ArticlePDF Available

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

April 2020
The New-England Medical Review and Journal 382(17)

DOI:10.1056/NEJMc2007575

Authors:

Yan Zhang

Sun Yat-Sen University

Meng Xiao

Peking Union Medical College Hospital

Shulan Zhang

Peking Union Medical College Hospital

Show all 35 authorsHide

Content uploaded by Wei Cao

Content may be subject to copyright.

Cor responde nce

The new england journal of medicine

n engl j med 382;17 nejm.org April 23, 2020

e38(1)

Covid-19 Cases

To rapidly communicate information on the global clinical effort against Covid-19, the Journal has initiated a

series of case reports that offer important teaching points or novel findings. The case reports should be viewed as

observations rather than as recommendations for evaluation or treatment. In the interest of timeliness, these reports

are evaluated by in-house editors, with peer review reserved for key points as needed.

Coagulopathy and Antiphospholipid Antibodies

in Patients with Covid-19

We describe a patient with Covid-19 and clinically

significant coagulopathy, ant iphospholipid ant i-

bodies, and multiple infarcts. He was one of three

patients with these findings in an intensive care

unit designated for patients with Covid-19. This

unit, which was managed by a multidisciplinar y

team from Peking Union Medical College Hospi-

tal in the Sino–French New City Branch of Tongji

Hospital in Wuhan, China, was set up on an

emergency basis to accept the most critically ill

patients during the outbreak of Covid-19. Severe

acute respirator y syndrome coronavirus 2 (SARS-

CoV-2) infection was confirmed in all the patients

by reverse-transcriptase–polymerase-chain-reaction

(RT-PCR) assay or serologic testing.

A 69-year-old man with a history of hyperten-

sion, diabetes, and stroke presented with fever,

cough, dyspnea, diarrhea, and headache. Covid-19

was diagnosed in the patient on January 25, 2020,

on the basis of RT-PCR testing that detected

SARS-CoV-2. The initial treatment was support-

ive; however, the illness subsequently progressed

to hypoxemic respiratory failure warranting the

initiation of invasive mechanical ventilation.

Table 1. Demographic and Clinical Characteristics and Laboratory Findings.*

Characteristic Patient 1 Patient 2 Patient 3

Demographic characteristics

Age — yr 69 65 70

Sex Male Female Male

Initial findings

Medical history Hypertension, diabetes,

stroke

Hypertension, diabetes,

coronary artery

disease, no history

of thrombosis

Hypertension, emphysema,

nasopharyngeal

carcinoma, stroke

Symptoms at disease onset Fever, cough, dyspnea,

diarrhea, headache

Fever, cough, dyspnea Fever, fatigue, dyspnea,

headache

Imaging features Ground-glass opacity,

bilateral pulmonary

infiltrates

Ground-glass opacity,

bilateral pulmonary

infiltrates

Bilateral pulmonary

infiltrates

Treatment before admission to ICU Oseltamivir, intravenous

immune globulin

Antibiotics Antibiotics, ribavirin,

rosuvastatin

Days from disease onset to thrombotic event 18 33 10

Findings on admission to ICU

Days since disease onset 24 21 24

Disease severity Critical Critical Critical

The New England Journal of Medicine

Downloaded from nejm.org on May 5, 2020. For personal use only. No other uses without permission.

The

new england journal

medicine

n engl j med 382;17 nejm.org April 23, 2020

e38(2)

On examination, the patient had evidence of

ischemia in the lower limbs bilaterally as well as

in digits two and three of the left hand. Computed

tomographic imaging of the brain showed bilat-

eral cerebral infarcts in multiple vascular territo-

ries. Pertinent laboratory results on admission of

the patient (Patient 1) to the intensive care unit are

summarized in Table 1. They included leukocyto-

sis, thrombocytopenia, an elevated prothrombin

time and partial thromboplastin time, and elevat-

ed levels of fibrinogen and

-dimer. Subsequent

serologic testing showed the presence of anti-

cardiolipin IgA antibodies as well as anti–β

glycoprotein I IgA and IgG antibodies.

Two other patients with similar findings were

seen at the specialized intensive care unit for pa-

tients with Covid-19 at Tongji Hospital. Serologic

tests in these patients were positive for anticardio-

lipin IgA antibodies as well as anti–β

-glycoprotein

I IgA and IgG antibodies. Further clinical details

are summarized in Table 1. Lupus anticoagulant

was not detected in any of the patients, although

Characteristic Patient 1 Patient 2 Patient 3

Laboratory findings

White-cell count (per mm

) 17,790 6730 8710

Differential count (per mm

)

Total neutrophils 16,290 6230 7090

Total lymphocytes 430 290 790

Total monocytes 800 170 430

Platelet count (per mm

) 78,000 79,000 180,000

Hemoglobin (g/liter) 111 99 92

Albumin (g/liter) 26.3 32.6 24.4

Alanine aminotransferase (U/liter) 15 11 8

Aspartate aminotransferase (U/liter) 23 20 20

Lactate dehydrogenase (U/liter) 632 233 417

Creatinine (μmol/liter) 80 58 86

Creatine kinase (U/liter) 63 335 16

EGFR (ml/min/1.73 m

) 86.6 93.2 78.5

High-sensitivity cardiac troponin I (pg/ml) 3876.8 14.3 125.4

Prothrombin time (sec) 17.0 17.2 15.1

Activated partial-thromboplastin time (sec) 43.7 45.3 47.6

Fibrinogen (g/liter) 4.15 4.42 6.42

Fibrin degradation products (mg/liter) 85.5 8.1 7.3

-dimer (mg/liter) >21.00 2.84 3.23

Serum ferritin (μg/liter) ND 2207.8 ND

Procalcitonin (ng/ml) 0.11 0.18 0.40

High-sensitivity C-reactive protein (mg/liter) 112.0 56.0 125.4

Antiphospholipid antibodies Anticardiolipin IgA,

anti–β

-glycoprotein I

IgA and IgG

Anticardiolipin IgA,

anti–β

-glycoprotein I

IgA and IgG

Anticardiolipin IgA,

anti–β

-glycoprotein I

IgA and IgG

Imaging features Multiple cerebral infarctions

in bilateral frontal parietal

occipital lobe and bilat-

eral basal ganglia, brain

stem, and bilateral cer-

ebellar hemispheres

Multiple cerebral infarc-

tions in right frontal

and bilateral parietal

lobe

Multiple cerebral infarctions

in frontal lobe, right fron-

tal parietal temporal oc-

cipital lobe, and bilateral

cerebellar hemispheres

* EGFR denotes estimated glomerular filtration rate, ICU intensive care unit, and ND not determined.

Table 1. (Continued)

The New England Journal of Medicine

Downloaded from nejm.org on May 5, 2020. For personal use only. No other uses without permission.

Cor re spondence

n engl j med 382;17 nejm.org April 23, 2020

e38(3)

testing was performed while the patients were

acutely ill.

Antiphospholipid antibodies abnormally t ar-

get phospholipid proteins, and the presence of

these antibodies is central to the diagnosis of the

antiphospholipid syndrome. However, these anti-

bodies can also arise transiently in patients with

critical illness and various infections.

The pres-

ence of these antibodies may rarely lead to throm-

botic events that are difficult to differentiate from

other causes of multifocal thrombosis in critically

patients, such as disseminated intravascular co-

agulation, heparin-induced thrombocytopenia,

and thrombotic microangiopathy.

Yan Zhang, M.D.

Meng Xiao, M.Sc.

Shulan Zhang, M.D.

Peng Xia, M.D.

Wei Cao, M.D.

Wei Jiang, M.D.

Huan Chen, M.D.

Xin Ding, M.D.

Hua Zhao, M.D.

Hongmin Zhang, M.D.

Chunyao Wang, M.D.

Jing Zhao, M.D.

Xuefeng Sun, M.D.

Ran Tian, M.D.

Wei Wu, M.D.

Dong Wu, M.D.

Jie Ma, M.D.

Yu Chen, B.S.

Dong Zhang, M.Sc.

Jing Xie, Ph.D.

Xiaowei Yan, M.D.

Xiang Zhou, M.D.

Zhengyin Liu, M.D.

Jinglan Wang, M.D.

Bin Du, M.D.

Yan Qin, M.D.

Peng Gao, M.D.

Xuzhen Qin, M.D.

Yingchun Xu, M.D.

Wen Zhang, M.D.

Taisheng Li, M.D.

Fengchun Zhang, M.D.

Yongqiang Zhao, M.D.

Yongzhe Li, M.D.

Shuyang Zhang, M.D.

Peking Union Medical College Hospital

Beijing, China

yongzhelipumch@ 126 . com

shuyangzhang103@ 163 . com

Dr. Yan Zhang, Mr. Meng Xiao, and Dr. Shulan Zhang and

Drs. Shuyang Zhang and Yongzhe Li contributed equally to t his

case.

Supported by gra nts to Dr. Yongzhe L i from t he Nation al

Natural Science Foundat ion of China (81671618 and 81871302)

and the Ch inese Ac ademy of Med ical Sciences Initi ative for In-

novat ive Medicine (2017-I2M-3-0 01 and 2017-I2M-B&R-01).

Disclosure forms provided by the authors are avail able wit h

the fu ll text of th is case at NEJM.org.

This case was published on April 8, 2020, at NEJM.org.

1. Uthma n IW, Gharav i AE. Viral infect ions and antiphospho-

lipid ant ibodies. Semin Art hrit is Rheum 2002; 31(4): 256-63.

DOI: 10.1056/NEJMc2007575

The New England Journal of Medicine

Downloaded from nejm.org on May 5, 2020. For personal use only. No other uses without permission.

Arterial floating mural thrombi are a characteristic imaging pattern in SARS-CoV-2-related ischemic stroke

Article

Full-text available

Oct 2024
PLOS ONE

Background Acute ischemic stroke (AIS) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to explore neurovascular imaging patterns in patients with SARS-CoV-2-related AIS. Methods We retrospectively analyzed clinical and radiological data of patients hospitalized with AIS and a positive PCR test for SARS-CoV-2 prior to AIS onset. The control group comprised of AIS patients from a pre-COVID-19 pandemic period matched for gender and age. Results Thirty-five SARS-CoV-2-related stroke patients, and 35 controls were included. Fifty-seven percent of SARS-CoV-2 patients had either mild or asymptomatic disease. A distinctive imaging pattern of floating arterial mural thrombus was detected in 5 patients of the SARS-CoV-2 group. In 4 patients thrombus was attached to a stenotic atherosclerotic plaque in the proximal internal carotid artery. In the 5th patient a cardiac CTA showed multiple floating thrombi in the descending aorta. In the control group, floating thrombus was only detected in one patient. Treatment with dual antiplatelet therapy was associated with thrombus dissolution and good clinical outcome. Patients with floating thrombi had a longer time from SARS-CoV-2 diagnosis to stroke onset (mean 7.4 versus 3.4 days). Conclusions Floating arterial mural thrombi attached to atherosclerotic plaques are unique characteristic source of AIS in SARS-CoV-2 patients. They may lead to ischemic stroke in patients with mild or asymptomatic infection up to 1–2 weeks from SARS-CoV-2 diagnosis. Patients with embolic AIS and SARS-CoV-2 diagnosis should perform high resolution cranio-cervical vascular imaging to evaluate floating thrombi as a potential embolic source.

Chapter -1 Risk Factor of Corona Virus infection in Diabetic Patients

Chapter

Full-text available

Mar 2023

Akanksha Jain

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the health of diabetic people in 2019 (COVID-19). Moreover, COVID-19 infection may increase a person's risk of developing hyperglycemia. Hyperglycemia may interact with other risk factors to modify immunological and inflammatory responses, making patients more susceptible to severe COVID-19 and potentially fatal results. The primary receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), which is part of the renin-angiotensin-aldosterone system (RAAS); however, dipeptidyl peptidase 4 (DPP4) may also operate as a binding target. However, preliminary findings do not indicate that DPP4 inhibitors, which lower blood sugar levels, have any discernible effect on susceptibility to SARS-CoV-2. Patients with COVID-19 should not take sodium-glucose cotransporter 2 (SGLT2) inhibitors because of the risk of side effects associated with this class of drugs. Acute glycemia should mostly be managed with insulin at present. Due to its great prevalence, type 2 diabetes mellitus is associated with the majority of the available evidence, which does not differentiate between the primary kinds of diabetes mellitus.

The well-defined antiphospholipid syndrome induced by COVID-19: a rare case report and review of the literature

Article

Full-text available

Nov 2024
Thromb J

COVID-19 may induce a state of hypercoagulability, particularly in critically ill patients, for reasons that remain unknown. Numerous studies have identified the presence of antiphospholipid antibodies in patients with COVID-19; however, the definitive diagnosis of antiphospholipid syndrome continues to pose challenges. Here, we present the case of a patient infected with SARS-CoV-2 who developed life-threatening severe thrombocytopenia, profound anaemia, acute pulmonary hypertension, right ventricular failure, and renal insufficiency. Laboratory investigations revealed significantly elevated levels of antiphospholipid antibodies. We conducted a one-year follow-up study with blood sampling performed every 12 weeks. The patient exhibited persistent high titres of antiphospholipid antibodies and ongoing renal dysfunction necessitating daily oral warfarin antithrombotic therapy. Antiphospholipid syndrome is a complex clinical condition that poses challenges for clinicians, particularly in critically ill patients, and is often associated with delayed and inaccurate diagnosis and treatment. Therefore, we extensively reviewed the literature and international guidelines to conduct a comprehensive analysis of the aetiology, pathogenesis, and treatment strategies of APS. We hope this work will provide a valuable reference for health care professionals.

Inflammation, immunity and biomarkers in procoagulant responses of critically ill patients

Article

Oct 2024

Hui Lian

Defined neuroaspergillosis in immunocompetent patients following COVID-19 infection: two cases and literature review

Preprint

Full-text available

Oct 2024

In recent years, the advent of the SARS-Cov-2 pandemic has seen the emergence of neurological aspergillosis as a rare complication in immunocompetent patients infected with this pathogen. Neuroaspergillosis is a rare but serious infection of the central nervous system, typically observed in patients with compromised immune systems. This article presents a case series of two patients with aspergillosis associated with SARS-CoV-2 infection at Peking Union Medical College Hospital and offers a literature review on this topic. This study included two cases of neuroaspergillosis associated with SARS-CoV-2 infection. A search was conducted on PubMed for reports of neuroaspergillosis related to SARS-CoV-2, and a literature review was subsequently performed. The study examined the characteristics of the patients, the clinical manifestations, the treatment, and the prognosis. The findings revealed that the primary symptoms of neuroaspergillosis associated with SARS-CoV-2 infection included impaired consciousness, focal neurological deficits, and headaches, with a high mortality rate. The clinical diagnosis and treatment of the disease were challenging due to the difficulty of early detection and diagnosis. This study reviews the mechanism, clinical manifestations, diagnosis, and treatment strategies of neuroaspergillosis in immunocompetent patients after SARS-CoV-2 infection. Furthermore, it discusses the clinical characteristics of the disease through two cases. Early diagnosis and treatment are essential for effective management of the disease.

Thromboembolism: the secret lethal weapon of coronavirus disease 2019

Article

Jan 2023

Covid-19 (COVID-19) is a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which began in Wuhan, China, and spread globally in the last few months. COVID-19 pandemic affects anticoagulation, in most patients who need regular anticoagulant care, not just those infected with (SARS-CoV-2). In patients with COVID-19, coagulopathy causes morbidity and mortality. Yet the mechanisms are uncertain and there are few biomarkers. Venous thromboembolism, a possible reason for unexplained mortality, has often been documented in cases of COVID-19, but because of the complexities of antithrombotic treatment and coagulation disorders, its management is still challenging. So, because of the emergency of the COVID-19 pandemic and the unknown risks about its coagulopathy management, we intended to provide such a literature review on the potential blood clotting disorder mechanisms, the unique characteristics of COVID-19 coagulopathy, the effect of heparin in COVID-19, prevention and risk assessment for venous thromboembolism, anticoagulation management in venous thromboembolism, diagnosis and treatment of thromboembolism, and thrombolytic therapy in pregnancy in COVID-19. Here, our overview may provide useful information for physicians to enable them to manage COVID-19 coagulopathy.

Postoperative multiple perforations of the small bowel in a patient with COVID-19 - case report

Article

Full-text available

Nov 2024
Rom J Morphol Embryol

During the coronavirus disease 2019 (COVID-19) pandemic, the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presented quite a diverse symptomatology, in addition to respiratory symptoms, while other clinical signs such as thrombosis, postoperative hemorrhages, acute kidney or liver failure, digestive disorders (vomiting and diarrheal stools) were also reported. We present the case of a patient diagnosed with transverse colon neoplasm and asymptomatic SARS-CoV-2 infection, who presented to the Emergency Room (ER) of the Emergency County Clinical Hospital, Craiova, Romania, with a clinical picture of low intestinal occlusion. Surgery was decided and a right hemicolectomy extended to the left, with terminal ileostomy performed. The postoperative evolution was favorable, with the resumption of intestinal transit and discharge on the third postoperative day. The patient returned to the ER Department on the fifth day after surgery, with diffuse abdominal pain, absence of intestinal transit and flatulence. Clinical examination of the abdomen revealed the presence of bloating sounds on palpation. Emergency laparotomy was again performed with the suspicion of postoperative occlusion and five perforations were found in the small bowel, associated with fecaloid peritonitis and mechanic-inflammatory occlusion. The perforations were without any obvious lesion substrate, four of them being located on the jejunum and one on the terminal ileum. The histopathological examination revealed hemorrhage and recent transmural thrombosis on the intestinal wall, most likely caused by COVID-19. Without any respiratory symptoms, the COVID-19 infection caused multiple intestinal lesions, leading to peritonitis and septic shock, followed by the patient’s death.

Determining the effectiveness of direct parenteral anticoagulants in patients infected with SARS-CoV-2

Article

Jan 2024

Role of ACE Inhibitors and Angiotensin Receptor Blockers in Covid19 Patients

Chapter

Jan 2024

Mukesh Nandave

COVID-19, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. The virus binds to angiotensin-converting enzyme-2 (ACE2) receptors to enter host cells, but its role in lung and heart injury remains debated. Angiotensin II (Ang-II) is implicated in severe lung damage due to ACE2 downregulation during infection. ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), widely used for hypertension, may increase ACE2 expression, raising concerns about their impact on COVID-19 patients. While some studies suggest ACEIs/ARBs could worsen COVID-19 outcomes, others propose protective effects by restoring ACE1/ACE2 balance. Despite limited conclusive data, professional bodies recommend continuing ACEIs/ARBs in COVID-19 patients. Meta-analyses indicate no significant increase in severe outcomes for hypertensive COVID-19 patients using these medications.

MANIFESTAÇÕES CUTÂNEAS DA COVID-19

Article

Full-text available

Oct 2024

Manifestações extrapulmonares da COVID-19 têm sido relatadas na literatura. Dentre elas, as manifestações cutâneas começaram a ser investigadas a partir da publicação de um artigo chinês e outro italiano. A partir daí, diversos estudos começaram a ser publicados relatando a apresentação de manifestações cutâneas da COVID-19, principalmente em pacientes com casos leves ou assintomáticos. Existem diferentes hipóteses para o aparecimento dessas lesões, que devem ser comprovadas ao longo das pesquisas subsequentes. No entanto, sabe-se que essas manifestações cutâneas podem ter relação direta do vírus SARS-CoV-2 sob as células da pele ou podem ser reações decorrentes de lesões vasculares causadas pelo vírus. É importante que enfermeiros tenham conhecimento sobre a possibilidade de lesões de pele serem decorrentes de manifestações da COVID-19 e que ainda conheçam as características dessas lesões. A equipe de enfermagem é responsável pelo primeiro atendimento dos pacientes, principalmente na Atenção Primária à Saúde que é a porta de entrada do serviço de saúde e de testagem da COVID-19 pelo Sistema Único de Saúde. Recomendamos que enfermeiros suspeitem de COVID-19 ao identificarem lesões de pele sem causa definida e que recomendem a realização de teste de COVID-19.

Viral infections and antiphospholipid antibodies

Article

Mar 2002
SEMIN ARTHRITIS RHEU

To study the relationship between viral infections and the induction of antiphospholipid (aPL) antibodies. We reviewed the medical literature from 1968 until 2000 using MEDLINE and the key words virus, infection, antiphospholipid, and anticardiolipin. Anticardiolipin antibodies and/or lupus anticoagulant were associated with a number of viral infections, including hepatitis C virus, human immunodeficiency virus, cytomegalovirus, varicella zoster, Epstein-Barr virus, adenovirus, and parvovirus B. In many instances, the presence of these antibodies was associated with thrombosis. The clinical significance of finding aPL antibodies in patients with viral infections remains unknown. In some patients, these antibodies may be transient and disappear within 2 or 3 months. In other susceptible individuals, they may persist and raise the question of whether infections may trigger the development of aPL antibodies in autoimmune diseases.