Frequency of positive antiphospholipid antibodies in pregnant women with SARS-CoV-2 infection and impact on pregnancy outcome: A single-center prospective study on 151 pregnancies.

Background: At the beginning of the SARS-CoV-2 pandemic, there was a lack of information about the infection's impact on pregnancy and capability to induce de novo autoantibodies. It soon became clear that thrombosis was a manifestation of COVID-19, therefore the possible contribution of de novo antiphospholipid antibodies (aPL) raised research interest. We aimed at screening SARS-CoV-2 positive pregnant patients for aPL. Methods: The study included consecutive pregnant women who were hospitalized in our Obstetric Department between March 2020 and July 2021 for either a symptomatic SARS-CoV-2 infection or for other reasons (obstetric complications, labour, delivery) and found positive at the admission nasopharyngeal swab. All these women underwent the search for aPL by means of Lupus Anticoagulant (LA), IgG/IgM anti-cardiolipin (aCL), IgG/IgM anti-beta2glycoprotein I (aB2GPI). Data about comorbidities, obstetric and neonatal complications were collected. Results: 151 women were included. Sixteen (11%) were positive for aPL, mostly at low titre. Pneumonia was diagnosed in 20 women (5 with positive aPL) and 5 required ICU admission (2 with positive aPL). Obstetric complications occurred in 10/16 (63%) aPL positive and in 36/135 (27%) negative patients. The occurrence of HELLP syndrome and preeclampsia was significantly associated with positive aPL (p=0,004). One case of maternal thrombosis occurred in an aPL negative woman. aPL positivity was checked after at least 12 weeks in 7/16 women (44%): 3 had become negative; 2 were still positive (1 IgG aB2GPI + IgG aCL; 1 IgM aB2GPI); 1 remained positive for IgG aCL but became negative for aB2GPI; 1 became negative for LA but displayed a new positivity for IgG aCL at high titre. Conclusions: The frequency of positive aPL in pregnant women with SARS-CoV-2 infection was low in our cohort and similar to the one described in the general obstetric population. aPL mostly presented as single positive, low titre, transient antibodies. The rate of obstetric complications was higher in aPL positive women as compared to negative ones, particularly hypertensive disorders. Causality cannot be excluded; however, other risk factors, including a full-blown picture of COVID-19, may have elicited the pathogenic potential of aPL and contributed themselves to the development of complications.

[Practice guidelines of thromboprophylaxis and management of anticoagulation in hospitalized patients with COVID-19].

Corona virus disease 2019 (COVID-19) can lead to thrombotic complications through multiple mechanisms. Venous thromboembolism (VTE) is one of the most important causes of death or poor prognosis in hospitalized patients with COVID-19. The prognosis of thrombosis in COVID-19 patients can be improved with VTE and bleeding risk assessment, as well as appropriate VTE prophylaxis. However, in current clinical practice, there still is much room for progress in choose of appropriate prevention methods, anticoagulant regimens, doses, and courses based on the severity and specific condition of COVID-19 patients and dynamically balancing the risk of thrombosis and bleeding. In the past three years, a series of authoritative guidelines related to VTE and COVID-19 and high-quality, evidence-based medical research evidence have been released both in domestic and internationally. Based on this, in order to better guide the clinical practice in China, multi-discipline expert discussions and Delphi expert demonstrations formulated the"Thromboprophylaxis and management of anticoagulation in hospitalized patients with COVID-19: an update of the CTS guidelines", aiming to address the issues of thrombosis risk and prevention strategies caused by COVID-19, anticoagulant management of hospitalized patients, diagnosis and treatment of thrombosis, anticoagulant management of special populations, interaction and adjustment strategies of antiviral and anti-inflammatory drugs and anticoagulant drugs, follow-up after discharge and many other aspects of clinical situations. Recommendations and clinical guidelines are provided for appropriate thromboprophylaxis and anticoagulation management strategies for VTE in patients with COVID-19.

Comprehensive collection of COVID-19 related prosthetic valve failure: a systematic review.

Since the beginning of the SARS-CoV-2 (COVID-19) pandemic, correlation of venous thromboembolism (VTE) and COVID-19 infection has been well established. Increased inflammatory response in the setting of COVID-19 infection is associated with VTE and hypercoagulability. Venous and arterial thrombotic events in COVID-19 infection have been well documented; however, few cases have been reported involving cardiac valve prostheses. In this review, we present a total of eight cases involving COVID-19-related prosthetic valve thrombosis (PVT), as identified in a systematic review. These eight cases describe valve position (mitral versus aortic) and prosthesis type (bioprosthetic versus mechanical), and all cases demonstrate incidents of PVT associated with simultaneous or recent COVID-19 infection. None of these eight cases display obvious non-adherence to anticoagulation; five of the cases occurred greater than three years after the most recent valve replacement. Our review offers insights into PVT in COVID-19 infected patients including an indication for increased monitoring in the peri-infectious period. We explore valve thrombosis as a mechanism for prosthetic valve failure. We describe potential differences in antithrombotic strategies that may offer added antithrombotic protection during COVID-19 infection. With the growing population of valve replacement patients and recurring COVID-19 infection surges, it is imperative to explore relationships between COVID-19 and PVT.

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.

Catastrophic Antiphospholipid Syndrome as a Complication of COVID-19 Infection.

COVID-19 infection has been found to precipitate hypercoagulability and transiently increase antiphospholipid antibodies. However, it is yet to be determined how likely these transient changes contribute to thrombotic events and antiphospholipid syndrome. We present a case in which antiphospholipid antibodies were detected in the presence of significant thromboses. The patient was subsequently treated for suspected catastrophic antiphospholipid syndrome following COVID-19 infection.

Obesity: A critical risk factor in the COVID-19 pandemic.

Obesity is an emerging independent risk factor for susceptibility to and severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Previous viral pandemics have shown that obesity, particularly severe obesity (BMI > 40 kg/m2 ), is associated with increased risk of hospitalization, critical care admission and fatalities. In this narrative review, we examine emerging evidence of the influence of obesity on COVID-19, the challenges to clinical management from pulmonary, endocrine and immune dysfunctions in individuals with obesity and identify potential areas for further research. We recommend that people with severe obesity be deemed a vulnerable group for COVID-19; clinical trials of pharmacotherapeutics, immunotherapies and vaccination should prioritize inclusion of people with obesity.

High incidence of common femoral Deep Vein Thrombosis in critically ill Covid19 patients.

Objective: To estimate the incidence and prevalence of deep venous thrombosis, and to evaluate the discriminative capacity of D-dimer in its diagnosis. METHODS: The prospective, observational study was conducted at the critical care unit of a tertiary care hospital in Pakistan from February to September 2021 and comprised consecutively admitted adult critically ill patients who were receiving therapeutic-dose anticoagulation therapy. All patients were screened on day one for deep venous thrombosis by colour doppler and compression ultrasonography. Patients who did not have deep venous thrombosis on the first scan were followed every 72 hours. Data was analysed using SPSS 26. RESULTS: Of the 142 patients, 99(69.7%) were male and 43(30.3%) were female. The overall mean age was 53.20+/-13.3 years. On the first scan, 25(17.6%) patients had deep venous thrombosis. Of the remaining 117 patients, 78(68.4%) were followed every 72 hours, and 23(29.48%) of them developed deep venous thrombosis. The most common site for DVT was the common femoral vein 46(95.8%) and most deep venous thrombosis cases were unilateral 28(58.33%). D-dimer levels showed no discriminative capacity for diagnosis of deep venous thrombosis (p=0.79). There were no significant risk factors for the development of deep venous thrombosis. Conclusion: There was a high incidence and prevalence of deep venous thrombosis despite therapeutic-dose anticoagulation therapy. The most common affected site was the common femoral vein and most deep venous thrombosis were unilateral. D-dimer levels had no discriminative capacity for the diagnosis of deep venous thrombosis DVT.

Readmission After COVID-19 for Late Acute Venous Thrombosis; CASE SERIES and Systematic Review of the Literature.

OBJECTIVE: Assess heterogeneity within patients with resolved COVID-19 to broaden the vision about post-discharge thrombotic cases and postulate possible related mechanisms in search of better anticoagulation guidelines. This study details patients' characteristics, medical history, treatment, and outcomes of readmitted patients with late acute thrombosis through a systematic review of the literature and patients from our academic center database. METHODS: We extracted the records of patients readmitted for venous thrombosis complications after discharge from the database of the first 2000 patients admitted with COVID-19 in our academic center; we also performed a systematic review of the literature using the Medical Subject Headings terms "late thrombosis," "COVID-19," + "venous thrombosis" in PubMed and Google Scholar according to PRISMA guideline. RESULTS: The literature review found 20 patients suitable for review matching the inclusion criteria. These patients were added to those in our database, summing up a total of 26 patients. The median age was 50 years old, 76.9% were male, and most were overweight or had grade 1 obesity (n = 11, 42.3%). None had a previous thrombotic history, but 50% had an underlying comorbidity. Thrombotic events presented on a median of 20 days (range: 4-150 days) from discharge. Pulmonary embolisms occurred in 23 patients (88.46%), deep vein thrombosis in 4, mesenteric thrombosis, and cerebral venous thrombosis in 1, respectively. CONCLUSION: This study found that most patients readmitted for thrombotic events after COVID-19 discharge were middle-aged men with Venous Thrombo Embolism events.

COVID-19 infection-associated platelet and neutrophil activation is blunted by previous anti-SARS-CoV-2 vaccination.

The effectiveness of vaccination against SARS-CoV-2 in preventing COVID-19 or in reducing severe illness in subjects hospitalized for COVID-19 despite vaccination has been unequivocally shown. However, no studies so far have assessed if subjects who get COVID-19 despite vaccination are protected from SARS-CoV-2-induced platelet, neutrophil and endothelial activation, biomarkers associated with thrombosis and worse outcome. In this pilot study, we show that previous vaccination blunts COVID-19-associated platelet activation, assessed by circulating platelet-derived microvesicles and soluble P-selectin, and neutrophil activation, assessed by circulating neutrophil extracellular trap (NET) biomarkers and matrix metalloproteinase-9, and reduces COVID-19-associated thrombotic events, hospitalization in intensive-care units and death.

Carotid free-floating thrombus in COVID-19: a cerebrovascular disorder of cytokine storm-related immunothrombosis.

BACKGROUNDS: Several neurological manifestations, including stroke, have been reported in COVID-19 patients. The putative role of the COVID-19-related hyperinflammatory state in cerebrovascular disorders remains unclear. METHODS: From March 2020 to September 2021, we searched for patients who exhibited an ischemic stroke related to carotid free-floating thrombus (CFFT) to investigate its incidence and relationship with COVID-19. RESULTS: Of 853 ischemic strokes referred to our Stroke Centre during the study period, 5.7% (n = 49) were positive for SARS-CoV-2. Six had CFFT, of which two tested positive for SARS-CoV-2 (2/49 = 4.1%), and four did not (4/802 = 0.5%). The former were two middle-aged men suffering from COVID-19 pneumonia. Floating thrombi were promptly extracted by endarterectomy and endovascular thrombectomy, respectively, with no early and long-term complications. Notably, our COVID-19 patients exhibited little or no atherosclerosis burden on CT angiography, markedly elevated D-dimer levels, and extensive thrombus length. CONCLUSIONS: COVID-19-induced immunothrombosis possibly played a significant pathogenic role in CFFT.

Dysregulation of Protein S in COVID-19.

Coronavirus Disease 2019 (COVID-19) has been widely associated with increased thrombotic risk, with many different proposed mechanisms. One such mechanism is acquired deficiency of protein S (PS), a plasma protein that regulates coagulation and inflammatory processes, including complement activation and efferocytosis. Acquired PS deficiency is common in patients with severe viral infections and has been reported in multiple studies of COVID-19. This deficiency may be caused by consumption, degradation, or clearance of the protein, by decreased synthesis, or by binding of PS to other plasma proteins, which block its anticoagulant activity. Here, we review the functions of PS, the evidence of acquired PS deficiency in COVID-19 patients, the potential mechanisms of PS deficiency, and the evidence that those mechanisms may be occurring in COVID-19.

How Does COVID-19 Affect the Heart?

PURPOSE OF REVIEW: Cardiac consequences occur in both acute COVID-19 and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, and molecular studies. RECENT FINDINGS: COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies of COVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfilling histologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation. The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.

Acute Kidney Injury in Coronavirus Disease and Association with Thrombosis.

INTRODUCTION: Coronavirus disease (COVID-19) is a global pandemic which continues to cause systemic inflammation, leading to multi-system organ damage including acute kidney injury (AKI) and thrombotic complications. We hypothesize that D-dimer level predicts an increased risk of AKI and thrombotic complications in COVID-19. METHODS: This was a retrospective cohort study performed at a single-center academic center. Patients hospitalized with COVID-19 between January 1, 2020, and January 1, 2021, were included in the analysis. Demographics and associated medical records were reviewed from the electronic medical record. Statistical analysis was done to determine the incidence of AKI and thrombosis and if D-dimer was predictive of an adverse event. RESULTS: The study included 389 patients with the diagnosis of COVID-19 who were hospitalized. AKI was evident in 143 patients with 59 experiencing a thrombotic event. Factors associated with AKI included age, chronic kidney disease, proteinuria, use of outpatient angiotensin-blocking medications, and D-dimer greater than 1.75 (p < 0.05). Factors associated with thrombosis included use of outpatient anticoagulants, elevated WBC, interleukin-6 (IL-6), and D-dimer greater than 1.75 (p < 0.05). When D-dimer was dichotomized at the median value for the entire dataset (value greater than 1.75), there was good discrimination for AKI and very good discrimination for thrombosis. CONCLUSIONS: Complications of acute renal failure and thrombosis are common in patients presenting with COVID-19. D-dimer was found to be predictive of both. Future studies to validate the association of these two events in patients presenting with COVID-19 are warranted as early treatment with antithrombotic agents may have a role in preventing adverse sequelae and outcomes.

Inferior vena cava and renal vein thrombosis: a rare cause of acute kidney injury in tuberculosis.

Recent studies show active tuberculosis induces a prothrombotic state and increases the risk of venous thromboembolism. We report a recently diagnosed case of tuberculosis who presented to our hospital with painful bilateral lower limb swelling and several episodes of vomiting with abdominal pain for 2 weeks. Investigations by a hospital elsewhere 2 weeks ago showed abnormal renal function, misdiagnosed as antitubercular therapy-induced acute kidney injury. D-dimer levels were increased on admission with us, with still deranged renal function. Imaging revealed thrombus at the origin of left renal vein, inferior vena cava and bilateral lower limbs. We started treatment with anticoagulants, which gradually improved kidney function. This case highlights that early diagnosis of renal vein thrombosis and prompt treatment are associated with good clinical outcomes. It also highlights the importance of further studies for risk assessment, prevention strategies and reduction of the burden of venous thromboembolism in patients with tuberculosis.

A Rare Case of Multiple Thrombosis Associated with COVID-19 Pneumonia.

Coronavirus disease 2019 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 virus. Hypoxic respiratory failure, multiorgan dysfunction, septic shock, thrombosis, and thromboembolic complications have been associated with the severe acute respiratory syndrome coronavirus 2 infection. We report the presentation of the severe acute respiratory syndrome coronavirus 2 infection with acute upper extremity ischemia and mesenteric ischemia clinic. We also report that this patient had an aortic arch mural thrombus as a possible source of thromboembolism, and we emphasize that the aorta should also be carefully evaluated in thromboembolic patients with coronavirus disease 2019.

The Perspective of Vitamin D on suPAR-Related AKI in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin-angiotensin-aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.

From COVID-19 to clot: the involvement of the complement system.

In December 2019, the world observed an unexpected outbreak of an emerging disease named coronavirus (COVID-19) that was first reported in Wuhan city of Hubei province of China. Recent literature has shown the association between COVID-19 infection and derangement in the coagulation profile. In this paper, we are discussing thrombo-genesis, especially the role of the complement system in the immune response against COVID-19 and the pathogenesis associated with tissue inflammation and thrombosis. This role can stipulate a groundwork for further investigation of the pathophysiologic importance of complement in COVID-19, and could propose targets for specific intervention. In addition, we delineated current treatments for thrombosis and the potential therapies by using agents to block the terminal complement pathway. Low molecular weight heparin for all (unless contraindicated) hospitalized COVID-19 patients can be lifesaving. Agents that inhibit the terminal events of the complement cascade might be crucial for ensuring an efficient treatment, decrease clots and permit early discharge in relation to COVID-19.Communicated by Ramaswamy H. Sarma.

An epidural brain abscess and thrombus in the superior sagittal sinus in a 12 year-old with sinusitis.

BACKGROUND: Upper respiratory infections can be complicated by acute bacterial sinusitis in pediatric patients, and usually resolve with antibiotic therapy (DeMuri and Wald, 2011). However, intracranial complications such as: epidural abscess, meningitis and more rarely cerebral sinus venous thrombosis (CSVT) can occur (Germiller et al., 2006). We report an unusual case of sinusitis complicated by an epidural abscess and later a CSVT in a young previously healthy patient. CASE DESCRIPTION: A 12-year-old female presented to the emergency department with a 9-day history of headaches and a 3-day history of fevers, rigors, nasal congestion and nonproductive cough. She later tested positive for Covid-19. CT and MRI showed extensive paranasal sinus disease and a right frontal epidural collection. MRV showed no sinovenous thrombosis. Washout and burr hole drainage alongside endoscopic sinus surgery was completed and post-op imaging showed evacuation of the epidural abscess with a small residual collection. Six days after the procedure, she experienced worsening headaches and MRV showed a nonocclusive thrombus in the superior sagittal sinus, which was treated with anticoagulation therapy. Upon follow-up, the patient showed improvement of the sinusitis, abscess and thrombus. CONCLUSION: This specific case encourages clinicians to be aware of complications, though rare, and to diagnose and treat sinusitis cases quickly. It is also important to be aware of any risk factors for thrombus formation, including an inflammatory and hypercoagulable state. In the patient's case, it was perceived that the CSVT was provoked due to the patient's Covid-19 infection, abscess, and sinus disease.

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF.

Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4-VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4-VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.