Skip to main content
Download PDF

Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis

Critical Care volume 24, Article number: 676 (2020) Cite this article

Abstract

Background

There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required.

Methods

We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients.

Results

Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction.

Conclusions

The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation.

Background

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has led to a global pandemic posing a major threat to humans [1]. More than 500 000 deaths related to COVID-19 have been so far reported [2].

SARS-CoV-2 primarily affects the respiratory system with a widely heterogeneous clinical presentation, ranging from none or minimal symptoms to significant hypoxia with viral pneumonia, potentially leading to severe acute respiratory distress syndrome (ARDS) and cytokine storm [3]. ARDS with related lung injury is considered one of the main causes of death in COVID-19 patients [4].

However, there is emerging evidence that involvement of other pathomechanisms contributes to morbidity and mortality. Both clinical and autopsy studies have revealed a high incidence of venous and arterial thromboembolic events, including pulmonary embolism, even in patients receiving therapeutic anticoagulation [5,6,7]. These findings have led to recommendations for higher anticoagulation targets; however, it remains unclear which patients are at increased risk and require anticoagulation [8]. While fibrinogen and D-dimer levels are frequently elevated, neither parameter reliably identifies patients at an increased risk of thromboembolic complications [8]. Although different markers of hypercoagulation have been reported among COVID-19 patients [6, 9], the exact mechanisms underlying the prothrombotic state in these patients remain unclear so far [10, 11]. In particular, it has not been clarified to which extent increased procoagulation and/or impaired fibrinolysis is involved.

In addition to conventional laboratory parameters, rotational thromboelastometry (ROTEM) provides evidence for net coagulation capacity and insight into clot formation time, clot firmness and fibrinolysis in the critically ill patients [12]. Here we report ROTEM data in 40 consecutive, severely ill COVID-19 patients treated in two tertiary intensive care units (ICUs) and assessed the association with thromboembolic complications.

Methods

Coagulation tests

After admission to our ICUs, blood samples were drawn and viscoelastic tests were performed once with citrated blood using a ROTEM sigma point-of-care device (Tem International, Munich, Germany) [13]. In each patient, intrinsically (contact activation, INTEM) and extrinsically (tissue factor activation, EXTEM) activated test assays were performed to analyze the clot dynamics in both coagulation pathways. Furthermore, FIBTEM and HEPTEM were performed. In the FIBTEM, platelets are inactivated with cytochalasin D to enable isolated evaluation of fibrinogen in clot firmness. The heparin effect was determined by comparing the clotting time of the INTEM with the clotting time of the HEPTEM, where heparinase is added.

The following ROTEM variables were analyzed: clotting time defined as the time until initiation of clotting; clot formation time (seconds until a clot strength reaches 20 mm), reflecting the kinetics of clot formation; maximum clot firmness (MCF) defined as the maximum amplitude of clot firmness; maximum lysis (ML; %) defined as the difference between MCF and the lowest clot amplitude after MCF, reflecting fibrinolytic activity (Fig. 1).

Fig. 1
figure 1

a All measured values in ROTEM analysis, including clotting time (CT [s]), clot formation time (CFT [s]), maximum clot firmness (MCF [mm]) and maximum lysis (ML [%(range)]). b A reduction of fibrinolysis in a COVID-19 patient with a thromboembolic event; the clot amplitude remains unchanged until the end. c A physiological fibrinolysis pattern in a healthy person, reflected by the subtle decrease of the MCF during the measurement

Full size image

Additional routine laboratory tests performed according to standardized protocols comprised hemoglobin concentration, white blood cell count, platelet count, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT) and inflammatory parameters (see Table 2). The levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen were determined using commercial ELISA Kits (t-PA Antigen ELISA Kit, PAI-1 Antigen ELISA Kit, Glu-Plasminogen, TECHNOZYM®/Technoclone).

To combine the parameters maximum D-dimers (mg/l) and ML (%), the difference (maximum D-dimers—ML EXTEM) was calculated and analyzed.

Anticoagulation therapy

In our Intensive care units, all patients included in this trial were treated with either low molecular weight heparin or in the case of ECMO therapy with argatroban. We aimed for a PTT of 50–55 s (normal 26–40 s), and in patients with thromboembolic events we aimed for a PTT of 60–80 s.

Ultrasound

We performed ultrasound examinations in all patients (GE Vivid S70 ultrasound machine with a 9L-D probe) to screen for venous thrombosis, focusing on the jugular, subclavian, brachial, femoral and popliteal veins upon admission to our ICU and subsequently at least once weekly.

Ethics

The study was approved by the ethics committees of Charité – Universitätsmedizin Berlin (EA4/115/20).

Statistics

Statistical analyses were performed using IBM® SPSS® Statistics version 26 (New York, USA). The descriptives are provided as median with limits of the interquartile range (IQR) for continuous variables or as absolute and relative frequencies for categorical variables.

Continuous data were primarily right skewed. Therefore, the Mann–Whitney U test was used to compare differences between patient groups in continuous variables, while Chi-square test was used for categorical data. A two-sided significance level of 0.05 was applied without adjustment for multiple comparison. All p values constitute exploratory data analyses and do not allow for confirmatory generalization of results. To evaluate the strength of different ROTEM variables to distinguish between patients with and without thromboembolic events, receiver operating characteristic (ROC) analysis was carried out including area under the curve measures (AUC) with 95% confidence intervals (CI). Sensitivity, specificity and accuracy (percentage of correctly classified patients) are reported.

Results

Characteristics of the cohort

Forty consecutive patients with COVID-19 confirmed by polymerase chain reaction in throat swabs were admitted to two ICUs within our department between March 25th and May 11th. All patients received viscoelastic testing using the ROTEM system and were included in the analysis, which was censored on May 11th.

Table 1 shows baseline characteristics of the study cohort. As most patients were referred from community hospitals within a regional network, patients were mostly severely ill with a median sequential organ failure assessment (SOFA) score of 9 and a mean acute physiology and chronic health evaluation (APACHE) II of 28 points. Mechanical ventilation via either endotracheal tube or tracheostomy was administered to 78% of patients, whereas extracorporeal membrane oxygenation was required for 25% and kidney replacement therapy for 53% of patients. Evidence for macrothromboembolic events was found in 23 of 40 patients (58%). In five patients, we identified thromboembolic events upon admission to our ICUs (N = 3 prediagnosed pulmonary emboli, N = 2 deep venous thrombosis). Nineteen patients developed thromboembolic complications during the ICU stay, comprising deep vein thrombosis (N = 14), pulmonary embolism (N = 4), ischemic stroke (N = 3), complete thrombosis of the ECMO-circuit requiring emergency circuit-change (N = 1) and a clotted ECMO cannula (N = 1).

Table 1 Patient characteristics of total cohort and subcohorts with and without thromboembolic events
Full size table

Laboratory parameters

Table 2 shows laboratory parameters for the study cohort and in patients with and without thromboembolic events. Hematological parameters were similar in both patient groups. Patients with thromboembolic events had a significantly higher maximum C-reactive protein (CRP) value, with a median value of 341 mg/l [IQR 261.1–370.7] versus 261.1 mg/l [IQR 175.3–312.9], respectively (p = 0.002). Other markers of inflammation such as procalcitonin (PCT), ferritin and interleukin-6 did not differ significantly between groups.

Table 2 Laboratory parameters of total cohort and subcohorts with and without thromboembolic events
Full size table

Analyses of the coagulation parameters revealed no significant differences between the groups with the exception of a prolonged PTT in the group with thromboembolic events. Patients had significantly elevated levels of fibrinogen without significant differences between groups.

Moreover, the median initial D-dimer levels were 4.84 mg/l [IQR 3.5–7.2] in the group with thromboembolic complications in comparison with 3.06 mg/l [IQR 2.3–3.9] in the group without thromboembolic complications (p = 0.003).

ROTEM parameters

Substantial abnormalities in the ROTEM analysis were found in the overall cohort. Maximum clot firmness in INTEM, EXTEM, FIBTEM and HEPTEM was markedly elevated in the entire cohort compared to reference values with median values of 74 mm [IQR 69–77], 75 mm [IQR 70.3–78], 34.5 mm [IQR 27.3–39.5] and 73 mm [IQR 67.5–75.3], respectively. Of note, there was no significant difference in these parameters between the subgroups with and without thromboembolic complications. However, the median clotting time detected in INTEM was significantly longer in the group of patients with thromboembolic complications: 215 s [IQR 197–251] versus 189 s [IQR 171.5–212]; p = 0.005. Clotting times in FIBTEM, EXTEM and HEPTEM showed no significant differences between groups.

Figure 2 depicts ML in INTEM and EXTEM. Under both conditions, ML was reduced and significantly lower in the group with thromboembolic complications (INTEM median 2% [IQR 0–3.0] versus 6% [IQR 2.5–6]; p = 0.001; EXTEM median 3% [IQR 0–5] versus 5% [IQR 3.5–8], p = 0.001), indicating substantially impaired fibrinolysis in both groups. This was observed to be more pronounced in patients with thromboembolic complications.

Fig. 2
figure 2

a Maximum lysis (ML) in EXTEM, b maximum lysis (ML) in INTEM, c D-dimers on the day of ROTEM and d max. CRP in COVID-19 patients with and without thromboembolic complications

Full size image

ROC analysis to distinguish patients with and without thromboembolic complications

Based on the above findings, we evaluated the potential of different ROTEM variables to distinguish between patients with and without thromboembolic events using ROC analysis (Fig. 3). Maximum lysis in EXTEM resulted in an area under the curve (AUC) of 0.8 [95% CI 0.7–0.9] for thromboembolic events (p = 0.001), while the ML in INTEM resulted in an AUC of 0.79 [95% CI 0.6–0.9] (p = 0.002). D-dimers showed an AUC of 0.78 [95% CI 0.6–0.9], and maximum D-dimers had an AUC of 0.82 [95% CI 0.7–1.0]. Combined analysis showed that the difference in D-dimers and ML EXTEM resulted in an AUC of 0.92 [95% CI 0.8–1].

Fig. 3
figure 3

ROC analysis of a maximum lysis (ML) in EXTEM, b D-dimer and c ML INTEM d difference of ML in EXTEM and max. D-dimer for prediction of thromboembolic events in our cohort [*AUC of 0·92 (p < 0.001)]

Full size image

Discussion

This study provides evidence that hypofibrinolysis is an important contributor to the hypercoagulable state in COVID-19 patients. Maximum lysis assessed in ROTEM analysis, especially in the EXTEM analysis, was reduced more profoundly in patients with thromboembolic events. Based on these observations, we propose that ROTEM analysis is useful for patient stratification according to their prothrombotic risk. In particular, combined consideration of ROTEM maximum lysis and D-dimers may identify patients that benefit from therapeutic anticoagulation.

In this small cohort of severely ill COVID-19 patients, we observed thromboembolic complications in more than 50% of patients. Analysis of routine coagulation parameters should be interpreted with caution, as many of the patients were treated with therapeutic anticoagulation. However, in accordance with previous studies, fibrinogen and factor VIII were elevated in our cohort and D-dimers were significantly elevated in the subgroup with thromboembolic complications [14]. Other conventional markers of the coagulation system showed no significant differences between the two groups.

In contrast to individual parameters, viscoelastic methods, such as thromboelastography and ROTEM, permit functional evaluations by recording most components of the coagulation process in vitro in the presence of cellular blood components. This provides insight into the different coagulation phases, including the initiation, formation and stabilization of a clot, and finally, clot lysis. The influence of the endothelium as an important co-factor of coagulation, however, is not directly reflected in ROTEM assessment. In several studies, hypercoagulable conditions were identified using ROTEM in disease states with an increased risk of thromboembolic events [15, 16]. Moreover, viscoelastic systems, such as ROTEM and thromboelastography, were successfully established to detect hypo- or hyperfibrinolysis in patients with traumatic injury or severe septic shock [17, 18].

Panigada et al. used thromboelastography in 20 patients with COVID-19 in addition to plasmatic tests of coagulation [19]. Similar to our study, they also found increased levels of fibrinogen and factor VIII, and almost normal routine coagulation tests. Thromboelastography data showed elevated clot firmness as reflected by maximal amplitude and reduced fibrinolysis measured as reduced clot lysis at 30 min (Lys 30), consistent with our observations. Spiezia and colleagues and Pavoni and co-workers also recently showed severe hypercoagulopathy in critically-ill COVID-19 patients using ROTEM [20, 21]. They found a significantly higher maximal clot firmness in INTEM, EXTEM and FIBTEM, and shorter INTEM clot formation time in comparison with a healthy control group. However, they observed no differences between COVID-19 patients with and without thrombosis [20]. In a cohort of 19 patients, Ibañez et al. noted markedly reduced fibrinolysis in COVID-19 patients; however, no distinction with respect to the presence of thromboembolic events was made [23].

While our findings confirm these results, we noted not only a markedly reduced fibrinolysis in the whole cohort but a significantly reduced ML in the group with thromboembolic complications. The clot lysis parameter ML provides information on the fibrinolytic activity, with low values providing evidence for hypofibrinolysis. In the current study, we found the ML in both EXTEM and INTEM to be markedly below normal values. Furthermore, the ML under both conditions was even lower in the group with thromboembolic complications. Therefore, we conclude that a severely impaired fibrinolysis plays an important role in the hypercoagulable state and thromboembolic risk in COVID-19 patients [23].

It is, however, somewhat surprising that highly elevated levels of D-dimers were found in a state of hypofibrinolysis. As a hypothesis, it has been suggested that intra-alveolar fibrin deposition accounts for local activation of fibrinolysis in ARDS.

The mechanisms leading to hypofibrinolysis in COVID-19 remain to be defined. Complex interactions between inflammation and the coagulation and fibrinolytic system have been examined and controversially discussed for decades [24,25,26]. One potential mechanism may be the production of alpha defense in neutrophils, which are known to promote fibrin polymerization and block fibrinolysis in vitro [27].

In our cohort, we found markedly elevated markers of inflammation, including interleukin-6, CRP and ferritin; however, only the maximum CRP level differed significantly between patients with and without thromboembolic complications. We could not detect significant differences among additional individual analytes (i.e., tPA or PAI concentrations) between both groups; however, we did not evaluate the effect of the complement or bradykinin system, which are both known to play crucial roles in connecting the inflammatory response and fibrinolytic activity. Future clinical trials should also focus on the role of thrombin-activatable fibrinolysis inhibitor (TAFI), plasmin-alpha-2-antiplasmin (PAP) complexes and antiplasmin, which would give valuable insights into the mechanisms of COVID-19-induced hypofibrinolysis. Furthermore, endothelial dysfunction is likely involved but was not assessed.

ROC analyses provided an AUC for ML in EXTEM of 0.8. As such, it might be a candidate as prediction marker of future thromboembolic complications. Zhou et al. reported D-dimers to be one of the most sensitive and specific factors predicting mortality in a large cohort of COVID-19-patients in China [14]. Cui et al. found a good sensitivity and specificity using a cutoff of 1.5 ng/ml for predicting thrombotic events in COVID-19 patients [8]. D-dimers were also markedly elevated in our cohort and were found to be significantly higher in the subgroup with thromboembolic events. ROC analysis for D-dimers revealed an AUC of 0.78. The combination of the maximum D-dimer and ML in EXTEM (D-dimer—ML) improved the AUC to 0.92, with a cutoff of 3.7 for a sensitivity of 94% and specificity > 90%. The predictive value of this D-dimer–ML parameter, however, requires validation in a second cohort.

In addition to providing insights in the mechanism of thrombus formation, our results may underline the possible therapeutic option of specific fibrinolytic therapy for ARDS caused by COVID-19. Administration of recombinant t-PA has already been suggested as a potential treatment and has shown promising results in a previous study independent of COVID-19 [28]. Currently, a phase IIa trial is underway to examine the effect of thrombolytics in COVID-19 patients with hypoxemic lung injury (ClinicalTrials.gov, NCT 04357730) [29].

There are several limitations to our study. First, ROTEM measurements were performed when patients were transferred to our ICUs after different treatment periods in other hospitals. Thus, the ROTEM results reflect different stages of the disease. Also, many, but not all patients, were previously treated with heparin when thromboelastometry measurements were performed. Second, the study is monocentric, performed in a tertiary care center, and the generalizability to other settings and patients with a less severe course and earlier stages of the disease needs to be tested. Third, our prediction models based on associations between poor clot lysis, D-dimers and the presence of thromboembolic events are hypotheses and require validation in independent patient cohorts and prospective observational studies. Fourth, thromboembolic events may have been underdiagnosed, as only ultrasound was routinely performed, while CT scans to exclude pulmonary embolism were only performed in some patients. Fifth, our results are descriptive in nature and do not provide explanatory models for the observed hypofibrinolysis. Future studies should focus on the examination of possible mechanisms.

Sixth, 25% of patients of our cohort received ECMO therapy, which may itself have had a thrombogenic effect and in part may have contributed to the high rates of thrombosis. However, the current literature points into the direction that in some cases ECMO rather leads to hyperfibrinolysis [30]. An ECMO-side effect as an explanation for a systematic hypofibrinolysis as observed in our cohort thus appears rather unlikely. Seventh, even though the statistical analysis showed robust values for our analysis, it may be difficult to guide clinical decision based on these values, as the difference in maximum lysis is 2%.

In summary, we found substantially reduced fibrinolysis in COVID-19 patients, which was more pronounced in patients with thromboembolic events. Clot ML time, as assessed by ROTEM as a single parameter, or in combination with D-dimers may prove valuable for thromboembolic risk stratification in COVID-19 patients and aid in decision-making regarding anticoagulation strategies.

Conclusions

ROTEM revealed severe hypofibrinolysis in COVID-19 patients. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. The combination of maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction. Hence, ROTEM may help to identify patients benefiting from therapeutic anticoagulation.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ROTEM:

Rotational thromboelastometry

COVID-19:

Coronavirus 2019

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

ARDS:

Acute respiratory distress syndrome

ICU:

Intensive care units

MCF:

Maximum clot firmness

ML:

Maximum lysis

PT:

Prothrombin time

INR:

International normalized ratio

aPTT:

Activated partial thromboplastin time

t-PA:

Tissue-type plasminogen activator

PAI-1:

Plasminogen activator inhibitor-1

IQR:

Interquartile range

ROC:

Receiver operating characteristic

AUC:

Area under the curve

CI:

Confidence intervals

PCT:

Procalcitonin

CRP:

C-reactive protein

References

  1. Jin Y, Yang H, Ji W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020;12:372.

    Article  CAS  Google Scholar 

  2. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20:533–4.

    Article  CAS  Google Scholar 

  3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China Lancet. 2020;395:497–506.

    Article  CAS  Google Scholar 

  4. Zangrillo A, Beretta L, Scandroglio AM, et al. Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy. Crit Care Resusc. 2020.

  5. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9–14.

    Article  CAS  Google Scholar 

  6. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;4:1–10.

    Google Scholar 

  7. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020;18:1743–6.

    Article  CAS  Google Scholar 

  8. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18:1421–4.

    Article  CAS  Google Scholar 

  9. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382:e38.

    Article  Google Scholar 

  10. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–7.

    Article  CAS  Google Scholar 

  11. Becker RC. COVID-19 update: Covid-19-associated coagulopathy. J Thromb Thrombolysis. 2020;50:54–67.

    Article  CAS  Google Scholar 

  12. Fletcher TE, Leblebicioglu H, Bozkurt I, et al. Rotational thromboelastometry alongside conventional coagulation testing in patients with Crimean-Congo haemorrhagic fever: an observational cohort study. Lancet Infect Dis. 2019;19:862–71.

    Article  Google Scholar 

  13. Gorlinger K, Bhardwaj V, Kapoor PM. Simulation in coagulation testing using rotational thromboelastometry: a fast emerging, reliable point of care technique. Ann Card Anaesth. 2016;19:516–20.

    Article  Google Scholar 

  14. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.

    Article  CAS  Google Scholar 

  15. Hincker A, Feit J, Sladen RN, Wagener G. Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. Crit Care. 2014;18:549.

    Article  Google Scholar 

  16. Akay OM, Ustuner Z, Canturk Z, Mutlu FS, Gulbas Z. Laboratory investigation of hypercoagulability in cancer patients using rotation thrombelastography. Med Oncol. 2009;26:358–64.

    Article  Google Scholar 

  17. Schmitt FCF, Manolov V, Morgenstern J, et al. Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care. 2019;9:19.

    Article  Google Scholar 

  18. Schochl H, Frietsch T, Pavelka M, Jambor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma. 2009;67:125–31.

    Article  Google Scholar 

  19. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18:1738–42.

    Article  CAS  Google Scholar 

  20. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost. 2020;120:998–1000.

    Article  Google Scholar 

  21. Pavoni V, Gianesello L, Pazzi M, Stera C, Meconi T, Frigieri FC. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb Thrombolysis. 2020;50:1–6.

    Article  Google Scholar 

  22. Ibanez C, Perdomo J, Calvo A, et al. High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there? J Thromb Thrombolysis. 2020;15:1–5.

    Google Scholar 

  23. Roberts I. Fibrinolytic shutdown: fascinating theory but randomized controlled trial data are needed. Transfusion. 2016;56(Suppl 2):S115–8.

    Article  Google Scholar 

  24. Lupu F, Keshari RS, Lambris JD, Coggeshall KM. Crosstalk between the coagulation and complement systems in sepsis. Thromb Res. 2014;133(Suppl 1):S28-31.

    Article  Google Scholar 

  25. Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost. 2007;5(Suppl 1):24–31.

    Article  CAS  Google Scholar 

  26. Gando S, Wada H, Thachil J. Scientific, Standardization Committee on DICotISoT, Haemostasis. Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013;11:826–35.

    Article  CAS  Google Scholar 

  27. Abu-Fanne R, Stepanova V, Litvinov RI, et al. Neutrophil alpha-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability. Blood. 2019;133:481–93.

    Article  CAS  Google Scholar 

  28. Hardaway RM, Harke H, Tyroch AH, Williams CH, Vazquez Y, Krause GF. Treatment of severe acute respiratory distress syndrome: a final report on a phase I study. Am Surg. 2001;67:377–82.

    CAS  PubMed  Google Scholar 

  29. Barrett CD, Moore HB, Moore EE, et al. Fibrinolytic therapy for refractory COVID-19 acute respiratory distress syndrome: Scientific rationale and review. Res Pract Thromb Haemost. 2020;4:524–31.

    Article  CAS  Google Scholar 

  30. Durila M, Smetak T, Hedvicak P, Berousek J. Extracorporeal membrane oxygenation-induced fibrinolysis detected by rotational thromboelastometry and treated by oxygenator exchange. Perfusion. 2019;34:330–3.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Open Access funding enabled and organized by Projekt DEAL. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. Jan Matthias Kruse and Abakar Magomedov have contributed equally to this work

Authors and Affiliations

  1. Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Jan Matthias Kruse, Frédéric H. Münch, Roland Koerner, Andreas Kahl, Inka Gotthardt, Kai-Uwe Eckardt & Daniel Zickler

  2. Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Abakar Magomedov

  3. Department of Hematology and Oncology, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Annika Kurreck

  4. Institute for Transfusion Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Julian Kamhieh-Milz

  5. Wimedko GmbH, Berlin, Germany

    Julian Kamhieh-Milz

  6. Institute of Biometry and Clinical Epidemiology, Charité – Universitätmedizin Berlin, Berlin, Germany

    Sophie K. Piper

  7. Berlin Institute of Health (BIH), Berlin, Germany

    Sophie K. Piper

  8. Department of Rheumatology Und Clinical Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Thomas Dörner

  9. Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany

    Thomas Dörner

Authors
  1. Jan Matthias Kruse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abakar Magomedov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annika Kurreck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frédéric H. Münch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roland Koerner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julian Kamhieh-Milz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andreas Kahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Inka Gotthardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sophie K. Piper
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kai-Uwe Eckardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Dörner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daniel Zickler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study was designed by Dr. Zickler and Dr. Kruse. Dr. Magomedov, Dr. Kamhieh-Milz, Dr. Körner and Dr. Kahl contributed to study design, data collection, data analyses and interpretation, Dr. Münch and Dr. Kurreck performed data collection. Dr. Piper performed statistical analyses. Dr. Dörner contributed to study design and interpretation. Drs. Zickler, Eckardt and Gotthardt wrote the first draft of the manuscript and revised subsequent versions. All authors read and approved the final manuscript..

Corresponding author

Correspondence to Daniel Zickler.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the ethics committees of Charité – Universitätsmedizin Berlin (EA4/115/20).

Consent for publication

Not applicable.

Competing interests

Dr. Kruse, Dr. Magomedov, Dr. Kurreck, Dr. Münch, Dr. Koerner, Dr. Kamhieh-Milz, Dr. Kahl, Dr. Piper and Dr. Dörner have nothing to disclose. Dr. Eckardt reports personal fees from Akebia, grants from Amgen, grants from Astra Zeneca, grants and personal fees from Bayer, grants from Fresenius, from Genzyme, from Shire and grants and personal fees from Vifor, outside the submitted work. Dr. Zickler reports grants and personal fees from Baxter, outside the submitted work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kruse, J.M., Magomedov, A., Kurreck, A. et al. Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis. Crit Care 24, 676 (2020). https://doi.org/10.1186/s13054-020-03401-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13054-020-03401-8

Keywords

Critical Care

ISSN: 1364-8535