ANTIPHOSPHOLIPID ANTIBODIES AND VASCULAR THROMBOSIS IN PATIENTS WITH THE MOST SEVERE FORMS OF COVID-19

BackgroundThe presence of antiphospholipid antibodies (aPL) has been observed in patients with COVID-19 (1,2), suggesting that they may be associated with deep vein thrombosis, pulmonary embolism, or stroke in severe cases (3). Antiphospholipid syndrome (APS) is a systemic autoimmune disorder and the most common form of acquired thrombophilia globally. At least one clinical criterion, vascular thrombosis (arterial, venous or microthrombosis) or pregnancy morbidity and at least one laboratory criterion- positive aPL two times at least 12 weeks apart: lupus anticoagulant (LA), anticardiolipin (aCL), anti-β2-glycoprotein 1 (anti-β2GPI) antibody, have to be met for international APS classification criteria(4). Several reports also associate anti-phosphatidylserine/prothrombin antibodies (aPS/PT) with APS.ObjectivesTo combine clinical data on arterial/venous thrombosis and pregnancy complications before and during hospitalisation with aPL laboratory findings at 4 time points (hospital admission, worsening of COVID-19, hospital discharge, and follow-up) in patients with the most severe forms of COVID-19 infection.MethodsPatients with COVID-19 pneumonia were consequetively enrolled, as they were admitted to the General hospital Pancevo. Exclusion criteria were previous diagnosis of inflammatory rheumatic disease and diagnosis of APS. Clinical data were obtained from the medical records. Laboratory results, including LA, aCL, anti-β2GPI, and aPS/PT antibodies were taken at hospital admission, worsening (defined as cytokine storm, connection of the patient to the respirator, use of the anti-IL-6 drug- Tocilizumab), at hospital discharge and at 3-months follow-up and sent to University Medical Centre Ljubljana, Slovenia for analysis. Statistics was performed by using SPSS 21.Results111 patients with COVID-19 pneumonia were recruited;7 patients died during hospitalisation (none were aPL-positive on admission and at the time of worsening), 3 due to pulmonary artery embolism. All patients were treated according to a predefined protocol which included antibiotics, corticosteroids, anticoagulation therapy and specific comorbidity drugs;patients with hypoxia were supported with oxygen. During hospitalisation, pulmonary artery thrombosis occurred in 5 patients, one was aPL-positive at all time points (was diagnosed with APS), others were negative. In addition, 9/101 patients had a history of thrombosis (5 arterial thrombosis (coronary and cerebral arteries), none of whom was aPL-positive on admission and at follow-up, and 4 venous thrombosis, one of which was aPL-positive at all time points and received an APS diagnosis). Among 9/101 patients with a history of thrombosis, 55.6% were transiently positive at the time of discharge, compared to patients without prior thrombosis, in whom 26.1% were transiently positive at the hospital release (p=0.074). Two patients had a history of pregnancy complications (both had miscarriage after 10th week of gestation), but did not have aPL positivity at any time point.ConclusionAlthough aPL was expected to be associated with vascular disease in the most severe forms of COVID-19, all patients that have died in our cohort were aPL negative. At hospital discharge, 56% of patients with a history of arterial or venous thrombosis had positive aPL that became negative at the 3-months follow-up (were transienlty positive), which should be considered when prescribing therapy after hospitalisation.References[1]Trahtemberg U, Rottapel R, Dos Santos CC, et al. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Annals of the Rheumatic Diseases 2021;80:1236-1240.[2]Stelzer M, Henes J, Saur S. The Role of Antiphospholipid Antibodies in COVID-19. Curr Rheumatol Rep. 2021;23(9):72-4.[3]Xie Y, Wang X, Yang P, Zhang S. COVID-19 complicated by acute pulmonary embolism. Radiology: Cardiothoracic Imaging 2020: 2: e200067.[4]Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, et al. J.Thromb.Haemost. 2006;4: 295-306.Acknowledgements:NIL.Disclosure of nterestsNone Declared.

An audit of paroxysmal nocturnal haemoglobinuria (PNH) requesting at University Hospitals of North Midlands

Early identification of PNH, a rare life-threatening disease is essential to ensure appropriate management via the UK PNH service. Since testing for PNH is expensive (75.97 per test), we set out to assess the suitability of PNH requests against guidelines with the aim to feedback to colleagues and reduce unnecessary testing. To determine whether PNH requests at UHNM were in line with criteria in British Society for Haematology (BSH) guidelines. All patients over 18 years of age who had PNH testing for the first time and those who had repeat testing for monitoring between 01/04/2019 and 31/03/2020 were included. Patients were selected from electronic records of PNH sample receipt to laboratories. Hospital records were reviewed for clinical details and investigation Results. 82 requests including 79 individual patients were audited. 57% were male and 43% were female. Median age was 56 years. 97.6% of PNH tests were requested by a haematologist whilst only 2.5% requests were done by non-haematology clinicians. 52.4% requests were in keeping with BSH recommendations, whilst 47.6% tests did not meet criteria for testing. All patients tested outside of guideline recommendations were negative. Of the reasonable requests, only 23.3% (10) were positive. Of the PNH positive patients, 8 patients were known to have a PNH clone with aplastic anaemia;one patient had a hypoplastic bone marrow and a known PNH clone whilst only one patient with cytopenia had a new positivity for PNH. The frequency monitoring for aplastic anaemia and a PNH clone was 100% concordant with BSH recommendations. With appropriate testing, only one new patient was identified. Our audit has limitations. We have not been able to assess whether any patients outside of those monitored for PNH in aplastic anaemia have been overlooked for testing. Also, the time period includes the COVID-19 pandemic so our findings may not reflect usual practice. New BSH guidelines for thrombophilia testing were published in 2022 and recommend testing for PNH in patients with thrombosis at unusual sites and abnormal haematological parameters and for patients with arterial thrombosis and abnormal blood parameters. This will likely limit excess tests although the sensitivity and specificity of such an approach has not been formally evaluated. In a finite health system, it is our responsibility to rationalise investigations. The cost of a year's testing was 6229.54 and that of inappropriate testing was 2962.83. As a department, we could, therefore, save 2962.83.

Catheter-Related Venous Thrombosis in Patients with Systemic Sclerosis: A Case Series

Background/Aims Systemic sclerosis (SSc) is characterised by endothelial dysfunction and vasculopathy, which may lead to venous thrombosis. Here, we report four cases of extensive venous thrombosis of the upper limbs and right atrium associated with implantable venous access devices (port-a-cath) in patients with a diagnosis of SSc, who presented to our specialist centre between 2018 and 2022. Methods We retrospectively reviewed four patients with SSc and port-a-cathassociated thrombosis who presented to the Department of Rheumatology, Royal Free Hospital NHS Trust between 2018 and 2022. All patients are diagnosed with systemic sclerosis according to the 2013 ACR/EULAR classification criteria. Results Three patients were diagnosed with a port-a-cath-associated thrombosis in 2022, and one in 2018. Two patients had limited cutaneous SSc with positive anti-centromere antibodies, and 2 had diffuse subset with anti-U3RNP antibodies. All patients had a right-sided port-a-cath that had been in-situ for at least 3 years. Two patients were diagnosed with right atrium thrombus (measuring 2.2 and 3cm respectively), one patient with an internal jugular vein and right subclavian thrombosis, and one with a left subclavian thrombosis. None had a history of previous thromboembolic event. A full thrombophilia screen was negative in 2 patients, and is pending in the others. Of note, 2 patients had COVID-19 infection within the 3 months prior the thrombotic event. 1 patient had tocilizumab administered through the line, 1 rituximab and IVIG, the other 2 had prostanoids only. Conclusion We described four recent cases of port-a-cath-associated thrombosis of the upper limbs and right atrium in SSc patients with no previous history of thrombosis. This highlights the increased risk of thrombosis related to long term indwelling catheters in SSc and demonstrates the potential interplay between covid microvasculopathy and the associated thrombotic risks reported with both ACA and antiU3RNP antibodies in SSc. We note that from previous reports the relative lower risk of adverse outcomes in SSc patient receiving parenteral nutrition. Further research into frequency of port-a-cath-related thrombosis in SSc patients is warranted, especially with use of prostanoids, and adequate screening and non-invasive follow up might be needed to avoid life-threatening thromboembolic complications. (Table Presented).

A Comprehensive Review of Risk Factors for Venous Thromboembolism: From Epidemiology to Pathophysiology.

Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1-2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE.

Multivessel Epicardial Coronary Artery Thrombosis after Heart Transplantation

Introduction: Although cardiac allograft vasculopathy (CAV) remains one of the leading causes of graft failure after heart transplantation (HTx), simultaneous thrombosis of multiple epicardial coronary arteries (CA) is an uncommon finding. Case Report: A 43-year-old male patient with non-ischemic dilated cardiomyopathy underwent successful HTx in 2019. The first two years after HTx were uneventful, surveillance endomyocardial biopsies (EMB) did not reveal any rejection episodes, coronary CTA revealed only minimal non-calcified CA plaques. The patient was admitted to hospital due to fever and chest pain in 2021. Immunosuppressive therapy consisted of tacrolimus, mycophenolate-mofetil and methylprednisolone. ECG verified sinus rhythm. Laboratory test revealed elevated hsTroponin T, NT-proBNP and CRP levels. Cytomegalovirus, SARS-CoV-2-virus and hemoculture testing was negative. Several high-titre donor-specific HLA class I and II antibodies (DSAs;including complement-binding DQ7) could have been detected since 2020. Echocardiography confirmed mildly decreased left ventricular systolic function and apical hypokinesis. EMB verified mild cellular and antibody-mediated rejection (ABMR) according to ISHLT grading criteria. Cardiac MRI revealed inferobasal and apical myocardial infarction (MI);thus, an urgent coronary angiography was performed. This confirmed thrombotic occlusions in all three main epicardial CAs and in first diagonal CA. As revascularization was not feasible, antithrombotic therapy with acetylsalicylic acid, clopidogrel and enoxaparin was started for secondary prevention. Tests for immune system disorders, thrombophilia and cancer were negative. Patient suddenly died ten days after admission. Necropsy revealed intimal proliferation in all three main epicardial CAs, endothelitis, thrombosis, chronic pericoronary fat inflammation, fat necrosis, and subacute MI. CA vasculitis owing to persistent high-titre DSAs, chronic ABMR and acute cellular and antibody-mediated rejection led to multivessel CA thrombosis and acute multiple MI. ABMR after HTx may be underdiagnosed with traditional pathological methods. Pathologies affecting coronary vasculature of HTx patients with DSAs, unique manifestations of CAV lesions and occlusive thrombosis of non-stenotic, non-atherosclerotic lesions should be emphasized.Copyright © 2023

Protein S Deficiency with Favourable Foetomaternal Outcome: A Case Report

Protein S is a multifunctional plasma protein, whose deficiency, results in a rare congenital thrombophilia, inherited in an autosomal dominant pattern. It can aggravate the hypercoagulable state of pregnancy, when it presents in parallel with the condition, leading to adverse maternal outcomes and foetal loss. A 35-year-old female third gravida having previous 2 deliveries by Lower Segment Caesarean Section (LSCS) presented to emergency at 10 weeks pregnancy with chief complaints of pain and swelling in left thigh since 4-5 days. After thorough investigations and work-up, the patient was diagnosed with Protein S deficiency. She was managed conservatively and was delivered by elective LSCS with bilateral tubal ligation at 38 weeks of gestation with good foetal and maternal outcomes.The rarity of Protein S deficiency along with the successful outcome of the pregnancy makes this a unique case.Copyright © 2023 Journal of Clinical and Diagnostic Research. All rights reserved.

PORTAL VEIN THROMBOSIS WHILE TAKING A COMBINED ORAL CONTRACEPTIVE AFTER EXPERIENCED CORONAVIRUS INFECTION.

Background: Contraceptives are an important component of women's reproductive health care, as they not only reduce the number of unwanted pregnancies, but also improve reproductive function. However, oral contraceptives are known to increase the risk of venous thromboembolism. This risk is increased by infection with the COVID-19 virus that predisposes patients to both venous and arterial thrombosis as a result of excessive inflammation, platelet activation, aggravated endothelial dysfunction, and congestive events. If these patients have hereditary thrombophilia, the risk of venous thromboembolism becomes fatal. Case report: The paper describes a clinical case of a patient with total portal vein thrombosis, who have been taking oral contraceptives for a long time and recovering from the novel coronavirus infection. Studying the blood coagulation system and folate cycle genes, by using PCR, has revealed a gene mutation in the plasminogen activator inhibitor (serpine). The authors demonstrate the data of spiral computed tomography of the abdominal organs, as well as changes in laboratory parameters. Conclusion(s): A balanced approach is required when prescribing combined oral contraceptives during the COVID-19 pandemic, especially in women with prothrombotic mutations.Copyright © A group of authors, 2023.

First reported case of parvovirus triggering painful widespread livedoid vasculopathy: another virus causing hypercoagulability?

Livedoid vasculopathy (LV) is a noninflammatory thrombotic disease caused by occlusion of dermal small vessels associated with systemic autoimmune disorders and coagulopathies. However, LV is often reported as being 'idiopathic', despite extensive investigation. We report a case of severe LV in an otherwise healthy 27-year-old woman, associated with parvovirus infection. The patient presented with a short history of a livedoid rash initially covering her torso, which spread to acral sites. Burning pains in the lower limb caused reduced mobility;systemically, she remained well and stable throughout. Examination revealed generalized acral skin pallor, livedoid patches of violet erythema and purpura with deep serpiginous ulcerations over extensor aspects of upper and lower limbs with a more broken/racemosa nonulcerated livedoid appearance on the trunk. On admission a transaminitisareas continued to ulcerate. Codeine was present with a creatine kinase of 1569 U L.1, but other blood test results were unremarkable including erythrocyte sedimentation rate, complement, cryoglobulins, antinuclear antibodies, antineutrophil cytoplasmic antibodies, extractable nuclear antigen, rheumatoid factor, myositis screen, antiphospholipid screen and thrombophilia screen. Parvovirus IgG and IgM were both positive and tested for, as the patient's young daughter had recently been diagnosed with 'slapped cheek disease'. Magnetic resonance imaging of the thighs showed a diffuse mild myositis;electromyography, nerve-conduction studies, barium swallow and computed tomography of the chest, abdomen and pelvis were all normal. An incisional skin biopsy was performed, which revealed a blood vessel with organizing (Solimani F, Mansour Y, Didona D et al. Development of severe pemphigus vulgaris following SARS-CoV-2 vaccination with BNT162b2. J Eur Acad Dermatol Venereol 2021;35: e649- 51) have been reported. The main proposed mechanisms for AstraZeneca vaccine-induced pemphigus could be a hyperimmune reaction in genetically predisposed individuals, with eventual formation of anti-desmoglein antibodies. An alternative hypothesis is that vaccine components could act as foreign antigens resulting in a cross-reaction with pemphigus antigens. The close association of COVID-19 vaccination with the acute onset of pemphigus in our patient, as well as exacerbations after subsequent vaccine administration, is more than coincidental. Considering the recent pandemic with COVID-19 and the widespread administration of the COVID-19 vaccine, continued observation and documentation of true adverse events is essential.

Venous and arterial thromboses in hospitalized patients with acute COVID-19 at University Hospital Dubrava

Since COVID-19 pandemic has started, there have been reports that SARS-CoV-2 infection induces pro-thrombotic state. Even though the disease presents foremost with respiratory symptoms, high frequencies of both venous and arterial thromboses have been observed while suggesting different molecular mechanisms. University Hospital Dubrava has been Croatia capital's COVID-19 centre for almost a year and a half treating almost 10.000 patients until today. We retrospectively analysed venous and arterial thrombotic events among 4014 patients hospitalized due to COVID-19. Venous thromboembolic events (VTE) occurred in 5.3% and arterial thrombotic events (ATE) in 5.8% of patients. Majority of ATE occurred prior or on the day of admission while VTE were mainly detected during hospitalization (screening). Majority of both occurred prior to intensive care unit (ICU) admission, but both were associated with higher need for ICU care and prolonged immobilization. In multivariate logistic regression analysis independent factors associated with VTE were metastatic malignancy, known thrombophilia, higher D-dimers, longer duration of disease on admission, bilateral pneumonia, longer duration of hospitalization and immobilization for at least one day. On the other hand, factors that showed to be associated with ATE were less severe COVID-19, higher Charlson comorbidity index, history of arterial diseases, aspirin use, lower C reactive protein, better functional status on admission and immobilization for at least one day. In conclusion, venous and arterial thromboses differ in all above mentioned factors thus leaving room for appropriate prevention, intervention and treatment.

PORTAL VEIN THROMBOSIS WHILE TAKING A COMBINED ORAL CONTRACEPTIVE AFTER EXPERIENCED CORONAVIRUS INFECTION.

Background: Contraceptives are an important component of women's reproductive health care, as they not only reduce the number of unwanted pregnancies, but also improve reproductive function. However, oral contraceptives are known to increase the risk of venous thromboembolism. This risk is increased by infection with the COVID-19 virus that predisposes patients to both venous and arterial thrombosis as a result of excessive inflammation, platelet activation, aggravated endothelial dysfunction, and congestive events. If these patients have hereditary thrombophilia, the risk of venous thromboembolism becomes fatal. Case report: The paper describes a clinical case of a patient with total portal vein thrombosis, who have been taking oral contraceptives for a long time and recovering from the novel coronavirus infection. Studying the blood coagulation system and folate cycle genes, by using PCR, has revealed a gene mutation in the plasminogen activator inhibitor (serpine). The authors demonstrate the data of spiral computed tomography of the abdominal organs, as well as changes in laboratory parameters. Conclusion(s): A balanced approach is required when prescribing combined oral contraceptives during the COVID-19 pandemic, especially in women with prothrombotic mutations.Copyright © A group of authors, 2023.

PORTAL VEIN THROMBOSIS WHILE TAKING A COMBINED ORAL CONTRACEPTIVE AFTER EXPERIENCED CORONAVIRUS INFECTION.

Background: Contraceptives are an important component of women's reproductive health care, as they not only reduce the number of unwanted pregnancies, but also improve reproductive function. However, oral contraceptives are known to increase the risk of venous thromboembolism. This risk is increased by infection with the COVID-19 virus that predisposes patients to both venous and arterial thrombosis as a result of excessive inflammation, platelet activation, aggravated endothelial dysfunction, and congestive events. If these patients have hereditary thrombophilia, the risk of venous thromboembolism becomes fatal. Case report: The paper describes a clinical case of a patient with total portal vein thrombosis, who have been taking oral contraceptives for a long time and recovering from the novel coronavirus infection. Studying the blood coagulation system and folate cycle genes, by using PCR, has revealed a gene mutation in the plasminogen activator inhibitor (serpine). The authors demonstrate the data of spiral computed tomography of the abdominal organs, as well as changes in laboratory parameters. Conclusion(s): A balanced approach is required when prescribing combined oral contraceptives during the COVID-19 pandemic, especially in women with prothrombotic mutations.Copyright © A group of authors, 2023.

Deep vein thrombosis during vaccination against SARS-CoV-2 period

Objectives: since the beginning of vaccination against SARS-CoV-2 virus one of the most frequent entities of venous thromboembolism (VTE), deep vein thrombosis (DVT), has been scarcely documented. We analyze DVT episodes during vaccination against SARS-CoV-2 period. Material(s) and Method(s): retrospective unicenter analysis including patients diagnosed with DVT (January -September 2021). Patients were divided into two groups, vaccinated and unvaccinated against SARS-CoV-2 28 days prior to DVT symptoms onset. Primary endpoint: DVT severity (pulmonary embolism (PE) and/or hospital admission). Secondary endpoints: DVT risk factors (unprovoked, VTE antecedent, immobilization, trauma, surgery, thrombophilia, hormone therapy and cancer). Result(s): there were 192 DVT diagnoses, 42 (21, 9 %) vaccinated and 150 (78, 1 %) unvaccinated. DVT severity: PE: 52, 4 % vaccinated vs. 62, 7 % controls (p = 0, 228);hospital admission: 52, 4 % vaccinated vs. 62, 4 % unvaccinated (p = 0, 536);unprovoked DVT: 28, 6 % vaccinated vs. 48 % unvaccinated (p = 0, 025);VTE antecedent: 21, 4 % vaccinated vs. 17, 3 % unvaccinated (p = 0, 543): immobilization: 7, 1 % vaccinated vs. 12, 7 % unvaccinated;trauma: 4, 8 % vaccinated vs. 6 % unvaccinated (p = 1);surgery: 4, 8 % vaccinated vs. 1, 3 % unvaccinated (p = 0, 209);thrombophilia: 16, 7 % vaccinated vs. 4 % unvaccinaed (p = 0, 009);hormone theraphy: 9, 5 % vaccinated vs. 3, 3 % unvaccinated (p = 0, 107);cancer: 28, 6 % vaccinated vs. 18, 7 % unvaccinated (p = 0, 162). Multivariate analysis showed a higher risk of DVT in vaccinated patients with thrombophilia, with an OR of 6, 10 (95 % CI, 1, 52-24, 37). Conclusion(s): vaccination against SARS-CoV-2 doesn't seem to increased DVT severity, although a higher incidence of DVT in vaccinated patients with thrombophilia was observed.© Copyright 2023 SEACV.

A successful thrombectomy in a case of progressive cerebral sinus thrombosis

Introduction: Cerebral venous sinus thrombosIs (CVST) is a rare condition compared to other categories encountered in stroke medicine.It occurs more frequently in patients with conditions that predispose them to other venous thrombosis, such as thrombophilias, acute malignancies, nephrotic syndrome, and COVID-19. CVST was identified as one of the rare causative of stroke. The exact mechanism of the stroke is not fully understood. However, a commonly agreed pathophysiology is that a dysfunction in arachnoid granulation can lead to sinus occlusion. Subsequently, this leads to a reduction in cerebral fluid drainage, which can increase intracranial pressure, causing capillary hypertension, cerebral oedema, decrease in cerebral perfusion pressure and venous haemorrhage. The European Stroke Organisation (ESO) supports using both MRI/MR Venogram and CT venogram as modalities for diagnosis of CVST, with no particular preference of one over the other. The standard practice in the management of cerebral venous sinus thrombosis includes treating the clot and its precipitating factors and treating the sequela of the clot as in the case we are reporting. Yet, there is no clinical guideline for the more aggressive measures to break down the clot in either AHA or European Stroke Organization, but they are used in clinical practice, with promising results in certain cases. Our case is an example of a successful mechanical thrombectomy with a lifesaving outcome. Method(s): We are reporting an unusual case of a 27- year- old lady who presented to the hyperacute stroke unit with dense right- sided weakness and expressive dysphasia. After an initial CT (Computerised Tomography) scan confirming extensive cerebral venous sinus thrombosis, she went for urgent mechanical thrombectomy. The clinical assessment after the procedure showed significant recovery in power of the right limbs and speech. She was discharged 7 days later with near full recovery. Venous thrombectomy is a rarely performed procedure. However, in this case, it was potentially lifesaving and resulted in an excellent clinical outcome. Result(s): An MRI/MRV follow up in a month demonstrated that the lesion on left centrum semiovale had regressed compared to the first scan. Also, there was some evidence of recanalization of her transverse sinuses. She was assessed by the therapist two months from the event. The patient reported some word finding difficulties and clumsiness in the right hand and leg. However, no further major event since her thrombectomy, and now aiming to get back to work. Conclusion(s): Mechanical thrombectomy in cerebral venous sinus thrombosis can be an effective, life-saving, and safe procedure with an extremely rewarding outcome. It should be considered in patients with acute neurological deterioration despite anticoagulant therapy.

SARS-CoV-2 infection results in upregulation of Plasminogen Activator Inhibitor-1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D-dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus disease 2019 (COVID-19) coagulopathy, 64 adult patients with SARS-CoV-2 infection (36 moderate and 28 severe) and 16 controls were studied. We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin-like) targeting the fibrinolytic system: Plasminogen Activator Inhibitor-1 (PAI-1), Tissue Plasminogen Activator/Plasminogen Activator Inhibitor-1 complex (t-PA/PAI-1), α-2-Antiplasmin, Plasmin-α2-Antiplasmin Complex, Thrombin-activatable Fibrinolysis Inhibitor (TAFI)/TAFIa, Protease Nexin-1 (PN-1), and Neuroserpin (the main t-PA inhibitor of the central nervous system). Inhibitors of the common (Antithrombin, Thrombin-antithrombin complex, Protein Z [PZ]/PZ inhibitor, Heparin Cofactor II, and α2-Macroglobulin), Protein C ([PC], Protein C inhibitor, and Protein S), contact (Kallistatin, Protease Nexin-2/Amyloid Beta Precursor Protein, and α-1-Antitrypsin), and complement (C1-Inhibitor) pathways, in addition to Factor XIII, Histidine-rich glycoprotein (HRG) and Vaspin were also investigated by enzyme-linked immunosorbent assay. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI-1 and Neuroserpin in the lungs from eight post-mortem cases was assessed by immunohistochemistry. Results show that six patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI-1, Neuroserpin, PN-1, PAP, and t-PA/PAI-1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI-1 in epithelial cells, macrophages, and endothelial cells of fatal COVID-19, while Neuroserpin was found in intraalveolar macrophages only. These results imply that the lungs in SARS-CoV-2 infection provide anti-fibrinolytic activity resulting in a shift toward a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated disseminated intravascular coagulation.

Role of Genetic Thrombophilia Markers in Thrombosis Events in Elderly Patients with COVID-19.

Thrombosis is an extremely dangerous complication in elderly patients with COVID-19. Since the first months of the pandemic, anticoagulants have been mandatory in treatment protocols for patients with COVID-19, unless there are serious contraindications. We set out to discover if genetic thrombophilia factors continue to play a triggering role in the occurrence of thrombosis in patients with COVID-19 with prophylactic or therapeutic anticoagulants. We considered the following genetic markers as risk factors for thrombophilia: G1691A in the FV gene, C677T and A1298C in the MTHFR gene, G20210A and C494T in the FII gene, and (-675) 4G/5G in the PAI-I gene. In a cohort of 176 patients, we did not obtain a reliable result indicating a higher risk of thrombotic complications when taking therapeutic doses of anticoagulants in carriers of genetic markers for thrombophilia except the C494T mutation in the FII gene. However, there was still a pronounced tendency to a higher incidence of thrombosis in patients with markers of hereditary thrombophilia, such as FV G1691A and FII G20210A mutations. The presence of the C494T (Thr165Met) allele in the FII gene in this group of patients showed a statistically significant effect of the mutation on the risk of thrombotic complications despite anticoagulant therapy.

Case report: Umbilical vessel aneurysm thrombosis and factor V Leiden mutation leading to fetal demise.

Complicated pregnancies are nowadays a major public health concern, with possible lethality or sequelae both for the mother and the fetus. Blood coagulation disorders (including antiphospholipid syndrome, factor V Leiden mutation and antithrombin deficiency) and hypertensive gestational disorders are very well-known contributors of complicated pregnancies with poor fetal outcome, such as intrauterine growth retardation (IUGR) and fetal demise. Less commonly, vascular malformations of the placenta can also potentially lead to serious complications such as IUGR and fetal death. These malformations include hypercoiled umbilical cord, umbilical cord knot, umbilical cord varix, umbilical cord arterial or venous aneurysm, and velamentous insertion of the umbilical cord potentially leading to Benckiser's hemorrhage. Here, we report the case of a 29-year-old Gravida 2 Para 0 mother with previous history of stillbirth and smoking, admitted to the obstetrics department for the absence of fetal movement at 38 weeks of amenorrhea (WA). First-trimester and second-trimester routine ultrasounds were otherwise normal. Ultrasound performed at 38 WA revealed a 83 × 66 × 54 mm cystic heterogenous mass at the umbilical cord insertion. After delivery, fetal and placental pathology as well as maternal blood testing were performed. Fetal pathology was otherwise normal, except for diffuse congestion and meconial overload suggesting acute fetal distress. Fetal karyotype was normal (46 XX). Placental pathology revealed an umbilical artery aneurysm (UAA) at the base of the insertion of the umbilical cord, lined with a CD34+ CD31+ endothelium. After dissection, the aneurysm was filled with hemorrhagic debris, indicating aneurysm thrombosis. Histopathology revealed associated maternal vascular malperfusion (MVM) and increased peri-villous fibrin (IPF). Maternal blood tests revealed heterozygous factor V Leiden mutation, without other associated auto-immune conditions (such as antiphospholipid syndrome). Umbilical artery aneurysms remain extremely rare findings in the placenta, with <20 reported cases. Umbilical artery aneurysms have tendency to be located at the base of the insertion of the placenta, and lead to fetal demise in more than 60% of cases, mainly due to aneurysmal thrombosis, hematoma, possible vascular compression and/or rupture. Umbilical vessel aneurysms can be associated with trisomy 18 or 13. In our case, the association of factor V Leiden mutation, a hypercoagulable state, with UAA could explain massive thrombosis of the aneurysmal lumen and sudden fetal demise. Further consideration of current guidelines for surveillance and management of UAA would allow appropriate planned delivery in maternal care settings.

Is Undected Inherited Thrombophilia The Hades Of COVID-19?

Introduction: Thrombophilia is a co-morbidity in the general population with a prevalence of 5%. However, it is not known whether it affects severity of COVID-19. It may be possible that undiagnosed thrombophilia exaggerates an already prothrombotic state in COVID- 19 patients and hence, results in severe disease. Aims & Objectives: To study the association of underlying thrombophilia with severity of COVID-19 in post COVID patients after a minimum of 6 weeks of recovery. Material(s) and Method(s): Eighty RT-PCR confirmed adult covid patients (40 severe,40 non-severe) post 6 weeks of recovery were included. The venous blood in EDTA and citrate vials was tested for complete blood counts and coagulation parameters such as Prothrombin time, activated partial prothrombin time, Lupus anticoagulant by dRVVT, Antithrombin-III, Protein C and S). Result(s): 6/40 patients had Protein C deficiency in severe category and none in non severe. 7/40 patients had Protein S deficiency in severe category and 1 patient was deficiant in non-severe group. Conclusion(s): Thrombophilia was detected significantly in patients with severe COVID even after 6 weeks of recovery, indicating that undetected underlying thrombophilia could be a factor affecting disease severity. The common abnormalities detected were Protein C & S deficiency. This is a novel finding which needs to be explored further with extensive thrombophilia profiles. The influence of underlying thrombophilia in patients who succumbed to the disease is not known and cannot be known retrospectively. However, the extrapolation of this study suggests that thrombophilia may be an important influence on severity and mortality. (Table Presented).

Contribution of genotypes in Prothrombin and Factor V Leiden to COVID-19 and disease severity in patients at high risk for hereditary thrombophilia.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.

factor V leiden mutation detection before astraZeneca vaccine

BacKgrouNd: on the beginning of 2020 the world woke up with a novel coronavirus disease (coVId-19) pandemic caused by sarscoV-2, started in Wuhan, china. several types of vaccine appeared, one of them was astraZeneca (astraZenca, cambridge, uK) vaccine. METHOD(S): This is a single-center retrospective study which included 9 patients who developed DVT after the first dose of AstraZeneca vaccine. they were screened for thrombophilia, including factor V leiden mutation. rEsults: they were found positive for factor V leiden mutation and were treated by Noacs. also, they were advised to delay second dose for 3 months and to shift to another vaccine like sinopharm (china National Pharmaceutical group, Beijing, china). coNclusIoNs: alert should be raised for patients with factor V leiden mutation having a second dose;and for the treatment of the thrombosis condition. Copyright © 2022 EdIZIoNI MINErVa MEdIca.