We appreciate the opportunity to respond to the comments by Drs. Rad et al. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are widely used in many countries for the relief of symptoms of pain, inflammation, and fever, which reduce the conversion of arachidonic acid to prostaglandins, prostacyclin (PGI2), and thromboxane (Tx) A2 by inhibiting cyclooxygenase (COX). At present, it is recognized that there are two related but different types of COX activity, COX‐1 and COX‐2. COX‐1 is continuously expressed in most tissues, and platelets containing COX‐1 are the main source of TXA2,1 which affects vascular smooth muscle contraction and platelet aggregation.2 COX‐2 is mainly expressed in the inflammatory response and is the main source of PGI2.3 According to the different selectivity for COX inhibition, NSAIDs are divided into nonselective and COX‐2 selective. Ibuprofen is a type of nonselective NSAIDs.
As the authors said, several studies have confirmed that NSAIDs (including ibuprofen) are significantly associated with the occurrence of venous thromboembolism, especially in selective COX‐2 inhibitors, and are related to the dose and duration of administration, but the mechanism is not clear. The primary hypothesis is that NSAIDs may create an imbalance between PGI2 and TXA2, resulting in a relative increase in TXA2, leaving the body in a hypercoagulable state.4 Moreover, the reduction of prostaglandin leads to the decrease of thrombomodulin, which increases the incidence of thrombosis.5
During COVID‐19 treatment, the use of NSAIDs was very common. In addition to increasing the risk of thrombosis, NSAIDs (including ibuprofen) may also reduce host defense capability during infection.6 On the one hand, NSAIDs may mask the early symptoms of the disease, leading to delays in diagnosis and treatment; on the other hand, NSAIDs can inhibit the immune response of the body through a variety of ways, leading to disease progression.7 Even though some studies have shown that NSAIDs may be beneficial to patients with viral infection, it is still necessary to use them with great caution.
In the clinical diagnosis and treatment of novel coronavirus patients, more attention should be paid to the use and management of NSAIDs. Clinicians need to determine whether patients have a history of gastrointestinal ulcers and cardiovascular events, and avoid overdose or long‐term medication. Now, more research is really needed to determine the effects of NSAIDs on the incidence of venous thromboembolism and viral infection in novel coronavirus patients.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTIONS
All the authors participated in the coordination and drafting of the text. All the authors read and approved the final manuscript.
Footnotes
Songping Cui, Shuo Chen, and Lihui Ke are contributed equally.
Manuscript handled by: David Lillicrap.
Final decision: David Lillicrap, 21 May 2020.
REFERENCES
- 1.Funk C.D., Funk L.B., Kennedy M.E., Pong A.S., Fitzgerald G.A. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J. 1991;5:2304–2312. [PubMed] [Google Scholar]
- 2.Catella‐Lawson F., Crofford L.J. Cyclooxygenase inhibition and thrombogenicity. Am J Med. 2001;110(Suppl 3A):28S–32S. doi: 10.1016/s0002-9343(00)00683-5. [DOI] [PubMed] [Google Scholar]
- 3.McAdam B.F., Catella‐Lawson F., Mardini I.A., Kapoor S., Lawson J.A., FitzGerald G.A. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)‐2: the human pharmacology of a selective inhibitor of COX‐2. Proc Natl Acad Sci USA. 1999;96:272–277. doi: 10.1073/pnas.96.1.272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bergendal A., Adami J., Bahmanyar S., et al. Non‐steroidal anti‐inflammatory drugs and venous thromboembolism in women. Pharmacoepidemiol Drug Saf. 2013;22:658–666. doi: 10.1002/pds.3436. [DOI] [PubMed] [Google Scholar]
- 5.Rabausch K., Bretschneider E., Sarbia M., et al. Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX‐2‐derived prostaglandins. Circ Res. 2005;96:1–6. doi: 10.1161/01.RES.0000153150.27690.f2. [DOI] [PubMed] [Google Scholar]
- 6.Bancos S., Bernard M.P., Topham D.J., Phipps R.P. Ibuprofen and other widely used non‐steroidal anti‐inflammatory drugs inhibit antibody production in human cells. Cell Immunol. 2009;258:18–28. doi: 10.1016/j.cellimm.2009.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Capuano A., Scavone C., Racagni G., Scaglione F. Italian Society of Pharmacology. NSAIDs in patients with viral infections, including Covid‐19: victims or perpetrators? Pharmacol Res. 2020;157:104849. doi: 10.1016/j.phrs.2020.104849. [DOI] [PMC free article] [PubMed] [Google Scholar]