Microthrombi and use of tPA

Clinical Question

What evidence do we have for microthrombi as cause of poor perfusion / difficult oxygenation in severe COVID-19? What evidence for use of tPA?

Key Findings

  • Thrombosis is a common and increasingly recognized complication for critically ill COVID-19 patients, with evidence of large vessel and microvascular thrombi. [1][2][3]
  • Overactive coagulation is an important part of ARDS pathogenesis.[4]
  • Use of tPA has only been documented in a handful of COVID-19 cases, but previous success of fibrinolytics in ARDS treatment suggest that tPA should be considered as a “salvage treatment” for severe COVID-19 cases.[3][5][6]
  • The benefit of anticoagulation (mainly LMWH), measured by reduction in 28-day mortality, is mainly seen in those with significantly elevated D-dimer or signs of DIC/SIC.[7][8]
  • Most evidence supports the use of pharmacologic thromboprophylaxis for all hospitalized COVID-19 patients, especially in the ICU.[4][8][9][10]

Summary of Information

SARS was known to be associated with a hypercoagulable state and thrombotic complications.[11] There is now a growing body of literature that suggests coagulation dysfunction and thrombosis are common complications of critically ill COVID-19 patients as well, affecting up to a third of ICU patients in a Dutch study.[1] Coagulation dysfunction in COVID-19 patients is thought to be due to a combination of 1) damaged endothelial cells generating excess thrombin and reducing fibrinolysis and 2) hypoxia increasing blood viscosity and activating transcription factor-dependent signaling pathways.[7] Some studies have shown a reduction in 28-day mortality for those with significantly elevated D-dimer or signs of DIC who were treated with heparin.[7][8] Heparin has also been suggested as a good option for anticoagulation due to its additional anti-inflammatory properties.[4][9]

Coagulation dysfunction is also a predictor of poorer outcome and higher risk of progressing to ARDS.[4][12] A comparison of lab values from hospitalized COVID-19 survivors and non-survivors from the Tang et al paper can be seen in Table 1 below. Swiss and Italian guidelines recommend regular monitoring of PT, D-dimer, fibrinogen, platelet count, LDH, creatinine and ALT, with Italians additionally recommending DVT ultrasound screening.[10][13] Both societies also recommend pharmacological thromboprophylaxis but do not discuss treatment with tPA.

The use of tPA in COVID-19 patients is only documented in a handful of cases.[3][5] However coagulation is thought to be an important part of the ARDS pathogenesis, and fibrinolytics have previously been used for treatment in non-COVID-19 ARDS with some success.[4][6] In reports from a news article, two of the five treated patients died after seeing initial improvement, while three saw improvement in their oxygenation but remained on ventilators at the time of publication.[3] In a case series looking at 3 ventilated patients receiving tPA infusions, one saw initial improvement in P/F ratio before declining to pre-tPA levels and expiring, one saw modest improvement in P/F ratios that allowed a return from prone to supine positioning, and one saw initial improvement before returning to pre-tPA P/F levels.[5] None of the patients were taken off of ventilators by the time of publication. The pattern of initial improvement in oxygenation after administration of tPA supports the theory that thrombi play a role in the disease process. However, more data is needed to determine if tPA produces any long term benefits or reduction in mortality. A team at Harvard Medical School and Beth Israel Deaconess Medical Center is enrolling patients in a clinical trial to evaluate tPA as a treatment for ARDS in COVID-19 patients.[14]

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(NPC - Novel coronavirus pneumonia)
Table 1: 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. https://doi.org/10.1111/jth.14768

Gaps in knowledge

The utility of tPA in COVID-19 patients has yet to be determined. More data is needed on the use of tPA in COVID-19 patients, and the dosage and length of treatment have yet to be defined. A team at Harvard Medical School and Beth Israel Deaconess Medical Center is enrolling patients in a clinical trial to evaluate tPA as a treatment for ARDS in COVID-19 patients.[14]

Author Information

Authors: Natalie Oberhauser-Lim MS3; UC San Diego School of Medicine
Completed on: April 17, 2020
Last updated on: Not yet revised

Reviewed by: Marsha-Gail Davis MD
Reviewed on: N/A

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

  1. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020.  [PMID:32291094]
  2. Luo W, Yu H, Gou J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). February 2020. https://www.preprints.org/manuscript/202002.0407/v1. Accessed April 23, 2020.
  3. Neergaard L. Doctor gambles on clot-busting drug to save virus patients. AP NEWS. https://apnews.com/5c0dc863f214d32a53c6280c31cf3f56. Published April 11, 2020. Accessed April 15, 2020.
  4. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020;18(5):1020-1022.  [PMID:32239799]
  5. Wang J, Hajizadeh N, Moore EE, et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series. J Thromb Haemost. 2020.  [PMID:32267998]
  6. Moore HB, Barrett CD, Moore EE, et al. Is There a Role for Tissue Plasminogen Activator (tPA) as a Novel Treatment for Refractory COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS)? J Trauma Acute Care Surg. 2020.  [PMID:32281766]
  7. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.  [PMID:32220112]
  8. Yin S, Huang M, Li D, et al. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2020.  [PMID:32246317]
  9. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020.  [PMID:32282949]
  10. Casini A, Alberio L, Angelillo-Scherrer A, et al. Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19 - a Swiss consensus statement by the Working Party Hemostasis. Swiss Med Wkly. 2020;150:w20247.  [PMID:32277760]
  11. Umapathi T, Kor AC, Venketasubramanian N, et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol. 2004;251(10):1227-31.  [PMID:15503102]
  12. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847.  [PMID:32073213]
  13. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020.  [PMID:32281926]
  14. Mitchell J. Old Drug, New Treatment? Harvard, News and Research. https://hms.harvard.edu/news/old-drug-new-treatment. Published April 8, 2020. Accessed April 17, 2020.