CSVT is a rare cerebrovascular disease that incidences only 0.5% to 1% of all stroke cases [13,14,15]. CSVT is more common in young individuals, with broad manifestation, depending on the site of the thrombosis [13, 16]. It is concomitant with multiple factors, for example prior medical conditions (thrombophilia, inflammatory bowel disease), transient situations (pregnancy, dehydration, infection), particular medications (oral contraceptives, substance abuse), and unpredictable events (head trauma) [15], with which thrombus formation becomes more intensified. The poor outcomes and prognosis of CSVT are associated with, age, gender, and medical conditions [15].
Cases from our reports have different neurological manifestations after the previous episode of upper respiratory tract symptoms with confirmed SARS-CoV-2 infection from nasopharyngeal swab rt-PCR. SARS-CoV-2 is transmitted mostly through respiratory droplets and infected the lungs [17]. The entry of SARS-CoV-2 into the human host cells relies on the surface angiotensin-converting enzyme 2 (ACE2), which is most expressed in the type II surfactant-secreting alveolar cells of the lungs [18]. The incubation period is approximately 4–5 days before the onset of symptoms [19, 20]. Almost all patients with COVID-19 have lung problems, such as cough, shortness of breath, or ARDS [19]. Guan and colleagues reported that the clinical outcomes of COVID-19 can be predicted by the amount of comorbidities for example hypertension, diabetes mellitus, cardiovascular disease, stroke, smoking, and age more than years old [21]. The first patient had two comorbidities of hypertension and diabetes mellitus, while the second patient has age > 60 years old as comorbid.
SARS-CoV-2 infection activates disproportionate inflammatory innate and adaptive immune response [22]. The interleukin (IL)-1β, IL-6, IL-12, interferon γ (IFN-γ), IFN-γ-inducible protein 10 (IP10), and monocyte chemoattractant protein (MCP) were associated with pulmonary inflammation and extensive lung damage in SARS-CoV-2 patients [23]. Both patients had severe pneumonia with GGO in their thorax CT scan. The worse clinical experience in the second patient was most likely the result of this immunity instability. Furthermore, elderly patients are more susceptible to being worsened against viral infections, due to decreased interferon production [24]. SARS-CoV-2 is known to suppress the induction of antiviral type I interferon (IFN-α/β) [24].
“Cytokine storm” has been a major cause of severe COVID-19 with high levels of inflammatory markers found in the blood (C-reactive protein, ferritin, and D-dimers) [25, 26]. Hematologic examination in severe COVID-19 showed lymphocytopenia and an increased sum of neutrophils (NEU) [27]. Neutrophils are activated and migrated to the infected. Elevation of the NLR predicts the adverse prognostic in COVID-19 patients [28]. Both patients had NLR of more than 5, especially the second patient had twofold NLR than the first patient. Extremely high leukocyte level is a bad predictor in the second patient. NEU induces DNA cell damage by releasing reactive oxygen species [28]. A study published by Huang and colleagues reported leukocytosis 2.0 rise and neutrophilia 4.4-fold rise [29] as predictor severity of the disease. This may be confused in myeloproliferative neoplasm (MPN), but we did not do the blood film examination to exclude the disease in this patient. The pathogenesis of thrombosis in MPN is related to an increase in blood cell counts (leukocytosis, erythrocytosis, and thrombocytosis) and the presence of JAK2 mutation. Patients with WBC > 15 × 109/L was a significant predictor for thrombosis [30].
Clinically, relevant hemostatic changes occur 50–70% in septic patients, with 35% meeting the criteria of disseminated intravascular coagulation [31]. Furthermore, patients with COVID-19 have diffused inflammation, which activates the coagulation system by consuming clotting factors and resulting in DIC [32]. The systemic infection of SARS-CoV-2 damages the endothelial cells, activates mononuclear cells, produces proinflammatory cytokines, and promotes coagulation [33]. Thrombin elicits the production of chemoattractant proteins, in monocytes, fibroblasts, mesothelial, and vascular endothelial cells, by interacting with protease-activated receptors (PARs) 1,3, and 4 [31]. PARs are transmembrane G-protein coupled receptors that have their functions from 1–4 [34]. The PARs 1, 3, and 4 are receptors activated by thrombin. Through PAR2, factor Xa and the tissue factor (VIIa) complex also upregulate chemoattractant proteins (IL-6, IL-8) in vascular endothelial cells [31]. The tissue factor (VIIa) catalyzes the conversion of factor X to Xa, forming prothrombinase complex with factor Va, prothrombin factor (II), and calcium, which results in generating thrombin factor (IIa) [32]. The physiological anticoagulant mechanisms and fibrinolysis inhibited by endothelial cells cause intravascular fibrin deposition [31].
The mortality rate in CSVT is 1% at discharge and continuing to decrease with the use of anticoagulant treatment [14]. The main cause of early death after acute CSVT is secondary trans-tentorial herniation, due to multiple lesions to diffuse brain edema [15]. Other causes are status epilepticus, medical complications, and pulmonary embolism [15]. According to the laboratory and thorax CTA results, the second patient had pulmonary embolism and thrombosis at the same time (Table 1).
The difference of the clinical presentation’s severity in both patients was also determined by the location of vein thrombosis and the brain edema. The first patient presented better clinical manifestation, because the edema was in the supratentorial brain area, while the second exhibited worse symptoms due to involvement of infratentorial brain edema (cerebellum and pons). Head NCCT scan of the second case showed direct signs of dense triangle sign (Fig. 2B white arrow) and cord at right TS (Fig. 2C white arrow). Furthermore, the CTV of the first patient showed a filling defect at bilateral TS and SSS (Fig. 1E, F white arrows). During the COVID-19 pandemic, CTV was preferred over MRI because it is an accurate and more rapid technique to detect cerebral venous thrombosis [35]. The massive thrombosis and emboli in the lungs were the consequences of the hypercoagulable state and body immobility. Thrombosis makes up 31% of thrombotic complications in ICU patients down with COVID-19 [36]. The second patient had late thrombosis complications although had been administered by heparin, which might be related to this immobilized condition and high level of D-dimer in the first presentation.
Critically ill patients develop a hypercoagulable state due to immobilization, mechanical ventilation, central venous access devices, and nutritional deficiencies [37]. COVID-19 and hypercoagulability are further implicating the risks of pulmonary embolism (PE), vein thromboembolism (VTE), disseminated intravascular coagulation (DIC), and stroke [38]. The dysfunction of endothelial cells plays role in thrombin generation and fibrinolysis shutdown [34]. The second patient had a more severe condition, because of being hospitalized with a ventilator, central venous catheter, and immobilized for 10 days.
Pro-coagulation state in COVID-19 generates CSVT. Hypercoagulability of SARS-CoV-2 serves as an increase in, D-dimer, LDH, fibrinogen, factor VIII (FVIII), von Willebrand factor (vWF), and decreased antithrombin [39]. Patients with severe pneumonia, especially ARDS, have low oxygen concentration that increases blood viscosity, while also inducing the hypoxia-inducible transcription factor-dependent signaling pathway [36]. After the COVID-19 swab had been negative, the second patient was observed to develop massive thrombosis. The second patient had more D-dimer levels than the first, and the length of treatment was longer. Furthermore, the thrombosis process was still ongoing even though COVID-19 was negative and the D-dimer level was decreased. It was a challenge to observe whether the second patient had the previous thrombosis or not, with a diagnostic approach taken in checking for D-dimer and heart thrombosis [40]. Therefore, it was concluded that this patient had brain, heart, and pulmonary thrombosis.
Three important physiological anticoagulant pathways are the antithrombin, the activated protein C, and tissue factor inhibitor (TFPI) system. Those pathways are deranging in sepsis, which is precipitated by cytokines [34]. In sepsis, a high level of cytokines is found in the circulation, with hemostatic activation mediated by TNF. The expression of tissue factor in mononuclear cells and subsequent exposure to blood results in thrombin generation, accompanied by fibrinogen to fibrin conversion. The interaction and activation of platelets and their walls contribute to microvascular clot formation [34].
The anticoagulant commonly used in preventing DIC and VTE is low molecular weight heparin (LMWH) because it has an anti-inflammatory effect [41]. The first patient was given LMWH, to minimalize the contact with the patient. The D-dimer was diagnosed after 4 days and observed to be decreased, with improvement in neurological manifestation. Due to being in ICU, heparin was intravenously administered to the second patient, to pay close attention to the APTT. Heparin interacts with pro-inflammatory and procoagulant cascades, to prevent inflammation, and coagulopathy associated with sepsis [41]. Unfractionated heparin and LMWH are mostly used, in the cases of acute CSVT [9]. Tissue-plasminogen activator (tPA), in fibrinolytic therapy, is used in patients with low compensating conditions and resilient from prior anticoagulant [42]. The second patient was given fibrinolytic therapy the following day, after the diagnosis of CSVT. Due to multiple organ failures and loss of consciousness, it was therefore concluded that the response was poor.
