key: cord-0701164-12mra0b9
authors: Vinayagam, Sathishkumar; Sattu, Kamaraj
title: SARS-CoV-2 and coagulation disorders in different organs
date: 2020-09-15
journal: Life Sci
DOI: 10.1016/j.lfs.2020.118431
sha: 0f72f5f852323948a5fce8e28c6ed6a967fb1c0c
doc_id: 701164
cord_uid: 12mra0b9

Coronavirus disease 2019 (COVID-19) is a prominent pandemic disease that emerged in China and hurriedly stretched worldwide. There are many reports on COVID-19 associated with the amplified incidence of thrombotic events. In this review, we focused on COVID-19 coupled with the coagulopathy contributes to severe outcome inclusive of comorbidities such as venous thromboembolism, stroke, diabetes, lung, heart attack, AKI, and liver injury. Initially, the COVID-19 patient associated coagulation disorders show an elevated level of the D-dimer, fibrinogen, and less lymphocyte count such as lymphopenia. COVID-19 associated with the Kawasaki disease has acute vasculitis in childhood which further affects the vessels found all over the body. COVID-19 linked with the thrombotic microangiopathy triggers the multiple vasculitis along with the arterioles thrombosis, medium, large venous and arterial vessels mediates the disseminated intravascular coagulation (DIC). SARS-Co-V-2 patients have reduced primary platelet production, increased destruction of the platelet, decreased circulating platelet leads to the condition of increased thrombocytopenia which contributes to the coagulation disorder. Endothelial dysfunction plays an important role in the coagulation disorders via increased generation of the thrombin and stops fibrinolysis further leads to hypercoagulopathy. Along with that endothelial dysfunction activates the complement system pathways and contributes to the acute and chronic inflammation via cytokine storm with the production of the cytokines and chemokines, coagulation in different organs such as lung, brain, liver, heart, kidney and further leads to multi-organ failure.

On the report of the World Health Organization (WHO), viral diseases pursue to become into sight and stand for major severe issues to the public health. Taxonomy of Viruses has named it as SARS-CoV-2 which would cause a similar outbreak caused by the SARS-CoVs and it was announced on 11 th February 2020 [1, 2] . These coronaviruses can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS) which further leads to pulmonary failure and multi-organ failure. According to WHO, till 29 th June, the total number of cases for COVID-19 is 10,021,401and it affected 216 countries and 499,913 people have been died [3] . The reproduction number of the COVID-19 was found to be 2.2 to 2.68 or it is in the range of between 1.4-6.5. It is a familial cluster of pneumonia; it was announced as a pandemic by the WHO by 11 th March and has become a major risk to the public. SARS-CoV2 is associated with the condition called coagulopathy, which is due to thrombosis in The increased coagulation in the SARS-CoV2 patients shows that there is an elevation of the Ddimer, the degradation products of fibrin/fibrinogen, and the increased level of fibrinogen [18] .

The lung autopsies of the 38 COVID-19 Italian patients, out of those 33 patients are having fibrin thrombi in the arterial vessels and increased level of the D-dimer in the blood [19] . Lung autopsies of 3 patients from China showed that there is a widened and congested blood vessels in the sputum of alveolar which has monocytes infiltration and lymphocyte found inside and in the region of the blood vessels and thrombi are observed in the microvessels. This injury and parenchymal cell necrosis and small vessel thrombi were determined in the blood vessels, heart, kidney, liver, and gut [20] . Along with that fibrin thrombi were observed in the area of glomerular connected with endothelial injury [21] . In 5 US patients, capillaries of the lungs were observed with the thrombosis associated vasculopathy and the microvascular injury was observed. Further, it was infiltrated by the monocyte and neutrophils found in the damage capillaries [22] . The presence of COVID-19 in 6month old baby was associated with the Kawasaki disease which is a rare disease, which has acute vasculitis in childhood which further affects the vessels found all over the body [23] . The study shows that children and adolescents admitted in ICU for COVID 19 along with the inflammatory condition in the multisystem are having a similar feature of the toxic shock syndrome and Kawasaki diseases. The patient illness caused by hyperinflammatory syndrome leads to multi-organ dysfunction and toxic shock [23] .

COVID-19 associated with the thrombotic microangiopathy might activate the multiple vasculitis along with the arterioles thrombosis, medium, large venous and arterial vessels mediates the disseminated intravascular coagulation (DIC). There are so many factors involved in COVID-19 patients to activate the coagulation system [24] . The changes in the whole J o u r n a l P r e -p r o o f Journal Pre-proof pathological contribute to the deterioration of the respiratory system and multi-organ failure, which contributes to the high level of mortality and morbidity [25] .

In this section, we are discussing the connection between the lymphopenia and COVID-19.

Lymphopenia acts as an important feature of the COVID-19. Lymphopenia is defined as a count of the lymphocyte is less than the value of 1.5X10 9 /L. It is highly associated with the elevated risk of the COVID-19 infection. Lymphocyte count and lymphopenia act as a quick tool to determine COVID-19 patients. The mechanism of SARS-CoV-2 is similar to the mechanism of SARS which includes the infection directly; lymphocyte destruction [26] and cytokine-induced destruction of the lymphocyte [27] . On the other hand, the other study shows with the limitations there are no fluctuations data in the counts of lymphocyte during COVID-19 and it also acts as an important factor to determine the COVID-19 disease. In a small sample, a study shows that a little change in the count of the lymphocyte would speculate the worsening of the COVID-19 disease [28] . But to conclude this we need to determine with the large samples [28] [29] [30] .

There are more symptoms associated with the complication are discussed in the above, there is another dysfunction such as the hematological changes. The COVID-19 patients associated with the level of D-dimer is high among the patients [33] . The other study in Beijing in 13 patients showed that thrombocytopenia (72.5%) [34] . Also, the study form Wuhan with the statistics showed that patients (5%) were having thrombocytopenia [35] . Since there is an increased level of the thrombocytopenia level among COVID-19 patients so, the researchers from the hospital of it decreases the capillary bed in pulmonary, fragmentation of MK, further decreases the platelet production. Altogether, these three mechanisms such as reduced primary platelet production, increased destruction of the platelet, decreased circulating platelet leads to the condition of increased thrombocytopenia in the SARS-CoV-2 patients [36] (represented in Fig. 1 ).

The COVID-19 patients showed the substantiation of the DIC in non-survivors (71.4%) and survivors (0.6%) which was reported by the Tang et al., 2020 [37] . This DIC has occurred in the COVID-19 patients during its worst condition and it is highly linked with the mortality of the COVID-19 patients. This DIC condition along with the elevated level of the D-dimer would be useful during the therapeutic condition. The DIC pathophysiology is a multi-factorial and J o u r n a l P r e -p r o o f complex factor that plays the connection between the cellular level and plasmatic elements of the hemostatic system. The components of it with the immune system mediates the collapse in the coagulation and systems of fibrinolytic systems which activates the thrombosis and bleeding in the patient [38] . The causes of DIC are due to the sepsis or the high infection, along with that the activation of the immune system and the pro-inflammatory pathway is highly observed in the COVID-19 patient which further activates the DIC. This homeostatic involvement during coronavirus astonished the demanding care patients and further develops into the DIC [38] . The incidence of the DIC in the COVID-19 patients is more compared to the SARS patients having the risk of DIC. The pandemic condition of the COVID-19 is increasing day by day, so many studies are required in COVID-19 patients along with the DIC severity to connect the immune system as well as the hemostatic system [39] (represented in Fig. 1 ).

The host immune system is responded upon interaction with the pathogen which activates the complement system. However, uncontrolled activation of the complement system leads to inflammation both acute and chronic, intravascular coagulation, injury of cell further leads to the multi-organ failure [40] . In the recently published article, the immunohistochemical studies in the lung tissue of the COVID-19 show that there is strong staining of the components of the complements system such as mannose-binding lectin (MBL), C3, C4, and C5b-9 (terminal membrane attack complex). Along with that, there is an increased level of serum C5a in COVID-19 patients [41] . In another study, an autopsy of the kidney shows that there is a strong deposition of the C5b-9, this activation of complement would contribute to the kidney failure [42] . This above study shows that the complement system is activated in the circulation, lungs, and kidney of the COVID-19 patients. There are 30 proteins are involved in the 3 active J o u r n a l P r e -p r o o f pathways of the complement system. These three pathways include the classical pathway, lectin pathway, and alternative pathway. The central component of this lectin and classical pathway is C3. This is cleaved by the enzymes in C3 convertases and produce the active products includes C3a, C3b, C4a, and C4b, this further eliminates the pathogens via magnetizing and triggers neutrophils and macrophages, activates humoral immunity and response of the T-cell and opsonization [40] . N protein of the SARS-CoV-2 activates the mannose-binding protein of the lectin associate with the serine protease 2 and mediates the deposition of the C4b both in the in vitro and the COVID-19 patient lung tissue [41] . The other study shows that the activated lectin pathway upon the pandemic virus may lead to a high level of the inflammatory response along with the infection of the virus [43] . Viral antigens associated with the immune response from both natural and induced antibodies generate the C1 level and initiate the activation of the complement system through the classical pathway [44] . Future studies are required for the determination of the association between the complement pathway (lectin and classical) involved in the clearance of the virus and its role in the inflammatory response and how it leads to tissue injury. COVID-19 coupled tissue injury with the inflammatory response is the terminal pathway, which constitutes the activation of the 3 complement cascades [45] . The C3b binding to the C3 convertases of the lectin/classical or alternative forms the convertases of the C5 which cleaves the C5 further produces the C5a and C5b. The potent complement peptides such as C5a is concerned in the triggering the response of the immune system [46] . C5b is involved in the generation of the C5b-9, which presses into the cell membrane, further causes the injury of the cell and organ dysfunction [47] . Two COVID-19 patients from China, received manifold injections of the C5a antibody BDB-001 reveals the normalization of the temperature of the body, elevated index of the oxygen, attenuated level of the C-reactive protein, and relive from J o u r n a l P r e -p r o o f Journal Pre-proof cough, oppression of the chest, and dyspnea [41] . COVID-19 connected with the vasculopathy and thrombosis pathological mechanism is not determined yet. But it has a central role in the dysfunction and injury of the endothelial cells. The COVID-19 patients are associated with endothelial dysfunction in different organs such as lung, kidney, liver, small bowel, and heart, along with the accumulation of the endothelial cells and inflammatory cells [48] . The classical pathway and lectin pathway activated by the SARS-CoV2 infected cells and organs leads to the production of the peptides such as C5a and C5b involved in the terminal pathway. This acts as a dysfunction of the endothelial cells associated with the COVID- 19 [49] . Along with the activation of the neutrophils and macrophages which promote the process of the inflammation, interaction of the C5aR on the C5a occurs in the endothelial cells [50] . The C5a changes the tissue factor by activating, thrombomodulin loss, which further mediates the process of coagulation and P-selectin exocytosis and von Willebrand factor, which nepotism the adhesion and aggregation of the platelet [51] . Along with that, C5b-9 activates the endothelial dysfunction, inclusive of the tissue factor expression and adhesion of the molecules [52] and it releases the platelet-activating factor and chemokines [53] , this further generates inflammation, augments the permeability of vascular, elicit the process of coagulation. C5b-9 acts as an influential agonist of the platelet by mediating the production of the storage granules and discharge microparticle of the platelet [54] . In the whole alterations mediated by the complement activation is observed in the COVID-19 patients. Along with the high level of lung dysfunction, to the extent, it includes the other organs such as blood vessels, heart, kidney, liver, brain, and gut [49, 55, 56] (represented in Fig. 2 ). computed chromatography (CT) shows that there is an abnormal lung with the alveolar damage which is responsible for acute respiratory distress syndrome in 8 patients. In almost all the cases there is an indication of mild pleurisy, inflammation is found in the thin layer of the tissue which separates the tissue of the lungs form the wall of the chest, patchy pattern with the pale areas, reddish and blue areas were found along with the increased the ratio of the capillary to fibre.

Also, it shows that there is an increased level of lactate dehydrogenase, D-dimer, C-reactive protein, and thrombocytopenia [58] . Some of the studies show that there is a tiny blood clot has been seen all over the lungs [59] . The earlier studies reported that COVID-19 patients are associated with the coagulopathy, which leads to the high-risk condition called pulmonary [63] . For concluding this, we need replication of the more data on pulmonary embolism patient with the COVID-19 especially ICU patients. Failure to determine and precisely deal with increases the worsening condition of the patients with COVID19 [64] (represented in Fig. 2, Fig. 3 , and table 1).

SARS-CoV-2 binds with the ACE2 receptor results in the deregulation of the angiotensin mechanism. It has mainly 3 roles, first, it activates angiotensin II via complement activation, this leads to hypercoagulability and microangiopathy with heme deregulation, this results in hypoxia and hypotension which leads to acute kidney injury (AKI). Second, the activated angiotensin II reduces angiotensin 1-7, causes hypercoagulability and microangiopathy. Third, the lymphopenia caused by it activates the myeloid cell which results in a cytokine storm further this leads to hypercoagulability and microangiopathy. These three result in hypoxia and hypotension via hypercoagulability and microangiopathy and further leads to the condition of acute kidney injury [65] . There is more evidence on SARS-Co-V2 and associated kidney disease. This is evidence that SARS-Co-V2 causes kidney injury. A kidney is one of the major organs which play an important role in the filters which excrete toxins, waste products, and extra water from our body.

This SARS-CoV2 condition causes the tiny clots in the bloodstream, which blocks the kidney's smallest blood vessels and further attenuates its function [66] . The other study recently shows J o u r n a l P r e -p r o o f Journal Pre-proof that kidney failure patients during SARS-Co-V2 conditions having a blood clot in the kidney.

Doctors form Sinai Hospital form New York are the first group who found the clots in both the kidney and lungs. Also, they found that the patients who have undergone kidney dialysis had clotted with blood in their catheters [67] . The study shows that the hospitals where the COVID-19 treatments are done in the need of ventilators but now they are required with the dialysis machine too. The study shows that 23% of the patients with COVID-19 admitted in intensive care are in the need of renal support [68] (represented in Fig. 2, Fig. 3, and table 1 ).

There are few studies with the evidence shows that COVID-19 patients with blood clots are having a higher risk of heart attack [69] . There is not much evidence for a blood clot in the heart.

One of the studies shows that the clot is observed in the heart. If it is untreated it leads to death or any other complications in the long term [70] (represented in Fig. 2, Fig. 3 and Table 1 ).

One of the studies from Washington post showed that the people who are died from the COVID-19 are having so many micro clots in their lungs which include maybe a hundred, shown during autopsies. This is not only due to pneumonia, but blood clot present in the lung might also cause severe damage in the liver [71] . The other study from China from the lab of the National Clinical Research Center for Respiratory Disease showed that there was a clot in organs of the small vessels, which includes the liver along with the lungs [72] . There is only a few evidence shows that there is a blood clot in the liver during SARS-CoV-2 infection. Much more studies are required on blood clot evidence as well as the mechanism behind it during COVID-19 infection (represented in Fig. 2, Fig. 3, and table 1 ).

A blood clot is found in the patients of COVID-19 in all over the world. The thrombosis occurs in the brain triggers a condition called a stroke. This is due to the blockage of large arteria due to the severe headache, fever, and cough. All those patients are having a high level of D-dimer.

Once the brain is affected by the virus through the nose, it was transmitted by the olfactory lobes in the neurons. This causes anosmia and loss of smell [68] . This makes the doctor challenging to manage this diseased condition along with the blood clot. Along with the severe problems in breathing, blood clots also became a significant problem in COVID-19 patients. The presence of clot in COVID-19 patients leads to heart attack and stroke. The patient is ill so, the doctor decided to give the drug called plasminogen activator (tPA) which is used to treat stroke to the COVID-19 patients. This is the powerful blood clot-busting drug with a high risk in case of improper usage. The patients show improvement after 30min of an implementation of the drug by regulating the carbon-di-oxide and oxygen. Patients survived for about one week but died later [73] . Ischemic strokes are found to be a common stroke, which is highly caused by the blood clots which block the brain blood vessel. COVID-19 patients associated with the strokes are having large vessel occlusions (LVOs). COVID-19 associated with heart dysfunction is at the high risk of the stroke due to the blood clot found in the heart and then movements into the brain. This is due to the reduced blood flow receiving into the brain provoked by the blood vessels with especially the treatment with the LMWH [17] . The unselected patients are still having the risk of COVID-19 associated coagulopathy after anti-coagulant treatment. The patients with a high level of prothrombotic conditions are treated with anticoagulation with the LMWH. This is highly beneficial to protect intracranial hemorrhage, inclusive of acute infarct hemorrhagic transformation via reducing the thromboembolism [75, 89] .

The baseline chest CT (non-contrast) would be measured in almost all the patients who are 

The catastrophe of the coagulation cascade contributes to the accumulation of the blood clot in the different organs and leads to multi-organ failure. The conclusion of this review is COVID-19 is associated with hypercoagulopathy in different organs. COVID-19 linked with the coagulopathy shows an increased level of the thrombin, fibrinogen and less lymphocyte count leads to lymphopenia. The activated platelet contributes to thrombocytopenia. COVID-19 connected with the Kawasaki disease in childhood has acute vasculitis, affects the vessels established all over the body. COVID-19 associated with the thrombotic microangiopathy aggravates the multiple vasculitis alongside with the arterioles thrombosis, medium, large venous and arterial vessels mediates the DIC. Endothelial dysfunction is associated with the 

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Features, evaluation and treatment coronavirus (COVID-19), StatPearls

Coronavirus disease (COVID-19) Pandemic

The first two cases of 2019-nCoV in Italy: Where they come from?

Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event

Bats may be SARS reservoir

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status

Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations: scientific brief

Aerosol and surface distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards

Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1

Coronaviruses pathogenesis, comorbidities and multiorgan damage-A review

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection

Serum concentrations of complement anaphylatoxins and proinflammatory mediators in patients with 2009 H1N1 influenza

A pathological report of three COVID-19 cases by minimally invasive autopsies, Zhonghua bing li xue za zhi= Chinese journal of pathology

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

COVID-19 and Kawasaki disease: novel virus and novel case

Haemostasis and innate immunity-a complementary relationship: a review of the intricate relationship between coagulation and complement pathways

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, The lancet

Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Proceedings of the biosimilars workshop at the International Symposium on Oncology Pharmacy Practice

Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

A familial cluster of pneumonia associated with the 2019 novel coronavirus J o u r n a l P r e -p r o o f indicating person-to-person transmission: a study of a family cluster

Clinical characteristics of 2019 novel coronavirus infection in China

Epidemiologic and clinical characteristics of novel coronavirus infections involving 13 patients outside Wuhan

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, The lancet

Mechanism of thrombocytopenia in COVID-19 patients

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia

COVID-19 Related Coagulopathy: A Distinct Entity?

Overview of complement activation and regulation

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

Mannose-binding lectin contributes to deleterious inflammatory response in pandemic H1N1 and avian H9N2 infection

Complement and viral pathogenesis

The role of C5a in acute lung injury induced by highly pathogenic viral infections, Emerging microbes & infections

Role of C5a in multiorgan failure during sepsis

Inhibition of C5 or absence of C6 protects from sepsis mortality

Expression of the anaphylatoxin C5a receptor in nonmyeloid cells

C5a induces tissue factor activity on endothelial cells

The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity

Neutrophil adhesion to human endothelial cells is induced by the membrane attack complex: the roles of P-selectin and platelet activating factor

Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity

A rampage through the body

Complement as a target in COVID-19?

Clinical pathology of critical patient with novel coronavirus pneumonia (COVID-19)

Autopsies of COVID-19 patients reveal clotting concerns

Mysterious blood clots in COVID-19 patients have doctors alarmed, Live science

Acute pulmonary embolism associated with COVID-19 pneumonia detected by pulmonary CT angiography

COVID-19 complicated by acute pulmonary embolism

Pulmonary embolism in patients with COVID-19: Time to change the paradigm of computed tomography

Acute pulmonary embolism in COVID-19 patients on CT Angiography and relationship to d-dimer levels

Pulmonary embolism in COVID-19 patients: Awareness of an increased prevalence

Acute Kidney Injury in COVID-19: Emerging Evidence of a Distinct Pathophysiology

Coronavirus: Kidney Damage Caused by COVID-19

COVID-19: Coronavirus causes blood clots to form in lungs, kidneys, US doctors reveal

From blood clots to ‗Covid toe': the medical mysteries of coronavirus

Blood clotting significant cause of death in COVID-19 patients: Study

Why COVID-19 could be causing blood clots-and what you can do to lower your risk

Coronavirus: Are blood clots killing COVID-19 patients?

COVID-19: Abnormal Clotting Common in More Severe Disease

Blood Clots Are Another Dangerous COVID-19 Mystery

COVID-19 Is Causing Blood Clots and Strokesin Some Patients-but Doctors Don't Know Why

Characteristics of ischaemic stroke associated with COVID-19

COVID-19 may increase blood clotting and blockage of brain blood vessels

Imaging reveals bowel abnormalities in patients with COVID-19

COVID-19: First bowel imaging study implicates blood clots

Blood Clots And More Possible Symptoms Of COVID-19

Unusual Symptoms of Coronavirus: What We Know So Far

Blood clots to ‗Covid Toes' -the virus attacks the whole body, not just the lungs

Coronavirus Causes Damaging Blood Clots From Brain to Toes

Pregnancy and perinatal outcomes of women with coronavirus disease (COVID-19) pneumonia: a preliminary analysis

Coronavirus disease 2019 (COVID-19) pandemic and pregnancy

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Coagulopathy of Coronavirus Disease

The third international consensus definitions for sepsis and septic shock (Sepsis-3)

Standardization Committee on DIC, t. Scientific, S.C.o. Perioperative, C.C.o.t.I.S.o. Thrombosis