ZHANG Mina,XU Xiaolong,LIU Qingquan

ZHANG Mina,Beijing Hospital of Traditional Chinese Medicine,Capital Medical University,Beijing 100010,China;Beijing Institute of Traditional Chinese Medicine,Beijing 100010,China;Beijing University of Chinese Medicine,Beijing 100029,China

XU Xiaolong,LIU Qingquan,Beijing Hospital of Traditional Chinese Medicine,Capital Medical University,Beijing 100010,China;Beijing Institute of Traditional Chinese Medicine,Beijing 100010,China

Coronavirus disease 2019 (COVID-19) is a systemic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),which can affect multiple organs and systems throughout the body.Dysfunction of the coagulation/fibrinolysis system is an important pathophysiological feature of COVID-19 patients and may be related to cytokine release syndrome,induced by viral infection.Coagulation disorders occur in approximately 20% of patients with COVID-19 and are present in almost all patients with severe disease.1,2A frequently reported relationship is that between the increase of D-dimer and the prognosis of COVID-19.One study showed that D-dimer concentrations were higher in non-survivors than in survivors.3The clinical and laboratory features of COVID-19-associated coagulopathy partially overlap with those of sepsis-induced coagulopathy and disseminated intravascular coagulation (DIC);however,they do not perfectly match.4Notably,the presence of coagulation dysfunction and whether it can be corrected are considered to be independent risk factors for the outcome of patients with severe infection.5

During microbial infection,coagulation activation plays a protective role,particularly in the formation of immune thrombi.Fibrin clots intercept microorganisms,which promotes phagocytic cell clearance of microorganisms and the recruitment of white blood cells.6Considering that immune thrombi involve only a limited number of microvessels,they generally do not result in complete vascular occlusion and do not significantly interfere with organ perfusion.7However,when limited beneficial immune thrombi transform into uncontrolled extensive microvascular thrombosis,it can lead to capillary obstruction,abnormal microcirculatory perfusion,tissue damage,and the further promotes inflammation.

The heart is closely related to the vascular systems.The role of the heart as a blood-supplying organ depends on the proper functioning of microcirculation.Inflammatory mediators lead to myocardial dysfunction by disrupting coronary microcirculation,causing myocardial edema,and damaging myocardial cells.8Coagulation dysfunction can lead to the formation of microthrombosis,which can impair cardiac function(insufficient blood volume return,aggravate the cardiac load,et al).If not treated or controlled in a timely fashion,microthrombosis may cause continuous aggravation of cardiopulmonary compensation.Respiratory failure is the most common cause of death during the course of COVID-19,while thrombosis and DIC can lead to the rapid progression of multi-organ failure(e.g.,cardiac insufficiency).9

According to Traditional Chinese Medicine (TCM)theory,coagulation dysfunction is classified to the pathogenesis of "blood stasis".Professor Liu Qingquan proposed that the process of sepsis-induced coagulopathy is in line with the theory of "strong fire consumesQi"in Yellow Emperor's Canon of Medicine PlainCon-versation-Chapter 5 Yinyang Yingxiang Dalunpian.The strong fire is an important reason why patients suffer fromQideficiency in the late stage.10,11In infectious diseases such as sepsis,the negative effects of internal heat lead to fever,which is called "strong fire".Strong fire results in the appearance of heart and lungQideficiency (fatigue,shortness of breath,anhelation,and other symptoms).From a physiologic point of view,early infection leads to an excessive inflammatory response in sepsis patients.However,the production of a large number of inflammatory mediators and cytokines is accompanied by excessive coagulation.The abnormal activation of inflammatory and coagulation results in excessive energy loss in the body,which is considered to be the key pathological factor for the paralysis of immune function and the inhibition of the anticoagulation system in the late stage of sepsis.12A previous study showed that septic patients with functional energy metabolism have a higher survival rate,while patients with energy deficiency and abnormal mitochondrial metabolism are more likely to develop multi-organ failure.13However,there is still a lack of systematic research on the role of energy metabolism in the activation of the anticoagulation system.During the treatment of patients with severe COVID-19,the generation of DIC was found to lead to poor circulation of the peripheral blood and insufficient blood return.This forces the heart to increase its compensatory output to maintain the body's energy metabolism.In this situation,cardiac hypertrophy and cardiac dysfunction are foreseeable.

No pharmacologic therapies have been definitively proven to be beneficial for treating COVID-19.Effective etiological treatment,systemic organ support,and the active treatment of complications should be provided to effectively alleviate the severity of a patient's condition.1Considering the increased risk of thrombosis caused by coagulation disorders in patients with COVID-19,anticoagulation is a preventative care option.While heparin may be helpful in the treatment of COVID-19-associated coagulopathy and has antiviral and anti-inflammatory effects,the balance between its benefits and risks should still be considered.14Organ functional support,such as continuous renal replacement therapy,extracorporeal membrane oxygenation,intra-aortic balloon pumping,and other techniques can improve the impaired heart function to a certain extent.These techniques are important for reducing the load of the heart and improving cardiac circulatory function.But these therapies cannot fundamentally address the clinical problem.Therefore,in addition to supportive treatments,we should further explore effective methods to treat the disease.

TCM has multi-channel,multi-target,and multi-level characteristics.Current studies show that TCM has certain advantages in treating infectious diseases and coagulation dysfunction.Many patented Chinese medicines have exhibited promising efficacy in pre-clinical and clinical studies,such as Xuebijing injection,15Shenmai injection,16Xinmailong injection,17Qishen Huoxue granule,18and Qiang-Xin 1 formula.19,20These drugs can improve cardiac function and protect myocardial cells in patients with sepsis by reducing inflammation,regulating immune function,and improving microcirculation.For instance,Xuebijing injection has multiple pharmacological effects including anti-viral,anti-shock,immunomodulatory regulation,and coagulation regulation ability.This treatment reportedly improves dyspnea and/or hypoxemia,acute respiratory distress syndrome,septic shock,and hemorrhagic dysfunction in patients with severe COVID-19.21

At present,the pathogeneses of COVID-19 and blood clotting are not fully clarified,and there is no specific treatment.Western medicine improves the function of damaged organs through a variety of life support methods,but with limited therapeutic effect and with a high financial cost.TCM has certain treatment advantages.It is necessary to conduct more in-depth pre-clinical and clinical studies to verify the potential of Chinese medicine.In addition to the urgent need to identify effective treatment options for patients with COVID-19,it is of paramount importance to improve the long-term prognosis of these patients.

ACKNOWLEDGMENTS

We thank Katherine Thieltges from Liwen Bianji,Edanz Editing China(www.liwenbianji.cn/ac),for editing the English text of a draft of this manuscript.

Additional Information

Disclosure summary:the author has nothing to disclose.

Data availability:data sharing is not applicable to this article because no data sets were generated or analyzed for this commentary.