Small Vessel Thrombosis Research Articles

COVID-19-Related Cholangiopathy: Histological Findings.

We subjected post-COVID-19 cholestasis liver samples to routine staining techniques and cytokeratin 7 immunostaining and semi-quantitatively analyzed the portal and parenchymal changes. All ten patients, five men, had a median age of 56, an interquartile range (IQR) of 51-60, and required intensive care unit and mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP 645 (390-1256); GGT 925 (664-2169); ALT 100 (86-113); AST 87 (68-106); and bilirubin 4 (1-9) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. We performed biopsies at a median of 203 (150-249) days after molecular confirmation of infection. We found portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy in all patients, while we observed hepatocyte biliary metaplasia in all tested cases. We observed mild-to-severe parenchymal cholestasis and bile plugs in nine and six cases. We also observed mild swelling of the arteriolar endothelial cells in five patients. We observed a thrombus in a small portal vein branch and mild periductal fibrosis in one case each. One patient developed multiple small biliary infarctions. We did not observe ductopenia in any patient. The alterations were like those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.

Antiphospholipid Patients Admitted in the Intensive Care Unit: What Must The Rheumatologist Know?

Antiphospholipid syndrome (APS) is a rare systemic autoimmune disorder that can escalate into a 'thrombotic storm' called the catastrophic antiphospholipid syndrome (CAPS), frequently requiring ICU admission for multiple organ failure. This review aims to offer insight and recent evidence on critically-ill APS patients. The CAPS classification criteria define this condition as the involvement of at least three organs/systems/tissues within less than a week, caused by small vessel thrombosis, in patients with elevated antiphospholipid antibodies levels. These criteria do not encompass the full spectrum of critically-ill thrombotic APS patients and they need to be cautiously used for the bedside diagnosis of CAPS. Thrombocytopenia is the laboratory hallmark of CAPS, sometimes dropping below 20G/L, but a complete thrombotic microangiopathy pattern is infrequent. Anticoagulation is the pivotal treatment for APS and CAPS, associated with improved outcome. Triple therapy - the combination of anticoagulation, high-dose corticosteroids, and either plasma exchange or intravenous immunoglobulins - remains the standard treatment for CAPS patients. Eculizumab, an anti-C5 monoclonal antibody, may be useful in refractory patients. Despite significant progress, CAPS mortality rate remains high. Its diagnosis and management are complex, requiring a close multidisciplinary cross talk between APS specialists and intensivists.

Cancer-associated thrombotic microangiopathy; a review article

Cancer-associated thrombotic microangiopathy (TMA) is a rare but is a serious complication that can occur in individuals with malignancy. It is characterized by widespread small blood vessel thrombosis (formation of blood clots) in various organs of the body, leading to organ damage and dysfunction. The exact mechanisms underlying cancer-associated TMA are not fully understood. However, several factors may contribute to its development. Cancer cells can release procoagulant substances that promote blood clot formation, since some tumors can directly invade blood vessels, leading to endothelial cell damage and activation of the coagulation system. Additionally, certain chemotherapeutic agents used in cancer treatment can have adverse effects on the endothelium, further increasing the risk of TMA. Clinically, cancer-associated TMA presents with a range of symptoms depending on the organs affected. Common manifestations include microangiopathic hemolytic anemia, thrombocytopenia, and organ-specific symptoms such as neurological deficits, renal dysfunction, or cardiac abnormalities.

High-Density Lipoprotein Inhibits Microvascular and Arterial Thrombosis in Mice By Attenuating VWF Self-Association

Background: Von Willebrand factor (VWF) mediates platelet adhesion and aggregation in primary hemostasis and thrombosis. The thrombogenicity of VWF depends on its self-association into fibers and its ability to efficiently capture platelets under high shear stress. We have shown that high shear promotes self-association of VWF into hyperadhesive strands and fibers, and that this process can be enhanced by low density lipoprotein (LDL) and attenuated by high density lipoprotein (HDL). In a model of thrombotic microangiopathy induced by VWF infusion into ADAMTS13-deficient mice, HDL attenuated the thrombocytopenia induced by the VWF challenge, suggesting that HDL may attenuate other types of thrombosis. Aims: To study the effect of HDL on microvascular and arterial thrombosis in mice by intravital microscopy. Methods: Microvascular thrombosis was induced in ADAMTS13-deficient mice by (1) local stimulation of mesenteric venules with calcium ionophore, and (2) infusion of high doses of recombinant human VWF (rVWF). The effect of HDL on VWF-platelet thrombus formation and deposition in the microvasculature was monitored microscopically. Arterial thrombosis was induced in wild-type (WT) mice by (1) laser-induced cremaster injury, and (2) FeCl 3-induced carotid artery injury. The effect of HDL on arterial thrombosis was also monitored microscopically. Results: When we induced microvascular thrombosis with ionophore, ADAMTS13-deficient mice evinced robust local platelet adhesion, platelet string formation, and thrombus embolization. Time to thrombus resolution was significantly prolonged (about 15 min) compared to that in WT mice (< 5 min). In mice pretreated with HDL (100 mg/kg), platelet deposition was largely prevented, with only occasional single platelets adhering. The differences in the extent of thrombi deposition and time to thrombus resolution between HDL-treated and untreated mice were both statistically significant. In the VWF challenge microvascular thrombosis model, rVWF infusion into ADAMTS13-deficient mice induced platelet adhesion to endothelium-associated VWF fibers in the cremaster microcirculation, forming long strings on the walls of arterioles and venules. Many microvessels became completely occluded. The prothrombotic effect persisted over 90 minutes. In contrast, pretreatment with HDL (100 mg/kg) led to significantly reduced platelet adhesion and string formation. Vessel occlusion was almost completely prevented. When thrombosis was induced in the cremaster arterioles of WT mice, HDL pretreatment resulted in notably decreased platelet accumulation and fibrin deposition in growing thrombi. HDL pretreatment also destabilized the thrombi and led to frequent embolization. In the FeCl 3-induced carotid artery injury model, HDL pretreatment slowed thrombus growth, enhanced thrombus embolization, and delayed vessel occlusion. Conclusion(s): The results demonstrate that VWF self-association is an important mechanism promoting thrombosis in large and small vessels. Our results show that HDL possesses a novel antithrombotic effect by inhibiting VWF self-association, preventing thrombosis in both small and large vessels. These results suggest that increasing the plasma HDL level can be exploited to prevent and treat thrombotic microangiopathies and arterial thrombosis.

Thrombosis in the coronary microvasculature may be responsible for impaired cardiac relaxation and diastolic dysfunction

Abstract Introduction Heart Failure with Preserved Ejection Fraction (HFpEF) is proposed to be caused by endothelial dysfunction in cardiac small vessels. We previously identified Hhipl1,as a gene upregulated in the coronary vasculature of Leptin receptor deficient mice (Leprdb/db) a well-established mouse model of HFpEF. Importantly, Hhipl1 encodes for a decoy receptor of Desert Hedgehog (DHH) which is known to be critical for endothelial integrity. Objective Our objective is to investigate the functional consequences of impaired Hedgehog (HH) signaling in the adult heart in order to identify novel mechanisms underlying the development of diastolic dysfunction. Method To do so, Cdh5-Cre/ERT2, DhhFlox/Flox (DhhECKO) mice and their control littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO. Their cardiac function, exercise tolerance, and the phenotype of their coronary vasculature were assessed one month later. Results DhhECKO mice presented significantly reduced exercise tolerance, increased end diastolic pressure (EDP) and Tau, with no change in their ejection fraction consistent with diastolic dysfunction. At molecular and cellular level, impaired cardiac relaxation in DhhECKO mice was associated with a significantly decreased phospholamban phosphorylation on Thr17 and an alteration of sarcomeric shortening in ex-vivo. Besides, as expected, DhhECKO mice exhibited phenotypic changes in their coronary vasculature including a prominent pro-thrombotic phenotype (63±6,2 vs 25±5,2 thrombi/mm²; p<0,001) leading to an impaired capillary perfusion and local hypoxia. Notably, antiaggregant therapies (aspirin and clopidogrel) prevented the occurrence of both diastolic dysfunction and exercise intolerance in DhhECKO mice demonstrating for the first time that thrombosis may promote diastolic dysfunction. Importantly, we confirmed the critical role of thrombosis in Leprdb/db mice which also displayed increased cardiac small vessel thrombosis in comparison to control mice. Alike DhhECKO mice, we found that antiaggregants decreased EDP (6,3±0,4 mmHg in aspirin-treated vs 11,3 ± 0,79 in control mice; p=0,001) and improved exercise tolerance in Leprdb/db mice (34 ± 2,52 min in aspirin-treated vs 24 ± 3,55 in control mice; p=0,004). Conclusion Altogether, these results demonstrate that small vessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.

HDAC inhibitor CS014 inhibits platelet activity, small and large vessel thrombosis while maintaining haemostasis in a dose-dependent manner

Abstract Background It is a significant challenge to develop new targets for prevention of platelet activity and clotting and clot formation leading to occlusive thrombosis remains a significant cause of cardiovascular morbidity and mortality. Using the HDAC inhibitor, CS014, we can show an in vivo benefit in reduced clotting without increased bleeding. Understanding the benefits of epigenetic modulation with CS014 would validate its utility in prevention of life-threatening clot formation in vivo. Purpose Develop a first-in-class HDAC inhibitor, CS014, that prevents clotting without a risk for bleeding. Compared to valproic acid (VPA), CS014 exhibits a better clot prevention profile. Methods Thrombosis and bleeding in mouse models were assessed with VPA and CS014 at multiple doses by labelling platelets and fibrin and measuring accumulation at the site of injury using intravital microscopy. HDAC inhibitor were given IP for 5 days at different doses. Thrombosis in the vessel was assessed in the 1) laser-induced cremaster arteriole thrombosis assay for assessment of clotting in the small vessel, 2) carotid artery FeCl3 thrombosis assay for assessment of clotting in the large vessel, and 3) saphenous vein rebleeding laser-induced assay for assessment of clotting and haemostasis in the vein. Bleeding was assessed in the tail vein bleeding assay. Results CS014 treatment significantly reduced clot formation and fibrin formation at the site of injury in the laser-induced cremaster assay. The observed inhibition of clot formation and fibrin accumulation at the site of injury was significantly greater than the inhibition observed with VPA at lower doses. FeCl3-induced injury of the carotid artery resulted in full occlusion of the vessel within 12-15 minutes. Treatment with CS014 or VPA were able to prevent full occlusion of the carotid artery, supporting their benefit in arterial injury conditions. In the saphenous vein rebleeding assay, fibrin and platelet accumulation at the site of injury wound was significantly inhibited, suggesting that CS014 and VPA function in both arterial and venous systems to attenuate clot and thrombosis. The tail vein bleeding assay confirmed that while the thrombus formation and stability was decreased based on the cremaster and carotid artery assays, no change was observed in bleeding time under these conditions. Conclusions We have shown for the first time that CS014, a first-in-class HDAC inhibitor, results in better inhibition of mouse thrombosis and decreased time to clot resolution without bleeding. This discovery represents a new class of treatment for prevention of platelet activation and thrombosis with potential for protection from myocardial infarction and stroke. Additionally, the decreased fibrin formation in the blood should limit the risk of thromboembolism. CS014 has proven that HDAC inhibition offers a new alternative for protection in the blood from thrombotic risk without an added risk of bleeding.CS014 prevents venous thrombosisCS014 doesn't cause bleeding risk

Antiphospholipid antibody carriers and patients with quiescent antiphospholipid syndrome show persistent subclinical complement activation.

Complement activation has been advocated as one mechanism by which aPLs can induce thrombosis. In patients with catastrophic APS or re-thrombosis, enhanced complement activation has been shown, even in the quiescent phase of the disease. We aimed to assess complement activation and to investigate its association with clinical variables in aPL-positive patients with a favourable disease course. Subjects with at least two consecutive positive aPL results obtained ≥12 weeks apart were enrolled. They were subjects without a history of thrombosis or pregnancy morbidity (aPL carriers), patients with pregnancy morbidity alone, i.e. obstetric APS patients (OAPS patients), and/or patients with arterial, venous, or small-vessel thrombotic APS (TAPS patients); for enrolment, all patients were required to have been free of symptoms for ≥2 years. Patients affected with systemic autoimmune diseases were excluded. Healthy age- and sex-matched subjects were included as controls. Plasma C5a and C5b-9 levels were assessed by commercially available ELISA assays. The non-parametric Mann-Whitney test and Spearman's correlation were applied. Thirty-seven OAPS patients, 38 TAPS patients, 42 aPL carriers and 30 healthy subjects were enrolled. The median C5a and C5b-9 levels were significantly higher in quiescent aPL-positive patients (OAPS, TAPS, aPL carriers) compared with controls: C5a ng/ml 10.61 [interquartile range (IQR) 6.87-15.46] vs 4.06 (2.66-7.35), P < 0.001; C5b-9 ng/ml 283.95 (175.8-439.40) vs 165.90 (124.23-236.8), P < 0.001. Similar C5a and C5b-9 levels were observed in OAPS and TAPS patients and aPL carriers. A positive correlation between the median C5b-9 levels and the number of aPL-positive tests was found (P = 0.002). The persistence of aPL antibodies is associated with a persistent subclinical activation of the complement cascade.

The oxylipin analog CS585 prevents platelet activation and thrombosis through activation of the prostacyclin receptor

AbstractCardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies.

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

Antiphospholipid Syndrome: State of the Art of Clinical Management.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder clinically characterized by recurrent arterial and venous thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies. Currently, treatment is mainly focused on anticoagulation, but therapies targeting mechanisms involved in APS autoimmune pathogenesis could play an important role in specific settings. An evidence-based therapeutic approach is limited by the broad clinical spectrum of the syndrome and the nature of a "rare disease" that makes it difficult to carry out well-designed prospective studies. Vitamin K antagonists (AVK), notably warfarin, are the standard treatment for preventing recurrent venous thrombosis and perhaps also arterial thrombosis. Direct oral anticoagulants (DOACs) are not recommended at least in patients with triple positivity APS. Treatment options for the prevention of pregnancy complications in obstetric APS, as combined use of aspirin and heparin, low-dose prednisolone, hydroxychloroquine, intravenous immunoglobulin (IVIG), may improve pregnancy outcome. The catastrophic antiphospholipid syndrome (CAPS) is the most severe form of APS with acute multiple organ involvement and small vessel thrombosis. Glucocorticoids, heparin, plasma exchange or IVIG, rituximab, or eculizumab must be added to concurrent treatment of precipitating factors (e.g. infections) as rescue therapies. Finally, it has been observed that SARS COV2 infection may produce vascular complications mimicking the clinical and pathophysiological features of APS and particularly of CAPS. From this point of view, attention has been focused on the "protective" role of anticoagulant therapy in preventing thrombotic complication when these clinical conditions coexist.

Abstract P2082: Thrombosis In The Coronary Microvasculature May Be Responsible For Impaired Cardiac Relaxation And Diastolic Dysfunction

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is proposed to be caused by endothelial dysfunction in cardiac small vessels. We previously identified Hhipl1,as a gene upregulated in the coronary vasculature of Leptin receptor deficient mice (Leprdb/db) a well-established mouse model of HFpEF. Importantly, Hhipl1 encodes for a decoy receptor of Desert Hedgehog (DHH) which is known to be critical for endothelial integrity. Objective: Our objective is to investigate the functional consequences of impaired Hedgehog (HH) signaling in the adult heart in order to identify novel mechanisms underlying the development of diastolic dysfunction. Method: Cdh5-Cre/ERT2, DhhFlox/Flox (DhhECKO) mice and their control littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO. Their cardiac function, exercise tolerance, and the phenotype of their coronary vasculature were assessed one month later. Results: DhhECKO mice presented significantly reduced exercise tolerance, increased end diastolic pressure (EDP) and Tau, with no change in their ejection fraction consistent with diastolic dysfunction. At molecular and cellular level, impaired cardiac relaxation in DhhECKO mice was associated with a significantly decreased phospholamban phosphorylation on Thr17 and an alteration of sarcomeric shortening in ex-vivo. Besides, as expected, DhhECKO mice exhibited phenotypic changes in their coronary vasculature including a prominent pro-thrombotic phenotype leading to an impaired capillary perfusion and local hypoxia. Notably, antiaggregant therapies (aspirin and clopidogrel) prevented the occurrence of both diastolic dysfunction and exercise intolerance in DhhECKO mice demonstrating for the first time that thrombosis may promote diastolic dysfunction. Importantly, we confirmed the critical role of thrombosis in Leprdb/db mice which also displayed increased cardiac small vessel thrombosis in comparison to control mice. Alike DhhECKO mice, we found that antiaggregants decreased EDP and improved exercise tolerance in Leprdb/db mice. Conclusion: Altogether, these results demonstrate that small vessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.

Thrombosis in the coronary microvasculature may be responsible for impaired cardiac relaxation and diastolic dysfunction

Heart failure with preserved ejection fraction (HFpEF) is proposed to be caused by endothelial dysfunction in cardiac small vessels. We previously identified Hhipl1, as a gene upregulated in the coronary vasculature of Leptin receptor deficient mice (Leprdb/db) a well-established mouse model of HFpEF. Importantly, Hhipl1 encodes for a decoy receptor of Desert Hedgehog (DHH) which is known to be critical for endothelial integrity. Our objective is to investigate the functional consequences of impaired Hedgehog (HH) signaling in the adult heart in order to identify novel mechanisms underlying the development of diastolic dysfunction. To do so, Cdh5-Cre/ERT2, DhhFlox/Flox (DhhECKO) mice and their control littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO. Their cardiac function, exercise tolerance, and the phenotype of their coronary vasculature were assessed one month later. DhhECKO mice presented significantly reduced exercise tolerance, increased end-diastolic pressure (EDP) and Tau, with no change in their ejection fraction consistent with diastolic dysfunction. At molecular and cellular level, impaired cardiac relaxation in DhhECKO mice was associated with a significantly decreased phospholamban phosphorylation on Thr17 and an alteration of sarcomeric shortening in ex-vivo. Besides, as expected, DhhECKO mice exhibited phenotypic changes in their coronary vasculature including a prominent pro-thrombotic phenotype (63 ± 6.2 vs. 25 ± 5.2 thrombi/mm2; P < 0.001) leading to an impaired capillary perfusion and local hypoxia. Notably, antiaggregant therapies (aspirin and clopidogrel) prevented the occurrence of both diastolic dysfunction and exercise intolerance in DhhECKO mice demonstrating for the first time that thrombosis may promote diastolic dysfunction. Importantly, we confirmed the critical role of thrombosis in Leprdb/db mice which also displayed increased cardiac small vessel thrombosis in comparison to control mice. Alike DhhECKO mice, we found that antiaggregants decreased EDP (6.3 ± 0.4 mmHg in aspirin-treated vs. 11.3 ± 0.79 in control mice; P = 0.001) and improved exercise tolerance in Leprdb/db mice (34 ± 2.52 min in aspirin-treated vs. 24 ± 3.55 in control mice; P = 0.004). Altogether, these results demonstrate that small vessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy

Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical hemolytic uremic syndrome (aHUS) and TMA in the setting of allogeneic stem cell transplant in pediatric patients. We hypothesized that germline mutations in the complement alternative pathway may similarly predispose MM patients to carfilzomib-associated TMA. We identified 10 MM patients with a clinical diagnosis of TMA in the context of carfilzomib treatment and assessed for the presence of germline mutations in the complement alternative pathway. Ten, matched MM patients exposed to carfilzomib but without clinical TMA were used as negative controls. We identified a frequency of deletions in the complement Factor H genes 3 and 1 (delCFHR3-CFHR1) and genes 1 and 4 (delCFHR1-CFHR4) in MM patients with carfilzomib-associated TMA that was higher as compared to the general population and matched controls. Our data suggest that complement alternative pathway dysregulation may confer susceptibility to vascular endothelial injury in MM patients and predispose to development of carfilzomib-associated TMA. Larger, retrospective studies are needed to evaluate whether screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use.

Клинико-лабораторные, инструментальные, морфологические особенности гангренозного и флегмонозного аппендицита у пациентов с COVID-19-инфекцией

Objective. To present clinical, laboratory, instrumental and morphological features of phlegmonous and gangrenous appendicitis in patients with COVID-19 infection. Patients and methods. During the period from March 2020 to August 2022, 23 patients were observed with positive results of testing of nasopharyngeal sample for SARS-CoV-2 RNA and performed appendectomy. The age group of children is 8–17 years old (the average age is 14.1 years), there were 13 boys, 10 girls. The premorbid state is not burdened. The rationale for appendectomy was: acute abdominal pain, local soreness on the right side of the abdomen, their preservation until the surgical removal of the appendix and their disappearance after surgery. During ultrasound of the abdominal cavity, all patients had ECHO signs of inflammatory transformation of the vermiform process. The disease was accompanied by repeated vomiting on the background of subfebrile (13 children) or normal temperature (10 children). Respiratory syndrome is poor, 4 children had abdominal pain, 9 children had hyperemia of the pharynx, chest CT did not reveal inflammatory changes. Repeated virological examination showed the positive result in 3 of 9 examined; EIA for IgM and IgG detection was positive in 7 (out of 7 examined) with diagnostic titers in 3 patients. During histological examination, the length of the removed appendixes is ~8.1 cm (4–12.5 cm), partial or complete desquamation of the epithelium, massive infiltration by lymphocytes or neutrophils, circulatory disorders, in some cases (gangrenous appendicitis) – the phenomena of thrombosis of small vessels, mesenteriolitis, periappendicitis. Typical E. Coli was found in 4 out of 23 abdominal fluid samples. Conclusion. The complex of clinical, laboratory, instrumental and morphological data confirmed the diagnosis of appendicitis and the course of COVID-19, indicating the need for surgical intervention and the appointment of antiviral therapy, noting the need to continue the study. Key words: phlegmonous, gangrenous appendicitis, children, laparoscopic removal, ultrasound of abdomen, morphological examination of the appendix

Combination of granulomatosis with polyangiitis with COVID-19: difficulties in differential diagnosis and treatment

The article presents a prospective clinical observation with a fatal outcome in a patient with severe granulomatosis with polyangiitis (GPA) complicated by COVID 19 on the background of immunosuppression. At the onset of the disease, there were difficulties in making a diagnosis; differential diagnosis between eosinophilic granulomatosis with polyangiitis (EGPA) and GPA was carried out. Against the background of combined therapy — the use of high and ultra-high doses of glucocorticoids (GC) and cytostatic drugs, a short-term improvement was noted. However, within a year and a half of treatment, it was not possible to achieve remission of the disease. Taking into account the ineffectiveness of the therapy, by the decision of the medical commission, the patient was prescribed genetically engineered biological therapy rituximab (RTM). There was a decrease in the activity of the disease, the achievement of depletion of B-cells. During the pandemic period, despite observing the isolation regime, the patient fell ill with a coronavirus infection. Immunosuppression contributed to severe infection. After the infection was treated, the activity of vasculitis increased, which required the repeated administration of RTM for health reasons. During the therapy it was short-term stabilization of the condition. But after short period — fever, an increase in respiratory failure, the development of neutropenia. Taking into account the initial lesion of the lungs in the patient, differential diagnostics was carried out between the complications of coronavirus infection and the activity of the underlying disease. Despite anti-inflammatory, anticoagulant, antibacterial therapy, the patient's condition progressively worsened, respiratory failure increased, hemoptysis appeared. Spontaneous pneumothorax on the right was diagnosed, pneumomediastinum. After repeated negative PCR results, the causative agent of SARS COV-2 was again detected in smears. The immediate cause of death, according to clinical observation and autopsy, was severe respiratory failure, thrombosis in small vessels of the lungs in a patient with a new coronavirus infection against the background of immunosuppression for GPA.

1026 MYOCARDIAL INFARCTION AND STROKE IN A YOUNG PATIENT AFFECTED BY LES: KEY ROLE OF AN INTEGRATED IMAGING APPROACH

Abstract A male patient, 33 years old, smoker, with a 20-year history of SLE, consulted the ER for right hand fatigue. He didn't assume his medications constantly. Computed Tomography showed a fronto-parieto-occipital cerebral infarction, and the angio-CT showed a plaque in left internal carotid artery. The patient was admitted to the Stroke Unit for minor ischemic stroke. The ECG showed pathological Q waves in the anterior leads from V1 to V4 revealing a likely previous silent myocardial infarction. The echocardiogram demonstrated moderate left ventricular dysfunction with 40% EF and segmental wall motion abnormalities, namely ipoakinesia of anterior wall and apex. This findings were confirmed by cardiac MRI highliting subendocardial LGE in these areas suggesting an ischemic genesis. Due to the hemorrhagic risk related to recent cerebral ischemic event, coronary angiography was postponed a month later. The coronary angiography revealed a significant stenosis of the proximal left anterior descending artery (iFR &amp;lt; 0.65). Qualitative assessment of the lesion with IVUS showed a “mixed” plaque. The lesion was treated with PCI and the implant of two overlapped DES and the patient underwent dual antiplatelet therapy. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with heterogeneous presentation, characterised by alternating periods of flares and remission, and irreversible organ damage. The skin, joints, heart, kidneys, central nervous system and haematologic system are some of the most affected organs. Although recent data suggest that mortality decreased in patients with SLE over the last 30 years, mortality due to cardiovascular disease (CVD), usually defined as a combination of coronary, cerebrovascular and/or peripheral arterial disease, has remained high. Stroke and myocardial infarction (MI) are major CVD events that are potentially life-threatening. Lupus specific cardiovascular risk factors are believed to contribute to the high risk for MI, such as renal involvement, that has been associated with increased subclinical atherosclerosis and ischaemic heart disease, and antiphospholipid syndrome (APS), defined by venous, arterial or small vessel thrombosis and/or obstetric complications together with persistent positivity for antiphospholipid antibodies (aPL). Though several risk factors have been suggested, the exact mechanisms behind the high MI incidence in SLE remain essentially unknown. MIs in SLE are in most cases associated with coronary atherosclerosis. Subclinical atherosclerosis has been reported in many case–control studies, but a direct causal relationship between coronary artery disease (CAD) and MI in SLE has not yet been well documented. The pathogenesis of cardiovascular diseases in SLE is not fully understood. The inflammatory nature of SLE is believed to be an important factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, promotes endothelial dysfunction and vascular injury. Our case showed the key role of an integrated imaging approach with echocardiography and cardiac MRI to confirm diagnosis of past myocardial infarction in a very young man affected by LES. IVUS played a great role to characterize the nature of the lesion, confirming the association between coronary atherosclerosis and MIs in SLE.

Histopathological pulmonary findings of survivors and autopsy COVID-19 cases: A bi-center study.

The coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), evolved into a global pandemic. As ACE2 on the surface of alveolar cells of the lung epithelium is one of the potential target receptors for SARS-CoV-2, the respiratory symptoms are the most common presentation of COVID-19. The aim of our study was to investigate the morphological findings in lung tissue after being infected by SARS-CoV-2 and compare histopathologic changes in patients with COVID-19 infection history who died to those who survived. We analyzed lung tissue samples from 9 patients who died from COVID-19 and from 35 patients with COVID-19 infection history who survived and had undergone lung surgery for different reasons. Most of histopathological changes in autopsy and survivors' cases overlapped; however, they occurred with different frequency. The predominant histologic finding both in the case of the deceased and the survivors was patchy distribution of foamy macrophages in the alveolar spaces. In comparison with autopsy cases viral cytopathic-like changes in hyperplastic pneumocytes were rarely observed in the survivors' lung tissue. Pulmonary edema, fibrin deposition within alveoli, bronchopneumonia, small vessel thrombosis and type II pneumocyte hyperplasia were also more often observed within autopsy cases. Life-threatening complications such as hyaline membrane formations and diffuse alveolar damage were present only within the deceased, whereas changes requiring enough time to progress to the fibrotic phase, such as organizing pneumonia, bronchiolization of the alveoli, and interstitial fibrosis were observed in the lung parenchyma only in survivors. Additionally, 14 cases of pulmonary pneumo-hematocele in patients with COVID-19 infection history who survived were observed. It is a newly observed entity in the form of a cystic lesion formed by large accumulation of blood and fibrin between the collapsed and rejected lung parenchyma and/or present with air-fluid levels. The thin wall of pneumo-hematocele is formed by the inter lobar interstitial fibroconnective tissue and has no epithelial lining or bronchial wall elements. As the COVID-19 pandemic continues, new complications following SARS-CoV-2 infection are identified. Newly observed entity in patients with COVID-19 infection history who survived is pulmonary pneumo-hematocele. The appearance of these lesion has become increasingly frequent.

Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts.

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

PSUN43 Anti-phospholipid syndrome presenting with bilateral adrenal hemorrhage in a young female

Abstract Patient is a 29-year-old female with PCOS and morbid obesity and recent admission for abdominal pain is found to have bilateral adrenal hemorrhage and prolonged PTT. Patient was found to be anemic with hemoglobin of 6.1 a week prior to presentation, attributed to dysfunctional uterine bleeding and was treated with subsequent transfusion. She presents a week after her initial presentation with recurrent constant sharp pulsating abdominal pain, and reported pain was worse in mid-epigastric area radiating into her back, with a temperature of 38.2 and heart rate of 135, troponin level 2.64, with a negative CT for PE, but incidental bilateral adrenal hemorrhage absent on CTA from last week, with a CBC showing WBC 21.7 RBC 3.5 Hgb 8.6 MCV 76.9 MCH 24.7 RDW 17.6, with normal folate and B12. Patient was monitored closely and was started on IV hydrocortisone 50 mg every six hours, her PTT was found to be 88 and PT of 17.5, so antiphospholipid syndrome was suspected and confirmed with positive lupus anti-coagulant (LAC) and anticardiolipin IgG ab, and B2 glycoprotein. Patient had no evidence of adrenal infract that could have converted to hemorrhage. Objectives Antiphospholipid syndrome (APS) is an autoimmune systemic disorder characterized by persistent antiphospholipid antibodies including lupus anticoagulant, anticardiolipin or anti B2- glycoprotein I antibodies, presenting with arterial venous or small vessel thrombosis or recurrent early pregnancy loss. Other manifestation including livedo reticularis, cutaneous ulceration, thrombocytopenia, and hemolytic anemia, valvular heart disease and nephropathy. In our case, the patient APS was confirmed by the presence of the markers, but no evidence of adrenal infracts what could have converted to hemorrhage was found. Conclusions Although APS leads to a hypercoagulable state which can lead to adrenal vein thrombosis, leading to adrenal hemorrhage which can be fatal. Screening for antiphospholipid antibodies should be considered in all patients with unknown etiology of adrenal hemorrhage to promote diagnosis and timely management. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Trombosis portal en Síndrome antifosfolipídico: Reporte de caso

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial, venous, or small vessel thrombosis and recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the context of persistent antiphospholipid antibodies. Characterized by the development of multiple thrombotic manifestations, simultaneously or within a short period of time; being portal vein thrombosis (DVT) a rare and serious clinical manifestation and a predictor of poor prognosis.The case of an elderly patient with abdominal pain and portal vein thrombosis associated with APS with antithrombotic treatment and analgesics of favorable evolution is presented.