A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients
Identifieur interne : 000601 ( Pmc/Corpus ); précédent : 000600; suivant : 000602A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients
Auteurs : J. Justin Mulvey ; Cynthia M. Magro ; Lucy X. Ma ; Gerard J. Nuovo ; Rebecca N. BaergenSource :
- Annals of Diagnostic Pathology [ 1092-9134 ] ; 2020.
Abstract
COVID-19, the disease caused by the novel Coronavirus, SARS-CoV-2, is increasingly being recognized as a systemic thrombotic and microvascular injury syndrome that may have its roots in complement activation. We had the opportunity to study the placental pathology of five full-term births to COVID-19 patients, making up the entirety of such deliveries at our hospital. All five exhibited histology indicative of fetal vascular malperfusion characterized by very focal avascular villi and thrombi in larger fetal vessels. Vascular Complement deposition in the placentas was not abnormal, and staining for viral RNA and viral spike protein was negative. While all cases resulted in healthy, term deliveries, these findings indicate the systemic nature of COVID-19 infection. The finding of vascular thrombosis without complement deposition may reflect the systemic nature of COVID-19's procoagulant effects unrelated to systemic complement activation.
Url:
DOI: 10.1016/j.anndiagpath.2020.151530
PubMed: NONE
PubMed Central: 7182529
Links to Exploration step
PMC:7182529Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients</title><author><name sortKey="Mulvey, J Justin" sort="Mulvey, J Justin" uniqKey="Mulvey J" first="J. Justin" last="Mulvey">J. Justin Mulvey</name><affiliation><nlm:aff id="af0005">Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, United States of America</nlm:aff></affiliation></author><author><name sortKey="Magro, Cynthia M" sort="Magro, Cynthia M" uniqKey="Magro C" first="Cynthia M." last="Magro">Cynthia M. Magro</name><affiliation><nlm:aff id="af0010">Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</nlm:aff></affiliation></author><author><name sortKey="Ma, Lucy X" sort="Ma, Lucy X" uniqKey="Ma L" first="Lucy X." last="Ma">Lucy X. Ma</name><affiliation><nlm:aff id="af0010">Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</nlm:aff></affiliation></author><author><name sortKey="Nuovo, Gerard J" sort="Nuovo, Gerard J" uniqKey="Nuovo G" first="Gerard J." last="Nuovo">Gerard J. Nuovo</name><affiliation><nlm:aff id="af0015">The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States of America</nlm:aff></affiliation><affiliation><nlm:aff id="af0020">Discovery Life Sciences, Powell, OH, United States of America</nlm:aff></affiliation></author><author><name sortKey="Baergen, Rebecca N" sort="Baergen, Rebecca N" uniqKey="Baergen R" first="Rebecca N." last="Baergen">Rebecca N. Baergen</name><affiliation><nlm:aff id="af0010">Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7182529</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182529</idno><idno type="RBID">PMC:7182529</idno><idno type="doi">10.1016/j.anndiagpath.2020.151530</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000601</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000601</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients</title><author><name sortKey="Mulvey, J Justin" sort="Mulvey, J Justin" uniqKey="Mulvey J" first="J. Justin" last="Mulvey">J. Justin Mulvey</name><affiliation><nlm:aff id="af0005">Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, United States of America</nlm:aff></affiliation></author><author><name sortKey="Magro, Cynthia M" sort="Magro, Cynthia M" uniqKey="Magro C" first="Cynthia M." last="Magro">Cynthia M. Magro</name><affiliation><nlm:aff id="af0010">Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</nlm:aff></affiliation></author><author><name sortKey="Ma, Lucy X" sort="Ma, Lucy X" uniqKey="Ma L" first="Lucy X." last="Ma">Lucy X. Ma</name><affiliation><nlm:aff id="af0010">Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</nlm:aff></affiliation></author><author><name sortKey="Nuovo, Gerard J" sort="Nuovo, Gerard J" uniqKey="Nuovo G" first="Gerard J." last="Nuovo">Gerard J. Nuovo</name><affiliation><nlm:aff id="af0015">The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States of America</nlm:aff></affiliation><affiliation><nlm:aff id="af0020">Discovery Life Sciences, Powell, OH, United States of America</nlm:aff></affiliation></author><author><name sortKey="Baergen, Rebecca N" sort="Baergen, Rebecca N" uniqKey="Baergen R" first="Rebecca N." last="Baergen">Rebecca N. Baergen</name><affiliation><nlm:aff id="af0010">Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</nlm:aff></affiliation></author></analytic><series><title level="j">Annals of Diagnostic Pathology</title><idno type="ISSN">1092-9134</idno><idno type="eISSN">1532-8198</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>COVID-19, the disease caused by the novel Coronavirus, SARS-CoV-2, is increasingly being recognized as a systemic thrombotic and microvascular injury syndrome that may have its roots in complement activation. We had the opportunity to study the placental pathology of five full-term births to COVID-19 patients, making up the entirety of such deliveries at our hospital. All five exhibited histology indicative of fetal vascular malperfusion characterized by very focal avascular villi and thrombi in larger fetal vessels. Vascular Complement deposition in the placentas was not abnormal, and staining for viral RNA and viral spike protein was negative. While all cases resulted in healthy, term deliveries, these findings indicate the systemic nature of COVID-19 infection. The finding of vascular thrombosis without complement deposition may reflect the systemic nature of COVID-19's procoagulant effects unrelated to systemic complement activation.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zhu, N" uniqKey="Zhu N">N. Zhu</name></author><author><name sortKey="Zhang, D" uniqKey="Zhang D">D. Zhang</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W. Wang</name></author><author><name sortKey="Li, X" uniqKey="Li X">X. Li</name></author><author><name sortKey="Yang, B" uniqKey="Yang B">B. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Diagn Pathol</journal-id><journal-id journal-id-type="iso-abbrev">Ann Diagn Pathol</journal-id><journal-title-group><journal-title>Annals of Diagnostic Pathology</journal-title></journal-title-group><issn pub-type="ppub">1092-9134</issn><issn pub-type="epub">1532-8198</issn><publisher><publisher-name>Published by Elsevier Inc.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7182529</article-id><article-id pub-id-type="publisher-id">S1092-9134(20)30071-X</article-id><article-id pub-id-type="doi">10.1016/j.anndiagpath.2020.151530</article-id><article-id pub-id-type="publisher-id">151530</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0005"><name><surname>Mulvey</surname><given-names>J. Justin</given-names></name><xref rid="af0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0010"><name><surname>Magro</surname><given-names>Cynthia M.</given-names></name><xref rid="af0010" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0015"><name><surname>Ma</surname><given-names>Lucy X.</given-names></name><xref rid="af0010" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0020"><name><surname>Nuovo</surname><given-names>Gerard J.</given-names></name><xref rid="af0015" ref-type="aff">c</xref><xref rid="af0020" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au0025"><name><surname>Baergen</surname><given-names>Rebecca N.</given-names></name><email>rbaergen@med.cornell.edu</email><xref rid="af0010" ref-type="aff">b</xref><xref rid="cr0005" ref-type="corresp">⁎</xref></contrib><aff id="af0005"><label>a</label>Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, United States of America</aff><aff id="af0010"><label>b</label>Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America</aff><aff id="af0015"><label>c</label>The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States of America</aff><aff id="af0020"><label>d</label>Discovery Life Sciences, Powell, OH, United States of America</aff></contrib-group><author-notes><corresp id="cr0005"><label>⁎</label>Corresponding author at: Weill Cornell Medicine, Surgical Pathology, Starr-1002, 520 East 70<sup>th</sup> Street, United States of America. <email>rbaergen@med.cornell.edu</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>25</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>25</day><month>4</month><year>2020</year></pub-date><elocation-id>151530</elocation-id><permissions><copyright-statement>© 2020 Published by Elsevier Inc.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="ab0005"><p>COVID-19, the disease caused by the novel Coronavirus, SARS-CoV-2, is increasingly being recognized as a systemic thrombotic and microvascular injury syndrome that may have its roots in complement activation. We had the opportunity to study the placental pathology of five full-term births to COVID-19 patients, making up the entirety of such deliveries at our hospital. All five exhibited histology indicative of fetal vascular malperfusion characterized by very focal avascular villi and thrombi in larger fetal vessels. Vascular Complement deposition in the placentas was not abnormal, and staining for viral RNA and viral spike protein was negative. While all cases resulted in healthy, term deliveries, these findings indicate the systemic nature of COVID-19 infection. The finding of vascular thrombosis without complement deposition may reflect the systemic nature of COVID-19's procoagulant effects unrelated to systemic complement activation.</p></abstract><abstract abstract-type="author-highlights" id="ab0010"><title>Highlights</title><p><list list-type="simple" id="l0005"><list-item id="li0005"><label>•</label><p id="p0005">This paper explores thrombosis in the placentas COVID-19-positive patients at our hospital which at the time of publication made-up 100% of COVID-19-positive delivering patients.</p></list-item><list-item id="li0010"><label>•</label><p id="p0010">Potential prothrombotic mechanisms are explored.</p></list-item><list-item id="li0015"><label>•</label><p id="p0015">Direct infection of the placentas is ruled out as a cause.</p></list-item></list></p></abstract></article-meta></front><body><sec id="s0005"><label>1</label><title>Introduction</title><p id="p0020">The severe acute respiratory distress syndrome-associated coronavirus-2 (SARS-CoV-2), etiologic agent of Coronavirus disease 2019 (COVID-19), emerged in December 2019 in Wuhan, China [<xref rid="bb0005" ref-type="bibr">1</xref>]. Now a global pandemic [<xref rid="bb0010" ref-type="bibr">2</xref>], the virus has infected over 2.2million people and claimed the lives of over 150,000 people [<xref rid="bb0015" ref-type="bibr">3</xref>]. The majority of people with COVID-19 have a self-limited illness; however, high mortality rates have been reported in the elderly and certain immune-suppressed populations [<xref rid="bb0020" ref-type="bibr">[4]</xref>, <xref rid="bb0025" ref-type="bibr">[5]</xref>, <xref rid="bb0030" ref-type="bibr">[6]</xref>]. Although there is evidence of vertical, intrauterine transmission [<xref rid="bb0035" ref-type="bibr">7</xref>,<xref rid="bb0040" ref-type="bibr">8</xref>], propitiously no maternal or neonatal mortalities have been reported to date.</p><p id="p0025">The SARS-CoV-2 virus shares its name with the SARS-CoV virus, which caused the 2002 outbreak in south China, as well as symptomology and a common cellular entry point, angiotensin converting enzyme 2 (ACE2) [<xref rid="bb0045" ref-type="bibr">[9]</xref>, <xref rid="bb0050" ref-type="bibr">[10]</xref>, <xref rid="bb0055" ref-type="bibr">[11]</xref>, <xref rid="bb0060" ref-type="bibr">[12]</xref>]. ACE2 is a zinc metalloprotease involved in the homeostatic balance of the renin-angiotensin-aldosterone axis, and is expressed in a variety of tissues including the nasopharynx, lung, and intestines, accounting for COVID-19's symptomatology of respiratory and digestive distress and diarrhea [<xref rid="bb0020" ref-type="bibr">4</xref>,<xref rid="bb0065" ref-type="bibr">13</xref>]. There are myriad mechanisms working in concert that seed the clinical and pathologic features of COVID-19; this virus is endotheliotropic, damaging endothelium primarily through complement activation and also causing vascular thrombosis [<xref rid="bb0070" ref-type="bibr">14</xref>].</p><p id="p0030">There is emerging body of literature and earlier evidence from the SARS-CoV era that the ACE2 entry mechanism, and the subsequent post entry deactivation of ACE2 plays an important role in COVID19 morbidity [<xref rid="bb0070" ref-type="bibr">14</xref>,<xref rid="bb0075" ref-type="bibr">15</xref>]. The ACE2 loss results in a pathologic increase in Angiotensin II over Angiotensin (1–7) tone systemically that leads, through their respective receptors AT1 and MAS, to complement activation, vasoconstriction, and thrombosis [<xref rid="bb0080" ref-type="bibr">[16]</xref>, <xref rid="bb0085" ref-type="bibr">[17]</xref>, <xref rid="bb0090" ref-type="bibr">[18]</xref>]. When ACE2 proteins are internalized and destroyed, or the cell hosting many such proteins are destroyed by the virus, the resultant imbalance of Angiotensin II and Angiotensin (1–7) in the blood decreases the activity of endothelial nitrous oxide synthase (eNOS) [<xref rid="bb0095" ref-type="bibr">19</xref>]. eNOS, a potent down-regulator of the production of tissue factor (TF) through nitrous oxide(NO), is also a well-known vasodilator [<xref rid="bb0100" ref-type="bibr">20</xref>]. Another effect of this angiotensin subtype imbalance is increasing NOX-2 activity, which produces radical oxygen species that causes cellular damage [<xref rid="bb0105" ref-type="bibr">21</xref>]. These inflammatory radical oxygen species react with and thereby are a mechanism for disabling NO, further increasing vasoconstriction [<xref rid="bb0110" ref-type="bibr">22</xref>]. The now contracted vessels associated with higher levels of TF and concurrent cellular damage from ROS made by NOX-2 creates a microenvironment conducive for inflammation and thrombosis [<xref rid="bb0115" ref-type="bibr">23</xref>].</p><p id="p0035">The same spike protein that gains entry to cells via ACE2 is suspected to activate the mannose-binding lectin (MBL) complement pathway via MASP-2, just as SARS-CoV was shown to do over a decade ago [<xref rid="bb0120" ref-type="bibr">24</xref>,<xref rid="bb0125" ref-type="bibr">25</xref>]. Complement deposition in major, blood-bathed organ systems can have systemic procoagulant effects. Complement activation product C3a activates platelets [<xref rid="bb0130" ref-type="bibr">26</xref>], and C5a increases the expression and activity of the potent coagulation initiator, tissue factor (TF), in both macrophages and the endothelium [<xref rid="bb0135" ref-type="bibr">[27]</xref>, <xref rid="bb0140" ref-type="bibr">[28]</xref>, <xref rid="bb0145" ref-type="bibr">[29]</xref>]. Reciprocally, there is the ability of FXa, thrombin, and FIXa to trigger the complement cascade by acting as independent C3 and C5 convertases [<xref rid="bb0145" ref-type="bibr">29</xref>] to create a feed forward mechanism. Uniquely fitting to the proposed MBL-pathway complement activation by SARS-CoV-2, MASP-2 can cleave prothrombin into thrombin [<xref rid="bb0150" ref-type="bibr">30</xref>].</p><p id="p0040">Viral-specific thrombus-promoting pathways aside, the placenta has many defenses against hemorrhage that predispose it to thrombosis, most notably high levels of TF in placental trophoblasts and Plasminogen Activator Inibitor-2 (PAI-2) production. After central nervous system (CNS) astrocytes and ahead of lung alveolar cells, placental trophoblasts are the most densely packed TF-expressing cells [<xref rid="bb0135" ref-type="bibr">27</xref>]. PAI-2 is a procoagulant suicide-inhibitor of tissue plasminogen activator (tPA) that is unique to the placental trophoblasts and to a far lesser extent, macrophages [<xref rid="bb0155" ref-type="bibr">31</xref>]. The inhibitor to fibrinolysis is nearly undetectable before pregnancy, and rises over the gravid course [<xref rid="bb0160" ref-type="bibr">32</xref>]. PAI-2 forms dense polymers in the placenta, and may be fragmented and activated by redox potential [<xref rid="bb0165" ref-type="bibr">33</xref>,<xref rid="bb0170" ref-type="bibr">34</xref>], and an important connection to the previously-discussed effect of Angiotensin II predominance on NOX-2 which produces oxidizing free radicals.</p><p id="p0045">In combination, the inherent thrombophilic state of pregnancy state including increased FVIII and vWF activities [<xref rid="bb0175" ref-type="bibr">35</xref>,<xref rid="bb0180" ref-type="bibr">36</xref>], the prothrombotic effects SARS-CoV-2 infection pathology, and placental physiography and molecular mechanics, provides a logical explanation for why placentas in COVID19 infected patients could potentially be susceptible to thrombus formation, as illustrated in the following 5 cases. Key placental histology is reviewed compared to healthy, normal-vaginal-delivery placental as a control. Components of complement activation and viral staining are explored to see whether or not there is direct infection of the placenta (<xref rid="t0005" ref-type="table">Table 1</xref>).<table-wrap position="float" id="t0005"><label>Table 1</label><caption><p>Patient information for five RT-PCR confirmed COVID-19 mothers.</p></caption><alt-text id="al0010">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Case</th><th>GA</th><th>Maternal age</th><th>Mode of delivery</th><th>Medical and antenatal history</th><th>Intrapartum course</th><th>Laboratory, abnormal only</th></tr></thead><tbody><tr><td rowspan="2">1</td><td rowspan="2">39</td><td rowspan="2">35</td><td rowspan="2">NSVD</td><td rowspan="2">Focal accreta ×2</td><td>Febrile to 38.2 °C</td><td>aPTT:26s<break></break><italic>[27.6–36.6]</italic></td></tr><tr><td>Long umbilical cord</td><td>Albumin 2.4 g/dL<break></break><italic>[3.2–4.8]</italic></td></tr><tr><td>2</td><td>38</td><td>30</td><td>NSVD</td><td>Pelvic fracture</td><td>Febrile to 38.1 °C</td><td>None</td></tr><tr><td>3</td><td>40</td><td>29</td><td>NSVD</td><td>Polycystic Ovary Syndrome, Iron Deficiency Anemia</td><td>Unremarkable</td><td>None</td></tr><tr><td>4</td><td>39</td><td>40</td><td>Repeat C-section</td><td>Hypothyroidism, C-section</td><td>1088 ml blood loss due to uterine atony</td><td>None</td></tr><tr><td>5</td><td>38</td><td>26</td><td>NSVD</td><td>C-section, history of IUFD</td><td>Unremarkable</td><td>None</td></tr></tbody></table><table-wrap-foot><fn><p>GA – gestational age (w), NSVD – normal spontaneous vaginal delivery, IUFD – intrauterine fetal demise.</p></fn></table-wrap-foot></table-wrap></p></sec><sec id="s0010"><label>2</label><title>Materials and methods</title><sec id="s0015"><label>2.1</label><title>Complement immunohistochemistry</title><p id="p0050">Routine light microscopy and immunohistochemical assessment for the deposition of C5b-9 (membrane attack complex, MAC), C3d, and C4d via a diaminobenzidene technique was conducted on formalin-fixed tissue. Identification of C5b-9, C3d, or C4d within epithelial basement membrane zones, elastic fibers, or the elastic lamina of vessels was considered nonspecific staining. Immunohistochemical (IHC) staining was performed using C3d (Cell Marque, Rocklin CA, 403A-78), C4d (Alpco, Salem NH, BI-RC4d), C5b-9 (Agilent, Santa Clara CA, M077701-5) antibodies on paraffin embedded sections using a modified Leica protocol. Heat-mediated antigen retrieval with Tris-EDTA buffer (pH = 9, epitope retrieval solution 2) was performed for 20 min followed by incubation with each antibody for 15 min. Targeted proteins were detected using an HRP-conjugated compact polymer system and DAB as chromogen. Hematoxylin counterstain was mounted with Leica Micromount. The absence of involvement of these complement components in placental tissue was documented by the author (CMM).</p></sec><sec id="s0020"><label>2.2</label><title>Spike immunohistochemistry</title><p id="p0055">Our immunohistochemistry protocol has been previously published [<xref rid="bb0185" ref-type="bibr">37</xref>,<xref rid="bb0190" ref-type="bibr">38</xref>]. The five placental cases and five normal controls obtained prior to 2019 were each tested for the covid-19 spike and envelope protein in a blinded fashion (ProSci, Poway, CA). Optimal pretreatment conditions included EDTA antigen retrieval solution (pH 9.0) for 30 min with dilutions of 1:4000 and 1:500, respectively. The analyses were done on the automated Leica Bond platform with the modification that the Enzo Life Sciences peroxidase anti-mouse/rabbit conjugate (catalogue # ADI-950-113-0100) was used in place of the equivalent Leica conjugate as this reduced background [<xref rid="bb0190" ref-type="bibr">38</xref>]. Each placenta yielded a strong signal for CD59 for the internal positive control.</p></sec><sec id="s0025"><label>2.3</label><title>Viral RNA In-situ hybridization</title><p id="p0060">Our in situ protocol for RNA viruses has been previously published [<xref rid="bb0195" ref-type="bibr">39</xref>]. In brief, the probe and detection kit were provided by ACD (RNAscope 2.5) (Newark, CA) and the assay was done per the manufacturer's recommendations. Positive viral controls for each assay included autopsy tissue from the lung of people who died of covid-19.</p></sec></sec><sec id="s0030"><label>3</label><title>Results</title><sec id="s0035"><label>3.1</label><title>Maternal history summary</title><p id="p0065">All 5 placentas from confirmed COVID-19 patients were delivered at full-term (range: 38 to 40 weeks gestational age). Maternal ages ranged from 26 to 40-years-old. Maternal medical histories were largely unremarkable – there were no diagnoses of known thrombotic diseases. Antenatal histories were also unremarkable – there were no cases of gestational hypertension, pre-eclampsia, or diabetes. Coagulation tests were sent in only one case (Case # 1), which showed minimal acceleration of APTT and normal PT, INR, and fibrinogen, typical for gravid state.</p><p id="p0070">Nasopharyngeal swabs were collected and sent for SARS-CoV-2 RT PCR testing in the intrapartum period, and all cases resulted positive. Of the 5 cases, 2 mothers had fevers (max temp: 38.2 C) which resolved following administration of acetaminophen. The mothers were otherwise mostly asymptomatic, with only one endorsing a sore throat and a mild cough. None of the mothers required supplemental oxygen and were discharged without complications. The testing for SARS-CoV-2 in asymptomatic patients was due to direct exposure to a person infected with COVID-19.</p></sec><sec id="s0040"><label>3.2</label><title>Routine histopathology and complement staining</title><p id="p0075">All five cases showed fetal vascular malperfusion. Specific lesions and other pathology are organized in <xref rid="t0010" ref-type="table">Table 2</xref>. In all cases, there was evidence of thrombosis in larger vessels in the fetal circulation. These thrombosed vessels were found within the chorionic plate and stem villi (<xref rid="f0005" ref-type="fig">Fig. 1</xref>a). While there was evidence of complement deposition within the villi and perivillous areas and decidua similar to the normal placental controls, there was no evidence of complement staining within the larger thrombosed vessels (<xref rid="f0005" ref-type="fig">Fig. 1</xref>b). Frank thrombosis of fetal chorionic plate vessels was seen in 3 cases while in two cases the larger vessel thrombosis was confined to the stem villi (<xref rid="f0005" ref-type="fig">Fig. 1</xref>c). Distal lesions in villi indicative of fetal malperfusion was seen in 2 cases represented in one case as foci of avascular villi (<xref rid="f0005" ref-type="fig">Fig. 1</xref>d) and in another case villous stromal-vascular karyorrhexis (not illustrated). Other findings not relative to thrombosis are shown in <xref rid="t0010" ref-type="table">Table 2</xref>.<table-wrap position="float" id="t0010"><label>Table 2</label><caption><p>Histology.</p></caption><alt-text id="al0015">Table 2</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Case</th><th>Histology FVM</th><th>Other histological findings</th></tr></thead><tbody><tr><td>1</td><td>Thrombosis, intramural fibrin deposition</td><td>Focal increase in perivillous fibrin focal chorangiosis, furcate insertion of umbilical cord</td></tr><tr><td>2</td><td>Thrombosis, intramural fibrin deposition</td><td>Meconium</td></tr><tr><td>3</td><td>Thrombosis, Villous stromal-vascular karyorrhexis</td><td>Meconium</td></tr><tr><td>4</td><td>Thrombosis intramural fibrin deposition, avascular villi</td><td>Meconium</td></tr><tr><td>5</td><td>Thrombosis, intramural fibrin deposition</td><td></td></tr></tbody></table></table-wrap><fig id="f0005"><label>Fig. 1</label><caption><p>Thrombosis in placental chorionic plate vessels (a). The thrombosed vessel was devoid of complement deposition. Illustrated is C5b-9 stained (b), adluminal thrombus in an artery (c), and downstream effects of occlusion on avascular villi (d).</p></caption><alt-text id="al0005">Fig. 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p><p id="p0080">Five normal control placentas were analyzed in the same manner as the pathologic placentas. None showed fetal vascular malperfusion, avascular villi, nor thrombosis in larger vessels. Complement staining of C3d, C4d, and C5b-9 was found within the decidua and in a number of villi and amidst perivillous fibrin deposition. Overall, the pattern of complement staining was similar between the COVID positive placentas and the COVID negative placentas.</p><p id="p0085">Viral spike protein and viral RNA staining within the COVID-19 placentas was rare, suggesting that direct viral infection of the placentas did not occur and that the effects of thrombosis were due to systemic, not local effects of the virus.</p></sec></sec><sec id="s0045"><label>4</label><title>Discussion</title><p id="p0090">While perivillous fibrin deposition and intervillous fibrin deposition is normal in every placenta, thrombosed larger vessels in the fetal circulation of delivered placentas is abnormal, as was found in these cases.</p><p id="p0095">Given the prothrombotic nature of the pregnancy state, the high placental expression of TF and PAI-2, and the SARS-CoV-2-related-destruction of ACE2 with the resultant inability of Angiotensin (1–7) to challenge outsized activity of Angiotensin II, placental thrombosis in these 5 patients is not surprising. Since, at the time of writing these patients represent 100% of the confirmed COVID-19 deliveries at New York Presbyterian Hospital, Cornell Campus, we suspect this may be a wide-spread phenomenon among COVID-19 patients. Case 1 featured a long umbilical cord and furcate insertion, which are thrombotic risk factors. None of the other patients had other known causes for thrombotic (VMP) such as cord abnormalities coagulopathies, diabetes or anti-phospholipid syndrome, [<xref rid="bb0200" ref-type="bibr">40</xref>,<xref rid="bb0205" ref-type="bibr">41</xref>].</p><p id="p0100">Though, all five patients delivered without significant morbidity or mortality to them or their newborns, findings of thrombotic fetal vascular malperfusive pathology or placental thrombosis result in placental insufficiency. All patients were approaching term at the time they developed COVID-19; infection earlier in the gestational course may be less benign, potentially leading to placental insufficiency and associated miscarriages or low birth weight infants.</p><p id="p0105">One point of interest in this pandemic has been irregularities to the pattern of mortality in COVID-19 patients. Some young patients do very poorly without predisposing factors, and Italy suffered a particularly high death rate. One potential reason may be mutations in thrombotic pathways or in complement inhibitory factors like complement factor H which are thought to exist in ~1% of the population [<xref rid="bb0210" ref-type="bibr">42</xref>]. Italians have a significant prevalence of a complement factor H mutation that redisposes them to complement activation [<xref rid="bb0215" ref-type="bibr">43</xref>]. The absence of findings in this paper of direct infection or complement deposition in the placentas of patients with non-severe COVID-19 infections is comforting. 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