Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent.
Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed.
A combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.
Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6 (IL-6), and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays [
The NHS Institutional Review Board waived the requirement of informed consent from each patient.
A 48-year-old South Asian woman (Patient A) from Bangladesh (height 168 cm, weight 80 kg) was admitted to the medical ward for three days after which she was transferred to the ICU; she had cough and increasing dyspnea for three days before hospital admission. Comorbidities included hypertension, hypercholesterinemia, coronary artery disease, previous stroke (fully recovered), and type 2 diabetes. On admission, her laboratory results were as follows: hemoglobin (Hb): 143 g/L, white blood cells (WBC): 9.0 × 109/L, lymphocytes: 1.4 × 109/L, platelets: 261 × 109/L, international normalized ratio (INR): 1.1, D-dimer: 510 μg/L, fibrinogen plasma concentration: 8.4 g/L, and C-reactive protein (CRP): 52 mg/L. Her chest radiograph showed cardiomegaly and extensive bilateral peripherally predominant ground-glass opacities. Polymerase chain reaction (PCR) result was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and negative for influence/respiratory syncytial virus (RSV). Blood cultures were negative. The patient was treated with nasal oxygen therapy and antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. Later, CRP increased to 137 mg/L on the second day of hospitalization. The patient was transferred to the ICU on the third day because of increased respiratory rate and oxygen requirement. ROTEM performed 2 hours after ICU admission (
A 68-year-old Caucasian man (Patient B) from the United Kingdom (height 177 cm, weight 85 kg) was admitted with cough and a week-long increasing dyspnea, before which he was healthy. His wife and daughter probably had COVID-19 with resolving symptoms, and they were all living in the same house. The patient markedly experienced shortness of breath on the day of admission to the emergency department (ED) and, therefore, called an ambulance. His laboratory results on admission were as follows: Hb: 140 g/L, creatinine: 117 μmol/L, WBC: 8.6 × 109/L, lymphocytes: 0.2 × 109/L, platelet count: 126 × 109/L, INR: 1.4, APTT ratio: 1.3, D-dimer > 20,000 μg/L (i.e., higher than the upper limit of the measurement range), fibrinogen plasma concentration: 6.8 g/L, and CRP: 336 mg/L. His chest radiograph showed dense bilateral mid-zone and right lower zone consolidation. PCR result was positive for SARS-CoV-2 and negative for influenza/RSV. Blood cultures showed coagulase-negative staphylococci. The patient was treated with antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. As the patient was severely hypoxemic in the ED, he was transferred directly to the ICU. Orotracheal intubation and IPPV (positive end-expiratory pressure 15 mmHg) were performed about 3 hours after ICU admission as respiratory effort was not improved by face mask CPAP therapy. Chest radiography repeated after intubation showed bilateral interstitial lung changes similar to the imaging conducted earlier on the same day. Prone position did not improve oxygenation. Laboratory results on the next day were as follows: Hb: 133 g/L, creatinine: 265 μmol/L, WBC: 16.3 × 109/L, platelet count: 56 × 109/L, INR: 1.6, APTT ratio: 1.5, D-dimer: 4,340 μg/L, fibrinogen plasma concentration: 2.9 g/L, and CRP: 478 mg/L. By ROTEM, Patient B presented with hypocoagulability in the EXTEM assay with a prolonged CT of 99 s, clot formation time (CFT) of 253 s, and decreased clot firmness amplitudes (A5, 22 mm and MCF, 48 mm) (
We have presented two cases that illustrate the additional value of using thromboelastometry to monitor patients with COVID-19. Increased clot firmness in EXTEM and INTEM (amplitude of clot firmness 10 minutes after CT (A10) > 61.5 mm or MCF > 68 mm) assays has been shown to be associated with an increased incidence of thrombosis in adults and neonates undergoing cardiac and non-cardiac surgery [
The case of Patient B demonstrated that not all critically ill patients with COVID-19 present the same thromboelastometric pattern. This might be attributed to ethnic and genetic difference, such as gene polymorphisms, bacterial superinfection, or the phase of the disease. Both hypocoagulability and fibrinolysis shutdown, as presented by Patient B, have been shown to be associated with increased mortality in cases involving bacterial sepsis [
Nevertheless, this case report has several limitations. First, no follow-up ROTEM analyses are available for these patients. Accordingly, the presented ROTEM analyses only represent a snapshot of the COVID-19-associated coagulopathy that can be considered as a dynamic process. Here, different thromboelastometric phenotypes may represent different conditions of the patients or different phases of the coagulopathy. Second, the cut-off values for fibrinolysis shutdown established in trauma and bacterial sepsis cases have been used as clear cut-off values for fibrinolysis shutdown in COVID-19-associated coagulopathy have not been established yet. Further studies are needed to characterize COVID-19-associated coagulopathy and its differences from trauma- and sepsis-induced coagulopathy.
These two cases demonstrate that the thromboelastometric phenotype can be different and thromboelastometry can easily distinguish between hyper- and hypocoagulability in critically ill patients with COVID-19. Furthermore, thromboelastometry can identify patients with fibrinolysis shutdown [
Klaus Görlinger is working as the Medical Director of Tem Innovations since July 2012. Robert Kong and Nevil Hutchinson reported no potential conflict of interest relevant to this article.
Robert Kong (Conceptualization; Investigation; Writing – review & editing)
Nevil Hutchiinson (Conceptualization; Investigation; Writing – review & editing)
Klaus Görlinger (Conceptualization; Writing – original draft)
ROTEM graphs and results of Patient A and Patient B. (A) Critically ill Patient A with COVID-19, with a hypercoagulable phenotype. (B) Critically ill Patient B with COVID-19 with a hypocoagulable phenotype. EXTEM: extrinsically activated (tissue factor) thromboelastometric assay, FIBTEM: extrinsically activated thromboelastometric assay with the addition of cytochalasin to eliminate platelet contribution to clot firmness, CT: coagulation time, CFT: clot formation time, alpha: alpha angle, A5: amplitude of clot firmness 5 minutes after CT, A10: amplitude of clot firmness 10 minutes after CT, MCF: maximum clot firmness, LI60: lysis index in percentage of maximum clot firmness 60 minutes after CT, ML: maximum lysis during run time, *Reference range for physiological fibrinolysis in EXTEM as published by Stettler et al. [