasminogen activator, and the Janssen vaccine has mutations for stabilizing the SP.83 Nuvaxovid is based on the SP produced by recombinant DNA technology using a baculovirus expression system in an insect cell line and is adjuvanted with Matrix-M. Effectiveness and safety of this vaccine have been demonstrated in clinical trials,85 but real-world evidence is still lacking.
Efficacy data of DNA- and mRNA-based vaccines against SARS-CoV-2 from clinical trials seem to be consistent with data on vaccine effectiveness from the real world. However, more data are urgently needed, considering both the rapidly emerging appearance of SARS-CoV-2 novel variants and the temporal waning of immunity after vaccination.86
By the end of March 2021, several scientific papers from different countries reported cases of devastating thrombosis in unusual sites, especially CVST, 5 to 30 days after the administration of the first dose of the ChAdOx1 nCoV-19 vaccine. These patients, who were otherwise young and healthy, also presented with thrombocytopenia, elevated D-dimer, sometimes low fibrinogen, and high levels of antibodies against PF4 (platelet factor 4)-heparin.87–89 Similar syndromes have also been reported after Janssen vaccination90 and after Moderna’s mRNA-1273 vaccine.91
The syndrome was named VITT92 since it resembles the heparin-induced immune thrombocytopenia (HIT),93 although in the absence of exposure to heparin.
PF4 is a cationic chemokine consisting of 4 monomers, released from the α-granules of activated platelets as an immune defense mechanism. It is capable of opsonizing negatively charged surfaces of bacteria, ultimately facilitating binding of anti-PF4 antibodies. In HIT, heparin, acting as a polyanion, causes a conformational change of PF4 tetramers and consequently the anti-PF4/heparin antibody induction.93 Things other than heparin, such as chondroitin sulphate, DNA and RNA, bacterial wall components, and high concentration of PF4 per se, can induce the exposure of HIT antigens leading to spontaneous or autoimmune HIT. Sera from patients with autoimmune HIT typically contain high-avidity IgG antibodies, which strongly activate platelets from healthy donors via FcγRIIa, one of the receptors for the Fc domain of IgG antibodies. As a consequence, platelet-derived procoagulant microvesicles are released, resulting in severe thrombocytopenia, leading to an increased frequency of disseminated intravascular coagulation, and atypical thrombotic events.93,94
Similarly to autoimmune HIT, sera from VITT patients contain high levels of PF4-heparin antibodies that activates platelets in the presence of, but also in the absence of, heparin. This activation is greatly enhanced in the presence of PF4.87–89 Notably, a cross-reaction between the anti–SARS-CoV-2 SP antibodies and PF4 or PF4/heparin complexes has been ruled out,95 and no correlation has been found between the anti-PF4 and the anti–SARS-CoV-2 neutralizing antibody levels after ChAdOx1 nCoV-19 vaccination.96 These data exclude the possibility that the anti-PF4 antibodies are a side product of the vaccine immune response.
Recently published data suggest that vaccine components, including the adenovirus hexon protein and also the adenovirus per se,97 can generate neoantigen complexes with PF4, thus inducing anti-PF4 antibody production.98 Anti-PF4 antibodies stimulate platelet aggregation. Cross talk of platelets and anti-PF4 antibodies activates neutrophils, leading to the formation of neutrophil extracellular traps and ultimately to the activation of monocytes and endothelial cells, further amplifying the activation of the coagulation cascade. The ChAdOx1 nCov-19 vaccine also contains EDTA, which increases the capillary leakage at the inoculation site, allowing the virus to spread via the bloodstream.98 Data based on an intriguing hypothesis about a possible transcription of spliceosome-mediated soluble SP fragments with thrombogenic properties in DNA vector vaccines have not yet been peer reviewed.99 However, preprinted data from our group seem to support this hypothesis. In fact, a soluble SP has been found in sera from 3 VITT patients and on a platelet-rich thrombus retrieved from middle cerebral artery (MCA) of 1 VITT patient, suggesting that SP could be one of the platelet activation triggers in VITT.100 Undoubtedly, additional experiments are required to fully understand the pathogenesis of this rare, devastating syndrome.
As of April 2021, descriptions of clinical features of patients affected by VITT in case series and case reports from different countries allowed us to delineate precise diagnostic criteria and inform the therapeutic approach.73,87–89,101–103 Guidelines from different medical societies have been developed,87,104–106 although some of the published cases do not strictly meet classification criteria. VITT is an evolving condition, and a low-probability diagnosis of VITT at presentation can rapidly evolve to a fully blown VITT in the subsequent days. Close monitoring of patients is then mandatory to rule out this diagnosis.107 Recently, a pre-VITT syndrome characterized by severe headache without associated CVST or other thrombosis has been described, highlighting the need for clinicians to be aware of different presenting onsets of VITT, and intravenous immunoglobulin (IVIG) therapy promptly.108
Diagnosis of VITT is clinical and radiological. Typical blood test results are needed to confirm the clinical suspicion. Patients with VITT typically present with a classical clinical triad of thrombosis (mainly CVST, pulmonary and splanchnic), thrombocytopenia (<150 000/µL), and elevated D-dimers (>4000 fibrinogen-equivalent units [FEU] or 4–8× the upper limit of normal range). As addressed by Greinacher et al,87 the different combination of these elements leads to 2 different scenarios: VITT likely and VITT unlikely (Table 1). Diagnosis of VITT is confirmed by demonstration of anti-PF4 antibodies by ELISA plate–based PF4/heparin (polyanion) antibody test (but a negative test still does not definitively rule out the diagnosis)87 and functional platelet activation assay.87–89,92,106
| VITT: unlikely | VITT: likely |
|---|---|
| 5–30 d after adenoviral vaccination (ChAdOx1, AstraZeneca/COVISHIELD; Ad26COV2.S, Janssen, Johnson & Johnson) | |
| Platelet count >150 000/µL; d-dimer <2000 FEU (or 4× the upper limit of normal range) | New onset of platelet count <150 000/µL; d-dimer >4000 FEU (or 8× the upper limit of normal range) |
| Negative antigen-binding assay (ELISA) for PF4/heparin antibodies (polyanion) | Positive antigen-binding assay (ELISA) for PF4/heparin antibodies (polyanion) |
| INR/PT, aPTT, and fibrinogen normal level excluding DIC | INR/PT, aPTT, and fibrinogen abnormal level as in DIC |
| Symptoms and signs suggestive for thrombosis: rule out alternative diagnosis than VITT | Symptoms and signs suggestive for multiple organ thrombosis: VITT confirmed. Consider high-dose IVIG and nonheparin anticoagulation |
aPTT indicates activated partial thromboplastin time; DIC, disseminated intravascular coagulopathy; FEU, fibrinogen-equivalent units; INR, international normalized ratio; IVIG, intravenous immunoglobulin; PF4, platelet factor 4; PT, prothrombin time; and VITT, vaccine-induced immune thrombotic thrombocytopenia.
Prompt recognition and treatment of this syndrome may reduce mortality. Education of the public and clinicians has reduced mortality of VITT from 50% in the first case series in April 2021 to 22% in June 2021 in the United Kingdom.87 The pillars of VITT therapy are nonheparin anticoagulants (direct oral anticoagulants, danaparoid, argatroban or fondaparinux, continued for at least 3 months) and high-dose IVIG (0.5–1 g/kg of actual body weight for 1 or 2 consecutive days).87,104,105 Steroids may be useful (especially if platelets are <50 000), and plasma exchange can be considered in selected cases.87,104,105 Rituximab can be prescribed in patients who are refractory to repeated doses of IVIG and plasma exchange, although evidence is limited.104
Ischemic stroke can be a rare and challenging symptom onset of VITT or can complicate its course. The real incidence of this serious and life-threatening condition is unknown.
We performed a systematic review using MEDLINE, PUBMED, and Google Scholar databases to collect all the published articles related to the development of ischemic stroke after vaccination against SARS-CoV-2. The search process was done on October 27, 2021 by the authors using the following terms in various combinations: “ChAdOx1 ncov19 vaccination,” “stroke,” “vaccine induced immune thrombotic thrombocytopenia,” “infarct,” “VITT,” “AstraZeneca,” “SARS-CoV-2 vaccination,” “COVID-19,” and “PF4.” Overall, 161 published articles were identified, but only 13 were relevant to this review. One article was removed due to insufficient workup to rule out other causes of stroke and for not testing anti-PF4 polyanion antibodies. Consequently, the search and sorting processes were finalized with 12 articles with data on 16 patients (Figure 1).
Figure 1. Systematic review flowchart.
| Authors | Country | Patients | Age, y | Sex | Comorbidities | Time from vaccination, d | Sites of occlusion | Malignant MCA infarct | Venous thrombosis and other relevant abnormalities | Platelet count (nv 150–400× 109/L) | d-dimer within 24 h (nv 0–550 μg/L) | PF4 IgG | Treatment | Outcome (time) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Al-Mayhani et al40 | United Kingdom | 1 | 35 | F | None | 11 | R MCA distal M1 | Yes | Right portal vein thrombosis | 64 | 11 220 | Yes | Hemicraniectomy; IVIG; PE; intermediate dose fondaparinux | Died (extensive hemorrhagic transformation of the left MCA infarct 14 d after stroke onset) |
| 2 | 37 | F | None | 12 | Bilateral extracranial ICA | No (bilateral acute infarcts in a borderzone distribution) | Pulmonary embolism and thromboses of the L transverse and sigmoid sinuses, L jugular, R hepatic, and both iliac veins | 9 | 34 000 | Yes | IVIG; 2 IV pulses of methylprednisolone; PE; fondaparinux | Alive (NA) | ||
| 3 | 43 | M | None | 21 | Anterior cortical territory of the L MCA | No (left frontal and insular infarct) | None | 48 | 24 000 | Yes | Platelet transfusion; IVIG; fondaparinux | Alive (NA) | ||
| Bayas et al41 | Germany | 4 | 55 | F | None | 18 | MCA territory | No (left parietal lobe) | Bilateral superior ophthalmic vein thrombosis | 30 | NA | No | IV dexamethasone; heparin switched to; phenprocoumon | Alive (26 d) |
| Blauenfeldt et al39 | Denmark | 5 | 60 | F | HTN; Hashimoto thyroiditis; high cholesterol | 9 | R MCA | Yes | Bilateral adrenal hemorrhages and a subcapsular renal hematoma | 118 | 41 800 | Yes | Platelet concentrates hemicraniectomy; dalteparin | Died (4 d after stroke onset) |
| De Michele et al38 | Italy | 6 | 57 | F | Hypothyroidism, in follow-up care after breast cancer | 9 | R MCA | Yes | Extensive pulmonary artery and portal vein thrombosis | 44 | 4318 | No (yes at a second control) | Platelet transfusion; mechanical thrombectomy; hemicraniectomy; IV betamethasone; IVIG; PE; fondaparinux | Alive (20 d) |
| 7 | 55 | F | Hypothyroidism | 10 | R ICA terminus and L MCA | Yes bilateral | Extensive portal vein thrombosis with occlusion of the L intrahepatic branches and L lower lobe subsegmental pulmonary arteries thrombosis | 133 | 5441 | Yes | IVIG; dexamethasone 40 mg UID | Died (48 h after stroke onset) | ||
| Kenda et al42 | Slovenia | 8 | 51 | F | Hyperlipidemia | 7 | Proximal L M1 segment of MCA plus chronic L ICA dissection with pseudoaneurysm | No | NA | 57 | 31 543 | Yes | Mechanical thrombectomy; IVIG; fondaparinux 2.5 mg | Alive (3 mo); NIHSS score, 1; mRS score, 1 |
| Costentin et al43 | France | 9 | 26 | F | Oestroprogestative; contraceptive use | 7 | L MCA; M1 | No | Pulmonary embolism and portal vein thrombosis | 57 | NA | Yes | Mechanical thrombectomy | Alive (24 h) |
| Walter et al44 | Germany | 10 | 31 | M | None | 8 | L MCA territory parietal plus solid thrombus in the L ICA | No | NA | 217 | 11 000 | Yes | IV thrombolysis; aspirin, 100 mg/d SC danaparoid, followed by phenprocoumon | Alive (28 d) |
| Scully et al20 | United Kingdom | 11 | 39 | F | NA | 10 | MCA | No | None | 57 | >5000 | Yes | NA | Alive (NA) |
| 12 | 21 | M | NA | 10 | MCA | No | None | 113 | 22 903 | Yes | NA | Alive (NA) | ||
| Bourguignon et al45 | Canada | 13 | 69 | M | NIDM; HTN; OSA; obesity; prostate cancer; aortic valve replacement; heparin exposure, 9 mo earlier | 12 | R MCA+R ICA | No | CVST, hepatic vein, distal lower limb vein, pulmonary embolism | 35 | NA | Yes | Fondaparinux, IVIG, rivaroxaban; PE | Alive (24 d) |
| Ceschia et al46 | Italy | 14 | 73 | F | HTN; high cholesterol | 14 | PCA | No | CVST, pulmonary embolism, DVT, L renal vein, R superficial femoral and popliteal artery | 20 | 32 559 | Yes | IVIG dexamethasone; fondaparinux; thromboendarterectomy with Fogarty catheter on the R tibial artery and fasciotomy of the calf | Alive (1 mo) |
| Patriquin et al47 | Canada | 15 | 45 | F | None | 11 | R VA+L ICA | No | L renal infarct, bilateral adrenal hemorrhage, subsegmental pulmonary emboli | 53 | 35 200 | Yes | IVIG; PE; rituximab; argatroban | Alive (14 d) |
| Jacob et al48 | United Kingdom | 16 | 36 | F | Migraine | 9 | R M1 MCA+large intraluminal thrombus extending superiorly from the origin of the R ICA | Yes | NA | 66 | 5000 | Yes | IVIG; IV methylprednisolone; argatroban followed by fondaparinux 2.5 mg; decompressive craniectomy (on day 5); platelet transfusion | Alive (21 d) |
IgG: anti-PF4-polyanion antibodies (ELISA assay). CVST indicates cerebral venous sinus thrombosis; DVT, deep vein thrombosis; F, female; HTN, hypertension; ICA, internal carotid artery; IV, intravenous; IVIG, intravenous immunoglobulin; L, left; M, male; M1, proximal segment of the middle cerebral artery; MCA, middle cerebral artery; NA, not available; NIDM, non–insulin-dependent diabetes mellitus; NIHSS, National Institutes of Health Stroke Scale; nv, normal value; OSA, obstructive sleep apnea; PCA, posterior cerebral artery; PE, plasma exchange; PF4, platelet factor 4; R, right; SC, subcutaneous; and VA, vertebral artery.
In Table 2, we have summarized the demographic information and clinical features of the 16 patients affected by ischemic stroke with VITT confirmed diagnosis, identified from case reports or case series published in peer-reviewed journals. All the patients had received the first dose of the ChAdOx1 ncov19 vaccine. Three cases were reported from Italy, 6 from the United Kingdom, 2 from Germany, 1 from Slovenia, 1 from France, 1 from Denmark, and 2 from Canada. The mean age of the reported patients was 46.6 (SD, ±15.2; range, 21–73) years. Twelve of 16 patients were women (75%). Median time between vaccination and onset of stroke was 10 days. All the individuals were healthy before vaccination, and half of them had no preexisting comorbidities in their medical history. Three of them experienced hypertension and three had hyperlipidemia. Three subjects had thyropathy (1 case of Hashimoto thyroiditis and 2 cases of hypothyroidism). One patient was in follow-up care after breast cancer, and another one had recently received the diagnosis of prostate cancer (not yet staged). Only 1 patient, a 69-year-old man, had multiple vascular risk factors (hypertension, diabetes, obstructive sleep apnea, obesity, and aortic valve replacement) and previous exposure to heparin (9 months earlier). One patient experienced migraine and the another one was on estroprogestative contraceptives. Most of the patients had occlusion of the MCA or its branches (81%), and 7 of them (43.7%) also had thrombotic occlusion of the intracranial internal carotid artery. Five of 11 patients with proximal MCA occlusion (45.4%) developed a malignant MCA infarct involving the whole territory of the MCA with space-occupying cerebral edema and rapid neurological deterioration, successfully treated with hemicraniectomy in 4 cases. In 1 case (case 7), surgical intervention was not performed since the malignant infarct was bilateral (Figure 2).109 Ten of 13 cases in which the data have been reported presented multiple sites of venous thrombosis, particularly of the splanchnic, portal, and hepatic veins and pulmonary embolism, while only 3 of them had CVST. Fifteen patients had low platelet count at admission (mean±SD, 70.33±54×109/L; range, 9–133×109/L), while 1 patient had 217×109/L platelets at admission, with subsequent decrease to a nadir of 152×109/L 2 days after stroke onset. Very high level of D-dimer (mean value, 21 580 μg/L; normal range, 0–550) was present in all 14 patients in which the data have been reported. ELISA for PF4 autoantibodies was positive in 14 of the 16 tested patients. In 1 negative patient at baseline, high levels of antibodies were found at day 15 from admission. Unfortunately, it is not possible to draw a precise follow-up of these patients since outcome at 3 months has only been reported for case 8. Three of the 16 patients died. Patient 6, who survived and was described from our group,109 died 2 months later from an unexpected cardiac arrest while she was hospitalized in a rehabilitation center. Brain computed tomography scan did not show any new vascular events, and platelet counts were in the normal range. Her relatives denied autopsy. Only 1 patient (case 10) with distal MCA occlusion received intravenous thrombolysis with alteplase since platelet count was in the normal range, while 3 patients underwent successful mechanical thrombectomy. Case 6, reported from our group,109 underwent a second mechanical thrombectomy 2 hours after a first successful endovascular procedure (and 3 hours after the symptom onset), due to worsening of the neurological conditions and evidence on brain magnetic resonance imaging of a reocclusion of the same vessel (M1 segment of right MCA), with salvageable penumbra. Unexpectedly, despite a second complete reperfusion of the MCA territory, the patient developed a malignant infarct because of a third reocclusion of the right MCA and extension of the clot to the ipsilateral internal carotid artery terminus 12 hours apart (Figure 3). We hypothesized that the postthrombectomy injured arterial endothelium, combined with the high prothrombotic state and endothelium dysfunction characteristic of VITT, could have been the cause of the repeated arterial occlusions of the same vessel. Unfortunately, at the time the patient was admitted to our hospital, articles on VITT had not still been published and, due to very low baseline platelet count (44×109/L), platelet transfusion was performed before the first thrombectomy, which may have contributed to exacerbate the thrombotic event. At present, guidelines recommend that prophylactic platelet transfusions should be avoided in the context of VITT but should be provided before major surgical interventions (ie, hemicraniectomy) or if life-threatening bleeding is present.87,105
Figure 2. Radiological findings from patient 7.
Case reported by De Michele et al.109A, Computed tomography (CT) demonstrated extensive ischemic changes in the bilateral middle cerebral artery (MCA) distribution with general hypodensity and loss of gray-white matter differentiation. CT angiography showed the occlusion of the right internal carotid artery terminus (white arrow in B) and the proximal M1 segment occlusion of the left MCA (white arrow in C); time-to-maximum (D) and mean transit time (E) in CT perfusion showed hypoperfusion without treatable penumbra; pulmonary artery thrombosis (white arrow in F) with pulmonary consolidation in the right lobe (G).
Figure 3. Radiological findings from patient 6.
Case reported by De Michele et al.109A, Computed tomography (CT) showed hyperdensity in the right middle cerebral artery. The CT angiography revealed proximal M1 segment occlusion of the right middle cerebral artery (MCA; white arrow in B and C); CT perfusion maps showed a large area of mismatch indicating salvageable penumbra (D); digital subtraction angiography confirming a proximal MCA occlusion (F) of the MCA occlusion (white arrow in E); MCA reocclusion on M2 segment 2 h after the procedure, 3-dimensional time-of-flight magnetic resonance imaging (MRI) sequence (white arrow in G), with extensive ischemic penumbra (time to peak map in H and cerebral blood flow in I). Second endovascular recanalization, oblique views showed occlusion of M2 segment (white arrow in J) with reopening of the vessel after the mechanical thrombectomy (K). Fourteen-day MRI follow-up after craniectomy showed the extension of ischemia to superficial and deep right MCA territory (M) with occlusion of right internal carotid artery at postcontrast sequences (yellow circle in L). N, Right portal vein thrombosis (black arrow).
Through the abovementioned systematic review of the literature, we also identified 2 additional studies relevant for the scope of this review, 1 from United Kingdom and 1 from Germany. A prospective multicenter cohort study from the United Kingdom evaluated VITT patients who presented to the hospital between March 22 and June 6, 2021.102 Among 220 patients with diagnosis of VITT classified as definite (ie, all 5 of the following criteria: [1] onset of symptoms 5–30 days after vaccination against SARS-CoV-2; [2] presence of thrombosis; [3] thrombocytopenia [platelet count <150 000 per mm3]; [4] D-dimer level >4000 FEU; [5] positive anti-PF4 antibodies on ELISA) or probable (ie, D-dimer level >4000 FEU but absence of one of the abovementioned criteria or D-dimer level unknown or 2000–4000 FEU and the presence of all other criteria), 17 subjects (7.7%) experienced cerebrovascular accidents. Unfortunately, no more details about these 17 patients have been reported by the authors, since data reported in the article are cumulative and related to all 220 VITT patients.
The second study comes from the German Society of Neurology SARS-CoV-2 Vaccination Study Group.101 Nine cases of ischemic stroke (mean age, 55.6; range, 31.0–82.0) of 62 cerebrovascular events (14.5%) within 31 days from a first dose of COVID-19 vaccination have been reported in the December 28, 2020, to April 14, 2021, time period. Eight of these patients had received the ChAdOx1 ncov19 vaccination, and only 1 received the BNT162b2 vaccine. Majority of cases were females (66.7%). Among these 9 ischemic patients, 5 with embolic stroke had a VITT score of >2 (which means a highly probable VITT defined as the presence of the following 2 criteria: [1] time from shot administration between 1 and 16 days; [2] thrombocytopenia, <150×109/L or relative thrombocytopenia, drop of thrombocytes of at least 50%; [3] positive ELISA to detect PF4-polyanion antibodies; [4] positive modified platelet activation assay) without signs of CVST. In four of them, thrombotic occlusion of the MCA or internal carotid artery and recurrent thrombotic material in duplex ultrasound were described.
Therapeutic approach of acute ischemic stroke due to large vessel occlusion in VITT is challenging. Based on the available literature89,110–119 and our personal experience,109 we propose the following management protocol for acute stroke patients presenting to the Emergency Department within the time window for reperfusion strategies (Figure 4):
Figure 4. Management flowchart of patients with acute ischemic stroke and suspected vaccine-induced thrombotic thrombocytopenia presenting to the Emergency Department within the time windows for reperfusion interventions. CT indicates computed tomography; CTA, computed tomography angiography; DTI, direct thrombin inhibitor; IVIG, intravenous immunoglobulin; MCA, middle cerebral artery; MRI, magnetic resonance imaging; and PF4, platelet factor 4. *According to the current international guidelines.
Keep in mind that ischemic stroke can be the first presentation symptom at onset of VITT.
If a patient has received the first dose of DNA vector vaccination against SARS-CoV-2 within the previous 5 to 30 days, wait for platelet count results before starting thrombolysis.
If large vessel occlusion is evident at cerebral computed tomography angiography without signs of malignant MCA infarct, mechanical thrombectomy is indicated according to guidelines from professional medical societies.
If low platelet count is evident, avoid platelet transfusion and consider steroid administration (prednisone 1–2 mg/kg per day or dexamethasone 40 mg/day for 4 days) possibly before the endovascular procedure, monitoring blood pressure and blood glucose.
Monitor the patient closely after mechanical thrombectomy since the risk of reocclusion and neurological deterioration is high.
Schedule a control brain computed tomography scan or magnetic resonance imaging in the next 12 hours to decide the timing for starting anticoagulation.
Start early full-dose anticoagulation with oral or parenteral direct thrombin inhibitors, or oral factor Xa inhibitors, or fondaparinux, only if brain infarct is small. If brain infarct is large, start with a reduced dose of anticoagulant (ie, fondaparinux, 2.5 mg daily) and increase the dosage after 2 weeks from stroke onset (ie, fondaparinux, 7.5 mg daily), due to the high risk of hemorrhagic transformation of the ischemic lesion.
Thrombocytopenia seems not to be a contraindication to therapeutic dose anticoagulation in VITT, since subjects with the lowest platelet count are at the highest risk of thrombosis.87 However, some of the available current guidelines suggest low-dose anticoagulants if platelet counts are <30 to 50×109/L.87
Consider IVIG treatment (1 g/kg for 2 consecutive days) immediately after reperfusion therapies if VITT diagnosis is probable (thrombosis, thrombocytopenia, high D-dimer after vaccination), without awaiting confirmation from PF4 antibodies ELISA immunoassay. Repeated IVIG may be required.
Perform anti-PF4 ELISA immunoassay and functional assay of platelet activation as soon as possible to confirm diagnosis (blood sample for functional assay should be obtained before IVIG administration since IVIG inhibits functional immunoassay).87
Consider plasma exchange (daily for up to ≥5 days) if extensive thrombosis and platelet count is <30×109/L.
Consider rituximab for patients who are refractory to repeat doses of IVIG and plasma exchange, although evidence of its efficacy in VITT is scarce.
Expert consultation from hematologist is necessary.
COVID-19 and VITT show some common elements that lead to hypercoagulability and vascular occlusion. The abnormal interaction between platelets, innate immune effectors (neutrophils, macrophages, and complement), and coagulation factors are the key features of both pathological conditions. The ultimate consequence yields clot formation—a phenomenon known as thromboinflammation.120
In contrast to patients with COVID-19 and ischemic stroke, VITT patients do not show the typical elevations in interleukins. Rather, as discussed, the combination between soluble SP, adenovirus, and vaccine excipients probably acts as trigger for platelet activation.99 This distinct mechanism yields very different histopathologic findings postmortem. Specifically, postmortem studies on VITT patients found diffuse vascular thrombosis with endothelial activation, dense recruitment of inflammatory cells, and complement pathway activation in multiple organs.121
While thrombocytopenia is a typical finding of VITT, it is less frequently seen in patients with COVID-19 but is associated with increased risk of serious illness and death.122 Mechanisms of thrombocytopenia in COVID-19 are different, however, and are speculated to be mostly secondary to cytokine release, viral bone marrow infiltration, and increased platelet consumption.123 More rarely, thrombocytopenia in patients with COVID-19 can result from anti-PF4 antibody production as a complication of prolonged exposure to unfractionated heparin. There are also reports of platelet internalization of SARS-CoV-2 inducing platelet apoptosis, release of granular content, reduced platelet functionality, and high prothrombotic and proinflammatory immune response.124
Other common characteristics to both pathologies are the marked endothelial activation with elevated VWF, coagulation abnormalities (which can culminate to disseminated intravascular coagulation), and increased production of neutrophil extracellular traps.123,125 A comparison is summarized in Table 3.
| Critical COVID-19 | VITT | |
|---|---|---|
| Venous vs arterial thrombosis | Venous predominance | Venous predominance |
| Thrombocytopenia | ↓ | ↓↓ |
| d-dimer | ↑↑ | ↑↑ |
| Fibrinogen | ↑=↓ | ↑=↓ |
| Interleukin 6 | +++ | − |
| Endothelial activation | ++ | ++ |
| Anti-PF4 antibodies | ± | +++ |
| Platelet activation | + | +++ |
| NETs | ++ | +++ |
| Pulmonary thrombosis | ++ | ++ |
| Thrombosis in unusual sites | + | +++ |
| Stroke with LVO | ++ | ++ |
| ARDS | ++ | − |
Anti-PF4 indicates antibodies against antiplatelet factor 4; ARDS, adult respiratory distress syndrome; LVO, large vessel occlusion; NET, neutrophil extracellular trap; and VITT, vaccine-induced immune thrombosis thrombocytopenia.
Stroke and other cerebrovascular complications of SARS-CoV-2 infection are a highly morbid problem, with multifactorial pathophysiology. Given the association between severe SARS-CoV-2 infection and cardiovascular risk factors common to stroke, there is some degree of confounding; however, multiple studies at this point suggest that SARS-CoV-2 infection is an independent risk factor for ischemic stroke.4
Cerebrovascular complications of vaccination, specifically VITT is a rare but devastating syndrome occurring more frequently in young people after inoculation of DNA adenoviral vector vaccines that should be promptly recognized. The VITT variant causing arterial stroke is an even rarer but catastrophic event, whose management in the acute phase is complex and challenging.
Some European Union countries have restricted the use of adenovirus vector vaccines to older age groups. In Italy, the Government’s Technical and Scientific Committee has limited the use of Oxford-AstraZeneca vaccines to people over 60 years of age, whereas in the United Kingdom, the Joint Committee on Vaccination and Immunization recommended that the Oxford-AstraZeneca vaccine should not be given to people under 40 years of age. Canada and France have restricted the use of this vaccine to people 55 years of age and over, while Germany has set the bar at 60 and Iceland at 70 years of age.
Despite this, to date, studies have demonstrated that the risk of stroke and other prespecified outcomes of interest (thrombocytopenia, venous thromboembolism, arterial thrombosis, CVST, and myocardial infarction) following a SARS-CoV-2 infection were significantly higher than following vaccination with either the Oxford-AstraZeneca or Pfizer vaccines.67 As such, because benefits of mass vaccination against COVID-19 far outweighed the risks of VITT, no age restrictions were announced either by the European Medicines Agency or the Food and Drug Administration.
A global immunization campaign is urgently needed, particularly in low-income countries, and all currently available vaccines are approved by emergency authorizations. Nevertheless, more studies about the pathogenesis of VITT are mandatory to ameliorate the risk of adenovirus-based vaccines and to identify those most at risk of VITT.
We would like to acknowledge Natalie Pacheco LeMoss and Jed Kaiser for their assistance with formatting and editing of this article.
angiotensin-converting enzyme 2
vaccine-induced immune thrombotic thrombocytopenia
*D. Toni and A.E. Merkler contributed equally.
For Disclosures, see page 1200.
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State High-Speed Rail officials this week adopted a track alignment for the San Jose to Merced section through southern Santa Clara County, following Pacheco Pass to a new station in Gilroy, then heading non-stop through downtown Morgan Hill.
On April 28, the California High-Speed Rail Authority board of directors certified the Final Environmental Impact Report and Environmental Impact Statement, and unanimously approved “Alternative 4” for the 90-mile section alignment.
The board’s vote completes the environmental clearance for nearly 400 miles of the High-Speed Rail’s 500-mile “Phase 1” alignment from San Francisco to Los Angeles and Anaheim, says a press release from the HSRA. The board’s April 28 actions also represent its first certification of a project section’s environmental studies in Northern California.
“Today’s approval represents another major milestone and brings us one step closer to delivering high-speed rail between the Silicon Valley and the Central Valley,” HSRA CEO Brian Kelly said. “The authority is poised to make the vision of high-speed rail in the Bay Area a reality. We look forward to continued collaboration with our federal, state and local partners to advance the project in Northern California.”
The HSRA began the EIR process for the San Jose to Merced section more than two years ago. The in-depth study considered the impacts of four section alignment alternatives, as well as a no-project alternative.
Alternative 4 will take the bullet train tracks through the downtown areas of Morgan Hill and Gilroy, along the existing Union Pacific Railroad tracks.
HSRA staff added that Alternative 4 will modernize and electrify the existing rail corridor between San Jose and Gilroy, allowing for both HSR and Caltrain service.
“Next to San Jose, Gilroy will be the next most significant transit hub on this stretch,” said Gilroy Mayor Marie Blankley. “Gilroy Transit Center is very much ready for this to happen.”
Morgan Hill city council members and city staff had expressed a number of concerns with Alternative 4 during the public comment period, including with the lack of HSR track grade separations at East Dunne, Tennant and Tilton. The council in June 2020 had sent feedback to the HSRA urging them to consider adding grade separations at those intersections, allowing vehicle, pedestrian and bicycle traffic to cross under the HSR tracks without the bullet train and road traffic interfering with each other.
“(Grade) separations at these crossings are the appropriate and necessary solutions to several environmental impacts specifically, but not limited to safety response times, circulation, and noise as disclosed in the EIR/EIS for which vague and unconvincing mitigation measures have been offered,” says the city’s June 2020 letter.
The HSRA board did not implement such considerations when adopting Alternative 4 on April 28.
Morgan Hill officials had preferred an alignment that took the HSRA system within the U.S. 101 right of way on the east side of town.
Mayor Rich Constantine said that when it comes to vehicle traffic, two of Morgan Hill’s intersections that cross existing railroad tracks—Dunne and Tennant avenues—are among the five busiest along the entire Caltrain corridor from San Francisco to Gilroy. That means the potential traffic hold ups and emergency response delays from High-Speed Rail crossings could be “significant” when the system is fully built out, Constantine said.
“If the (High-Speed Rail crossing) gates are down for 30 seconds for each train, that’s a significant amount of time” to delay vehicle traffic, said Constantine, who is a retired firefighter. “If it’s an emergency—I’ve been in that situation where we respond to a call and have to stop because of a train.”
Morgan Hill Assistant City Manager Edith Ramirez added that city staff has continued to provide comments on the High-Speed Rail EIR, and continued to advocate for grade separations along the route as it crosses busy intersections in the city limits.
The San Jose to Merced section goes from Scott Boulevard in Santa Clara to Carlucci Road in Merced County. The segment will travel through or near the communities of Santa Clara, San Jose, Morgan Hill, Gilroy and Los Banos. The project includes high-speed rail stations at San Jose Diridon and in Gilroy, as well as a maintenance facility south or southeast of Gilroy.
The section will connect existing HSR construction in the Central Valley with Diridon Station. The HSR will take travelers from Fresno to San Jose in one hour, according to HSRA staff.
San Jose Mayor Sam Liccardo said, “I am grateful, as are all of us in the City of San Jose, for the extraordinary work that’s now culminated in this environmental document reflecting thousands of hours of stakeholder outreach and an enormous amount of environmental analysis. Completion of this critically important high-speed rail project helps the state expand economic opportunity and affordable housing, two critical goals for all of us.”
The board’s certification of the EIR and EIS marks a key milestone in the statewide project, moving the project section closer to “shovel ready,” says the press release. Construction of the project section is not yet fully funded.
East of Gilroy, the alignment includes more than 15 miles of tunnels through the Pacheco Pass in the Diablo Range. The Board will consider certification for the final environmental document for the San Francisco to San Jose project section this summer.
California High-Speed Rail is currently under construction along 119 miles in the Central Valley at 35 active job sites, says the press releases. To date, more than 7,500 construction jobs have been created since the start of construction.
When voters approved a $9.95 billion bond measure in 2008 to kick start the High-Speed Rail project, the total projected cost was about $30 billion and it was slated to be complete by 2030. Since then, the price tag has ballooned higher than $100 billion, and officials have yet to identify where most of the funding will come from to complete the first phase between San Francisco and Anaheim
Como uma onda no mar… Para uma vida mais saudável e equilibrada, nada melhor do que aumentar o consumo de pescados no cardápio. E para você começar já, trouxemos uma receita de Filé de Pescada levemente defumado com Laranja e Farofa de Maracujá. Feito com Filé de Pescada Swift, um peixe de carne branca, saborosa e textura suave. Seu teor de gordura é baixo e contém boas quantidades de cálcio, fósforo, ômega 3 e potássio.
⤵ INGREDIENTES
Filé de Pescada
– 2 laranjas bahia em rodelas
– 500 g de Filé de Pescada Swift
– ½ laranja-baía em meia-lua
– 1 colher (sopa) de Sal para Parrilla com Pimenta Swift
– 1 maço pequeno de tomilho fresco
– 3 colheres (sopa) de azeite para pincelar
– 150 g de Woods Chips para Defumação – Laranjeira Swift
Farofa de Maracujá
– 2 colheres (sopa) de manteiga
– 2 colheres (sopa) de Cebola Picada Swift
– ½ xícara (chá) de maracujá
– 3 xícaras (chá) de Farofa Tradicional Swift
– Salsa fresca picada a gosto
– Sal para Parrilla com Pimenta Swift a gosto
⤵ MODO DE PREPARO
Filé de Pescada
1. Disponha as rodelas de laranja em uma assadeira perfurada, placa perfurada ou panela perfurada própria para churrasqueira, formando uma “cama” para colocar os filés de pescada. Acomode os filés por cima das rodelas de laranja e tempere com sal para parrilla com pimenta a gosto.
2. Coloque por cima de cada filé duas meias-luas de laranja e um pequeno ramo de tomilho.
3. Acenda a churrasqueira e deixe formar a brasa. Deve levar cerca de 20 minutos.
4. Junte na brasa, aos poucos, pequenas porções de woods chips para defumação – laranjeira. Crie assim a fumaça necessária para assar e defumar os filés. Repita o processo quantas vezes forem necessárias. É importante evitar as labaredas. Se ocorrerem, é só espalhar um pouco a brasa.
5. Disponha a assadeira perfurada na segunda altura da churrasqueira, a 45 cm da brasa.
6. Deixe assar por 25 minutos aproximadamente, ou até que os filés estejam cozidos por completo.
7. Retire com cuidado da assadeira perfurada. Use sempre as rodelas de laranja como apoio. Sirva quente.
Farofa de Maracujá
1. Aqueça uma panela e coloque a manteiga para derreter. Acrescente a cebola picada para dourar levemente e cozinhe por 3 minutos em fogo médio.
2. Junte o maracujá e mexa bem para incorporar todos os ingredientes.
3. Adicione a farofa e mexa para absorver todo o tempero.
4. Finalize com a salsa picada e o sal para parrilla com pimenta a gosto.
5. Sirva com os filés de pescada.
Dica: acrescente mais Farofa Tradicional Swift para uma farofa mais sequinha.
Rendimento: 5 porções
Tempo de preparo: 50 minutos
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It takes a lot to start a vegetable garden: choosing the right vegetables to grow and buying seeds, and then there’s planning the actual yard space. Of course, there’s nothing like the neat and tidy rows of traditional raised garden beds, with everything lined up and planted in an orderly fashion. But, sometimes, you simply don’t have the space. If you live in an apartment with a balcony, a condo, or house with a small yard, you’ve got to get a little more creative. Fortunately, there are vegetable garden layout ideas for any size of yard.
A few factors will help you decide the best layout plan for your vegetable garden. Depending on your plant hardiness zone, you’ll want to make sure you find a location for your garden that receives full sun, which is considered 6 or more hours of direct sunlight per day. Many garden favorites, such as tomatoes and bell peppers, like it even hotter, so 8 or more hours is ideal. Very few vegetables will tolerate mostly shade, so if your yard is shaded all day, your best bet is to opt for a container garden that you can place where you do have full sun exposure. Also, make sure you have access to water; that sounds obvious, but if you have to haul watering cans or drag a hose too far in the heat of summer, it’s not the most pleasant experience! Still feel up to the challenge? To inspire you, here are the best vegetable garden layout ideas including designs, products, and tips to make your garden even more productive.
Short on space? Try various hanging pots, which works well for many different types of edibles including strawberries, herbs, and lettuce. Bonus: it keeps your plants away from animals in your garden such as bunnies!
A repurposed ladder makes the perfect foundation for lots of pots of herbs without taking up a ton of space on your patio or deck. It also accommodates different sizes of pots and window boxes, as shown here, for a pretty and appealing display.
This layout is the most traditional, and it definitely is appealing! You can plant tight rows of plants that don’t mind chilly weather such as lettuce, then pull them out when they go to seed as hot weather hits. Replant a heat lover such as beans in the same space.
Growing up is always a space-saving option. Plus, some veggies, such as cukes and squash, are more productive and less vulnerable to disease with vertical support (due to better air circulation).
Many gardeners believe that by planting certain combinations of plants together, they’re mutually beneficial—keeping away bad insects and attracting the good ones. Here, cabbage is interplanted with signet marigolds (also edible!) for a pretty and practical display.
Raised beds are the best way to deal with poor soil; they also warm up a bit faster in the spring than the ground. You can purchase one or DIY one from wood (don’t use pressure-treated, which can leach chemicals) or concrete paver stones.
If hungry garden visitors keep munching on your produce, try this ingenious solution: Long metal containers, such as repurposed gutters, can be mounted to stakes. Just be sure to punch holes in the bottom of each container, and plant shallow-rooted veggies such as various types of leaf lettuce, creeping herbs such as thyme, or kale.
If you don’t have a bit of space outdoors, a windowsill garden still allows you to grow something useful! Herbs are the best choice because they’re easy to grow, many adapt to indoor conditions, and they’re so expensive to buy at the grocery store. Just make sure they get plenty of bright light.
Stock tanks keep having a moment! Why? They’re nearly indestructible, last for years, and are just about the right height for comfortable access–especially if you have back issues. Look for bottomless tanks or poke lots of holes in a traditional stock tank for drainage.
Why buy lettuce that just ends up going bad in the crisper? Plant shallow containers with various kinds of lettuce, and harvest when you need it. Wait a week or two in between sowings. That way, you’ll keep the harvest going longer.
You don’t have to forgo the fun of gardening if you have a bad back or achy knees. Raised bed planters at waist height can accommodate you and make gardening more fun, less painful.
Fabric bags are a great way to grow vegetables because you can fold these bags up for storage at the end of the season. They’re especially good for crops such as potatoes because it’s easier to layer soil and to harvest.
Believe it or not, you can grow vegetables in straw bales! It’s fun, clean, and can be done anywhere, such as the edge of your property or even on pavement. The bales typically last a season or two, and you can recycle the rest in your compost bin.
These cat fails are absolutely hilarious. Our newest compilation of funny animal videos will surely leave you roll laughing! Featuring some of the funniest cats who are just so silly and funny, sometimes acting just like a jerk 😂. So grab a snack and get ready to laugh until you cry. Oh, there are some cute moments in here too so don’t worry if you’re not into laughing at animal videos 😂.
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