We reported the two cases of cerebral venous thrombosis with two different onsets of neurological complications. The first patient had comorbidities of hypertension and diabetes mellitus. The later was without any comorbidities except old age (72 years-old). Patients with comorbidities are known have greater disease severity of COVID-19(13). In this case, the second case has poorer outcome. Cerebral venous thrombosis in this series are neurological manifestation of COVID-19. Both of patients had been confirmed being infected by SARS-CoV2 with respiratory symptoms as first presentation. The CSVT itself is rare condition in cerebrovascular disease for approximately 0.5% to 1% to all stroke cases (14–16), with multiple factors associated such as prior medical conditions (thrombophilia, inflammatory bowel disease), transient situations (pregnancy, dehydration, infection), selected medication (Oral contraceptives, substance abuse), and unpredictable events (Head trauma) (16) by which thrombus formation become more aggravated. In this case report, COVID-19 had caused proinflammatory and pro coagulation state to create CSVT.
CSVT is more common in young individuals with broad manifestation depends on the location of thrombosis(14,17). The difference in clinical presentation of both patient was determined by the location of CSVT and location brain edema. First patient showed better clinical presentation since It only involved supratentrorial brain. The second patient showed worse clinical presentation and grave prognosis due to involvement of infratentorial brain edema. Head NCCT scan of the second case showed direct signs of dense triangle sign (Figure 2B white arrow) and cord sign at right TS (Figure 2C white arrow). CTV of the first patient showed filling defect at bilateral TS and SSS (Figure 1E, F white arrows). We choose CTV over MRI during COVID 19 since CTV is more rapid and also an accurate technique to detect cerebral venous thrombosis (18). The massive thrombosis and emboli in the lungs were the consequences of patients with hypercoagulable and immobile condition, for 31% incidence of thrombotic complications in ICU patients with COVID-19 (19). He had late complications because of worse coagulation marker at first admission in hospital, also had been immobilized for 10 days.
The mortality in CSVT is 1% at discharge and continuing to decrease with the use of anticoagulant treatment(15). The poor outcome and prognosis of CSVT are associated with age more >37 years, male, coma, neurological deficits, encephalopathy, decreased level of consciousness, hemiparesis, and seizures (16). The main cause of early death after acute CSVT is trans-tentorial herniation secondary due to multiple lesions or to diffuse brain edema (16). Another causes are status epilepticus, medical complications, and pulmonary embolism (16). The second patients had pulmonary embolism and thrombosis at the same time, but other organ still in good condition from the laboratory results (Table 1).
Almost all patients with COVID-19 present with involvement of the lung such as cough, shortness of breath or acute respiratory distress syndrome (ARDS)(20). SARS-CoV-2 is transmitted primarily via respiratory droplet and infects the lung and the conjunctival mucosa as a portal of infection (21). The entry of SARS-CoV-2 into the human host cells rely on the surface angiotensin-converting enzyme 2 (ACE2) which is most expressed in the type II surfactant-secreting alveolar cells of the lungs(22). The incubation period is approximately 4-5 days before the onset of symptoms (20,23).
SARS-CoV-2 infection activates innate and adaptive immune response by rapid and well-coordinated immune response, excessive inflammatory innate response and dysregulated adaptive host immune defense(24). The hyperinflammation SARS-CoV-2 known as “cytokine storm” is being a major cause of disease severity and death confirmed by the higher levels of inflammatory markers in blood such as C-reactive protein, ferritin, and D-dimers (25,26). Severe COVID-19 are correlated with lymphocytopenia and increase total neutrophils (27). NEU can induce cell DNA damage and free the virus from the cell by releasing reactive oxygen species(28). Neutrophils (NEU) are leukocyte that activates and migrates from the venous system to the immune organ or system. Elevation NLR may predict the worse prognostic in COVID-19 patients(28). The NLR in both patients are high and the second case had larger NLR and ended with death.
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 patients(29). Both patients had severe pneumonia, seen with Thorax CT scan as GGO. Elderly patients are more susceptible to worsening due to immune system instability against viral infections due to decreased interferon production(30). The worse clinical experience in the second patient was most likely the result of this immunity instability. SARS-CoV-2 known to suppress the induction of antiviral type I interferon (IFN-α/β)(30). If we have modalities to counting the cytokines serum, we assumed that both patients had elevated cytokines mentioned before.
Clinically relevant hemostatic changes occurs 50-70% in septic patients, with 35% patients meet the criteria of disseminated intravascular coagulation(31). Patient with COVID-19 has diffused inflammation that activates coagulation system. This system consumes clotting factor and resulting in DIC(32). The systemic inflammatory damages the endothelial cells and activates mononuclear cells to produce proinflammatory cytokines that promotes coagulation(33). These cells expressed proteins that initiate coagulation. Thrombin elicits the production of monocyte chemoattractant protein 1 and IL-6 in monocytes, fibroblasts, and mesothelial cells, and the production of IL-6 and IL-8 in vascular endothelial cells by interacting with protease-activated receptors (PARs)1,3, and 4(31). PARs are a transmembrane G-protein coupled receptors that has their own function from PAR1-4 (34). The PAR1,3,4 are receptors that are activated by thrombin. Via PAR2, factor Xa, and the issue factor-VIIa complex also upregulate IL-6 and IL-8 in vascular endothelial cells (31). The tissue factor VIIa catalyzes the conversion of factor X to Xa, which will form the prothrombinase complex with factor Va, prothrombin factor (II), and calcium, thereby generating thrombin (factor IIa)(32).The physiologic anticoagulant mechanisms and fibrinolysis are inhibited with by endothelial cells causes intravascular fibrin deposition (31).
Coagulation is controlled by three important physiological anticoagulant pathways: the antithrombin system, the activated protein C system and tissue factor inhibitor (TFPI). That three pathways are derange in sepsis that precipitated by cytokines(34). In sepsis, the high level of cytokines is found in the bloodstream. Hemostatic activation was mediated by TNF in sepsis. The expression of tissue factor in mononuclear cells and subsequent exposure to blood results in thrombin generation followed by fibrinogen to fibrin conversion. The platelet vessel wall interaction and activation of platelets contribute to microvascular clot formation(34).
The dysfunction of endothelial cell induced by COVID-19 results in thrombin generation and fibrinolysis shutdown(34). COVID-19 and hypercoagulability are implicating the pulmonary embolism (PE), vein thromboembolism (VTE), disseminated intravascular coagulation (DIC), and stroke(35). In critically ill patients may develop hypercoagulable state due to immobilization, mechanical ventilation, central venous access devices, and nutritional deficiencies(36). The second patient has more severe condition because he had been hospitalized with ventilator, central venous catheter, and immobilized for 10 days.
Hypercoagulability of SARS-CoV-2 manifesting as increase in D-dimer, LDH, fibrinogen, factor VIII (FVIII), von Willebrand factor (vWF), and decreased antithrombin(37). Patient with severe pneumonia especially ARDS has low oxygen concentration that increase the blood viscosity and inducing the hypoxia-inducible transcription factor-dependent signaling pathway (19). After the COVID-19 swab had been negative, the second patient was developed massive thrombosis. He had more D-dimer level than the first patient and length of treatment was longer, so the thrombosis process was still ongoing even though COVID-19 was negative and D-dimer level was decreased. It was a challenge to find out whether the second patient had previous thrombosis or not, therefore we take diagnostic approach in pulmonary embolism by checking D-dimer, while troponin I was used to check heart thrombosis(38). The second patient also had troponin I increased and normal ECG. We concluded this patient had brain, heart, and pulmonary thrombosis.
Anticoagulant that most commonly used to preventing DIC and VTE is low molecular weight heparin (LMWH) because it has anti-inflammatory effect(39). The first patient was given LMWH to minimalize the contact with the patient. We checked again the D-dimer after 4 days and the D-dimer was decreased with improvement in neurological manifestation. The heparin intravenous is used to our second patient because he was in ICU and we can do close monitoring to the patient’s APTT. Heparin interacts with may pro-inflammatory and procoagulant cascades to prevent inflammation and coagulopathy associated with sepsis (39). The use unfractionated heparin and LMWH are used in acute CSVT (9). The use of tissue- plasminogen activator (t-PA) fibrinolytic therapy were used in decompensated patients with no options for escalation of care(40). The second patient get fibrinolytic therapy the next day after the diagnosis CSVT. The response was not good, due to the condition going to be multiple organ failure on the third days of loss of consciousness.