Presence of antiphospholipid antibodies in

COVID-19: case series study

Oleh :

1. Dayanti Hajrianah Nsumaso (P10120002)

2. Fahira Maharani (P10120104)

3. Nurul Amalia (P10120014)

KELAS B

FAKULTAS KESEHATAN MASYARAKAT

PRODI KESEHATAN MASYARAKAT

UNIVERSITAS TADULAKO

2021
 Kehadiran antibodi antifosfolipid pada COVID-19: studi seri kasus

American Society of Hematology baru-baru ini menyatakan bahwa

'saat ini, hanya ada data yang sangat terbatas tentang antibodi aPL pada
COVID-19 dan tidak jelas apakah mereka mewakili epifenomenon atau
benar-benar terlibat dalam kelainan hemostatik yang terlihat pada penyakit
COVID-19. Selain itu, hampir semua informasi yang tersedia mengacu pada
antikoagulan lupus, dengan frekuensi berkisar antara 45% hingga 87%.3 4
Kurangnya data ini mendorong kami untuk menguji panel antibodi aPL dalam
spesimen darah dari 21 pasien yang dirawat di unit perawatan intensif antara
12 dan 19 April, karena COVID-19 yang parah atau kritis, dan diterima di
laboratorium kami pada 20 April untuk mengukur tingkat interleukin-6.
Antikardiolipin, anti-β glikoprotein I, antiprotrombin, antiphosphatidylserine,
antiphosphatidylinositol dan antibodi antiannexin V diukur, masing-masing
dalam isotipe IgM dan IgG. Selanjutnya, data demografi dan klinis diperoleh
dari rekam medis elektronik. Sera yang dikumpulkan sebelum pandemi
SARS-CoV-2 dari 12 orang sehat, cocok untuk usia dan jenis kelamin, diuji
sebagai kontrol.Hasil terkait dirangkum dalam Tabel 1. Usia rata-rata pasien
adalah 62 tahun; 43% adalah laki-laki; dan sejumlah besar komorbiditas
diamati (median Charlson Comorbidity Index dari 3). Sebanyak 19 pasien
(90%) mengalami sesak napas saat masuk, dan 12 (57%) akhirnya
membutuhkan ventilasi mekanis invasif selama rawat inap. Peningkatan
kadar Ddimer, feritin dan protein reaktif C ditemukan pada presentasi.Dari 21
pasien dengan COVID-19 yang diteliti, 12 memiliki setidaknya satu antibodi
aPL yang bersirkulasi, sedangkan hanya 1 dari 12 kontrol yang memberikan
hasil positif (57% vs 8%; uji eksak Fisher, p=0,009). Antibodi aPL yang paling
sering terdeteksi adalah antibodi antiannexin V IgM (19%), anticardiolipin IgM
(14%), antiphosphatidylserine IgM (14%), anticardiolipin IgG (10%) dan
antiphosphatidylserine IgG (10%). Satu pasien memiliki hasil positif tiga kali
lipat (8%); tiga pasien positif ganda (25%); dan delapan sisanya memiliki satu
kepositifan (67%). Usia dan jumlah penyakit penyerta cenderung lebih rendah
pada pasien dengan antibodi aPL. Sebaliknya, kadar D-dimer, feritin dan
protein reaktif C lebih tinggi baik saat masuk dan selama dirawat di rumah
sakit pada pasien ini. Peningkatan kadar interleukin-6 (> 40 pg/mL) hanya
ditemukan pada pasien dengan antibodi aPL. Jenis terapi yang diberikan
pada kedua kelompok serupa, kecuali untuk sejumlah besar pasien dengan
antibodi aPL yang menerima glukokortikoid (50% vs 0; Fisher's exact test,
p=0,018)

Dua pasien mengalami tromboemboli paru meskipun menggunakan

heparin: seorang pria berusia 28 tahun dengan diagnosis sebelumnya
hipertensi pulmonal idiopatik yang memiliki antibodi IgG anticardiolipin dan
seorang wanita 63 tahun dengan riwayat sindrom Fahr dan
hipoparatiroidisme yang memiliki antibodi antiannexin V IgM. Kedua pasien
memiliki tingkat D-dimer dan protein reaktif C yang sangat tinggi selama
masa tindak lanjut dan akhirnya meninggal karena komplikasi hemodinamik.
Studi nekropsi tidak dilakukan. Terlepas dari kenyataan bahwa sebagian
besar pasien menerima heparin, satu-satunya perdarahan yang signifikan
secara klinis adalah hematoma retroperitoneal spontan pada pria berusia 44
tahun dengan antibodi antiphosphatidylserine IgM dan antiannexin V IgM
yang pulih dengan manajemen konservatif. Dua pasien yang tidak ditemukan
antibodi aPL akhirnya meninggal karena kegagalan organ multisistem. Pada
18 Mei, 13 pasien (62%) telah dipulangkan dari rumah sakit; 4 (19%) tetap
dirawat di rumah sakit;

Dalam studi seri kasus ini, frekuensi tinggi (57%) antibodi aPL 'kriteria
dan non-kriteria' ditemukan pada pasien dengan COVID-19 parah dan kritis.
Antibodi aPL ini tampaknya terkait dengan keadaan hiperinflamasi yang
ditandai dengan kadar feritin, protein C reaktif, dan interleukin yang sangat
tinggi; sementara itu, hubungan dengan tromboemboli paru mungkin
disarankan. Selama infeksi akut, trombosis, atau peradangan, antibodi aPL
yang berbeda dapat timbul sementara, dan tidak boleh diasumsikan bahwa
pasien dengan koagulopati terkait COVID-19 dan antibodi aPL memiliki APS
katastrofik. Memang, meskipun koagulopati terkait COVID-19 dan APS
bencana dapat berbagi fitur klinis dan laboratorium, kedua penyakit tersebut
cenderung memiliki patofisiologi dasar yang berbeda. Namun, frekuensi tinggi
dan berbagai macam antibodi aPL yang diamati pada pasien dengan COVID-
19 tidak dapat diabaikan.
 Correspondence

Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218100 on 4 August 2020. Downloaded from http://ard.bmj.com/ on August 5, 2020 by guest. Protected by copyright.
Presence of antiphospholipid antibodies in Table 1  Main clinical and laboratory data of 21 patients with
COVID-19: case series study severe or critical COVID-19
Positive aPL Negative aPL
Total antibodies antibodies
The severe acute respiratory syndrome coronavirus 2 (N=21) (n=12) (n=9)
(SARS-­ CoV-2) infection and its associated coagulopathy are
Age (years) 62 (54–67) 55 (49–63) 67 (62–68)
particularly worrisome in patients with systemic lupus erythe- Male sex, n (%) 9 (43) 6 (50) 3 (33)
matosus (SLE) and antiphospholipid syndrome (APS), as these Days of symptom onset 7 (5–9) 7 (4–8) 7 (5–9)
diseases carry an increased risk of thrombotic complications. Charlson Comorbidity Index 3.0 (1.0–4.0) 1.5 (1.0–3.0) 4.0 (2.0–5.0)
Mathian et al recently reported the clinical course of COVID-19 Coexisting conditions, n (%)
in a series of 17 patients with SLE under chronic hydroxychloro-  Hypertension 12 (57) 5 (42) 7 (78)
quine therapy.1 Of note, only one patient (6%) presented throm-  Diabetes mellitus 8 (38) 3 (25) 5 (56)
bosis despite the fact that four patients (24%) had a history  Dyslipidaemia 7 (33) 3 (25) 4 (44)
of secondary APS, and five patients (29%) were receiving oral  Obesity 7 (33) 5 (42) 2 (22)
anticoagulants. Antiphospholipid (aPL) antibodies were not  Coronary artery disease 3 (14) 2 (17) 1 (11)
measured in these patients during active SARS-­CoV-2 infection.1  Stroke 1 (5) 0 1 (11)
The American Society of Hematology recently stated that  Current smoker 2 (10) 2 (17) 0
‘at the current time, there are only very limited data on aPL  Pulmonary disease 2 (10) 2 (17) 0
antibodies in COVID-19 and it is unclear if they represent an  Chronic kidney disease 3 (14) 1 (8) 2 (22)

epiphenomenon or are actually involved in any haemostatic  Chronic heart failure 2 (10) 0 2 (22)

abnormalities seen in COVID-19 disease’.2 Furthermore, almost  Cancer 1 (5) 0 1 (11)

all the available information refers to the lupus anticoagulant, Main findings at hospital admission

with frequencies ranging from 45% to 87%.3 4 This paucity of  Fever, n (%) 13 (62) 7 (58) 6 (67)
 Shortness of breath/respiratory 19 (90) 12 (100) 7 (78)
data led us to test a panel of aPL antibodies in blood specimens distress, n (%)
from 21 patients hospitalised in the intensive care unit between  White cell count (×103 per mm3) 6.5 (4.9–10.4) 7.0 (5.4–12.1) 6.2 (4.9–9.6)
12 and 19 April, due to severe or critical COVID-19, and received  Platelet count (×103 per mm3) 179 (146–198) 179 (156–193) 171 (143–240)
at our laboratory on 20 April to measure interleukin-6 levels.  D-­dimer (ng/mL) 339 (177–484) 387 (207–484) 303 (132–446)
Anticardiolipin, anti-β2 glycoprotein I, antiprothrombin, anti-  Ferritin (μg/L) 557 (156–882) 677 (490–1249) 199 (112–326)
phosphatidylserine, antiphosphatidylinositol and antiannexin V  C reactive protein (mg/L) 139 (57–210) 200 (95–256) 86 (57–144)
antibodies were measured, each in IgM and IgG isotypes. Subse-  Intubation, n (%) 12 (57) 7 (58) 5 (56)
quently, demographic and clinical data were obtained from elec- Laboratory values at the time of aPL
measurements
tronic medical records. Sera collected before the SARS-­CoV-2
 White cell count (×103 per mm3) 7.8 (6.9–10.6) 8.6 (6.7–13.2) 6.4 (5.7–9.8)
pandemic from 12 healthy individuals, matched for age and sex,
 Platelet count (×103 per mm3) 260 (212–349) 262 (201–332) 259 (229–349)
were tested as controls.
 D-­dimer (ng/mL) 417 (216–613) 437 (206–601) 403 (278–621)
Pertinent results are summarised in table 1. The median age
 Ferritin (μg/L) 604 (365–1353) 1038 (580–1392) 443 (237–547)
of patients was 62 years; 43% were men; and a high number
 C reactive protein (mg/L) 90 (17–219) 140 (60–270) 39 (17–129)
of comorbidities were observed (median Charlson Comor-  Serum interleukin-6 levels>40 pg/ 2 (10) 2 (17) 0
bidity Index of 3). A total of 19 patients (90%) had shortness mL, n (%)
of breath on admission, and 12 (57%) eventually required inva- Treatment, n (%)
sive mechanical ventilation during hospitalisation. Elevated  Heparin 18 (86) 9 (75) 9 (100)
levels of D-­dimer, ferritin and C reactive protein were found at  Glucocorticoids 6 (29) 6 (50) 0
presentation.  Hydroxychloroquine 15 (71) 9 (75) 6 (67)

Of the 21 patients with COVID-19 studied, 12 had at  Azithromycin 18 (86) 10 (83) 8 (89)

least one circulating aPL antibody, whereas only 1 of the 12  Lopinavir plus ritonavir 11 (52) 6 (50) 5 (56)

controls yielded a positive result (57% vs 8%; Fisher’s exact Positive aPL antibodies, n (%)
 Anticardiolipin IgM 3 (14) 3 (25) 0
test, p=0.009). The most frequently detected aPL antibodies
 Anticardiolipin IgG 2 (10) 2 (17) 0
were antiannexin V IgM (19%), anticardiolipin IgM (14%),
 Anti-β2 glycoprotein I IgM 0 0 0
antiphosphatidylserine IgM (14%), anticardiolipin IgG
 Anti-β2 glycoprotein I IgG 1 (5) 1 (8) 0
(10%) and antiphosphatidylserine IgG (10%) antibodies. One
 Antiprothrombin IgM 1 (5) 1 (8) 0
patient had triple positivity (8%); three patients had double
 Antiprothrombin IgG 0 0 0
positivity (25%); and the remaining eight had a single posi-
 Antiphosphatidylserine IgM 3 (14) 3 (25) 0
tivity (67%). Age and number of comorbidities tended to be
 Antiphosphatidylserine IgG 2 (10) 2 (17) 0
lower in patients with aPL antibodies. In contrast, levels of  Antiphosphatidylinositol IgM 0 0 0
D-­dimer, ferritin and C reactive protein were higher both on  Antiphosphatidylinositol IgG 0 0 0
admission and throughout the hospital stay in these patients.  Antiannexin V IgM 4 (19) 4 (33) 0
Elevated levels of interleukin-6 (>40 pg/mL) were found only  Antiannexin V IgG 1 (5) 1 (8) 0
in patients with aPL antibodies. The type of therapies adminis- Pulmonary thromboembolism 2 (10) 2 (17) 0
tered in both groups was similar, except for a greater number Major bleeding, n (%) 1 (5) 1 (8) 0
of patients with aPL antibodies who received glucocorticoids Ventilator-­associated pneumonia, 3 (14) 1 (8) 2 (22)
(50% vs 0; Fisher’s exact test, p=0.018). n (%)

The occurrence of hospital outcomes was followed up In-­hospital deaths, n (%) 4 (19) 2 (17) 2 (22)
Discharged, n (%) 13 (62) 9 (75) 4 (44)
to 30 days after aPL antibody measurement. Two patients
Data are presented as median (IQR) unless otherwise specified.
presented pulmonary thromboembolism despite being on aPL, antiphospholipid.
heparin: a 28-­ year-­
old man with a previous diagnosis of
Ann Rheum Dis Month 2020 Vol 0 No 0    1
 Correspondence
idiopathic pulmonary hypertension who had anticardiolipin
IgG antibodies and a 63-­year-­old woman with a history of
Fahr syndrome and hypoparathyroidism who had antiannexin
V IgM antibodies. Both patients had extremely high levels of
D-­dimer and C reactive protein throughout the follow-­up and
eventually died of haemodynamic complications. Necropsy
studies were not performed. Despite the fact that most patients
received heparin, the only clinically significant bleeding was
spontaneous retroperitoneal haematoma in a 44-­year-­old man
with antiphosphatidylserine IgM and antiannexin V IgM anti-
bodies who recovered with conservative management. Two
patients in whom no aPL antibodies were observed eventually
died of multisystem organ failure. As of 18 May, 13 patients
(62%) had been discharged from the hospital; 4 (19%)
remained hospitalised; and 4 (19%) died.
In this case series study, a high frequency (57%) of both
‘criteria and non-­criteria’ aPL antibodies was found in patients
with severe and critical COVID-19. These aPL antibodies
appear to be associated with a hyperinflammatory state charac-
terised by extremely high levels of ferritin, C reactive protein
and interleukin-6; meanwhile, an association with pulmonary
thromboembolism may be suggested. During acute infection,
thrombosis or inflammation, different aPL antibodies may
transiently arise, and it should not be assumed that a patient
with COVID-19-­associated coagulopathy and aPL antibodies
has catastrophic APS.5 Indeed, although COVID-19-­associated
coagulopathy and catastrophic APS may share clinical and
laboratory features, both diseases are likely to have a different
underlying pathophysiology. However, the high frequency
and wide variety of aPL antibodies observed in patients with
COVID-19 cannot be ignored.
Currently, there are limited data on the occurrence of aPL
antibodies during SARS-­CoV-2 infection, and further studies
are required to determine whether these represent a simple
epiphenomenon or are actually involved in COVID-19-­
associated coagulopathy.
Luis M Amezcua-­Guerra ‍ ‍,1 Gustavo Rojas-­Velasco,2
Malinalli Brianza-­Padilla,1 Armando Vázquez-­Rangel,2
Ricardo Márquez-­Velasco,1 Francisco Baranda-­Tovar,2 Rashidi Springall,1
Hector Gonzalez-­Pacheco,2 Yaneli Juárez-­Vicuña,1 Claudia Tavera-­Alonso,2
Fausto Sanchez-­Muñoz,1 Marisol Hernández-­Salas2
1 Covid‐19. J Thromb Haemost 2020.
Immunology, Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico
2
Intensive Care Unit, Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City,
Mexico
Correspondence to Dr Luis M Amezcua-­Guerra, Departamento de Inmunología,
Instituto Nacional de Cardiologia Ignacio Chavez, 14080 Tlalpan, Mexico;
​lmamezcuag@​gmail.c​ om
2 Ann Rheum Dis Month 2020 Vol 0 No 0
Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218100 on 4 August 2020. Downloaded from http://ard.bmj.com/ on August 5, 2020 by guest. Protected by copyright.
Contributors  All the authors made contributions in the acquisition, analysis and
interpretation of data. In addition, they revised it critically for important intellectual
content and gave their final approval of the version published.LMAG additionally
conceived and designed the study and drafted the manuscript.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient and public involvement  Patients and/or the public were not involved in
the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication  Not required.
Provenance and peer review  Not commissioned; internally peer reviewed.
This article is made freely available for use in accordance with BMJ’s website
terms and conditions for the duration of the covid-19 pandemic or until otherwise
determined by BMJ. You may use, download and print the article for any lawful,
non-­commercial purpose (including text and data mining) provided that all copyright
notices and trade marks are retained.
© Author(s) (or their employer(s)) 2020. No commercial re-­use. See rights and
permissions. Published by BMJ.
To cite Amezcua-­Guerra LM, Rojas-­Velasco G, Brianza-­Padilla M, et al.
Ann Rheum Dis Epub ahead of print: [please include Day Month Year]. doi:10.1136/
annrheumdis-2020-218100
Received 23 May 2020
Accepted 25 May 2020
►► http://​dx.​doi.​org/​10.​1136/​annrheumdis-​2020-​218145
Ann Rheum Dis 2020;0:1–2. doi:10.1136/annrheumdis-2020-218100
ORCID iD
Luis M Amezcua-­Guerra http://​orcid.​org/​0000-​0002-​6258-​5732
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