Analysis and diagnosis and treatment strategies of coagulation

dysfunction in patients with new coronavirus pneumonia (COVID-19).

Characters, causes, diagnosis and treatment of coagulation
dysfunction in patients with COVID-19.
Heng Mei and Yu Hu.
Guest Editor (s): Xu Maoqiang.

The new coronavirus pneumonia (COVID-19) is an acute respiratory infection caused by a

beta-genus RNA coronavirus. Since December 2019, the outbreak has spread to China,
South Korea, Japan, Italy and other countries and regions. As of February 24, 2020,
Chinese mainland31 provinces (autonomous regions, municipalities directly under the
Central Government) and Xinjiang Production and Construction Corps have reported a
cumulative total of 77,658 confirmed cases (64,786 cases in Hubei Province), with a severe
illness rate of 19.9 14% (Hubei 20.00%), the fatality rate of 3.42% (Hubei 3.96%), Hong
Kong, Macao and Taiwan region reported a cumulative total of 121 confirmed cases, the
fatality rate of2.48%.
2019 new coronavirus (2019-nCoV virus) infected with COVID-19 is the main source of
infection, the virus through respiratory droplets and close contact transmission mainly,
spread strong. The in vitro survival time of the virus can be up to 5 d, insensitive to low
temperature and other characteristics are the prevention and control work to increase the
difficulty. The population is generally susceptible, and the incubation period and the onset
of the disease are contagious, most patients with an incubation period of 1 to 14 d,
individual patients up to 20 d or more. China has this disease as a Class B infectious
disease, according to Class A infectious disease management. The clinical manifestations
of the disease are diverse, most patients have good prognosis, but it is worth noting that
some serious, critically ill patients in addition to fever, fatigue, cough, breathing difficulties
and other symptoms, there are different degrees of blood clotting dysfunction. Based on the
practice of the author's clinical front-line work in Wuhan, combined with the recent clinical
research reports, this paper analyzes and discusses the clinical and laboratory
characteristics, causes and mechanisms of COVID-19 with coagulation dysfunction, with a
view to providing relevant experience for coVID-19 clinical diagnosis and treatment.
Go to:

First, COVID-19 out of coagulation dysfunction clinical

characteristics.
1. Thrombosis tendency: The rate of thrombosis in patients with COVID-19 has not yet
been determined, and about 50% of COVID-19 patients have increased D-D-djubo levels
during disease progression, which is as high as 100% in deaths. The level of D-djubo in
severe patients is significantly higher than that of mild illness, and some patients suddenly
deteriorate in the course of treatment, or even sudden death, suggesting that COVID-19
patients, especially those with severe conditions,have a higher risk ofthrombosis. The
occurrence of cerebral infarction in patients with severe COVID-19 is 4.5%, which may be
related to the underlying disease of severe patients, but it is also enoughto attract our
attention. The changes are mainly concentrated in the lungs, where the veins are congested
and edema, and transparent blood clots can be seen in the blood vessels, which is different
from the white blood clots in the lungs of SARS patients, which may be one reason why the
rate of plate plate reduction in COVID-19 patients is lower than in SARS patients. The
occurrence of deep vein thrombosis was 20.5% in SARS patients and 11.4% in pulmonary
embolism, while the rate of thrombosis in COVID-19 patients was not reported. In
addition, studies have shown that 4% of patients experience an increase in reactive plate
plateplates,which is related to an increased risk of thrombosis and requires large-sample
clinical trials to confirm. Taking into account the blood concentration, endovascular
endoskin injury and high blood clotting status of COVID-19 patients, together with their
own bedridden, obesity, old age and other risk factors to further increase the risk of
thrombosis. Therefore, venous thromboembolism (VTE) can not be ignored during the
prevention, control and treatment of COVID-19. Be alert to the occurrence of VTE if there
is asymmetric pain, swelling or partial swelling or shallow vein filling of the lower limb
after the central venous tube, such as COVID-19 unsophicized chest pain, healing,
breathing difficulties, hypoxemia, etc., should be alert to the occurrence of pulmonary
embolism (PTE).
2. Diffuse microvascular damage: Multi-organ failure caused by diffuse microvascular
damage is an important cause of deathin patientsat risk ofCOVID-19. The results of a
multi-center retrospective study involving 1,099 COVID-19 patients by a team of
academicians in ZhongNanshan showed sepsis shock (6.4% to 0), acute respiratory distress
syndrome (ARDS) (15.6% to 1 The rates of .1%) and dispersive vascular clotting (DIC)
(2.9% to 0.1%) were significantly higher than in non-severe patients, and the mortality rate
was significantly higher than in non-severe patients (8.1% to0.1%). The first 99 confirmed
cases of COVID-19 patients with ARDS, acute renal dysfunction, sepsis shock rate of 17%,
3%, 4%, of which 11% of patients in a short period of time the condition deteriorated
anddied of multi-organ dysfunction (MODF). From the hospital management of tracheal
intestion critically ill patients, without exception are combined clotting disorders, about
80% of patients meet the DIC diagnostic standards, and mostly in the DIC high coagulation
period, some even accompanied by gangrene, to give anticoagulant treatment effective.
COVID-19 combined DIC belongs to sepsis DIC, also known as high coagulation DIC, due
to extensive micro-thrombosis in microvascular thrombosis leading to microvascular
embolism, shock, organ failure, etc. , clinical manifestations are diverse, easy to be
misdiagnosed, missed diagnosis. At present, the coVID-19 literature, the occurrence of
shock, organ damage or failure statistics are more, but the DIC mentioned less. In a recent
retrospective analysis of 21 COVID-19 deaths, 71.4% of the patients who died were
combined with a significant DIC, with a 4 d time from hospitalization to diagnosis, while
the DIC was only 0.6% ofnon-fatal patients. It can be seen that COVID-19 severe patients
clotting disorders and even DIC problems are very prominent, is an important cause of
death in serious patients, so the clinical urgent need to pay attention to early prevention and
treatment.
3. Bleeding risk assessment: COVID-19 Patients may also have an increased risk of
bleeding due to plateplate production and destruction imbalances and blood clotting
disorders. In the course of COVID-19 diagnosis and treatment, it was found that almost all
patients with severe and critical conditions have clotting dysfunction. From the current
clinical data, the vast majority of COVID-19 patients plate plate plate levels are in the
normal range, plateplate reduction rate is not the same, plate plateboard count . . . 100 x
10.9。/L patients accounted for 5%, slt;125 x 10.9。/L patients accounted for 12%, slt;150 x
10.9。/L patients accounted for 36.2%, which may be related tothe number ofcases and the
composition of light and severe patients. In addition, recent autopsy results showed that
COVID-19 patients with pulmonary thrombosis and haemorrhagic lesions weremixed, but
no cerebral hemorrhage was found, while another study of central nervous system lesions
showed that 1.1% of severe patients had cerebral hemorrhage and minor patients did not
have cerebral hemorrhage. The consumption of plateplates and clotting factors can lead to
an increased risk of bleeding, which is not conducive to the control of primary disease and
treatment of anticoagulants and intages, and will increase the risk of death in COVID-19
patients, which still needs attention in clinical practice.
Go to:

Second, COVID-19 patients out of clotting dysfunction laboratory

examination.
Although it has been clinically recognized that COVID-19 patients are prone to and emit
clotting dysfunction, data on bleeding and thrombosis events are lacking, and only some
literature describes abnormal coagulation indicators. In 50% of PATIENT COVID-19
patients, D-dispolymer elevation was significantly higher than in mild and surviving
patients with D-dispolymers, and the level of fibrin primary degradation products (FDP)
and D-DMOsin severe and fatal patients was significantly higher thanin patientswith mild
andsurviving diseases. Fibrinogen, as an acute reactive protein, can be significantly
increased in the course of the disease in patients with mild COVID-19 and in patients with
severe illness, while in patients with severe illness can be significantly reduced in the
advanced stages. 30% of COVID-19 patients had a reduction in coagulase primary time
(PT), 16% had a reduction in active partial clotting enzyme time (APTT), and only 5% and
6% of patients with PT and APTT extensionIt may be related to thehigh coagulation
coagulation disorder in most COVID-19 patients, and a few patients can progress to
expendable low coagulation type, so they should monitor its changes dynamically, be alert
to high coagulation period and give anticoagulant intervention in a timely manner. Plate
plate counts in most COVID-19 patients are in the normal range or slightly elevated,
and their averagelevels are disputedin severe and non-severe patients. The level of
plateplates in patientscan be reduced by a small plate plate level of 4,, , , ,, , , , , , , , , , , , , , ,
,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , CoVID-19
combined coagulation dysfunction and even DIC is a dynamic process, the above-
mentioned routine screening experiments in the high coagulation period may not be
abnormal or easy to be ignored. The sensitivity and specificity of individual indicators to
DIC diagnosis are poor, and the rational use of DIC integral system is beneficial to the
early diagnosis, guidance, prevention and judgment of disease. The International
Thrombosis and Hemostotting Association Standard (ISTH), the Japan Ministry of Health
and Welfare Standard (JMHW), the Japan Society of Emergency Medicine Standard
(JAAM) integral system, and the China Dispersive Vascular Coagulation Diagnostic
Integral System (CDSS) can all useconventional blood clotting indicatorsand clinical
manifestations to judgethe DIC. For COVID-19 combined sepsis DIC, JAAM in the above
four integral systems has the best death sensitivity, CDSS death sensitivity is slightly lower
than JAAM, but CDSS death specificity is 2 times that of JAAM, the comprehensive
diagnostic efficiency is higher thanJAMM. Sepsis-related clotting disorder (SAC) standards
developed in the United States utilize only two indicators, the International Standardized
Ratio (INR) and plate plate count, so the SAC standard is an easy and accessible tool for
selection in emergency situations or primary hospitals. Recently, ISTH recommended a
"two-step approach" to diagnose sepsis-related clotting disorders or DICs, the first step
being to use the Sepsis-induced coagulopathy integration system to identify high
coagulation period guidance anticoagulant therapy as early as possible,and then using the
ISTH explicit DIC integration system to make the next judgment and reasonably guide
treatment.
The diagnostic effect of the above-mentioned DIC integral system on the pre-DIC or high
coagulation period still needs to be improved, and the specific molecular markers of
clotting fiber solution can better reflect the pathological process of DIC at an early stage,
such as soluble thrombosis protein (sTM) can reflect endoskin damage, clotting enzyme-
anticoagulant enzyme. Complex (TAT) can reflect the degree of clotting activation, fibly
lysosin active inhibitor 1 (PAI-1) can reflect the situation of clotting inhibition, in the stage
of clotting disorder not up to DIC can be abnormally elevated, conducive to early diagnosis
and timely intervention. In addition, thrombosis (TEG) and rotary thrombosis elasticity
meter (ROTEM) can provide continuous, real-time information from clotting initiation to
fibrin formation, plate plate aggregation, fibrination, blood clot formation to dissolution,
and the method can reduce occupational exposure with less blood, simple steps and a
certain degree. In addition, high-risk patients with abnormally elevated D-D-diamers and
deep vein thrombosis should promptly go through angiosound, angioscopy and other
examinations to assist in diagnosis and treatment.
Go to:

Third, coVID-19 coagulation dysfunction causes and mechanisms.

1. Viral infection: 2019-nCoV is the 7th human-infected coronavirus, unlike 229E, NL63,
OC43 and HKU1, which can causeatypical pneumonia in combination with SARS-CoV
and MERS-CoV. Both 2019-nCoV and SARS-CoV infect the human body through
angiosin-converting enzyme 2 (ACE2), but the ability to bind 2019-nCoV to ACE2 is 10 to
20 times that of SARS-CoV, which may be the reason why 2019-nCoV is more
contagious. ACE2 is expressed to varying degrees in alptic endotring cells, arterial
endotrectoty cells, small intestineendotring cells,immune tissues, etc. 2019-nCoV into the
body, can be quickly identified by the body's pathogen-related molecular patterns (PAMP),
activated the immune system to remove the virus, but excessive activation can cause
cytokine storms, resulting in damage to the microvascular system, activation of the clotting
system while suppressingfibrination and anticoagulant system, microvascular thrombosis
formation DIC, resulting in microcirculation disorders and even MODF. Specific
mechanisms include: (1) the virus overactivates the immune system, a large number of
white blood cells in the inflammatory tissue are soaked, and systemic inflammatory factors
are significantly increased, resulting in uncontrolled inflammatory damage. (2) Virus-
induced over-active immune system leads to cd4, CD8 T and other immune cell depletion,
lymphocyte count is reduced, and there are reports that SARS-CoV and MERS-CoV can
induce T apoptosis, resulting in immunosuppression can lead to bacterialor opportmunic
infections. In the first 41 cases of COVID-19 patients, the risk of secondaryinfection was
10%. (3) Viruses or secondary infections that cause nonse specific tissue damage can
release a large number of dangerously related molecular patterns (DAMP), such as high
migration rate family protein B1 (HMGB-1), histogenes, etc. can also activate the immune
system, resulting in a vicious cycle.++
2. CRS: Past analysis of viral infections such as SARS, MERS and Ebola virus infection
has found that CRS is a major cause of ARDSand MODF. Il-1 beta, IL-6, IL-12, IFN-yuan,
IL-10, and monocyte degeneration factor 1 (MCP1) in SARS patients were associated with
inflammation of the lungs and severe lung damage. MERS-infected patients with IFN-
thymain, TNF-alpha, IL-15, and IL-17 are elevated. Multiple cytokines (IL-1 beta, IL-6, IL-
2, IL-2R, IL-7, IL-10, GSCF, IP-10, The concentration of MCP1 MIP1A, TNF-alpha, etc.
increased significantly, and the degree of increase in criticallyill patients was significantly
higher than in ordinary patients, indicating that cytokine stormsmay be an important cause
of exacerbation ofthe disease. Although cytokine storms may be a common pathogenic
mechanism for theabove-mentioned viralinfectious diseases,the changes incytokines of
different viral infections are different. After a comprehensive analysis of 30 immunological
indicators in the blood of 33 COVID-19 patients, the research team of the First Hospital
affiliated with China University of Science and Technology speculated that IL-6 is an
important path path to induce CRS, and that its mechanism may be: after 2019-nCoV
infection, T cells are activated to produce a large number of granulocyte-macrophage
collection stimulants and IL-6, thus inducing cytokine waterfall. IL-6 is an important
position in the inflammatory media network, which can cause blood clotting disorders in a
variety of ways, such as stimulating the liver to synthesize more plateabin, cellulogens, etc.,
by raising the expression of endothrial growth factors to destroy the stability of the vascular
barrier, stimulate the single Nuclear cells express more tissue factors to increase the activity
of the exogenetic clotting system, and the resulting clotting enzymes in turn can induce the
enditeral skin of blood vessels to produce more IL-6 and other cytokines, so that cytokine
storms and clotting disorders form a vicious circle. CrS, similar to IL-6 as the core in cell
immunotherapy, is the key mechanism for coagulation disorder, and for patients with IL-6
elevation, timely giving IL-6 inhibitor toad monoantigen may improve CRS and reduce the
risk of DIC.
3. Immune damage to the hematopoietic system: Previous studies have reported that
coronavirus subjects include CD13, while human hematopoietic stem cells, cytopertes
andplate plates are usuallyhighly expressed CD13. The virus can directly damage troll cells
and plateplates by binding to CD13, invading hematopoietic stem cells or infecting bone
marrow substrate cells to cause hematopoietic inhibition, resulting in reduced plate
plateplate production, or increased plateplate damage caused by immunologic activation of
complements. The lung is one of the organs of mature cytocytocytes releasing hemorrhagic
plates,and the lung damage in patients with COVID-19 reduces the division of macrocytes
in the lungs, resulting in a decrease in plateplate production, and the inflammatory damage
caused by it causes plateplates in the lungs to gather and thrombosis, resulting in an
increase in plateplate consumption and destruction. CoVID-19 patients' immune system
is over-activated, releasing a large number of inflammatory factors, whichcan cause
immune response-mediated hematologic system damage, or cause immunostititis damage to
surrounding autocytocytes, microvascular system damage, abnormal activation of the
clotting system, fibrination and anticoagulant system suppression.
4. Istemia isooxygen refill damage: normal endothroty cells have anticoagulant properties,
hypoxia can make endothroty cell anticoagulant properties weakened, permeability and
white blood cell adhesion increased. Isoemia refill damage is often secondary to hypoxia
and reoxidation of endothroty cells, which can trigger oxidative stress, promote superoxide
production and inhibit nitric oxide production, resultingin endothred cell damage. Endoskin
cell expression ACE2(41)-s42,2019-nCoV may aggravate endoskin cell damage, increased
expression of tissue factors on the cell surface, anticoagulant enzyme III., tissue factor (TF)
pathway inhibitors and protein C system damage and loss of anticoagulant The inhibitors of
the fibrouslysaseprimary activator from the endoskin source are essential for the regulation
of fibrin dissolution, and damage to the endoskin can also lead to coagulation caused by
fibrin dissolution imbalance, which eventually leads to clottingdysfunction.
5. Medications and operational factors: Previous reports have found that certain antiviral
drugs (alpha-interferon, libavirin, abidor, osetavir, etc.), certain antimicrobial drugs
(moxisa, etc.), and certain Chinese medicines can reduce the synthesis of clotting factors by
directly suppressing the hematopoietic systemor inducing liverdamage. Patients may
themselves be taking certain medications (aspirin, warfarin, etc.) that can cause changes
inblood clotting function due to underlying diseases. During in vitro membrane pulmonary
oxygenation (ECMO) treatment, artificial biomass on the surface of the in vitro circulatory
line causes abnormal activation of the clotting system. Improper use of anticoagulants such
as heparin during invasive operation can also lead to abnormal clotting.
6. Improper use of blood products: COVID-19 patients need to pay attention to blood
transfusion safety, combined trauma, blood system diseases and pregnancy, etc. in the
short-term infusion of a large amount of stock blood will dilute blood components,
resulting in hypothermia of the body and other effects on blood clotting function, a serious
threat to life. Therefore, accurately assess the patient's blood loss status and clotting
function before blood transfusion, strictly grasp the proportion of blood products when a
large number of components of blood transfusion, according to blood clotting function and
other related indicators to supplement plateplates, plasma, cold precipitation, etc., is
conducive to correcting the patient's blood clotting disorders.
Go to:

Fourth, COVID-19 coagulation dysfunction diagnosis and treatment

strategy.
1. Dynamic monitoring, early detection, early prevention: COVID-19 combined
coagulation dysfunction is a dynamic process, dynamic monitoring of blood clotting
indicators, rational use of TEG, ROTEM and other technologies, the active use of CDSS,
SAC, SIC-ISTH integration system to facilitate early detection, early diagnosis, early
prevention. COVID-19 combined thrombosis can be a clinical manifestation of DIC's high
coagulation period, or it can be caused by the sudden shedding of deep static thrombosis
(DVT) in the lower limbs of long-term bedridden patients. Clinically widely used tools for
assessing DVT risk include the Autor DVT Risk Assessment Form and the Caprini Risk
Assessment Form. The Autar scale uses seven dimensions, such as age, BMI, high-risk
diseases, activity, trauma, and special risk factors for surgical machines, to assess VTE
risk for greater convenience and effectiveness. The Caprini scale covers 40 risk factors such
as general condition, BMI, and VET history, and is effective in identifying high-risk
patients with VTE. In clinical practice, different scales can be reasonably selected, and
corresponding prevention and treatment measures can be given according to the score.
2. Venous thrombosis prevention and treatment: COVID-19 patients are mostly in high
coagulation, should dynamically monitor the patient's condition changes, monitor blood
clotting indicators, as early as possible VTE risk assessment, if necessary, anti-thrombosis-
related examination. It is recommended to routinely carry out VTE preventive health
education for patients, to drink more water, conditions should be regularly at the bedside
activities, seriously ill patients timely rehydration. For all patients with heavy, critical and
heavy COVID-19 and light, general-type patients with a higher risk of thrombosis
assessment, VTE preventive treatment should be considered if there is no taboo, with low
molecular weight heparin preferred (3,000 U or 4,000 U,1time daily), and 5,000 U
subsulpheric injections of common heparin can be used for renal insufilation, 2times daily .
For patients with ECMO support, if heparinization is already possible, additional drug
prevention is not necessary to avoid an increased risk of bleeding. Pregnant women at risk
of VTE, if there are drug prevention taboos, it is recommended to use mechanical
prevention, such as intermittent inflatable pressurized pumps, graded pressurized elastic
socks and so on. In addition, patients with high clinical suspicion of DVT or PTE are
advised to initiate anticoagulant therapy immediately if there is no anticoagulanttreatment
taboo; During VTE prevention, pay attention to observe whether there is bleeding or
clotting abnormality after the use of anticoagulant drugs, once the drug can be stopped and
treated accordingly, in the anticoagulant must weigh the advantages and disadvantages of
reducing the risk of thrombosis and bleeding increased.
3. Timely correction of DIC: early identification of DIC parting or phased, according to
DIC clinical phased treatment. DIC high coagulation period to anticoagulant-based, should
not simply supplement plateplates and clotting factors, do not use anti-fibre-soluble drugs,
small doses of heparin enough to play anticoagulant effect and have a certain anti-
inflammatory effect, it is recommended to use low molecular weight heparin 3,000 to 5,000
U/d injection, generally linked 3 to 5 d; Expendable low coagulation period, anticoagulant
treatment is still essential, but due to the coagulation factor for sexual consumption, so on
the basis of adequate anticoagulant, plate plate plates and clotting factors should be
supplemented;
4. Prevention and treatment of bleeding: first of all, the active use of antiviral, antibacterial
drugs to treat the original disease, reduce the loss of plateplates and clotting factors
infected. Secondly, plate plate plate infusion can quickly and effectively improve plate
plate count and reduce the incidence and mortality rate of haemorrhage. When the
plateplate count is 20 x 10.9。At /L, preventive infusion of plateplates, and for active
bleeding, surgery, or interventional operation, plateplate counts are required to be 50 x 10.9
。
/L; When plateboard count is 50 x 10.9。/L, consider injecting recombined human
plateplate production. In addition, for active bleeding patients can use hemostamine drugs
such as paracetamol, phenolic ethylamine, etc., can also be supplemented with fresh frozen
plasma, cold precipitation, fibrinogen concentrates and other blood products, but need to
pay attention to a large number of plasma supplementation caused by circulatory overload
and fibrinogen supplementation dosage problems.
5. Attention to drug taboos: patients using antiviral, antibiotics, Chinese medicine or other
drugs that can cause blood clotting abnormalities at the same time, must closely monitor the
patient's blood image and blood clotting function indicators, if adverse reactions need to
adjust the dose as appropriate, if serious clotting abnormalities should be stopped, until the
indicators resume to consider use.
6. Support and other treatment: severe patients need active oxygen therapy, nasal catheters
or mask oxygen absorption and timely assessment of efficacy, if lack of oxygen continues
to improve then consider high-flow nasal catheter oxygen therapy or mechanical breathing;
Anticoagulant therapy prevention , protection of important organs,timely organ functional
support, the improvement of microcirculation and vascular permeability of drugs (such as
high doses of vitamin C), enhance immunity to play an antiviral role, antioxidant
prevention and control of lung damage and improve microcirculation . Il-6 monoants,
interstate stem cell infusions, JAK2 inhibitors, etc., which inhibit the storm of
inflammatory factors, may also improve coagulation dysfunction, and related clinical trials
are under way (ChiCTR2000030073, ChiCTR20000302242020).
In summary, COVID-19 as a new type of coronavirus caused by respiratory infectious
diseases, coagulation dysfunction can be seen in four clinical subtypes, but the
characteristics are different; CrS correlation caused by immune imbalance, how to balance
physiological and pathological immune response is an urgent problem to be solved in
COVID-19 treatment, and it is necessary to closely monitor patients' blood clotting index in
clinical diagnosis and treatment, and make reasonable use of TEG, ROTEM and other
technologies. Actively promoting the integration system related to coagulation diagnosis is
particularly important for COVID-19 diagnosis, in addition, critically ill patients and issued
clotting dysfunction after the death rate is high, prevention and control is difficult, so it is
urgent to pay attention to, so early prevention and treatment, to avoid from light to heavy.
Go to:

Funding Statement.
Fund projects: National Natural Science Foundation of China (81873434, 81770132);
Go to:

References.
1. Seven days in medicine: 8-14 Jan 2020 (EB/OL) BMJ. 2020:368. doi:
10.1136/bmj.m132. . (PubMed) CrossRef Google Scholar.
2. Health Emergency Office Update on the outbreak of new coronavirus pneumonia
at 24 hours on 24 February .EB/OL, National Health and Health Commission of the
People's Republic of China; 2020. ( Google Scholar) .
3. Casanova LM, Jeon S, Rutala WA, et al. Effects of air source and relative humidity on
coronavirus survival on surfaces .J. Appl Environ Microbiol. 2010; 76(9): 2712-2717.
doi: 10.1128/AEM.02291-09. (PMC free article) (PubMed) . .. CrossRef. . . . . . . . . . . . . . .
.......................
4. Guan WJ, Ni ZY, Hu Y, et al. Clinical State of Coronavirus Disease 2019 in China .J. N
Engl J Med. . . 2020 doi: 10.1056/NEJMoa2002032. . (PMC free article) (PubMed) . ..
CrossRef. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. 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
doi: 10.1111/jth.14768. . (PMC free article) (PubMed) . .. CrossRef. . . . . . . . . . . . . . . . . .
....................
6. Mao L, Jin H, Wang M, et al. Neurologic Solutions of Patients With Coronavirus
Disease 2019 in Wuhan, China .J. JAMA Neurol. 2020 doi:
10.1001/jamaneurol.2020.1127. (PMC free article) (PubMed) . .. CrossRef. . . . . . . . . . . .
..........................
7. Liu Xi, Wang Rongshuai, Qu Guoqiang, et al. General Observation Report of the
Autopsy System for the Death of New Coronavirus Pneumonia . 36(1): 19-21. . Google
Scholar.
8. Lang Z, Zhang L, Zhang S, et al. Pathological study on severe acute acute life
syndrome .J. Chin Med J. . . 2003; 116(7): 976-980. doi: 10.3760/cma.j.issn.0366-
6999.2003.07.105. (PubMed) CrossRef Google Scholar.
9. Chong PY, Chui P, Ling AE, et al. Analysis of the deaths when the severe acute
respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a
SARS diagnosis s.J. Arch Pathol Lab Med. 2004; 128(2): 195-204. . (PubMed) Google
Scholar.
10. Chen N, Zhou M, Dong X, et al. Electable and clinical characters of 99 cases of 2019
novel coronavirus pneumonia in Wuhan, China: a descriptive study .J.
Lancet. 2020; 395(10223): 507-513. doi: 10.1016/S0140-6736 (20)30211-7. (PMC free
article) (PubMed) . .. CrossRef. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. 史 振宇, 符 伟国. 新型冠状病毒肺炎相关孤立性远端深静脉血栓的诊疗方案[J] 上海医

学 2020:1–7. [Google Scholar]

12. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China[J] Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-
6736(20)30183-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Jiang H, Liu L, Guo T, et al. Improving the safety of CAR-T cell therapy by
controlling CRS-related coagulopathy[J] Ann Hematol. 2019;98(7):1721–1732. doi:
10.1007/s00277-019-03685-z. [PubMed] [CrossRef] [Google Scholar]
14. Wong RS, Wu A, To KF, et al. Haematological manifestations in patients with severe
acute respiratory syndrome: retrospective analysis[J] BMJ. 2003;326(7403):1358–1362.
doi: 10.1136/bmj.326.7403.1358. [PMC free article] [PubMed] [CrossRef] [Google
Scholar]
15. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with
2019 novel coronavirus-infected pneumonia in Wuhan, China[J] JAMA. 2020 doi:
10.1001/jama.2020.1585. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Chen G, Wu D, Guo W, et al. Clinical and immunologic features in severe and
moderate forms of Coronavirus Disease 2019[J] medRxiv. 2020 doi:
10.1101/2020.02.16.20023903. [CrossRef] [Google Scholar]
17. Taylor FB, Jr, Toh CH, Hoots WK, et al. Towards definition, clinical and laboratory
criteria, and a scoring system for disseminated intravascular coagulation[J] Thromb
Haemost. 2001;86(5):1327–1330. [PubMed] [Google Scholar]
18. Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of
disseminated intravascular coagulation diagnostic criteria for critically ill patients:
comparing current criteria[J] Crit Care Med. 2006;34(3):625–631. doi:
10.1097/01.ccm.0000202209.42491.38. [PubMed] [CrossRef] [Google Scholar]
19. Luo L, Wu Y, Niu T, et al. A multicenter, prospective evaluation of the Chinese
Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular
coagulation[J] Thromb Res. 2019;173:131–140. doi:
10.1016/j.thromres.2018.11.022. [PubMed] [CrossRef] [Google Scholar]
20. Wu Y, Luo L, Niu T, et al. Evaluation of the new Chinese Disseminated Intravascular
Coagulation Scoring System in critically ill patients: A multicenter prospective
study[J] Sci Rep. 2017;7(1):9057. doi: 10.1038/s41598-017-09190-5. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
21. Yamakawa K, Yoshimura J, Ito T, et al. External Validation of the Two Newly
Proposed Criteria for Assessing Coagulopathy in Sepsis[J] Thromb
Haemost. 2019;119(2):203–212. doi: 10.1055/s-0038-1676610. [PubMed]
[CrossRef] [Google Scholar]
22. Iba T, Levy JH, Warkentin TE, et al. Diagnosis and management of sepsis-induced
coagulopathy and disseminated intravascular coagulation[J] J Thromb
Haemost. 2019;17(11):1989–1994. doi: 10.1111/jth.14578. [PubMed] [CrossRef] [Google
Scholar]
23. Mei H, Jiang Y, Luo L, et al. Evaluation the combined diagnostic value of TAT, PIC,
tPAIC, and sTM in disseminated intravascular coagulation: A multi-center prospective
observational study[J] Thromb Res. 2019;173:20–26. doi:
10.1016/j.thromres.2018.11.010. [PubMed] [CrossRef] [Google Scholar]
24. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia
in China, 2019[J] N Engl J Med. 2020;382(8):727–733. doi:
10.1056/NEJMoa2001017. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
25. Wan Y, Shang J, Graham R, et al. Receptor recognition by novel coronavirus from
Wuhan: An analysis based on decade-long structural studies of SARS[J] J
Virol. 2020;pii:JVI.00127–00120. doi: 10.1128/JVI.00127-20. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
26. Silver MA, Bohnert M, Beck AT, et al. Relation of depression of attempted suicide
and seriousness of intent[J] Arch Gen Psychiatry. 1971;25(6):573–576. doi:
10.1001/archpsyc.1971.01750180093015. [PubMed] [CrossRef] [Google Scholar]
27. Kowalczuk S, Bröer A, Tietze N, et al. A protein complex in the brush-border
membrane explains a Hartnup disorder allele[J] FASEB J. 2008;22(8):2880–2887. doi:
10.1096/fj.08-107300. [PubMed] [CrossRef] [Google Scholar]
28. Cohen J. The immunopathogenesis of sepsis[J] Nature. 2002;420(6917):885–891.
doi: 10.1038/nature01326. [PubMed] [CrossRef] [Google Scholar]
29. van der Poll T, van de Veerdonk FL, Scicluna BP, et al. The immunopathology of
sepsis and potential therapeutic targets[J] Nat Rev Immunol. 2017;17(7):407–420. doi:
10.1038/nri.2017.36. [PubMed] [CrossRef] [Google Scholar]
30. Chu H, Zhou J, Wong BH, et al. Middle East Respiratory Syndrome Coronavirus
Efficiently Infects Human Primary T Lymphocytes and Activates the Extrinsic and
Intrinsic Apoptosis Pathways[J] J Infect Dis. 2016;213(6):904–914. doi:
10.1093/infdis/jiv380. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
31. Mahallawi WH, Khabour OF, Zhang Q, et al. MERS-CoV infection in humans is
associated with a pro-inflammatory Th1 and Th17 cytokine
profile[J] Cytokine. 2018;104:8–13. doi: 10.1016/j.cyto.2018.01.025. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
32. Beijing Group of National Research Project for SARS. Dynamic changes in blood
cytokine levels as clinical indicators in severe acute respiratory syndrome[J] Chin Med
J(Engl) 2003;116(9):1283–1287. [PubMed] [Google Scholar]
33. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines
in severe acute respiratory syndrome[J] Clin Exp Immunol. 2004;136(1):95–103. doi:
10.1111/j.1365-2249.2004.02415.x. [PMC free article] [PubMed] [CrossRef] [Google
Scholar]

34. 陈 蕾, 刘 辉国, 刘 威, et al. 2019新型冠状病毒肺炎29例临床特征分析[J/OL] 中华结核和

呼吸杂志 2020;43(2020-02-06) doi: 10.3760/cma.j.issn.1001-
0939.2020.0005. http://rs.yiigle.com/yufabiao/1180104.htm. [CrossRef] [Google
Scholar]
35. Zhou YG, Fu BQ, Zheng XH, et al. Aberrant pathogenic GM-CSF+T cells and
inflammatory CD14+CD16+monocytes in severe pulmonary syndrome patients of a
new coronavirus[J] bioRxiv. 2020 doi: 10.1101/2020.02.12.945576. [CrossRef] [Google
Scholar]
36. Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6
blockade for cytokine storm[J] Immunotherapy. 2016;8(8):959–970. doi: 10.2217/imt-
2016-0020. [PubMed] [CrossRef] [Google Scholar]
37. 杨 默, 韩 锦伦, 李 桂霞, et al. SARS冠状病毒对血液系统的影响及可能的机制[J] 中国实验
血液学杂志 2003;11(3):217–221. doi: 10.3969/j.issn.1009-
2137.2003.03.001. [CrossRef] [Google Scholar]
38. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet
biogenesis and a reservoir for haematopoietic
progenitors[J] Nature. 2017;544(7648):105–109. doi: 10.1038/nature21706. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
39. Ten VS, Pinsky DJ. Endothelial response to hypoxia: physiologic adaptation and
pathologic dysfunction[J] Curr Opin Crit Care. 2002;8(3):242–250. doi:
10.1097/00075198-200206000-00008. [PubMed] [CrossRef] [Google Scholar]
40. De Pascali F, Hemann C, Samons K, et al. Hypoxia and reoxygenation induce
endothelial nitric oxide synthase uncoupling in endothelial cells through
tetrahydrobiopterin depletion and
Sglutathionylation[J] Biochemistry. 2014;53(22):3679–3688. doi:
10.1021/bi500076r. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
41. Zhao Y, Zhao ZX, Wang YJ, et al. Single-cell RNA expression profiling of ACE2, the
putative receptor of Wuhan 2019-nCov[J] bioRxiv. 2020 doi:
10.1101/2020.01.26.919985. [CrossRef] [Google Scholar]
42. Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the
functional receptor for SARS coronavirus. A first step in understanding SARS
pathogenesis[J] J Pathol. 2004;203(2):631–637. doi: 10.1002/path.1570. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
43. Vallet B, Wiel E. Endothelial cell dysfunction and coagulation[J] Crit Care
Med. 2001;29(7 Suppl):S36–41. doi: 10.1097/00003246-200107001-00015. [PubMed]
[CrossRef] [Google Scholar]
44. Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation
and coagulation[J] Trends Cardiovasc Med. 2016;26(4):297–303. doi:
10.1016/j.tcm.2015.12.001. [PubMed] [CrossRef] [Google Scholar]
45. Keller TT, Mairuhu AT, de Kruif MD, et al. Infections and endothelial
cells[J] Cardiovasc Res. 2003;60(1):40–48. doi: 10.1016/s0008-6363(03)00354-
7. [PubMed] [CrossRef] [Google Scholar]

46. 张 瑞祺. α干扰素的血液学不良反应及处理[J] 肝脏 2004;9(9):36–39. [Google Scholar]

47. 彭 碧苗, 王 启跃, 徐 秀余. 利巴韦林注射液不良反应分析[J] 临床合理用

药 2010;3(15):103–104. [Google Scholar]

48. Lee DU, Je SH, Yoo SJ, et al. Hematological adverse effects and pharmacokinetics of
ribavirin in pigs following intramuscular administration[J] J Vet Pharmacol
Ther. 2017;40(5):561–568. doi: 10.1111/jvp.12394. [PubMed] [CrossRef] [Google
Scholar]
49. Mailman JF, Stigant C, Martinusen D. Moxifloxacin-Induced Immune-Mediated
Thrombocytopenia in a Chronic Kidney Disease Patient Receiving Hemodialysis[J] Ann
Pharmacother. 2014;48(7):919–922. doi: 10.1177/1060028014529929. [PubMed]
[CrossRef] [Google Scholar]

50. 孙 闻续, 吴 逢波, 吴 斌, et al. 9例莫西沙星致血小板减少症的文献分析[J] 药物流行病学

杂志 2019;28(7):464–467. [Google Scholar]

51. Chen G, Fei X, Ling J. The effects of aminoglycoside antibiotics on platelet

aggregation and blood coagulation[J] Clin Appl Thromb Hemost. 2012;18(5):538–541.
doi: 10.1177/1076029611430955. [PubMed] [CrossRef] [Google Scholar]

52. 宋 祖益. 近年来阿司匹林被发现的新作用及副作用[J] 中国实用医药 2013;8(30):161–

162. [Google Scholar]
53. Oliver WC. Anticoagulation and coagulation management for ECMO[J] Semin
Cardiothorac Vasc Anesth. 2009;13(3):154–175. doi:
10.1177/1089253209347384. [PubMed] [CrossRef] [Google Scholar]

54. 张 瑚敏. 输注不同比例血浆和红细胞对凝血功能障碍及的影响[J] 血栓与止血

学 2017;23(5):783–785. doi: 10.3969/j.issn.1009-6213.2017.05.020. [PubMed]
[CrossRef] [Google Scholar]
55. Autar R. Nursing assessment of clients at risk of deep vein thrombosis(DVT): the
Autar DVT scale[J] J Adv Nurs. 1996;23(4):763–770. doi: 10.1111/j.1365-
2648.1996.tb00049.x. [PubMed] [CrossRef] [Google Scholar]
56. Golemi I, Salazar Adum JP, Tafur A, et al. Venous thromboembolism prophylaxis
using the Caprini score[J] Dis Mon. 2019;65(8):249–298. doi:
10.1016/j.disamonth.2018.12.005. [PubMed] [CrossRef] [Google Scholar]
57. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock, 2012[J] Intensive Care
Med. 2013;39(2):165–228. doi: 10.1007/s00134-012-2769-8. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
58. Duranteau J, Taccone FS, Verhamme P, et al. European guidelines on perioperative
venous thromboembolism prophylaxis: Intensive care[J] Eur J
Anaesthesiol. 2018;35(2):142–146. doi: 10.1097/EJA.0000000000000707. [PubMed]
[CrossRef] [Google Scholar]

59. 中国医师协会呼吸医师分会危重症医学专业委员会, 中华医学会呼吸病学分会危重症医学

学组 体外膜式氧合治疗成人重症呼吸衰竭推荐意见[J] 中华结核和呼吸杂志 2019;42(9):660–
684. doi: 10.3760/cma.j.issn.1001?0939.2019.09.006. [PubMed] [CrossRef] [Google
Scholar]

60. 《中国血栓性疾病防治指南》专家委员会 中国血栓性疾病防治指南[J] 中华医学杂

志 2018;98(36):2861–2888. doi: 10.3760/cma.j.issn.0376-
2491.2018.36.002. [CrossRef] [Google Scholar]
61. 中华医学会血液学分会血栓与止血学组 弥散性血管内凝血诊断中国专家共识(2017年版
)[J] 中华血液学杂志 2017;38(5):361–363. doi: 10.3760/cma.j.issn.0253-
2727.2017.05.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

62. 中国老年医学学会, 国家老年疾病临床医学研究中心(解放军总医院), 解放军老年医学专

业委员会 感染诱发的老年多器官功能障碍综合征诊断与治疗中国指南2019[J] 中华老年多器
官疾病杂志 2019;18(11):801–838. doi: 10.11915/j.issn.1671-
5403.2019.11.174. [CrossRef] [Google Scholar]

63. 梅 恒, 胡 豫. 我如何用纤维蛋白原替代疗法治疗获得性出血[J] 中华血液学杂

志 2018;39(10):803–806. doi: 10.3760/cma.j.issn.0253-2727.2018.10.003. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]

64. 陆 世珉, 田 山, 董 卫国. 维生素C在脓毒症治疗中的应用研究进展[J] 中华全科医师杂

志 2018;17(10):827–829. doi: 10.3760/cma.j.issn.1671-
7368.2018.10.021. [CrossRef] [Google Scholar]