iloprost and Vascular-Diseases

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.

Topics: Administration, Inhalation; Anticoagulants; Blood Coagulation Disorders; Blood Platelet Disorders; COVID-19; COVID-19 Drug Treatment; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Epoprostenol; Heart Disease Risk Factors; Humans; Iloprost; Inflammation; Nitric Oxide; Platelet Aggregation Inhibitors; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Thrombosis; Thrombotic Microangiopathies; Vascular Diseases; Vasodilator Agents; Venous Thromboembolism

Topics: Alprostadil; Clinical Trials as Topic; Epoprostenol; Humans; Iloprost; Prostaglandins; Prostaglandins, Synthetic; Vascular Diseases

Topics: Alprostadil; Amputation, Surgical; Cardiovascular Agents; Clinical Trials as Topic; Epoprostenol; Humans; Iloprost; Infusions, Intravenous; Leg Ulcer; Vascular Diseases

Topics: Alprostadil; Clinical Trials as Topic; Epoprostenol; Humans; Iloprost; Prostaglandins; Prostaglandins, Synthetic; Vascular Diseases

In 2 randomized, double-blind studies, 109 diabetic patients with trophic lesions and 101 non-diabetics suffering from peripheral vascular disease (PVD) stage IV (Fontaine) received daily 6-hour i.v. infusions of iloprost (less than or equal to 2ng/kg/min) or of placebo over 28 days. Iloprost treatment was superior to placebo, showing ulcer healing in more than 60% of patients compared to less than 25% in the control group. The beneficial effects were sustained during a 1 year follow-up period. Platelet activation, adhesion, aggregation and release reaction on atherosclerotic lesions, impaired microvascular perfusion, loss of microvascular barrier function, increased white blood cell - vessel wall interaction and hemorheological disturbances are all believed to play a role in PVD. Stable PGI2-mimetics inhibit platelet activation by all endogenous mediators as well as platelet release of mitogenic factors (PDGF).

Topics: Animals; Blood Platelets; Cardiovascular Agents; Clinical Trials as Topic; Diabetic Angiopathies; Disease Models, Animal; Double-Blind Method; Epoprostenol; Humans; Iloprost; Infusions, Intravenous; Microcirculation; Random Allocation; Rats; Thrombosis; Ulcer; Vascular Diseases

Topics: Aged; Blood Platelets; Clinical Trials as Topic; Double-Blind Method; Epoprostenol; Humans; Iloprost; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Vascular Diseases

Topics: Adenosine Diphosphate; Blood Platelets; Cardiovascular Agents; Clinical Trials as Topic; Collagen; Epoprostenol; Humans; Iloprost; Male; Pain; Platelet Aggregation; Random Allocation; Vascular Diseases

We investigated the effect of suppressing plasma angiotensin II (ANG II) levels on arteriolar relaxation in the hamster cheek pouch.. Arteriolar diameters were measured via television microscopy during short-term (3-6days) high salt (HS; 4% NaCl) diet and angiotensin converting enzyme (ACE) inhibition with captopril (100mg/kg/day).. ACE inhibition and/or HS diet eliminated endothelium-dependent arteriolar dilation to acetylcholine, endothelium-independent dilation to the NO donor sodium nitroprusside, the prostacyclin analogs carbacyclin and iloprost, and the KATP channel opener cromakalim; and eliminated arteriolar constriction during KATP channel blockade with glibenclamide. Scavenging of superoxide radicals and low dose ANG II infusion (25ng/kg/min, subcutaneous) reduced oxidant stress and restored arteriolar dilation in arterioles of HS-fed hamsters. Vasoconstriction to topically-applied ANG II was unaffected by HS diet while arteriolar responses to elevation of superfusion solution PO2 were unaffected (5% O2, 10% O2) or reduced (21% O2) by HS diet.. These findings indicate that sustained exposure to low levels of circulating ANG II leads to widespread dysfunction in endothelium-dependent and independent vascular relaxation mechanisms in cheek pouch arterioles by increasing vascular oxidant stress, but does not potentiate O2- or ANG II-induced constriction of arterioles in the distal microcirculation of normotensive hamsters.

Topics: Acetylcholine; Angiotensin II; Animals; Arterioles; Blood Pressure; Captopril; Cheek; Cricetinae; Cromakalim; Endothelium, Vascular; Epoprostenol; Glyburide; Iloprost; Male; Mesocricetus; Microscopy; Microscopy, Video; Nitroprusside; Oxidants; Oxygen; Peptidyl-Dipeptidase A; Superoxides; Vascular Diseases

Thorascopic sympathectomy is a widely used procedure for the treatment of intractable palmar hyperhidrosis.. A 24-year-old woman who underwent thorascopic sympathectomy for hyperhidrosis in 2005 presented on more than 30 occasions with recurrent right distal upper limb ischaemia secondary to repetitive episodes of vasospasm. The patient did not have preoperative symptoms consistent with Raynaud's syndrome. We observed a reduction in the symptomatic relief offered by Iloprost treatment over a period of five years.. This is the first report of distal upper limb ischaemia following thorascopic sympathectomy. We highlight the development of resistance to repeated Iloprost infusions that we observed in this case.

Topics: Drug Resistance; Female; Humans; Hyperhidrosis; Iloprost; Infusions, Parenteral; Ischemia; Radiography; Recurrence; Spasm; Sympathectomy; Thoracoscopy; Treatment Outcome; Upper Extremity; Vascular Diseases; Vasodilator Agents; Young Adult

The European League Against Rheumatism/EULAR Scleroderma Trials and Research group (EULAR/EUSTAR) has published recommendations for the management of systemic sclerosis (SSc). Members of the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group were surveyed regarding their level of agreement with the recommendations.. A survey containing the 14 EULAR/EUSTAR recommendations asked participants to indicate their level of agreement with each on a 10-point scale, from 0 (not at all) to 9 (completely agree). The survey was sent to 117 people, and 66 replies were received (56% response rate).. Exceptions to generally high agreement included the use of iloprost and bosentan for digital vasculopathy, methotrexate for skin involvement, and bosentan and epoprostenol for pulmonary arterial hypertension (PAH; all < 69% agreement, defined as ≥ 7 rating). Vasculopathy and PAH treatment had differences in agreement between North America and Europe (p < 0.006). Respondents who were EULAR/EUSTAR recommendation authors shared a similar level of agreement compared to those who were not, except for the use of proton pump inhibitors for the prevention of SSc-related gastroesophageal reflux disease, esophageal ulcers, and strictures.. EULAR/EUSTAR recommendations were relatively well accepted among SSc experts. Overall reduced agreement may be due to the modest efficacy of some agents (such as methotrexate for the skin). Some regional disagreement is likely because of access differences.

Topics: Bosentan; Canada; Epoprostenol; Europe; Health Surveys; Humans; Hypertension, Pulmonary; Iloprost; Methotrexate; North America; Practice Guidelines as Topic; Scleroderma, Systemic; Skin Diseases; Societies, Medical; Sulfonamides; Treatment Outcome; Vascular Diseases

Prostacyclin, a potent inhibitor of platelet function and vasodilator, has been used to treat peripheral vascular disease. The aim of this study was to monitor the thrombotic status of patients treated by infusion of a stable prostacyclin analogue, iloprost.. Thirteen patients with peripheral vascular disease underwent iloprost infusion for 3 days (8 hours each day) in a dose ranging from 0.5 to 2 ng/kg/minute. Variable parameters of thrombosis such as platelet reactivity (shear-induced hemostatic plug formation and thrombus formation on a collagen fiber), coagulation, and spontaneous thrombolysis (dislodgment of hemostatic plugs) were measured from non-anticoagulated blood samples by hemostatometry immediately before and 1 hour after the infusion and on the last day, 4 hours after initiation of the infusion.. Analysis of data from all patients 1 hour after the infusion showed no changes in platelet reactivity and spontaneous thrombolysis, but coagulation was significantly enhanced. In four patients, significant platelet hyperreactivity was observed after the infusion. Four of the five patients tested while undergoing iloprost infusion showed an enhanced thrombotic reaction and markedly enhanced coagulation. Iloprost employed in vitro in a concentration that corresponds to the therapeutic peak blood level caused no inhibition of platelet function but significantly enhanced coagulation. The threshold in vitro iloprost concentration at which anti-platelet effect and increased spontaneous thrombolysis were observed was twice that of the therapeutic blood level.. These findings challenge the view that antagonism of platelet function is an important factor of iloprost therapy. Furthermore, platelet hyperreactivity in some patients and markedly enhanced coagulation during and after infusion of iloprost in general, represent a risk of thromboembolism, especially as patients are already in a prethrombotic condition.

Topics: Adult; Aged; Blood Coagulation; Blood Platelets; Female; Humans; Iloprost; Infusions, Intravenous; Middle Aged; Platelet Activation; Risk; Thromboembolism; Vascular Diseases

Topics: Animals; Cardiovascular Agents; Ear; Epoprostenol; Iloprost; Ischemia; Mice; Mice, Hairless; Necrosis; Perfusion; Vascular Diseases

Topics: Aged; Blood Platelets; Epoprostenol; Humans; Iloprost; Infusions, Intravenous; Kinetics; Platelet Aggregation; Receptors, Epoprostenol; Receptors, Prostaglandin; Vascular Diseases

Two unfractionated heparins (UH), a porcine intestinal mucosal heparin (PIM), a bovine lung heparin (BLH) and a low molecular weight heparin (LMWH), CY 222, were assessed for their capacity to enhance platelet aggregation in vitro. Their potential proaggregatory effect was investigated in four systems: (a) enhancement of submaximal platelet aggregation induced by conventional agonists in platelet rich plasma and (b) in whole blood; (c) reversal of inhibition of platelet aggregation induced by iloprost, a stable analogue of prostacyclin; (d) the direct aggregatory effect of these anticoagulants on hyperactive platelets prepared from patients with severe peripheral vascular disease or anorexia nervosa. Whereas BLH and PIM, at therapeutic concentrations, had a proaggregatory effect in all four systems, CY 222 had no significant effect when compared with the controls. BLH was more potent than PIM in three of the four systems studied. These observations confirm that conventional UH are more proaggregatory than LMWH, and thus the latter may be potentially safer. These observations are also consistent with the fact that BLH administration causes thrombocytopenia more frequently than PIM. The direct activation by UH of platelets from patients not previously exposed to heparin also challenges the hypothesis that heparin-induced platelet activation and thrombocytopenia is solely mediated by classical heparin-dependent immune mechanisms.

Topics: Adult; Anorexia Nervosa; Cardiovascular Agents; Epoprostenol; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Iloprost; Male; Platelet Aggregation; Vascular Diseases

Topics: Adenylyl Cyclases; Blood Platelets; Drug Resistance; Enzyme Activation; Epoprostenol; Humans; Iloprost; Kinetics; Prostaglandin D2; Prostaglandins D; Receptors, Epoprostenol; Receptors, Prostaglandin; Vascular Diseases