COVID-19 is well-known to be frequently associated with coagulation/fibrinolysis abnormalities8)-10). Thus far, we have managed six serious COVID-19 patients, and all of whom had already developed CAC at the time of ICU admission without exception.
Recently, DIC (i.e., coagulation/fibrinolysis abnormalities) has been classified into three types depending on the pattern of the fibrinolytic system11)12). All three types involve significant activation of coagulation. The first pattern is “suppressed-fibrinolytic-type” abnormalities. This pattern in characterized by severe coagulation activation but mild fibrinolytic activation, and is typically seen in sepsis. Because there is a marked increase in the fibrinolytic inhibitory factor PAI-1, an important factor for DIC characterization, fibrinolysis is strongly suppressed. The second pattern is “enhanced-fibrinolytic-type” abnormalities. This pattern is characterized by marked fibrinolysis activation that corresponds to coagulation activation, and is typically seen in acute promyelocytic leukemia (APL), abdominal aortic aneurysm, and prostate cancer. Fibrinolysis is strongly activated, with hardly any elevation of PAI, and hemostatic plugs (thrombi due to hemostasis) are quite easily dissolved. Laboratory findings show marked elevations in both TAT and PIC, as well as elevations in FDP and D-dimer. The third pattern is “balanced-fibrinolytic-type” abnormalities. This pattern is characterized by a balance between the coagulation and fibrinolytic activations and is thus an intermediate pathology between the other two types of DIC described above.
In “fibrinolysis-suppressed type” abnormalities derived from infectious diseases, microthrombi formed in peripheral blood vessels due to hypercoagulability are difficult to dissolve, and systemic microcirculatory disorders occur, resulting in complications such as organ failure, cerebral infarction, and myocardial infarction. However, bleeding symptoms are relatively mild. Meanwhile, in “fibrinolysis-enhanced type” abnormalities, almost no increase in PAI is observed, and thus the microthrombi are easily dissolved and the risk of complications with bleeding symptoms such as cerebral hemorrhage, epistaxis, and subcutaneous hematoma increases. However, organ dysfunction seldom occurs.
Because our six cases were all serious COVID-19 patients, we expected that they would have “fibrinolysis-suppressed type” coagulation/fibrinolysis abnormalities. However, in all cases except Case 6 at ICU admission, the coagulation markers PT-INR and APTT were within the normal ranges, and APTT was prolonged within the set range because of UFH use as an anticoagulant for ECMO. Meanwhile, PT-INR and APTT did not deviate from the normal values any more than expected. PAI-1 on ICU admission was within the normal range except for two cases (Cases 1 and 6) and no significant increases were observed thereafter except in Case 6. However, both TAT and PIC were significantly increased on admission to the ICU. The levels of these markers then decreased once, but increased again on hospital day 6 or 7. Similarly, FDP and D-dimer were significantly increased on admission to the ICU, then decreased once and subsequently increased again on hospital day 7. From these results, we strongly suspected that serious COVID-19 patients had sufficiently enhanced fibrinolysis as well as coagulation at the time of ICU admission, and that despite COVID-19 being an infectious disease, the pattern of CAC was of the “enhanced-fibrinolysis type” rather than the “suppressed-fibrinolysis type”.
Levi et al.8) commented that coronavirus infections are associated with surprising activation of the fibrinolytic system and that this can be explained by elevated FDP/D-dimer due to massive release of plasminogen activators in response to inflammation-induced endothelial cell damage in patients with severe COVID-19. In addition, Iba et al.13) suspected that secondary hyperfibrinolysis following coagulation activation plays a dominant role in the CAC, based on the results of an observational study, in which the maximum score among the DIC parameters in non-survivors was the D-dimer level14). In particular, two cases (Cases 1 and 3) were complicated with stroke on hospital day 6 and we confirmed that FDP/D-dimer and PIC were re-elevated at the same time as the stroke onset. In addition, TAT was re-elevated at 1 day before these markers became re-elevated. However, we also confirmed that the coagulation markers PT-INR and APTT were within the normal ranges and that Fbg was not decreased, reflecting inflammation. In other words, these two cases that developed stroke appeared to shift their pattern of coagulation/fibrinolysis abnormalities to the “enhanced-fibrinolysis type” before and after the onset of stroke. For this reason, we suspect that serious COVID-19 patients need to be observed carefully for not only thrombus formation due to hypercoagulability, but also hemorrhagic complications due to hyperfibrinolysis.
In a review article, Connors et al.15) described that, unlike other RNA-type viruses associated with hemorrhagic manifestations such as Ebola and hemorrhagic fever viruses, the coagulopathy seen with SARS-CoV-2 has not been reported to result in significant bleeding. We experienced stroke complications in two of our six cases with serious COVID-19. Therefore, we consider that the frequency of intracranial events is as not low as previously indicated, especially when the condition of COVID-19 patient progresses to the serious stage.
Several other hypotheses can be considered as the underlying mechanism of stroke in serious COVID-19 patients. First, including the cases we experienced in this series, serious COVID-19 patients exhibit multiple microthrombi formation in the peripheral vessels because elevated FDP/D-dimer is often observed, and are considered to be at high risk of cerebral infarction. Second, some severely ill patients with SARS-CoV-2 infection may have severe thrombocytopenia, a high-risk factor for cerebral hemorrhage. In addition, we believe that increased fibrinolysis associated with multiple microthrombi may be a risk factor for hemorrhagic cerebral infarction.
We speculate that neurologic injury will be another mechanism leading to stroke in patients with COVID-19. Researchers have reported the detection of SARS-CoV nucleic acids in cerebrospinal fluid samples from patients infected with respiratory viruses such as SARS and Middle East respiratory syndrome (MERS) as well as in their brain tissues such as glial cells and neurons on autopsy, which makes them a potential target for COVID-1916)-18). SARS-CoV-2 belongs to the same large family of coronaviruses as SARS-CoV and MERS-CoV, and may thus be able to enter the central nervous system via the hematogenous or retrograde neural pathways. The latter is supported by findings that SARS-CoV can lead to neuronal death in mice by invading the brain through the nose close to the olfactory epithelium18) and that some patients with COVID-19 have smell impairment19).
Similar to SARS-CoV, SARS-CoV-2 has been shown to interact with host angiotensin-converting enzyme (ACE) 2 receptor to invade inside cells. It was also demonstrated that the ACE2-binding affinity of the SARS-CoV-2 spike protein was 10–20 fold higher than that of the SARS-CoV spike protein20). After SARS-CoV-2 invades nerve cells and vascular endothelial cells, it damages these tissues, leading to fluctuations in vasoconstriction. For these reasons, there may be an increased risk of cerebrovascular disease in serious COVID-19 patients.
The following mechanism is considered a secondary factor. Serious COVID-19 patients frequently undergo V-V ECMO to avoid continuous hypoxemia. In our series, V-V ECMO was performed in all cases, except for Case 2 who was contraindicated for this intervention. Usually, a relatively high dose of anticoagulant is administered to prevent thrombus formation during V-V ECMO. Together with this factor, one of the main adverse events during ECMO is hemorrhage complications. During ECMO performance in a previous study, ≥ 50% of patients had bleeding complications and 3.8% experienced intracranial hemorrhage21). When we re-examined our serious COVID-19 patients who underwent V-V ECMO, UFH was used as an anticoagulant in the early stages of their management in the ICU. Cases 1, 3, and 4 fell into this category. In Cases 5 and 6, the anticoagulant was changed to nafamostat mesylate to avoid hemorrhagic complications as much as possible. As a result, no hemorrhagic complications were observed. Therefore, we conclude that use of UFH as an anticoagulant for V-V ECMO may have indirectly contributed to intracranial hemorrhage. When serious COVID-19 patients are administered UFH as an anticoagulant for V-V ECMO, the dose should be reduced below the usual dose and APTT, which is normally controlled at 60–80 s for monitoring the UFH dose, should be controlled at 40–60 s (or usually less than twice the upper limit)22)-24). To determine the dose of UFH more precisely, use of thromboelastography (TEG), such as TEG® or ROTEM® (rotational thromboelastometry), to accurately evaluate the blood coagulation fibrinolytic kinetics over time is one possible strategy. In addition, the dose of UFH should be adjusted frequently. Alternatively, the use of nafamostat mesylate, which has few hemorrhagic complications, as an anticoagulant may be considered. This is possible because nafamostat mesylate effectively blocks the early stages of SARS-CoV-2 infection by blocking the viral entry process through inhibition of fusion between the virus outer membrane and the cell membrane of SARS-CoV-2-infected host cells25).
In this series, four of six serious COVID-19 patients were diagnosed with DIC according to the JAAM DIC diagnostic criteria, and were administered rhsTM. In Japan, when attempting anticoagulant therapy for DIC, it is necessary to calculate DIC scores using DIC diagnostic criteria. In the most recent Japanese sepsis guidelines26), use of the JAAM DIC diagnostic criteria is recommended for diagnosis of DIC in patients with infection, especially sepsis. Furthermore, rhsTM is the most frequently used anticoagulant for treatment of DIC in Japan. Meanwhile, the DIC pattern in serious COVID-19 patients is not “suppressed-fibrinolysis type” abnormalities, but rather “enhanced-fibrinolysis type” abnormalities, and this pattern is different from the usual DIC pattern of infectious diseases. Therefore, the necessity of DIC treatment is also debated.
We decided to administer rhsTM to serious COVID-19 patients with DIC for the reasons described below. Use of rhsTM as an anticoagulant is a promising treatment strategy to safely rescue patients with APL from life-threatening coagulopathy27). APL is also a representative disease with the pattern of “enhanced-fibrinolysis type” coagulation/fibrinolysis abnormalities. Furthermore, resolution of DIC by rhsTM administration was reported to improve overall survival, regardless of disease severity, in patients with infectious diseases28). The reason why we choose rhsTM as an anticoagulant was that it only exhibits anticoagulant effects under conditions of thrombin over-production29), resulting in fewer adverse bleeding events. Furthermore, thrombin activatable fibrinolysis inhibitor, which is physiologically activated by the thrombin-thrombomodulin complex, down-regulates fibrinolysis and has the potential to regulate hyperfibrinolysis-induced hemorrhage30). Patients were administered rhsTM at 380 U/kg/day for around 1 week with daily evaluation of the JAAM DIC score. DIC was resolved in three of the four cases within ICU day 4, and the other one case complicated with cerebral hemorrhage (Case 3) had a score decrease to 4 and improved coagulation/fibrinolysis abnormalities. Therefore, we consider that the anticoagulant rhsTM is well worth using for serious COVID-19 patients who undergo V-V ECMO. However, in Case 3, FDP/D-dimer and PIC increased from the day after the end of rhsTM administration and TAT increased from the end of administration, resulting in recurrent coagulation/fibrinolysis abnormalities. Therefore, we suggest that rhsTM administration should be prolonged to prevent stroke in serious COVID-19 patients.
There are some limitations to the present study. First, the case series comprised only six patients and the study had a retrospective observational design. Second, ECMO was performed in all patients except one from the day of ICU admission, and anticoagulants such as UFH and nafamostat mesylate were administered to prevent blood clots in the ECMO circuit.