Autoimmune Diseases Affecting Hemostasis: A Narrative Review.

Hemostasis reflects a homeostatic mechanism that aims to balance out pro-coagulant and anti-coagulant forces to maintain blood flow within the circulation. Simplistically, a relative excess of procoagulant forces can lead to thrombosis, and a relative excess of anticoagulant forces can lead to bleeding. There are a wide variety of congenital disorders associated with bleeding or thrombosis. In addition, there exist a vast array of autoimmune diseases that can also lead to either bleeding or thrombosis. For example, autoantibodies generated against clotting factors can lead to bleeding, of which acquired hemophilia A is the most common. As another example, autoimmune-mediated antibodies against phospholipids can generate a prothrombotic milieu in a condition known as antiphospholipid (antibody) syndrome (APS). Moreover, there exist various autoimmunity promoting environments that can lead to a variety of antibodies that affect hemostasis. Coronavirus disease 2019 (COVID-19) represents perhaps the contemporary example of such a state, with potential development of a kaleidoscope of such antibodies that primarily drive thrombosis, but may also lead to bleeding on rarer occasions. We provide here a narrative review to discuss the interaction between various autoimmune diseases and hemostasis.

Triple Positive Antiphospholipid Antibody Syndrome in Pregnancy with High Frequency Plasma Exchange: A Case Report.

Introduction: Triple antibody positive antiphospholipid syndrome during pregnancy carries a poor prognosis. The placental vasculature is particularly vulnerable to these antibodies resulting in a marked increased risk of fetal growth restriction, placental infarction, abruption, stillbirth, and preterm severe preeclampsia. Case Presentation: We report a case of a primigravida with triple antibody positive antiphospholipid syndrome that demonstrated placental insufficiency and fetal compromise at a previable gestation. The patient underwent plasma exchange every 48 h for 11 weeks resulting in delivery of a viable infant. Placental blood flow was improved after complete absence of end-diastolic flow in the fetal umbilical artery. Conclusion: Scheduled plasmapheresis every 48 h can be considered in select cases of antiphospholipid antibody syndrome.

Evaluating the Relationship Between Antiphospholipid Antibodies and COVID-19 Severity.

Coronavirus 2 (COVID-19) has emerged as a new global pandemic, causing severe acute respiratory syndrome. Furthermore, the existence of antiphospholipid (APL) antibodies (Abs) and ultimately patient death may be linked to the occurrence of thrombotic events in patients with COVID-19. We aimed to investigate if there was a link between the presence of APL Abs and the severity of COVID-19 disease in patients at the Vali-Asr Hospital in Zanjan from June to July 2021. Real-time PCR was used to diagnose COVID-19 in 76 hospitalized patients. A total of 38 patients were hospitalized in the internal medicine ward and another 38 people were admitted to the intensive care unit of the Vali-Asr Educational Hospital in Iran's Zanjan region. Lupus anticoagulant (LAC) detection was done using the dilute Russell viper venom time method, and tests for anticardiolipin (ACL) Abs, IgG and IgM, and anti-beta2 glycoprotein 1 Abs, IgG and IgM, were done on blood and plasma samples of linked patients using the enzyme-linked immunosorbent assay technique. SPSS 24 was used to analyze data. Our findings showed that the presence of LAC was associated with disease severity in COVID-19 patients (p = 0.001). However, there was no significant relationship between APL Abs and mortality in patients affected with COVID-19. The evaluation of APL Abs, particularly LAC, in COVID-19 patients appears to be helpful in predicting the severity of the disease.

The third inactivated vaccine booster dramatically enhanced SARS-CoV-2 antibody responses and did not influence the profile of prothrombotic antibody.

OBJECTIVE: The purpose of this study is to investigate the production of both SARS-CoV-2-specific antibodies and autoantibodies in serum following the third booster vaccination of the inactivated COVID-19 vaccine, and to study the effect of B cell subsets with CD27 and CD38 phenotypes in peripheral blood on antibody production. METHODS: Routine blood indexes, SARS-CoV-2 antibodies, platelet factor 4 and seven antiphospholipid antibodies were detected both before and 2 months after vaccination in the medical staff of the Zhongnan Hospital of Wuhan University. Peripheral blood B cell subtypes were detected prior to vaccination. RESULTS: Following immunization, the positive rate of anti-N-S1 IgG had increased from 24.8% to 91.3% and the average antibody concentration had increased by 11 times. The positive rate of NAb had increased from 24.8% to 91.3%, the average antibody concentration had increased by 12 times, and the primary increased anti-S1 IgG subtype was that of IgG1. Peripheral blood CD27+CD38+ B cells were positively correlated with antibody levels after vaccination and were a predictor of the antibody response. In addition, although some indicators showed slight absolute changes, the blood parameters and antiphospholipid antibodies of most volunteers were normal both before and after COVID-19 inactivated vaccine inoculation, and there was no statistical difference in abnormal rates either before or after inoculation. CONCLUSION: Antibodies in vivo were increased after vaccination with the inactivated vaccine, and IgG1 was the main subtype involved in response to the vaccine. Vaccination with the inactivated COVID-19 vaccine did not appear to affect thrombus-related autoantibodies. This article is protected by copyright. All rights reserved.

Antiphospholipid Antibody Role in Acute Ischemic Stroke Patients with COVID-19: A Narrative Review

Antiphospholipid antibodies (aPL) are commonly found in humans after an infection. Its action can promote thrombosis via the activation of endothelial cells, platelets, and neutrophils. This autoantibody is the leading cause of antiphospholipid antibody syndrome (APS), characterized by widespread thrombosis in various vascular beds. COVID-19 also causes acute ischemic stroke (AIS) in the younger demographic, who previously was not considered a population at risk for AIS, which may be related to APS. This narrative review will discuss the role of aPL in COVID-19 patients who experienced AIS during infection. © 2022 University of the Philippines Manila. All rights reserved.

COVID-19 HASTALARINDA ANTÍFOSFOLÍPÍD ANTÍKOR (AFA) VARLIĞI

Objective: In our study, we aimed to show whether there is a relationship between antiphospholipid antibody (aPL) positivity and complications of COVID-19. Material and Methods: Eighty-three patients who were diagnosed with COVID-19 infection and hospitalized in the intensive care unit (ICU) of Bakirkoy Dr. Sadi Konuk Research and Training Hospital were included in our study as the case group and 79 healthy volunteers as the control group. Only patients with a positive Polymerase Chain Reaction (PCR) test were included in the case group. Serum antiphospholipid antibodies (aPL IgM/G), C-Reactive Protein (CRP), ferritin, procalcitonin (PCT), plasma D-Dimer levels, prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) were analyzed by routine laboratory methods. Results: Both groups were found statistically similar in terms of gender (χ2 test, p=0.236). The mean age of the case group and control group was 60.54±16.86 and 51.47±14.64 years, respectively. When aPL positivity was evaluated between the case and control groups, a statistically remarkable difference was found between the groups (p=0.046). The case group showed an aPL positivity of 7.5% and the control group 1%. The correlation between D-Dimer, PT, INR, aPTT levels, and aPL IgM/G positivity in the case group was significant. Conclusion: Our results revealed that aPL positivity in patients with COVID-19 infection relate to the severity of the disease, in dependent from age and gender. To confirm the result of this study further studies with participation of larger patient groups from national and international hospitals are required. (English) [ FROM AUTHOR] Amaç: Çalışmamızda antifosfolipid antikor (AFA) pozitifliği ile COVID-19 komplikasyonları arasında bir ilişki olup olmadığını göstermeyi amaçladık. Gereç ve Yöntem: Bakırköy Dr. Sadi Konuk Eğitim ve Araştırma Hastanesi yoğun bakım servisinde yatan COVID-19 enfeksiyonu tanısı almış 83 hasta olgu grubu olarak, 79 sağlıklı gönüllü de kontrol grubu olarak çalışmamıza dahil edildi. Olgu grubuna sadece Polimeraz Zincir Reaksiyon (PZR) test sonucu pozitif olan hastalar alındı. Serum antifosfolipid antikorları (AFA IgM/G), C-Reaktif Protein (CRP), ferritin, prokalsitonin (PCT) ve plazma D-Dimer seviyeleri, protrombin zamanı (PT) ve uluslararası normalleştirilmiş oran (INR), aktive parsiyel tromboplastin zamanı (aPTT), rutin laboratuvar yöntemleriyle analiz edildi. Bulgular: Her iki grup cinsiyet açısından istatistiksel olarak benzer bulundu (χ2 testi, p=0,236). Olgu grubu ve kontrol grubunun yaş ortalaması sırasıyla 60,54±16,86 ve 51,47±14,64 yıl idi. Olgu ve kontrol grupları arasında AFA pozitifliği değerlendirildiğinde, gruplar arasında istatistiksel olarak anlamlı fark bulundu (p=0,046). Olgu grubu %7,5 ve kontrol grubu %1 AFA pozitifliği gösterdi. Olgu grubunun D-Dimer, PT, INR, aPTT seviyeleri ile AFA IgM/G pozitifliği arasındaki korelasyon anlamlı bulundu. Sonuç: Sonuçlarımız, COVID-19 enfeksiyonu olan hastalarda AFA pozitifliğinin yaş ve cinsiyetten bağımsız olarak hastalığın şiddeti ile ilişkili olduğunu ortaya koydu. Bu çalışmanın sonucunu doğrulamak için ulusal ve uluslararası hastanelerden daha geniş hasta gruplarının katılımıyla daha ileri çalışmalara ihtiyaç vardır. (Turkish) [ FROM AUTHOR] Copyright of Istanbul Tip Fakültesi Dergisi is the property of Istanbul Tip Fakultesi Dergisi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Scrub Typhus and COVID-19 Coinfection Unmasking Antiphospholipid Antibody Syndrome.

Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi with a clinical course varying from mild to fatal. Vascular thrombosis is rare in scrub typhus. There is an increased risk of thrombotic events in Coronavirus disease 19 (COVID-19). We report a young diabetic female who presented with pulmonary embolism, followed by deep venous thrombosis (DVT) and was found to have coinfection with scrub typhus and COVID-19 with underlying antiphospholipid antibody syndrome.

ANTIPHOSPHOLIPID ANTIBODY (aPL) PRESENCE IN COVID-19 PATIENTS

Objective: In our study, we aimed to show whether there is a relationship between antiphospholipid antibody (aPL) positivity and complications of COVID-19. Material and Methods: Eighty-three patients who were diagnosed with COVID-19 infection and hospitalized in the intensive care unit (ICU) of Bakirkoy Dr. Sadi Konuk Research and Training Hospital were included in our study as the case group and 79 healthy volunteers as the control group. Only patients with a positive polymerase chain reaction (PCR) test were included in the case group. Serum antiphospholipid antibodies (aPL IgM/G), C-Reactive Protein (CRP), ferritin, procalcitonin (PCT), plasma D-Dimer levels, prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) were analyzed by routine laboratory methods. Results: Both groups were found statistically similar in terms of gender (chi(2) test, p=0.236). The mean age of the case group and control group was 60.54 +/- 16.86 and 51.47 +/- 14.64 years, respectively. When aPL positivity was evaluated between the case and control groups, a statistically remarkable difference was found between the groups (p=0.046). The case group showed an aPL positivity of 7.5% and the control group 1%. The correlation between D-Dimer, PT, INR, aPTT levels, and aPL IgM/G positivity in the case group was significant. Conclusion: Our results revealed that aPL positivity in patients with COVID-19 infection relate to the severity of the disease, in-dependent from age and gender. To confirm the result of this study further studies with participation of larger patient groups from national and international hospitals are required.

A Novel ELISA Assay for the Detection of Anti-Prothrombin Antibodies in Antiphospholipid Syndrome Patients at High Risk of Thrombosis.

Autoantibodies targeting prothrombin (aPT) can be found in antiphospholipid syndrome (APS) patients. However, their detection has proven difficult to standardize. Here, we developed a new ELISA assay to improve the identification of aPT and compared its performance with currently available anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and autoantibodies targeting prothrombin bound to the plastic plate (aPT-A) assays using a cohort of 27 APS patients at high risk of thrombosis. We generated a novel prothrombin variant, ProTS525A-Biot, carrying an artificial tag at the C-terminus suitable for site-specific biotinylation and added the mutation S525A to improve stability. ProTS525A-Biot was immobilized to neutravidin-coated plates at the desired density and with a defined orientation, i.e., pointing the N-terminal fragment-1 toward the solvent. Antibodies against ProTS525A-Biot (aPT-Bio) were found in 24 out of 27 triple-positive APS patients (88%). When compared to aPS/PT and aPT-A, aPT-Bio showed an excellent linear correlation with aPS/PT (R2 = 0.85) but not with aPT-A (R2 = 0.40). Since aPS/PT but not aPT-A are an emerging biomarker of thrombosis in APS, this method may find utility for detecting pathogenic aPT in APS but also other prothrombotic conditions such as COVID-19.

Inactivated SARS-CoV-2 vaccine does not influence the profile of prothrombotic antibody nor increase the risk of thrombosis in a prospective Chinese cohort.

The presence of antiphospholipid antibodies was shown to be associated with thrombosis in coronavirus disease 2019 (COVID-19) patients. Recently, according to reports from several studies, the vaccine-induced immune thrombotic thrombocytopenia is mediated by anti-platelet factor 4 (PF4)-polyanion complex in adenovirus-vectored COVID-19 vaccine recipients. It is impendent to explore whether inactivated COVID-19 vaccine widely used in China influences prothrombotic autoantibody production and induces thrombosis. In this prospective study, we recruited 406 healthcare workers who received two doses, 21 days apart, of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (BBIBP-CorV, Sinopharm). Paired blood samples taken before vaccination and four weeks after the second vaccination were used in detecting prothrombotic autoantibodies, including anticardiolipin (aCL), anti-ß2 glycoprotein I (aß2GP1), anti-phosphatidylserine/prothrombin (aPS/PT), and anti-PF4-heparin. The seroconversion rate of SARS-CoV-2 specific antibodies was 95.81% (389/406) four weeks after vaccination. None of the subjects had spontaneous thrombosis or thrombocytopenia over a minimum follow-up period of eight weeks. There was no significant difference in the presence of all ten autoantibodies between samples collected before and after vaccination: for aCL, IgG (7 vs. 8, P = 0.76), IgM (41 vs. 44, P = 0.73), IgA (4 vs. 4, P = 1.00); anti-ß2GP1, IgG (7 vs. 6, P = 0.78), IgM (6 vs. 5, P = 0.76), IgA (3 vs. 5, P = 0.72); aPS/PT IgG (0 vs. 0, P = 1.00), IgM (6 vs. 5, P = 0.76); aPF4-heparin (2 vs. 7, P = 0.18), and antinuclear antibody (ANA) (18 vs. 21, P = 0.62). Notably, seven cases presented with anti-PF4-heparin antibodies (range: 1.18-1.79 U/mL) after vaccination, and none of them exhibited any sign of thrombotic disorder. In conclusion, inactivated SARS-CoV-2 vaccine does not influence the profile of antiphospholipid antibody and anti-PF4-heparin antibody nor increase the risk of thrombosis.

Antiphospholipid Antibodies and Infection: Non Nova Sed Nove.

The clinical significance of antiphospholipid antibodies (aPL) in the context of infections has attracted attention since their first discovery in patients with syphilis. In fact, the recognition of aPL in patients with infections has been described in parallel to the understating of the syndrome. Since the first description of aPL-positive tests in three patients with COVID-19 diagnosed in January 2020 in Wuhan, China, a large number of studies took part in the ongoing debate on SARS-2-Cov 2 induced coagulopathy, and many following reports speculated a potential role for aPL. In order to get further insights on the effective role of detectable aPL in the pro-thrombotic status observed in COVID-19 patients, we performed an observational age-sex controlled study to compare the aPL profile of hospitalized patients with COVID with those observed in a) patients with thrombotic APS and b) patients with cultural/serologically-proved infections. Our data showed positive aPL testing in about half of the patients (53%) with COVID-19 and patients with other viral/bacterial infections (49%). However, aPL profile was different when comparing patients with overt APS and patients with aPL detected in the contest of infections. Caution is therefore required in the interpretation and generalization of the role of aPL s in the management of patients with COVID-19. Before introducing aPL testing as a part of the routine testing in patients with COVID-19, larger well-designed clinical studies are required. While the pro-thrombotic status in patients with COVID-19 is now unquestionable, different mechanisms other than aPL should be further investigated.

Systemic lupus erythematosus and varicella-like rash following COVID-19 in a previously healthy patient.

Emerging reports show that coronavirus disease 2019 (COVID-19) may lead to autoimmune and autoinflammatory diseases. However, COVID-19 triggered systemic lupus erythematosus (SLE) has never been reported to our knowledge. COVID-19 also has associated cutaneous manifestations. Here we present a case of SLE with antiphospholipid antibody syndrome in a previously healthy patient with COVID-19, who subsequently developped a varicella-like exanthem on the trunk. The disease resulted in death of the patient. The pathophysiological mechanisms resulting in overlapping disorders in our patient remain unknown, adding to the growing mystery of this virus and raising questions about the nature of its link with cutaneous, autoimmune, and autoinflammatory manifestations. Sharing the images of this case may benefit physicians dealing with similar patients during this pandemic.

Prevalence of autoantibody responses in acute coronavirus disease 2019 (COVID-19).

Immunopathology may play a significant role in the pathogenesis of Coronavirus-Induced Disease-19 (COVID-19). Immune-mediated tissue damage could result from development of rapid autoimmune responses, characterized by production of self-reactive autoantibodies. In this study, we tested specimens from acutely ill patients hospitalized with COVID-19 for autoantibodies against nuclear, vasculitis-associated, and phospholipid antigens. Detectable autoantibodies were present in 30% of the patients in our cohort, with the majority of reactive specimens demonstrating antibodies to nuclear antigens. However, antinuclear antibodies were only weakly reactive and directed to single antigens, as is often seen during acute infection. We identified strongly reactive antibodies to nuclear antigens only in patients with a prior history of autoimmune disease. In our cohort, the prevalence of antiphospholipid antibodies was low, and we did not detect any vasculitis-associated autoantibodies. We found similar levels of inflammatory markers and total immunoglobulin levels in autoantibody positive versus negative patients, but anti-SARS-CoV-2 antibody levels were increased in autoantibody positive patients. Together, our results suggest that acute COVID-19 is not associated with a high prevalence of clinically significant autoantibody responses of the type usually associated with autoimmune rheumatic disease.

Coronavirus Disease 2019 (COVID-19) Infection Associated With Antiphospholipid Antibodies and Four-Extremity Deep Vein thrombosis in a Previously Healthy Female.

Infection caused by novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been associated with coagulopathy. We present a case of a previously healthy 49-year-old female who was admitted to the hospital for coronavirus disease 2019 (COVID-19) pneumonia and later found to have extensive deep vein thrombosis (DVT) in all four extremities. This was accompanied by a steep rise in D-dimer levels and positive antiphospholipid antibodies (APLA) on further testing. She clinically improved on hydroxychloroquine and therapeutic anticoagulation. This is one of the first case reports describing APLA-associated DVT in a patient with COVID-19 pneumonia. Transient elevation of APLA from the viral illness may play a role in thrombosis associated with COVID-19.

Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients.

The outbreak of novel coronavirus disease 2019 (COVID-19) has now become a global pandemic. Coagulopathy has been reported widely in critically ill COVID-19 patients and was related to high mortality. However, the comprehensive coagulation profiles have not been examined and the underlying mechanism of the coagulopathy in COVID-19 patients is unclear. To study the coagulation profiles of routine hemostasis tests, natural anticoagulants, coagulant factors and antiphospholipid antibodies in critically ill COVID-19 patients. This single-center and cross-section study included 19 patients with COVID-19, who were admitted to intensive care unit (ICU) at Tongji hospital in Wuhan, China, from Feb 23 to Mar 3, 2020. Demographic data, laboratory parameters, treatments and clinical outcomes of the patients were collected and analyzed. The final date of follow-up was Mar 31, 2020. In this study, 12 thrombotic events occurred in 9 patients, including 4 cerebral infarctions, 7 acro-ischemia and 1 internal jugular vein thrombosis. The common abnormalities of routine coagulation tests included evelated D-Dimer level (100%), prolonged prothrombin time (73.7%) and hyperfibrinogenemia (73.7%). The median activities of natural anticoagulants including protein C, protein S and antithrombin were all below the normal range. Factor VIII activities were significantly above normal range (median value 307%, IQR 198-441) in all patients. Factor V and factor VII activities were significantly lower in near-terminal stage patients. Anti-phospholipid antibodies were present in 10 patients. Strikingly, 4 cerebral infarction events were in patients had anti-phospholipid antibodies of multiple isotypes. Sustained hypercoagulable status and thrombotic events were common in critically ill patients with COVID-19. The low activities of natural anticoagulants, elevated factor VIII level and the presence of antiphospholipid antibodies, together, may contribute to the etiopathology of coagulopathy in COVID-19 patients.