Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Janusz Sielski
 -- 1366 2022-11-05 14:00:31 |
2 format corrected.
Beatrix Zheng
 Meta information modification 1366 2022-11-07 04:13:08 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Zając, P.;  Kaziród-Wolski, K.;  Oleś, I.;  Sielski, J.;  Siudak, Z. Fibrinolysis for Patients with COVID-19. Encyclopedia. Available online: https://encyclopedia.pub/entry/33129 (accessed on 17 November 2024).
Zając P,  Kaziród-Wolski K,  Oleś I,  Sielski J,  Siudak Z. Fibrinolysis for Patients with COVID-19. Encyclopedia. Available at: https://encyclopedia.pub/entry/33129. Accessed November 17, 2024.
Zając, Patrycja, Karol Kaziród-Wolski, Izabela Oleś, Janusz Sielski, Zbigniew Siudak. "Fibrinolysis for Patients with COVID-19" Encyclopedia, https://encyclopedia.pub/entry/33129 (accessed November 17, 2024).
Zając, P.,  Kaziród-Wolski, K.,  Oleś, I.,  Sielski, J., & Siudak, Z. (2022, November 05). Fibrinolysis for Patients with COVID-19. In Encyclopedia. https://encyclopedia.pub/entry/33129
Zając, Patrycja, et al. "Fibrinolysis for Patients with COVID-19." Encyclopedia. Web. 05 November, 2022.
Fibrinolysis for Patients with COVID-19
Edit
This entry is adapted from the peer-reviewed paper 10.3390/jcdd9100356

An impaired fibrinolytic process has been demonstrated in patients infected with SARS-CoV-2, including those in severe or critical condition. Disruption of fibrinolysis leads to fibrin deposition, which exacerbates inflammation and fibrosis and damages the pulmonary surfactant. Numerous authors point out the different course of coagulopathy in patients with COVID-19. It is reported that they may have a state of secondary hyperfibrinolysis, which may explain, at least in part, the increased incidence of venous thromboembolism, even among those patients already receiving appropriate anticoagulant treatment. This raises the question of whether current guidelines for the prevention and treatment of embolic–thrombotic complications, among patients with severe COVID-19, are sufficient. Some studies show evidence of clinical improvement in patients who have received fibrinolytic therapy, beyond the current indications for its implementation. 

fibrinolysis COVID-19 venosus thromboembolism pulmonary embolism

1. Fibrinogen

Fibrinogen, produced by the liver, is an important protein involved in the final step of blood clotting. After conversion to fibrin via a reaction with thrombin, fibrinogen forms an insoluble clot to prevent bleeding. Fibrinogen is also an acute-phase protein. Its elevated levels are found in patients with infections, injuries, cancer, stress-related disorders and increased cardiovascular disease (CVD) mortality [1][2]. During Coronavirus Disease 2019 (COVID-19) infection, a mean fibrinogen concentration around the upper limit of normal was observed, while patients who died showed a sudden reduction in fibrinogen before death [3][4]. Li et al. [5] studied hematological covariates in 1449 hospitalized patients with COVID-19. At baseline, patients who died had higher fibrinogen levels than survivors (median, 4.3 g/L (interquartile range [IQR], 3.2–5.2 g/L) vs. 3.6 g/L (IQR, 2.9–4.5 g/L)), but they had lower minimum fibrinogen levels (2.6 g/L (IQR, 1.7–3.9 g/L)) vs. 3.2 g/L (IQR, 2.6–3.9 g/L) [5]. The authors concluded that the dynamic changes in fibrinogen levels are correlated with the risk of death in patients with COVID-19. While fibrinogen testing is not routinely performed in all COVID-19 patients on admission to the hospital [6], this parameter might be useful in the early assessment of coagulation in this population.

2. Fibrinolysis

Fibrinolysis is a normal body process that is an integral part of the hemostatic system. The activation of the fibrinolytic cascade results in fibrin degradation. Fibrinolysis is regulated by numerous enzymes, with plasmin being the key enzyme involved in the fibrinolytic system. Plasmin is responsible for the lysis of the fibrin clot, thus producing fibrin degradation products. Thrombin is also an important enzyme in the regulation of the coagulation system. Endogenous fibrinolysis is also strongly linked to thrombin, an enzyme responsible for significant resistance to fibrinolysis. High thrombin levels act as a potent platelet activator and facilitate the formation of stable clots by converting fibrinogen into fibrin, which binds platelets together. Moreover, thrombin inhibits endogenous fibrinolysis by activating thrombin-activatable fibrinolysis inhibitor, which prevents the binding and activation of plasminogen into plasmin [7]. Finally, it indirectly inhibits endogenous fibrinolysis by releasing plasminogen activator inhibitor-1 (PAI-1) from platelets, a principal inhibitor of tissue plasminogen activator (tPA) [7].

3. Fibrinolysis and COVID-19

An impaired fibrinolytic process has been demonstrated in patients infected with SARS-CoV-2 with interstitial lung disease, including critically ill patients [8][9][10]. Hypercoagulation in these patients is a complex and multifactorial process. SARS-CoV-2 enters the cells via the angiotensin-converting enzyme 2 (ACE2) receptor. It is considered that with SARS-CoV-2 virus attachment, excess angiotensin increases the expression of PAI-1, which inhibits fibrinolysis on endothelial cells [3][11]. Patients with interstitial lung disease were also reported to have elevated levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor (plasminogen activator inhibitor-3) [9]. SARS-CoV-2 infection leads to acute inflammation, which leads to an increase in bradykinin and tPA. However, increased tPA levels are not sufficient to counterbalance the high levels of PAI-1, which likely explains the impaired fibrinolysis and fibrin accumulation in the lung alveoli [12]. Fibrin deposits enhance inflammation and fibrosis, and lead to lung surfactant damage [9].

4. Role of Plasmin in COVID-19

Plasmin is the major fibrinolytic protease. In their review article, Hong-Long et al. [13] summarized the current evidence for the presence of elevated plasmin levels in COVID-19 patients with hypertension, diabetes, coronary artery disease, cerebrovascular disorders, chronic obstructive pulmonary disease and kidney dysfunction. Plasmin, along with other proteases, may contribute to increased SARS-CoV-2 infectivity, and antiproteases targeting the plasmin(ogen) system may be a promising therapeutic option in patients with COVID-19 [13]. There is also an increasing body of evidence that systemic fibrinolysis may be an effective therapeutic approach in critically ill patients with COVID-19 [12][13][14]. Medcalf et al. [15] described the so-called plasmin paradox in patients with COVID-19, wherein plasmin formation can be either harmful or beneficial, although not at the same time. The authors suggested that an appropriate therapeutic approach aimed either at promoting or inhibiting fibrinolytic activity depends on the severity of infection. In patients with mild or moderate infection, suppression of fibrinolysis may reduce the amount of the virus and improve the immune response. On the other hand, activation of the fibrinolytic system may be protective in severe cases [15]. These conclusions may have important implications for management decisions in patients with COVID-19.

5. Fibrinolysis in Critically Ill Patients with COVID-19: Yes or No?

Considering that coagulopathy in patients with COVID-19 has different features that have not been fully understood so far, clinicians have made attempts to use different treatment options, including fibrinolysis. Della Bona et al. [14] reported a case series of four patients who developed PE despite heparin use, including during treatment with sodium heparin. In most cases, systemic fibrinolysis with alteplase proved effective. Other authors also reported clinical improvement in critically ill patients with COVID-19 after fibrinolytic therapy [14][16][17][18]. It is suspected that pulmonary microemboli may contribute to respiratory failure in patients with COVID-19. Therefore, tPA therapy may offer clinical benefits in these patients [17][19], including those with comorbidities [20]. In a retrospective study in critically ill patients with COVID-19, So et al. [21] administered tPA to patients with a suspicion of PE. tPA infusion was associated with an improvement in 49.1% of patients. All-cause mortality in this population was 89.5% [21].
Plasminogen may be another interesting therapeutic agent in the fight against COVID-19. In a study by Della-Morte et al. [22], patients with COVID-19 with low plasminogen levels showed a 12-fold higher risk of mortality than COVID-19 patients with normal or high plasminogen levels (odds ratio, 12.57; 95% CI, 2.46–64.0; β = 2.53; p = 0.002). Wu et al. [23] studied the effect of atomization inhalation with freeze-dried plasminogen in patients with moderate to severe COVID-19. They showed that additional plasminogen may be effective in treating lung lesions and hypoxemia in these patients. The authors concluded that while further studies are needed, this fibrinolytic agent may be an adequate therapeutic option in this population of patients [23].
Consideration of systemic fibrinolysis should always involve a careful risk-to-benefit assessment in terms of possible adverse events. The risk of bleeding in COVID-19 patients was reported at 4.8%, with a slightly higher risk of 7.6% in those with critical disease [24]. Moreover, the initial enthusiasm as to the continuation of fibrinolytic therapy in critically ill patients with COVID-19 was dampened by the results of a randomized clinical trial in patients receiving thrombolytic therapy. Based on preliminary findings, thrombolytic therapy does not improve oxygenation in these patients. Moreover, major bleeding was reported in 10.2% of patients within 7 days of the infusion of recombinant tPA, while concomitant anticoagulation and tPA resulted in a higher risk of bleeding (in 5 of 6 patients with major bleeding) [25]. On the other hand, coagulopathy in critically ill patients with COVID-19 has prothrombotic potential. A large, multicenter, randomized controlled trial showed that the combination of tPA bolus and heparin is safe in COVID-19 patients with severe respiratory failure. None of the patients experienced major bleeding, including intracranial bleeding, although the authors noted that this might have been due to the careful patient selection [26].
Thus, based on current knowledge, it is difficult to conclusively answer the question of whether the routine use of fibrinolysis in COVID-19 patients with a severe course and/or with coexisting pulmonary embolism in hemodynamically stable patients is warranted.
Nevertheless, the distinct features of coagulopathy in this patient population have been well described. It is possible that the point-of-care testing with thromboelastography and rotational thromboelastometry could be helpful in selecting candidates for fibrinolytic therapy. Although the general vaccination program and virus evolution have changed the dynamics of the pandemic, the large discrepancies in the current literature necessitate further research to clarify treatment recommendations for patients with severe COVID-19.

References

  1. Koenig, W. Fibrinogen and coronary risk. Curr. Cardiol. Rep. 1999, 1, 112–118.
  2. Pieters, M.; Ferreira, M.; de Maat, M.P.M.; Ricci, C. Biomarker association with cardiovascular disease and mortality—The role of fibrinogen. A report from the NHANES study. Thromb. Res. 2021, 198, 182–189.
  3. Meizoso, J.P.; Moore, H.B.; Moore, E.E. Fibrinolysis Shutdown in COVID-19: Clinical Manifestations, Molecular Mechanisms, and Therapeutic Implications. J. Am. Coll. Surg. 2021, 232, 995–1003.
  4. 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, 844–847.
  5. Li, Q.; Cao, Y.; Chen, L.; Wu, D.; Yu, J.; Wang, H.; He, W.; Chen, L.; Dong, F.; Chen, W.; et al. Hematological features of persons with COVID-19. Leukemia 2020, 34, 2163–2172.
  6. Thachil, J.; Tang, N.; Gando, S.; Falanga, A.; Cattaneo, M.; Levi, M.; Clark, C.; Iba, T. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J. Thromb. Haemost. 2020, 18, 1023–1026.
  7. Kanji, R.; Gue, Y.X.; Memtsas, V.; Gorog, D.A. Fibrinolysis in Platelet Thrombi. Int. J. Mol. Sci. 2021, 22, 5135.
  8. Bachler, M.; Bösch, J.; Stürzel, D.P.; Hell, T.; Giebl, A.; Ströhle, M.; Klein, S.J.; Schäfer, V.; Lehner, G.F.; Joannidis, M.; et al. Impaired fibrinolysis in critically ill COVID-19 patients. Br. J. Anaesth. 2021, 126, 590–598.
  9. Boknäs, N.; Laine, C.; Hillarp, A.; Macwan, A.S.; Gustafsson, K.M.; Lindahl, T.L.; Holmström, M. Associations between hemostatic markers and mortality in COVID-19—Compounding effects of D-dimer, antithrombin and PAP complex. Thromb. Res. 2022, 213, 97–104.
  10. Whyte, C.S.; Morrow, G.B.; Mitchell, J.L.; Chowdary, P.; Mutch, N.J. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J. Thromb. Haemost. 2020, 18, 1548–1555.
  11. Coccheri, S. COVID-19: The crucial role of blood coagulation and fibrinolysis. Intern. Emerg. Med. 2020, 15, 1369–1373.
  12. Manzoor, D.; Bui, C.; Makhoul, E.; Luthringer, D.; Marchevsky, A.; Volod, O. Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression: Case reports. Medicine 2021, 100, e25255.
  13. Ji, H.L.; Zhao, R.; Matalon, S.; Matthay, M.A. Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility. Physiol. Rev. 2020, 100, 1065–1075.
  14. Della Bona, R.; Valbusa, A.; La Malfa, G.; Giacobbe, D.R.; Ameri, P.; Patroniti, N.; Robba, C.; Gilad, V.; Insorsi, A.; Bassetti, M.; et al. Systemic fibrinolysis for acute pulmonary embolism complicating acute respiratory distress syndrome in severe COVID-19: A case series. Eur. Heart J. Cardiovasc. Pharmacother. 2021, 7, 78–80.
  15. Medcalf, R.L.; Keragala, C.B.; Myles, P.S. Fibrinolysis and COVID-19: A plasmin paradox. J. Thromb. Haemost. 2020, 18, 2118–2122.
  16. Barrett, C.D.; Moore, H.B.; Moore, E.E.; Benjamin Christie, D., 3rd; Orfanos, S.; Anez-Bustillos, L.; Jhunjhunwala, R.; Hussain, S.; Shaefi, S.; Wang, J.; et al. MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study. Res. Pract. Thromb. Haemost. 2022, 6, e12669.
  17. Ghia, S.; Bhatt, H.; Lazar, M. Role of Tissue Plasminogen Activator for Diffuse Pulmonary Microemboli in Coronavirus Disease 2019 Patient. J. Cardiothorac. Vasc. Anesth. 2021, 35, 2137–2139.
  18. Wang, J.; Hajizadeh, N.; Moore, E.E.; McIntyre, R.C.; Moore, P.K.; Veress, L.A.; Yaffe, M.B.; Moore, H.B.; Barrett, C.D. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series. J. Thromb. Haemost. 2020, 18, 1752–1755.
  19. Poor, H.D.; Ventetuolo, C.E.; Tolbert, T.; Chun, G.; Serrao, G.; Zeidman, A.; Dangayach, N.S.; Olin, J.; Kohli-Seth, R.; Powell, C.A. COVID-19 Critical Illness Pathophysiology Driven by Diffuse Pulmonary Thrombi and Pulmonary Endothelial Dysfunction Responsive to Thrombolysis. Clin. Transl. Med. 2020, 10, e44.
  20. Sehgal, T.; Gupta, N.; Kohli, S.; Khurana, A.; Dass, J.; Diwan, S.; Mahendran, A.J.; Khan, M.; Aggarwal, M.; Subramanian, A. A Prospective Study of Specialized Coagulation Parameters in Admitted COVID-19 Patients and Their Correlation With Acute Respiratory Distress Syndrome and Outcome. Cureus 2021, 13, e17463.
  21. So, M.; Steiger, D.J.; Takahashi, M.; Egorova, N.N.; Kuno, T. The characteristics and outcomes of critically Ill patients with COVID-19 who received systemic thrombolysis for presumed pulmonary embolism: An observational study. J. Thromb. Thrombolysis 2021, 52, 1061–1067.
  22. Della-Morte, D.; Pacifici, F.; Ricordi, C.; Massoud, R.; Rovella, V.; Proietti, S.; Iozzo, M.; Lauro, D.; Bernardini, S.; Bonassi, S.; et al. Low level of plasminogen increases risk for mortality in COVID-19 patients. Cell Death Dis. 2021, 12, 773.
  23. Wu, Y.; Wang, T.; Guo, C.; Zhang, D.; Ge, X.; Huang, Z.; Zhou, X.; Li, Y.; Peng, Q.; Li, J. Plasminogen improves lung lesions and hypoxemia in patients with COVID-19. QJM Int. J. Med. 2020, 113, 539–545.
  24. Zuo, Y.; Warnock, M.; Harbaugh, A.; Yalavarthi, S.; Gockman, K.; Zuo, M.; Madison, J.A.; Knight, J.S.; Kanthi, Y.; Lawrence, D.A. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci. Rep. 2021, 11, 1580.
  25. Available online: https://nil.org.pl/aktualnosci/5395-tromboprofilaktyka-i-leczenie-przeciwkrzepliwe-u-doroslych-chorych-hospitalizowanych-z-powodu-covid-19 (accessed on 24 March 2021).
  26. Rashidi, F.; Barco, S.; Rezaeifar, P.; Sadeghipour, P.; Ghodrati, S.; Bakhshandeh, H.; Mousavi-Aghdas, S.A.; Sadeghi, A.; Sharifi, A.; Valizadeh, H.; et al. Tissue plasminogen activator for the treatment of adults with critical COVID-19: A pilot randomized clinical trial. Thromb. Res. 2022, 216, 125–128.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Patrycja Zając
,
Karol Kaziród-Wolski
,
Izabela Oleś
,
Janusz Sielski
,
Zbigniew Siudak
View Times: 588
Revisions: 2 times (View History)
Update Date: 07 Nov 2022
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback