Multiple small pulmonary emboli associated with transient antiphospholipid syndrome in human Parvovirus B19 infection

Antiphospholipid antibodies (aPL) have been reported to occur in several conditions other than antiphospholipid syndrome, including infections. We herein report the case of a 21-year-old Japanese woman with Parvovirus B19 infection, who developed multiple pulmonary emboli associated with aPL, a lupus anticoagulant and IgM anticardiolipin antibody. Eight weeks later, antiphospholipid antibodies spontaneously disappeared and normal pulmonary flow was observed. Considering the high prevalence of Parvovirus B19 infection, we should be aware of thrombosis associated with transient aPL antibodies in this infectious disease.     

Coagulopathy in COVID-19 and anticoagulation clinical trials

Severe acute respiratory disease coronavirus 2 (SARS-COV-2) first emerged in Wuhan, China, in December 2019 and has caused a global pandemic of a scale unprecedented in the modern era. People infected with SARS-CoV-2 can be asymptomatic, moderate symptomatic or develop severe COVID-19. Other than the typical acute respiratory distress syndrome (ARDS), patients with moderate or severe COVID-19 also develop a distinctive systemic coagulopathy, known as COVID-19-associated coagulopathy (CAC), which is different from sepsis-related forms of disseminated intravascular coagulation (DIC). Endotheliopathy or endotheliitis are other unique features of CAC. The endothelial cell perturbation can further increase the risk of thrombotic events in COVID-19 patients. In this review, we will summarize the current knowledge on COVID-19 coagulopathy and the possible mechanisms for the condition. We also discuss the results of clinical trials testing methods for mitigating thrombosis events in COVID-19 patients.     

Apport de la détection des anticorps antiphosphatidylsérine/prothrombine (aPS/PT) dans le diagnostic et la prise en charge du syndrome des antiphospholipides (SAPL)

Antiphospholipid syndrome (APS) is an autoimmune disease and one of the most common causes of acquired thrombophilia. It is characterised by the occurrence of thrombotic or obstetric events associated with the presence of persistent antiphospholipid antibodies. The diagnosis can be challenging, particularly because some biological tests can be disturbed by anticoagulant treatment or inflammation.In the recent years, new antiphospholipid antibodies, including anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT), have emerged but their clinical significance and causality remain uncertain.Biologically, several studies have found a strong correlation between the presence of lupus anticoagulant (LA) and anti-PS/PT antibodies. Clinically, the presence of anti-PS/PT antibodies is associated with an increased risk of thrombosis and obstetric complications. There is also an association with thrombocytopenia, suggesting that the presence of anti-PS/PT antibodies may be associated with more severe clinical APS. Among seronegative APS patients, 6–17% of patients are positive for anti-PS/PT antibodies. This might influence the therapeutic management of patients.This article aims to provide an update on contribution of anti-PS/PT antibodies detection for the diagnosis and management of APS.     

COVID-19–related laboratory coagulation findings

The alterations in the hemostatic balance in COVID-19 patients are strongly disturbed and contribute to a high prothrombotic status. The high rate of venous thromboembolism in COVID-19 patients goes along with derangements in coagulation laboratory parameters. Hemostasis testing has an important role in diagnosed COVID-19 patients. Elevated D-dimer levels were found to be a crucial laboratory marker in the risk assessment of thrombosis in COVID-19 patients. The diagnostic approach also includes prothrombin time and platelet count. Fibrinogen might give an indication for worsening coagulopathy. Other markers (activated partial thromboplastin time (aPTT), fibrinolysis parameters, coagulation factors, natural anticoagulants, antiphospholipid antibodies and parameters obtained by thromboelastography or thrombin generation assays) have been described as being deranged. These may help to understand the pathophysiology of thrombosis in COVID-19 patients but have currently no place in diagnosis or management in COVID-19 patients. For monitoring the heparin anticoagulant therapy, the anti-Xa assay is suggested, because the severe acute-phase reaction (high fibrinogen and high factor VIII) shortens the aPTT.     

The complicated relationships of heparin-induced thrombocytopenia and platelet factor 4 antibodies with COVID-19

COVID-19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of platelet factor 4/heparin antibodies being present in COVID-19-infected patients. This has thus been identified in some publications as representing a high incidence of heparin-induced thrombocytopenia (HIT), whereas in others, findings have been tempered by general lack of functional reactivity using confirmation assays of serotonin release assay (SRA) or heparin-induced platelet aggregation (HIPA). Moreover, in at least two publications, data are provided suggesting that antibodies can arise in heparin naïve patients or that platelet activation may not be heparin-dependent. From this literature, we would conclude that platelet factor 4/heparin antibodies can be observed in COVID-19-infected patients, and they may occur at higher incidence than in historical non-COVID-19-infected cohorts. However, the situation is complex, since not all platelet factor 4/heparin antibodies may lead to platelet activation, and not all identified antibodies are heparin-dependent, such that they do not necessarily reflect “true” HIT. Most recently, a “HIT-like” syndrome has reported in patients who have been vaccinated against COVID-19. Accordingly, much more is yet to be learnt about the insidious disease that COVID-19 represents, including autoimmune outcomes in affected patients.     

Coagulation System Activation for Targeting of COVID-19: Insights into Anticoagulants,Vaccine-Loaded Nanoparticles,and Hypercoagulability in COVID-19 Vaccines

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection.     

Anti-SARS CoV-2 IgG in COVID-19 Patients with Hematological Diseases: A Single-center,Retrospective Study in Japan

Objective Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally. Although the relationship between anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies and COVID-19 severity has been reported, information is lacking regarding the seropositivity of patients with particular types of diseases, including hematological diseases. Methods In this single-center, retrospective study, we compared SARS-CoV-2 IgG positivity between patients with hematological diseases and those with non-hematological diseases. Results In total, 77 adult COVID-19 patients were enrolled. Of these, 30 had hematological disorders, and 47 had non-hematological disorders. The IgG antibody against the receptor-binding domain of the spike protein was detected less frequently in patients with hematological diseases (60.0%) than in those with non-hematological diseases (91.5%; p=0.029). Rituximab use was significantly associated with seronegativity (p=0.010). Conclusion Patients with hematological diseases are less likely to develop anti-SARS-CoV-2 antibodies than those with non-hematological diseases, which may explain the poor outcomes of COVID-19 patients in this high-risk group.     

Thrombotic manifestations of the antiphospholipid syndrome in patients with malignancies

The presence of antiphospholipid antibodies has been reported in a large variety of patients with malignancies. Many case reports and reviews have appeared indicating that the presence of the antiphospholipid antibodies is related to thrombotic associations with the antiphospholipid syndrome (APS) in a proportion of these patients. We investigated the frequency of the thrombotic manifestations in 58 patients demonstrating antiphospholipid antibodies and with a history of neoplasia, including haematologic and lymphoproliferative malignancies. Antiphospholipid antibodies were detected by clotting assay [lupus anticoagulant (LAC)] or by enzyme-linked immunosorbent assay [anticardiolipin antibodies (aCL)] according to the Sapporo criteria. Patients, 39/58, suffered from solid tumours and 19/58 patients from malignant haematologic or lymphoproliferative diseases. One patient was suffering simultaneously from two solid tumours and a malignant lymphoma. Among the patients with solid tumours, 18/39 (46%) patients had thromboembolic complications of the antiphospholipid syndrome. Among the patients with haematologic and lymphoproliferative malignancies, only 6/19 (32%) suffered from thromboembolic complications. There was, however, no relation between the titres of aCL antibodies and the clinical manifestations. The presence, but not the titres, of antiphospholipid antibodies may identify a subset of cancer patients with a high risk of developing thrombotic complications. The frequency of thrombosis, however, is lower in aPL-positive patients with lymphoproliferative and haematological malignancies.     

Acute upper limb ischemia in a patient with COVID-19

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with upper and lower respiratory tract symptoms, with complications related to cytokine storm syndrome and acute respiratory distress syndrome. It has also been described to predispose to venous and arterial thromboembolism; however, limited published data is available regarding thrombosis in coronavirus disease 2019 (COVID-19). Here we are presenting a case of arterial thrombosis in a patient with COVID-19 and a systematic review on coagulopathy associated with COVID-19.     

Syndrome des antiphospholipides « séronégatif » : mythe ou réalité ?

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or obstetrical manifestations and the persistent presence, at least 12 weeks apart, of antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL) and/or anti-β2 glycoprotein I antibodies (aβ2GPI). The finding of patients with clinical profile highly suggestive of APS but who are negative for conventional biological criteria has led to the concept of seronegative APS. In the last few years, new antigen targets and methodological approaches have been employed to more clearly identify this syndrome in patients with thrombosis or obstetrical complications without conventional aPL. Although seronegative APS is still controversial, there is increasing recognition of the existence of this subgroup. However, clinical relevance of non conventional aPL need to be confirmed by efforts toward standardizing new biological tools and longitudinal studies involving large cohort of patients.     

Cardiac manifestations in primary antiphospholipid syndrome and their association to antiphospholipid antibodies’ types and titers—cross-sectional study of Serbian cohort

Clinical Rheumatology - Antiphospholipid syndrome (APS) is multisystem autoimmune coagulopathy with antiphospholipid antibodies (aPL) in its ground, manifested as a primary disease (PAPS) or in the...     

Segmental small bowel necrosis associated with antiphospholipid syndrome:A case report

Antiphospholipid syndrome is a multi-system disease characterized by the formation of thromboembolic complications and/or pregnancy morbidity, and with persistently increased titers of antiphospholipid antibodies. We report the case of a 50-year-old, previously healthy man who presented with fever and new-onset, dull abdominal pain. A contrast-enhanced computed tomography scan showed segmental small bowel obstruction, for which an emergency laparotomy was performed. Histopathologic examination of resected tissues revealed multiple intestinal and mesenteric thromboses of small vessels. Laboratory tests for serum antiphospholipid(anticardiolipin Ig M) and anti-β2-glycoprotein I antibodies were positive. Despite proactive implementation of anticoagulation, steroid, and antibiotic therapies, the patient's condition rapidly deteriorated, and he died 22 d after admission. This case highlights that antiphospholipid syndrome should be suspected in patients with unexplainable ischemic bowel and intestinal necrosis presenting with insidious clinical features that may be secondary to the disease, as early diagnosis is critical to implement timely treatments in order to ameliorate the disease course.     

Liver dysfunction during COVID-19 pandemic: Contributing role of associated factors in disease progression and severity

In December 2019, a new strain of coronavirus was discovered in China, and the World Health Organization declared it a pandemic in March 2020. The majority of people with coronavirus disease 19 (COVID-19) exhibit no or only mild symptoms such as fever, cough, anosmia, and headache. Meanwhile, approximately 15% develop a severe lung infection over the course of 10 d, resulting in respiratory failure, which can lead to multi-organ failure, coagulopathy, and death. Since the beginning of the pandemic, it appears that there has been consideration that pre-existing chronic liver disease may predispose to deprived consequences in conjunction with COVID-19. Furthermore, extensive liver damage has been linked to immune dysfunction and coagulopathy, which leads to a more severe COVID-19 outcome. Besides that, people with COVID-19 frequently have abnormal liver function, with more significant elevations in alanine aminotransferase and aspartate aminotransferase in patients with severe COVID-19 compared to those with mild/moderate disease. This review focuses on the pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the liver, as well as the use of liver chemistry as a prognostic tool during COVID-19. We also evaluate the findings for viral infection of hepatocytes, and look into the potential mechanisms behind SARS-CoV-2-related liver damage.     

Antiphospholipid Antibodies in Young Adults with Stroke

Background. Antiphospholipid antibodies have been associated with a clinical syndrome consisting thrombosis and recurrent, unexplained fetal loss. Methods. The literature pertaining to stroke associated with antiphospholipid antibodies, with emphasis on stroke in young adults, was reviewed. Results. Antiphospholipid antibodies are an independent risk factor for stroke in young adults in five of six studies. Multiple antiphospholipid specificities or the Lupus Anticoagulant were tested in addition to anticardiolipin antibody in these studies. In the single study that found no increased risk for stroke, only anticardiolipin antibody was tested. Only one of these studies evaluated for risk of recurrent stroke in young adults with antiphospholipid antibodies and found it to be increased. No treatment trials have been conducted in young adults with antiphospholipid antibodies and stroke. In the single treatment trial comparing aspirin and low-INR producing doses of warfarin to prevent recurrent stroke, both were found to be equally effective. Conclusions. Antiphospholipid antibodies, particularly Lupus Anticoagulant, is an independent risk factor for first and possibly recurrent ischemic stroke in young adults. The best therapeutic strategy for preventing antiphospholipid antibody-associated recurrent stroke is not clear.     

Interventions for Improving Long COVID-19 Symptomatology: A Systematic Review

Introduction: Although the understanding of several aspects of long COVID-19 syndrome is increasing, there is limited literature regarding the treatment of these signs and symptoms. The aim of our systematic review was to understand which therapies have proved effective against the symptoms of long COVID-19. Methods: A systematic search for randomized controlled or clinical trials in several databases was conducted through 15 May 2022. Specific inclusion criteria included: (1) intervention studies, either randomized controlled (RCTs) or clinical trials; (2) diagnosis of long COVID-19, according to the World Health Organization criteria; (3) presence of long COVID-19 for at least 12 weeks after SARS-CoV-2 infection. Results: We initially found 1638 articles to screen. After removing 1602 works based on their title/abstract, we considered 35 full texts, and among them, two intervention studies were finally included. The first RCT focused on the greater improvement of treatment combining olfactory rehabilitation with oral supplementation with Palmitoylethanolamide and Luteolin in patients with olfactory dysfunction after COVID-19. The second study evaluated the positive impact of aromatherapy vs. standard care in adult females affected by fatigue. Conclusion: Our systematic review found only two intervention studies focused on patients affected by long COVID-19. More intervention studies are needed to investigate potentially positive interventions for long COVID-19 symptoms.     

Chronic alcohol consumption and COVID-19 infection risk: A narrative review

During the COVID-19 pandemic, many potential risk groups have been identified, such as those with obesity, diabetes, preexisting organ injuries, and several other conditions. Smoking is the most reported substance use disorder linked to increased COVID-19 hospitalization rate and disease severity. In relation to smoking, we discuss the impairment of the innate and the adaptive immune systems as being among the main potential reasons for increased COVID-19 infection risk and severity. Chronic alcohol consumption and alcohol use disorder (AUD) also have a negative impact on the immune system, but when it comes to COVID-19 risk, they produce diverse outcomes. Some studies provide evidence that chronic alcohol consumption and AUD increase the risk of COVID-19 infection and severe disease progression, while others report reduced hospitalization and death rates. In this review, we summarize the current state of epidemiological and molecular data concerning alcohol consumption and AUD as risk factors for COVID-19 infection, hospitalization, and mortality.     

Anti-PF4 antibodies associated with disease severity in COVID-19

Severe COVID-19 is characterized by a prothrombotic state associated with thrombocytopenia, with microvascular thrombosis being almost invariably present in the lung and other organs at postmortem examination. We evaluated the presence of antibodies to platelet factor 4 (PF4)–polyanion complexes using a clinically validated immunoassay in 100 hospitalized patients with COVID-19 with moderate or severe disease (World Health Organization score, 4 to 10), 25 patients with acute COVID-19 visiting the emergency department, and 65 convalescent individuals. Anti-PF4 antibodies were detected in 95 of 100 hospitalized patients with COVID-19 (95.0%) irrespective of prior heparin treatment, with a mean optical density value of 0.871 ± 0.405 SD (range, 0.177 to 2.706). In contrast, patients hospitalized for severe acute respiratory disease unrelated to COVID-19 had markedly lower levels of the antibodies. In a high proportion of patients with COVID-19, levels of all three immunoglobulin (Ig) isotypes tested (IgG, IgM, and IgA) were simultaneously elevated. Antibody levels were higher in male than in female patients and higher in African Americans and Hispanics than in White patients. Anti-PF4 antibody levels were correlated with the maximum disease severity score and with significant reductions in circulating platelet counts during hospitalization. In individuals convalescent from COVID-19, the antibody levels returned to near-normal values. Sera from patients with COVID-19 induced higher levels of platelet activation than did sera from healthy blood donors, but the results were not correlated with the levels of anti-PF4 antibodies. These results demonstrate that the vast majority of patients with severe COVID-19 develop anti-PF4 antibodies, which may play a role in the clinical complications of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), the most devastating pandemic to have plagued the world in more than a century (1). Although effective vaccines have been developed and deployed at an unprecedented pace on a global scale (2–5), morbidity and mortality remain at alarming levels, particularly in areas with limited access or resistance to vaccination. Furthermore, the virus, because of its RNA nature, continues to evolve and generate novel variants that escape from neutralizing antibodies and other immunologic mechanisms of protection elicited by current vaccines (6–8). Thus, a further delineation of the mechanisms of COVID-19 disease remains a high priority, as it may foster the development of increasingly effective therapeutic strategies.The clinical spectrum of COVID-19 is broad, ranging from an asymptomatic state to severe disease leading to multisystemic involvement and death (9–11). The lung is the most frequently targeted organ, with the development of acute respiratory distress syndrome for which patients may require mechanical ventilation. Among the distinctive features of COVID-19 are vascular changes affecting the lung as well as other organs. Although clinically apparent thrombosis of major vessels can occur in severely ill patients with COVID-19 (12, 13), disseminated microthrombosis affecting multiple organs is an almost invariable finding at postmortem examination, particularly in the lungs, where diffuse platelet microthrombi are associated with alveolar damage (14–16). In addition, mortality in COVID-19 is associated with progressive thrombocytopenia, apparently as a consequence of disseminated platelet activation and consumption rather than of immune-mediated platelet destruction or splenic sequestration (9, 17). Thus, even in the absence of clinically apparent thrombosis, systemic microvascular thrombosis with thrombocytopenia may represent a common pathological mechanism underlying multiple organ failures in fatal COVID-19.The simultaneous presence of thrombosis and thrombocytopenia is the hallmark of heparin-induced thrombocytopenia (HIT), a dramatic clinical syndrome associated with heparin treatment especially in patients recovering from cardiac or orthopedic surgery (18). The pathogenic mechanism of the HIT syndrome involves the elicitation of autoantibodies that target partially cryptic epitopes in the α-chemokine platelet factor 4 (PF4 or CXCL4), which are fully revealed upon binding to heparin or other polyanionic molecules. Severe thrombosis associated with thrombocytopenia and anti-PF4–polyanion (anti-PF4) antibodies has also recently been reported as a rare complication of adenovirus-vectored anti–SARS-CoV2 vaccines, such as AZD1222 and Ad26.COV2.S, and defined as vaccine-induced thrombosis with thrombocytopenia (VITT) (19–22).Given the simultaneous occurrence of thrombosis, especially systemic microthrombosis, and thrombocytopenia in patients with severe COVID-19, we investigated the presence of anti-PF4 antibodies in the serum of patients with COVID-19.     

The role and delicate balance of Host Immunity in Coronavirus Disease-19

Severe Acute Respiratory Syndrome (SARS) associated with SARS-CoV-2, causes a severe form of the respiratory illness known as Coronavirus Disease-19 (COVID-19). COVID-19 has emerged as a worldwide pandemic with a high number of fatalities. Approximately 112,654,202 people have been infected so far with this disease which has led to the death of more than one point seven million (2,496,749) till 24th Feb, 2021. Measures to counter this disease have led to a global economic slowdown. Multiple drug trials are ongoing and several putative candidates for vaccination against the virus have been approved and are in the pipeline. Many studies have also characterized the immunological profile of patients infected with COVID-19. Some studies suggest that the severity of the COVID-19 infection is directly associated with the cytokine storm. In this review, we aim to compile the available knowledge and describe the nature of immune responses in patients infected with COVID-19 in different age groups, comorbidity, and immune-compromised state and their association with disease severity.     

Antiphospholipid antibodies--we are not quite there yet

The diagnosis of antiphospholipid syndrome is predominantly made in the laboratory and depends on the persistent presence of antiphospholipid antibodies in individuals with thrombosis or pregnancy morbidity. Correct diagnosis of the syndrome is imperative to prevent unnecessary long secondary thromboprophylaxis. Three antiphospholipid antibody subtypes are included in the classification criteria of the antiphospholipid syndrome: lupus anticoagulants, anticardiolipin antibodies and anti-β2-glycoprotein I antibodies. Only lupus anticoagulants are undisputedly associated with thrombosis, which is why the serological criteria of the antiphospholipid syndrome are under debate. All of the assays used to detect antiphospholipid antibodies are in need of better standardization, although progress has been made in the detection of lupus anticoagulants. The inconsistent association between both anticardiolipin and anti-β2-glycoprotein I antibodies and thrombosis is a cause for alarm. We are in need of better assays to detect those individuals at risk for thrombosis and population-based prospective studies to provide us with accurate risk assessments.