Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis

Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases.Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019(COVID-19)infection.COVID-19 causes pulmonary embolisms,thus new therapeutic options are required to target thrombosis,as conventional treatment options are either not effective due to the complexity of the immunethrombosis pathophysiology.In this review,we discuss regulation of immune response in respiratory diseases especially COVID-19.We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles,which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases.We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways,and thus can be recommended to treat respiratory infectious diseases.

Application of ultrasonography-elastography score to suspect porto-sinusoidal vascular disease in patients with portal vein thrombosis

Background:Porto-sinusoidal vascular disease(PSVD)and portal vein thrombosis(PVT)are causes of portal hypertension characterized respectively by an intrahepatic and a pre-hepatic obstacle to the flow in the portal system.As PVT may be a consequence of PSVD,in PVT patients at presentation,a pre-existing PSVD should be suspected.In these patients the identification of an underlying PSVD would have relevant implication regarding follow-up and therapeutic management,but it could be challenging.In this setting ultrasonography may be valuable in differential diagnosis.The aim of the study was to use ultrasonography to identify parameters to discriminate between PSVD and“pure”PVT and then to suspect PVT secondary to a pre-existing PSVD.Methods:Fifty-three patients with histologically proven PSVD and forty-eight patients affected by chronic PVT were enrolled and submitted to abdominal ultrasonography with elastography by acoustic radiation force impulse(ARFI).Results:ARFI was higher and superior mesenteric vein(SMV)diameter was wider in PSVD patients than in PVT patients.Thus,a prognostic score was obtained as linear combinations of the two parameters with a good discrimination capacity between PSVD and PVT(the area under the curve=0.780;95%confidence interval:0.690-0.869).Conclusions:A score based on ARFI and SMV diameter may be useful to suspect an underlying PSVD in patients with PVT and to identify a subgroup of patients to be submitted to liver biopsy.

Diagnostic Value of the Padua Score Combined with Thrombotic Biomarker Tissue Plasminogen Activator Inhibitor-1 (tPAI-1) Detection for the Risk of Deep Vein Thrombosis in Patients with Pulmonary Heart Disease

This study explores the diagnostic value of combining the Padua score with the thrombotic biomarker tissue plasminogen activator inhibitor-1(tPAI-1)for assessing the risk of deep vein thrombosis(DVT)in patients with pulmonary heart disease.These patients often exhibit symptoms similar to venous thrombosis,such as dyspnea and bilateral lower limb swelling,complicating differential diagnosis.The Padua Prediction Score assesses the risk of venous thromboembolism(VTE)in hospitalized patients,while tPAI-1,a key fibrinolytic system inhibitor,indicates a hypercoagulable state.Clinical data from hospitalized patients with cor pulmonale were retrospectively analyzed.ROC curves compared the diagnostic value of the Padua score,tPAI-1 levels,and their combined model for predicting DVT risk.Results showed that tPAI-1 levels were significantly higher in DVT patients compared to non-DVT patients.The Padua score demonstrated a sensitivity of 82.61%and a specificity of 55.26%at a cutoff value of 3.The combined model had a significantly higher AUC than the Padua score alone,indicating better discriminatory ability in diagnosing DVT risk.The combination of the Padua score and tPAI-1 detection significantly improves the accuracy of diagnosing DVT risk in patients with pulmonary heart disease,reducing missed and incorrect diagnoses.This study provides a comprehensive assessment tool for clinicians,enhancing the diagnosis and treatment of patients with cor pulmonale complicated by DVT.Future research should validate these findings in larger samples and explore additional thrombotic biomarkers to optimize the predictive model.

Neutrophil extracellular traps mediate neuro-immunothrombosis

Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms.Histones,von Willebrand factor,fibrin,and many other factors participate in the interplay between inflammation and thrombosis.Neuroimmunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases,providing cutting-edge insights into post-neurotrauma thrombotic events.The blood-brain barrier defends the brain and spinal cord against external assaults,and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases.Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis,but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis,and identified modulators of neuro-immunothrombosis.However,these neurological diseases occur in blood vessels,and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury.This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.

Venous thrombosis and prothrombotic factors in inflammatory bowel disease

Patients with inflammatory bowel disease (IBD) may have an increased risk of venous thrombosis (VTE). PubMed, ISI Web of Knowledge and Scopus were searched to identify studies investigating the risk of VTE and the prevalence of acquired and genetic VTE risk factors and prothrombotic abnormalities in IBD. Overall, IBD patients have a two- to fourfold increased risk of VTE compared with healthy controls, with an overall incidence rate of 1%-8%. The majority of studies did not show significant differences in the risk of VTE between Crohn’s disease and ulcerative colitis. Several acquired factors are responsible for the increased risk of VTE in IBD: inflammatory activity, hospitalisation, surgery, pregnancy, disease phenotype (e.g., fistulising disease, colonic involvement and extensive involvement) and drug therapy (mainly steroids). There is also convincing evidence from basic science and from clinical and epidemiological studies that IBD is associated with several prothrombotic abnormalities, including initiation of the coagulation system, downregulation of natural anticoagulant mechanisms, impairment of fibrinolysis, increased platelet count and reactivity and dysfunction of the endothelium. Classical genetic alterations are not generally found more often in IBD patients than in non-IBD patients, suggesting that genetics does not explain the greater risk of VTE in these patients. IBD VTE may have clinical specificities, namely an earlier first episode of VTE in life, high recurrence rate, decreased efficacy of some drugs in preventing further episodes and poor prognosis. Clinicians should be aware of these risks, and adequate prophylactic actions should be taken in patients who have disease activity, are hospitalised, are submitted to surgery or are undergoing treatment.

Thrombosis and inflammatory bowel disease-the role of genetic risk factors

Thromboembolism is a significant cause of morbidity and mortality in patients with inflammatory bowel disease （IBD）. Recent data suggest thromboembolism as a disease-specific extraintestinal manifestation of IBD, which is developed as the result of multiple interactions between acquired and genetic risk factors. There is evidence indicating an imbalance of procoagulant, anticoagulant and fibrinolitic factors predisposing in thrombosis in patients with IBD. The genetic factors that have been suggested to interfere in the thrombotic manifestations of IBD include factor V Leiden, factor Ⅱ （prothrombin, G20210A）, methylenetetrahydrofolate reductase gene mutation （MTHFR, 6777T, plasminogen activator inhibitor type 1 （PAI-1） gene mutation and factor X Ⅲ （val34leu）. In this article we review the current data and future prospects on the role of genetic risk factors in the development of thromboembolism in TBD.

Cerebral sinus thrombosis in patients with inflammatory bowel disease: A case report

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the gastrointestinal tract. The pathophysiology of IBD is probably the result of the complex interaction of genetic susceptibility and environmental influences. There is a well-known risk of thrombosis in patients with IBD. We present the case of a 53-year-old man with ulcerative colitis, who spontaneously developed intracranial sinus thrombosis that was treated with low molecular weight heparin. Literature was searched to assess the frequency and characteristics of cerebral sinus thrombosis in IBD and the role of certain etiopathological factors in such thrombotic patients.

Significant cohort of non-alcoholic fatty liver disease with portal vein thrombosis in transplant waiting list

AIM: To characterize non-alcoholic fatty liver disease(NAFLD) presentation with esophageal varices. METHODS: We carried out a retrospective cohort study on 258 patients with esophageal varices at a single tertiary referral center. These patients underwent diagnosis of several liver diseases, including: NAFLDassociated cirrhosis, hepatitis B, hepatitis C, Wilson disease, autoimune liver diseases, and others. RESULTS: Of the 258 patients, 39% of patients exhibited esophageal varices due to NAFLD-associated cirrhosis. Of the 38(14.7%) patients developed hepatocellular carcinoma during follow-up, 52% were due to hepatitis B, 26% due to hepatitis C and 13.2% due to NAFLD. Of the 258 patients, 50.0% with NAFLD, 33.3% with hepatitis B, 26.3% with hepatitis C, and 58.3% with other diseases were alive at the end of the 5-year period with a significant difference according to the Kaplan-Meier log Rank test(P = 0.040). Portal vein thrombosis was detected in 47.5% of patients with NAFLD, in 29% of patients with hepatitis B, in 17% of patients with hepatitis C, and in 62% of patients with other related diseases(P < 0.0001). CONCLUSION: Our study showed a proportionally greater elevation in liver transplant candidacy in patients with NAFLD and portal vein thrombosis. Older patients were more prone to developing cirrhosis, hepatocellular carcinoma and a high mortality rate. However, younger patients exhibited more portal vein thrombosis and gastric varices.

Is porto sinusoidal vascular disease to be actively searched in patients with portal vein thrombosis?

Porto sinusoidal vascular liver disease (PSVD) and portal vein thrombosis (PVT) are distinct vascular liver diseases characterized, respectively, by an intrahepatic and a prehepatic obstacle to the flow in the liver portal system. PVT may also occur as a complication of the natural history of PSVD, especially if a prothrombotic condition coexists. In other cases, it is associated to local and systemic pro-thrombotic conditions, even if its cause remains unknown in up to 25% despite an active search. In our opinion, the presence of PSVD should be suspected in patients with PVT especially in those with PVT “sine causa” and the active search of this condition should be included in their diagnostic work-out. However, sometimes the diagnosis of pre-existing PSVD is very hard. Biopsy cannot be fully discriminant as similar histological data have been described in both conditions. Liver stiffness may help as it has been shown to be higher in PSVD than in “pure” PVT, due to the presence of sclerosis in the portal venous radicles observable in PSVD patients. Nevertheless, comparing liver stiffness between PVT and PSVD has until now been restricted to very limited series of patients. In conclusion, even if it is still totally hypothetical, our point of view may have clinical consequences, especially when deciding to perform a liver biopsy in patients with a higher liver stiffness and suspending the anticoagulation in patients with PVT and no detectable prothrombotic factors.

Large-vessel thrombosis in intestinal Behet's disease complicated with myelodysplastic syndrome and trisomy 8

Behet's disease is characterized by recurrent oral ulcers, genital ulcers, uveitis and skin lesions. Myelodysplastic syndrome (MDS) is characterized by problems due to ineffective hematopoiesis. Several studies have identified a relationship between MDS and Behet's disease, especially intestinal Behet's disease. Trisomy 8 seems to play an important role in these disorders as well. The present case was a 24-year-old woman who had a huge tonsil ulcer with initial symptoms of odynophagia and intermittent fever. We also noted folliculitis on her upper back. Five days later, she began to experience diarrhea and abdominal pain. Abdominal computed tomography and subsequent surgery revealed ileum perforation and enterocolitis with multiple ulcers. Later, she was admitted again for a vulvar suppurative ulcer and suspicious Bartholin's cyst infection. The patient's clinical presentations met the criteria for Behet's disease. Six months after the bowel perforation event, we noted the development of pancytopenia in a routine laboratory examination. All the examinations led to the diagnosis of MDS with trisomy 8. The most unusual finding was that multiple large vessel thrombi developed during follow-up. Previous studies have suggested that trisomy 8 in MDS leads to concurrent intestinal Behet's disease. Moreover, the inflammatory and immune genes related to thrombus formation are overexpressed in cases of MDS with trisomy 8. Trisomy 8 must play a role in thrombosis. Further studies are needed to help clarify the pathophysiology and pathogenesis of these disorders.

Varicose Veins, Retinal Tears and Deep Vein Thrombosis, New Insights into the Causes from Adams Disease

Adams disease is the consequence of overly active transient receptor potential cation channels (TRP). This case report presents a patient suffering from multiple vascular problems and may provide new insights into the causes of venous problems. Endothelial and smooth muscle cells in veins contain TRP. These channels when activated excessively result in calcium accumulation, oxygen radical formation and apoptosis of endothelial and smooth muscle cells. The death of critical cells in vein valves, may lead to varicose veins. The loss of endothelial cells in venules may lead to retinal tears. Damage to vein walls may lead to a deep vein thrombosis. Transient receptor potential cation channels may be new drug targets of interest in the treatment or prevention of these conditions.

Left intracardiac thrombosis: An exceptional complication revealing BehCet’s disease

Although cardiac involvement during Behcet syndrome is uncommon and intracardiac thrombosis is exceptional, it concerns the right ventricle much more than the left one. We report an illustrative case of left intracardiac thrombosis revealing Behcet’s disease in a 33-year-old Tunisian man.

The Behcet’s Disease: An Uncommon Cause of Venous Thrombosis in the Tropical Area: 10 Cases

Introduction: The Behcet’s disease is deemed to be scarce in Black Africa where data are still scattered. The purpose of our study is to describe the epidemiological, clinical, paraclinic and evolutive particularities of the patients whose presenting symptoms of the Behcet’s diseases were a venous thrombosis. Patients and Methods: It was a descriptive, multicenter, and cross-sectional study lasting 15 months. We brought together all the cases of the Behcet’s disease revealed by venous thrombosis. The diagnosis was based on clinical criteria of the international group of study of the Behcet’s disease in 2007. Results: We have grouped 10 revealing thrombosis cases of the Behcet’s diseases during our study period. The average age was 34. The average wait period between the appearances of the early symptoms and the diagnosis of the very disease was 30 months. The admission motives were the abdominal pain (2 cases), a thrombophlebitis of the lower limb (2 cases), headaches (1 case), coma (1 case), a thrombophlebitis of the upper limb (3 cases). The thrombotic symptoms were exclusively venous-located. The seats of the thrombosis were the vena cava superior in 30% of the cases, the vena cava inferior in 20% of the cases, the veins of the lower limb in 20% of the cases, the cerebral vein in 20% of the cases, and the auxiliary vein in 10% of the cases. The treatment of the deep venous thrombosis consisted in all the cases of an effective anticoagulation associated with the colchicine. Primarily, the corticotherapy with a high dose was used in all the patients. One of them in the comatose stage, manifesting both cerebral thrombophlebitis and aseptic meningitis, had died. Conclusion: Behcet’s disease is a disease of the young adult, but it must be evoked even in old age, with a view to appropriate management, in order to avoid the complications of the disease. Although it is rare in our regions, it should be sought in the etiological assessment of venous thrombosis whatever the location.

Deep vein thrombosis and pulmonary embolism in cirrhotic patients:Systematic review

Patients with liver cirrhosis were traditionally believed to be protected against development of blood clots.Lately,studies have shown that these patients may probably be at an increased risk of venous thrombotic complications.Although the hemostatic changes in the chronic liver disease patients and the factors that may predict bleeding vs thrombotic complications remains an area of active research,it is believed that the coagulation cascade is delicately balanced in these patients because of parallel reduced hepatic synthesis of pro and anticoagulant factors.Thrombotic state in cirrhotic patients is responsible for not only portal or non-portal thrombosis[deep vein thrombosis(DVT)and pulmonary embolism(PE)];it has also been associated with progression of liver fibrosis.The use of anticoagulants in cirrhosis patients is a challenging,and often a scary situation.This review summarizes the current literature on the prevalence of venous thrombosis(DVT and PE),risk factors and safety of prophylactic and therapeutic anticoagulation in patients with chronic liver disease.

Role of gut microbiota in cardiovascular diseases

The human gut is colonized by a community of microbiota,primarily bacteria,that exist in a symbiotic relationship with the host.Intestinal microbiota-host interactions play a critical role in the regulation of human physiology.Deleterious changes to the composition of gut microbiota,referred to as gut dysbiosis,has been linked to the development and progression of numerous diseases,including cardiovascular disease(CVD).Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression.Most CVD risk factors,including aging,obesity,dietary patterns,and a sedentary lifestyle,have been shown to induce gut dysbiosis.Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier,which in turn increases circulating levels of bacterial structural components and microbial metabolites,including trimethylamine-N-oxide and short-chain fatty acids,that may facilitate the development of CVD.This article reviews the normal function and composition of the gut microbiome,mechanisms leading to the leaky gut syndrome,its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention.As CVD is the leading cause of deaths globally,investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.

Etiology and portal vein thrombosis in Budd-Chiari syndrome

AIM: To research the etiology, portal vein thrombosis and other features of Budd-Chiari syndrome (BCS) patients prospectively. METHODS: A total of 75 patients (40 female, 35 male) who were diagnosed between January 2002 and July 2004 as having BCS were studied prospectively. Findings from on physical examination, ultrasonography, duplex ultrasonography and venography were analyzed. Hemogram and blood chemistry were studied at the time of diagnosis and on each hospital visit. Bone marrow examination and immune phenotyping were performed by a hematologist when necessary. Protein C, S, antithrombin Ⅲ, activated protein C resistance, and anticardiolipin antibodies, antinuclear antibodies, and anti ds-DNA were studied twice. The presence of ascite, esophageal varices, and portal thrombosis were evaluated at admission and on every visit. RESULTS: At least one etiological factor was determined in 54 (72%) of the patients. The etiology could not be defined in 21 (28%) patients. One etiological factor was found in 39, 2 factors in 14 and 3 factors in 1 patient. The most common cause was the web (16%), the second was Hydatid disease (11%), the third was Behcet’s disease (9%). Portal vein thrombosis was present in 11 patients and at least one etiology was identified in 9 of them (82%). CONCLUSION: Behcet’s disease and hydatid disease are more prominent etiological factors in Turkey than in other countries. Patients with web have an excellent response to treatment without signs of portal veinthrombosis while patients having thrombofilic factors more than one are prone to develop portal vein thrombosis with worse clinical outcome.

Venous and arterial thromboembolism in patients with inflammatory bowel diseases

The risk of thromboembolism(TE)is increased in patients with inflammatory bowel disease(IBD),mainly due to an increased risk of venous TE(VTE).The risk of arterial TE(ATE)is less pronounced,but an increased risk of cardiovascular diseases needs to be addressed in IBD patients.IBD predisposes to arterial and venous thrombosis through similar prothrombotic mechanisms,including triggering activation of coagulation,in part mediated by impairment of the intestinal barrier and released bacterial components.VTE in IBD has clinical specificities,i.e.,an earlier first episode in life,high rates during both active and remission stages,higher recurrence rates,and poor prognosis.The increased likelihood of VTE in IBD patients may be related to surgery,the use of medications such as corticosteroids or tofacitinib,whereas infliximab is antithrombotic.Long-term complications of VTE can include post-thrombotic syndrome and high recurrence rate during post-hospital discharge.A global clot lysis assay may be useful in identifying patients with IBD who are at risk for TE.Many VTEs occur in IBD outpatients;therefore,outpatient prophylaxis in high-risk patients is recommended.It is crucial to continue focusing on prevention and adequate treatment of VTE in patients with IBD.

Cerebral venous thrombosis and heparin-induced thrombocytopenia in an 18-year old male with severe ulcerative colitis

The risk of thromboembolism is increased in inflammatory bowel disease and its symptoms may be overlooked. Furthermore, its treatment can be complex and is not without complications. We describe a case of an adolescent boy who developed a cerebral sinus venous thrombosis during a relapse of his ulcerative colitis and who, while on treatment with heparin, developed heparin-induced thrombocytopenia (HIT). The treatment was then switched to fondaparinux, a synthetic and selective inhibitor of activated factor .

Portal venous gas and thrombosis in a Chinese patient with fulminant Crohn’s colitis: A case report with literature review

Ever since its earliest reports, portal venous gas (PVG) has been associated with numerous intraabdominal catastrophes and has served as an indication for urgent surgical exploration. It is traditionally regarded to be an ominous finding of impending death, with highest mortality reported in patients with underlying bowel ischemia. Today, computed tomography has demonstrated a wider range of clinical conditions associated with PVG, some of which are ‘benign’ and do not necessarily require surgery, unless when there are signs of intraabdominal catastrophe or systemic toxicity. One of these ‘benign’ conditions is Crohn’s disease. The present report describes a 19-year-old Chinese boy with Crohn’s pancolitis who presented with septic shock associated with PVG and portal vein thrombosis, and was successfully managed surgically. To our knowledge, this is the fi rst report of PVG and portal vein thrombosis associated with Crohn’s disease in a Chinese patient. In addition, we have also reviewed the reports of another 18 Crohn’s patients with PVG previously described in the English literature. Specifi c predisposing factors for PVG were identified in 8 patients, including barium enema, colonoscopy, blunt abdominal trauma, and enterovenous f istula. The patients who developed PVG following barium enema and blunt trauma were all asymptomatic and no specifi c treatment was necessary. Eleven patients (58%) who presented with signs of intraabdominal catastrophe or systemic toxicity required either immediate or eventual surgery. The overall mortality rate among the 19 patients was only 11%. The present literature review has shown that the f inding of PVG associated with Crohn’ s disease does not always mandate surgical intervention. It is the clinical features and the related complications that ultimately determine the treatment approaches. The overall outcome of PVG associated with Crohn’s disease has been favourable.

Levels and activities of von Willebrand factor and metalloproteinase with thrombospondin type-1 motif, number 13 in inflammatory bowel diseases

To evaluate the levels of von Willebrand factor (VWF) and metalloproteinase with thrombospondin type-1 motif, number 13 (ADAMTS13) in inflammatory bowel disease (IBD) and correlate them with the disease activity. METHODSConsecutive patients with IBD aged 18 years or older were enrolled in the study. Forty-seven patients with ulcerative colitis (UC), 38 with Crohn’s disease (CD), and 50 healthy controls were included. The white blood cell count, haematocrit, platelet count, fibrinogen, partial activated thromboplastin time, C-reactive protein, albumin, VWF antigen level (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen-binding activity (VWF:CB), and ADAMTS13 antigen level (ADAMTS13:Ag) and activity (ADAMTS13act) were measured. The following ratios were assessed: VWF:RCo/VWF:Ag, VWF:CB/VWF:Ag, VWF:Ag/ADAMTS13act, and ADAMTS13act/ADAMTS13:Ag. RESULTSCompared to controls, the odds ratio (OR) of an elevated VWF: Ag > 150% was 8.7 (95%CI: 2.7-28.1) in the UC group and 16.2 (95%CI: 4.8-54.0) in the CD group. VWF:CB was lower in UC patients, and active CD was associated with a higher VWF: RCo (+38%). The ORs of VWF:CB/VWF:Ag < 0.7 (a marker of acquired von Willebrand syndrome) in the UC and CD groups were 11.9 (95%CI: 4.4-32.4) and 13.3 (95%CI: 4.6-38.1), respectively. Active UC was associated with lower ADAMTS13:Ag (-23%) and ADAMTS13act (-20%) compared to UC in remission. Patients with active CD had a 15% lower ADAMTS13act than controls. The activity of UC, but not that of CD, was inversely correlated with ADAMTS13:Ag (r = -0.76) and ADAMTS13act (r = -0.81). CONCLUSIONComplex VWF-ADAMTS13-mediated mechanisms disturb haemostasis in IBD. A reduced WVF:CB is a risk factor for bleeding, while a lower ADAMTS13 level combined with an elevated VWF:Ag could predispose one to thrombosis.