iloprost and Thrombosis

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: Cyclooxygenase Inhibitors; Dipyridamole; Humans; Iloprost; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prostaglandin Antagonists; Purinergic P2 Receptor Antagonists; Thrombosis

Thrombotic microangiopathy, including the two related syndromes thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, is a rare and severe multisystem disorder, due to widespread deposition of intravascular microthrombi consisting mainly of platelets, with subsequent consumption thrombocytopenia, microangiopathic hemolytic anemia, renal abnormalities, and neurologic disturbances. The epidemic, verotoxin-induced hemolytic-uremic syndrome, typically associated with prodromal diarrhea, mainly affects young children in small outbreaks. By contrast, idiopathic thrombotic microangiopathy generally affects adults in a sporadic form; it has a more devastating course and a less favourable outcome. Over 90% of the reported cases in the adult, when untreated, have progressed to death within three months of diagnosis. Since the introduction of plasma exchange, a dramatic change in the prognosis of the disease has taken place, although the mortality rate still remains considerable. Indeed, improved survival is the most striking feature of adult thrombotic microangiopathy compared to some decades ago. In the present article we will focus on the evolving concepts able to exert a considerable impact in the management of the adult idiopathic form of thrombotic microangiopathy.

Topics: Adult; Hemolytic-Uremic Syndrome; Humans; Iloprost; Multiple Organ Failure; Plasma Exchange; Platelet Aggregation; Platelet Aggregation Inhibitors; Purpura, Thrombotic Thrombocytopenic; Thrombosis

More than a decade has gone by since the detailed clinical description of the Antiphospholipid (Hughes) Syndrome. Because of the wide spectrum of manifestations, virtually any physician may encounter patients with this potentially treatable condition. Because of limited controlled, prospective data, current therapy remains empirical and directed at coagulation mechanisms, immune mechanisms, or both. There is now good evidence that patients with antiphospholipid-associated thrombosis will be subject to recurrences and require prophylactic therapy. Although most authorities agree about the efficacy of warfarin alone or warfarin plus low-dose aspirin in preventing recurrences of venous and arterial thrombosis, there is still doubt regarding the intensity and duration of warfarin therapy. Steroids and immunosuppressive drugs have not provided long-term benefit. Controlled clinical trials of the treatment of pregnant women with antiphospholipid antibody demonstrated that prednisolone is ineffective, and possibly detrimental, in treatment of recurrent pregnancy loss and that heparin plus low-dose aspirin is beneficial.

Topics: Abortion, Habitual; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Aspirin; Autoimmune Diseases; Contraindications; Drug Therapy, Combination; Female; Heparin; Humans; Iloprost; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Recurrence; Thrombophilia; Thrombosis; Warfarin

Prostacyclins (PGl2) inhibit platelet-platelet interactions at concentrations that do not affect platelet adhesion to collagen and other arterial subendothelial structures exposed during injury. Such compounds can be encapsulated within platelets by reversible electroporation and, using the platelet's natural haemostatic propensity, they can be targeted to injured vessels in vivo. In rat (aorta), rabbit (ileofemoral) and pig (carotid) angioplasty models, autologous platelets, electro-loaded with the stable prostacyclin iloprost and given intravenously after balloon overstretch injury, substantially reduced platelet deposition at the lesion site as compared with control platelets. In the pig model, when the drug-loaded platelets were delivered directly to the injury site during angioplasty via a double balloon delivery catheter, platelet deposition was restricted to monolayer coverage (> 80% reduction compared with controls). Candidate antiproliferative drugs (for co-encapsulating with iloprost) are being investigated in order to develop a combined antithrombotic/antirestenosis strategy for use during angioplasty and thrombolysis procedures. Autologous platelets as drug-targeting vehicles should obviate many of the immunological, toxicological and biodegradability concerns inherent in the use of other drug transport vectors such as antibodies, viruses, liposomes and synthetic polymer microcapsules.

Topics: Angioplasty, Balloon; Animals; Arterial Occlusive Diseases; Arteries; Blood Platelets; Drug Carriers; Drug Delivery Systems; Humans; Iloprost; Infusions, Intravenous; Platelet Aggregation Inhibitors; Postoperative Complications; Rabbits; Rats; Swine; Thrombosis

Topics: Arterial Occlusive Diseases; Blood Platelets; Cell Adhesion; Clinical Trials as Topic; Endothelium, Vascular; Humans; Iloprost; Leukocytes; Microcirculation; Thrombosis

Topics: Animals; Arachidonic Acid; Cyclooxygenase Inhibitors; Drug Synergism; Epoprostenol; Fibrinolytic Agents; Graft Survival; Humans; Iloprost; Ischemia; Lipoxygenase; Lipoxygenase Inhibitors; Nitric Oxide; Postoperative Complications; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Skin; Skin Transplantation; Surgical Flaps; Thrombosis; Vasodilator Agents

There are three distinct syndromes of heparin-induced thrombocytopenia: an acute reversible from seen immediately after intravenous bolus injection, a delayed-onset antibody-mediated form seen several days after the initiation of therapy, and an intermediate type characterized by mild thrombocytopenia developing just a few days after starting therapy. Delayed-onset heparin-induced thrombocytopenia, clinically the most important form, results from the formation of heparin-dependent antibodies that are directed against the platelet membrane. In the presence of heparin, these antibodies may induce in vitro or in vivo platelet aggregation. Consequently, the course may be complicated by arterial thromboses. Treatment of this syndrome includes the prompt cessation of heparin. Since continued or future anticoagulation is usually necessary, alternative means of anticoagulation have been explored. Oral anticoagulation is often started but requires several days to take effect. Other options include low-molecular-weight heparins, antiplatelet agents, prostacyclin analogues, and low-molecular-weight dextran. In vitro laboratory tests may be helpful in guiding alternative therapy in some, but not all cases. Unfortunately, none of these agents have proved to be uniformly effective and additional agents and clinical investigation are needed before a definitive option becomes available.

Topics: Aspirin; Cardiopulmonary Bypass; Chondroitin Sulfates; Dermatan Sulfate; Epoprostenol; Fibrinolytic Agents; Glycosaminoglycans; Heparin; Heparinoids; Heparitin Sulfate; Humans; Iloprost; Necrosis; Platelet Aggregation Inhibitors; Skin; Skin Diseases; Thrombocytopenia; Thrombosis

Thrombosis following microvascular anastomosis requires further surgical intervention, involving anastomotic resection and reanastomosis or interpositional vein grafting. This study was undertaken to investigate different methods of salvaging thrombosed vessels, using a rat-vein model of error-induced thrombosis. Vessels were reconstructed 4 hr after the onset of thrombosis, using one of three methods: Group 1--removal of the erroneously placed stitch; Group 2--anastomotic resection and re-anastomosis; and Group 3--resection and replacement with a vein graft. Adjuvant antithrombotic therapy was simultaneously evaluated, assessing the influence of systemic Iloprost or heparin. Patency rates at one day postoperatively were 0 percent, 12.5 percent and 37.5 percent for Groups 1, 2, and 3, respectively. Following Iloprost infusion, these rates increased to 25 percent, 25 percent, and 56.3 percent, respectively and, following heparin administration, to 50 percent, 68.8 percent, and 81.8 percent, respectively. Significant increases were found for vein grafting (Group 3), and for the heparin-treated subgroups using all three methods. Effective levels of both Iloprost and heparin were confirmed by increases noted in rat-tail bleeding times. Significant rates of recanalization by three days following one-day occlusion were found in Groups 1 and 2. These results support the application of vein-graft replacement for thrombosed veins, concurrently with systemic heparinization. This study further confirms the high rate of recanalization seen in thrombosed rat femoral veins.

Topics: Anastomosis, Surgical; Animals; Chemotherapy, Adjuvant; Fibrinolytic Agents; Heparin; Iloprost; Male; Microsurgery; Rats; Rats, Inbred Strains; Reoperation; Thrombosis; Vascular Patency

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

Thrombospondin-1 (TSP-1) is released by platelets upon activation and can increase platelet activation, but its role in hemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of hemostasis that promotes platelet activation by modulating inhibitory cyclic adenosine monophosphate (cAMP) signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of hemostasis and thrombosis showed that TSP-1-deficient mice had prolonged bleeding, defective thrombosis, and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild-type (WT) but not TSP-1-/- platelets ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1-deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation, and arrest under flow by prostacyclin (PGI2). Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1-/- platelets. By contrast, incubation of TSP-1-/- platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1-/- platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1-/- mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This scenario suggests that the release of TSP-1 regulates hemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.

Topics: Animals; Bleeding Time; Blood Platelets; CD36 Antigens; Cells, Cultured; Chlorides; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cytoplasmic Granules; Epoprostenol; Ferric Compounds; Hemorrhagic Disorders; Hemostasis; Humans; Iloprost; Mice; Mice, Inbred C57BL; Platelet Transfusion; Second Messenger Systems; Thrombosis; Thrombospondin 1

Case report of a patient with age-related macular degeneration whose digital ischemia can most plausibly be attributed to ranibizumab.. To report ranibizumab as the probable cause of digital ischemia in a patient treated for age-related macular degeneration.. Single-patient case report.. An 83-year-old woman with an unremarkable medical history suffered acute ischemia in her left hand with necrosis of the distal phalange of the fifth finger after six intravitreal injections of ranibizumab. Her etiological work-up was negative. Her condition improved after endovascular revascularization and remained good at six months' follow-up after three months of dual antithrombotic therapy (low molecular weight heparin then rivaroxaban, both with aspirin) followed by rivaroxaban alone and four courses of intravenous iloprost.. The increased incidence of peripheral arterial thromboembolic events in patients under ranibizumab treatment is slight but significant, with 0.8-5% of patients affected, most of which suffer strokes. These events seem to occur at a random time after ranibizumab treatment is initiated and no reliable marker has yet been identified. The most probable cause of digital ischemia in our patient was ranibizumab.

Topics: Aged, 80 and over; Angiogenesis Inhibitors; Angioplasty; Aspirin; Combined Modality Therapy; Female; Fingers; Heparin, Low-Molecular-Weight; Humans; Iloprost; Intravitreal Injections; Ischemia; Macular Degeneration; Radial Artery; Ranibizumab; Rivaroxaban; Thrombectomy; Thrombosis; Ulnar Artery; Vascular Endothelial Growth Factor A

Severe frostbite can result in devastating injuries leading to significant morbidity and loss of function from distal extremity amputation. The modern day management approach to frostbite injuries is evolving from a historically very conservative approach to the increasingly reported use of early interventional angiography and fibrinolysis with tPA. The aim of this study was to evaluate the results of our frostbite treatment protocol introduced 3 years ago.. All frostbite patients underwent first clinical and then Doppler ultrasound examination. Angiography was conducted if certain clinical criteria indicated a severe frostbite injury and if there were no contraindications to fibrinolysis. Intra-arterial tissue plasminogen activator (tPA) was then administered at 0.5-1mg/h proximal to the antecubital fossa (brachial artery) or popliteal fossa (femoral artery) if angiography confirmed thrombosis, as well as unfractionated intravenous heparin at 500 units/h. The vasodilator iloprost was administered intravenously (0.5-2.0ng/kg/min) in selected cases.. 20 patients with frostbite were diagnosed between 2013-2016. Fourteen patients had a severe injury and angiography was performed in 10 cases. The total number of digits at risk was 111. Nine patients underwent fibrinolytic treatment with tPA (including one patient who received iloprost after initial non response to tPA), 3 patients were treated with iloprost alone and 2 patients received neither treatment modality (due to contraindications). The overall digital salvage rate was 74.8% and the Hennepin tissue salvage rate was 81.1%. One patient developed a catheter-site pseudoaneurysm that resolved after conservative treatment.. Prompt referral to a facility where interventional radiology and 24/7 laboratory services are available, and the combined use of tPA and iloprost, may improve outcome after severe frostbite.

Topics: Adult; Aged; Angiography; Clinical Protocols; Disease Management; Female; Fibrinolytic Agents; Frostbite; Humans; Iloprost; Infusions, Intra-Arterial; Ischemia; Male; Middle Aged; Radiology, Interventional; Referral and Consultation; Thrombosis; Tissue Plasminogen Activator; Ultrasonography, Doppler; Vasodilator Agents; Young Adult

The decision for an anticoagulant for renal replacement therapy (RRT) in patients with acute renal failure and heparin-induced thrombocytopenia (HIT) has to be made carefully. Based on results from the literature argatroban is favoured in patients without hepatic dysfunction, referring to its short halftime and easy feasable monitoring. In the case of coexsisting hepatic disorder, danaparoid provides a safe alternative therapy. However, long halftime and the difficult elimination of the substance are unfavourable. Lepirudin represents another possible anticoagulant therapy. Bleeding complications and monitoring of the ecarin clotting time imposes limitations. Experiences with bivalirudin, fondaparinux and prostaglandines are limited and future trials will have to determine the significance of their application in RRT in HIT patients. Furthermore it has to be proven whether the combination of alternative anticoagulants with citrate prolongates circuit halftime of CVVH.

Topics: Acute Kidney Injury; Anticoagulants; Arginine; Blood Coagulation Tests; Chondroitin Sulfates; Citrates; Critical Care; Dermatan Sulfate; Diagnostic Errors; Dose-Response Relationship, Drug; Epoprostenol; Fondaparinux; Hemofiltration; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Iloprost; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sodium Citrate; Sulfonamides; Thrombocytopenia; Thrombosis

In its more severe form heparin induced thrombocytopenia (HIT) is a rare immune mediated complication of heparin administration that potentially has catastrophic results, and significant mortality. In view of the severity of this condition it is important for the clinician to maintain a high index of suspicion and get alerted to the HIT syndrome by the precocity of platelet count decrease in any patient group, and especially in those previously exposed to heparin. We report on a 72-year-old woman who developed HIT syndrome that was complicated by recurrent arterial thromboses after receiving postoperative antithrombotic prophylaxis with tinzaparin, a low molecular weight heparin. The patient was successfully treated with iloprost (Ilomedin, iloprost tromethamine, Schering) a stable prostacyclin analogue, at the acute phase of the syndrome, followed by long-term treatment with clopidogrel (Plavix, clopidogrel bisulfate, Sanofi) an inhibitor of adenosine diphosphate (ADP) receptor. Although direct thrombin inhibitors have been proven to be effective for the treatment of HIT thrombosis, they do not completely eliminate the morbidity and mortality of this disorder. Our case report suggests that antithrombotic treatment by targeting of the activated platelets with a potent platelet inhibitor during the acute phase of type II HIT syndrome followed by long-term administration of oral anticoagulation may be an additional, safe and effective therapeutic alternative that merits to be systematically studied.

Topics: Aged; Arterial Occlusive Diseases; Clopidogrel; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Iliac Artery; Iloprost; Leg; Platelet Aggregation Inhibitors; Popliteal Artery; Radiography; Recurrence; Syndrome; Thrombocytopenia; Thrombosis; Ticlopidine; Tinzaparin

A 69-year-old amateur carpenter complained of a sudden stabbing pain and a white discoloration of D4 and D5 of the right hand while shoveling snow. On admission in our clinic twelve days later, clinical inspection showed a gangrene of the distal bone of D5 and proximal garland-shaped radial and ulnar subcutaneous haemorrhage and already ischemic contracture. D4 showed pale livid colour.. According to the results of an arteriography acral pulse oscillography revealed a occlusion of the digital arteries. Duplex sonography showed a thrombotic occluded aneurysm of the right ulnar artery over the hypothenar area.. Hypothenar hammer syndrome with a thrombotic occlusion of an aneurysm of the distal ulnar artery and multiple thromboembolic occlusions of the digital arteries of D4 and D5 of the right hand.. After initial therapy with Iloprost, treatment of pain and local treatment, an intraarterial locoregional lysis therapy with urokinase was performed. Acral blood circulation improved significantly and the patient was completely painless after treatment.. In case of an acute onset of unilateral digital ischemia hypothenar hammer syndrome should be considered. Regional thrombolysis can be performed in case of severe digital ischemia.

Topics: Acute Disease; Aged; Aneurysm; Angiography, Digital Subtraction; Fingers; Humans; Iloprost; Ischemia; Male; Plasminogen Activators; Platelet Aggregation Inhibitors; Syndrome; Thrombosis; Ulnar Artery; Ultrasonography, Doppler, Duplex; Urokinase-Type Plasminogen Activator; Vasodilator Agents

Topics: Anesthesia, Epidural; Contraindications; Humans; Iloprost; Platelet Aggregation Inhibitors; Thrombosis

Topics: Female; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors; Scleroderma, Systemic; Thrombosis; Vasodilator Agents

Vascular prostheses of small diameter perform poorly in vivo, in part because of the high thrombogenicity of available biomaterials. This study examined the thrombogenicity of expanded polytetrafluoroethylene (ePTFE) vascular graft segments (10 mm long x 4 mm i.d.) in vitro before and after impregnation with saline, alginate, or alginate containing the stable prostacyclin analog, iloprost. Each segment was immersed in activated whole blood and the weight of the adherent thrombus was measured at specified intervals. At 6 and 7 min the saline-denucleated group accumulated significantly less thrombus than control (p < .05). Alginate alone was not significantly different from controls. The graft segments treated with alginate + iloprost accumulated significantly less thrombus (p < .05) than all other groups after 6 min. These data demonstrate that denucleation of ePTFE with iloprost in alginate dramatically decreases its in vitro thrombogenicity.

Topics: Alginates; Biocompatible Materials; Blood Vessel Prosthesis; Glucuronic Acid; Graft Occlusion, Vascular; Hexuronic Acids; Humans; Iloprost; Platelet Aggregation Inhibitors; Polytetrafluoroethylene; Thrombosis

Here we report that streptokinase is responsible for forming thrombi both in vitro on blood-superfused endothelial cells of rabbit aorta and in vivo on blood-superfused collagen strips in extracorporal circulation of anesthetized cats. This short-lasting paradoxical thrombogenic phase is followed by the expected long-lasting thrombolysis. The biphasic action of streptokinase occurred in vitro at concentrations of 100-2000 U/ml and in vivo at doses of 1000-3000 U/kg i.v. Both phases are mediated by endogenous plasmin as evidenced by deleting the streptokinase-induced thrombogenesis and thrombolysis following pretreatment with epsilon-aminocaproic acid or aprotinin. On the other hand, selective block of the paradoxical thrombogenesis was achieved after pretreatment with camonagrel, a thromboxane synthase inhibitor which raises plasma levels of endogenous prostacyclin, or with iloprost, a stable analog of prostacyclin. It is suggested that endogenous or exogenous prostacyclin inhibits activation of platelets by plasmin, and hence the thrombogenesis by streptokinase is abolished, while the beneficial thrombolytic action of streptokinase is augmented.

Topics: Animals; Cats; Endothelium, Vascular; Fibrinolytic Agents; Iloprost; Indans; Platelet Aggregation Inhibitors; Rabbits; Streptokinase; Thrombolytic Therapy; Thrombosis

Despite the alluring pharmacological properties of prostacyclin and its stable analogue (iloprost), these substances are little used in plastic surgery. A case is presented in which iloprost resulted in persistent patency of the vessels supplying a free flap. A patient who had had failure of a free flap because of thrombosis distal to the arterial anastomosis had a second free flap. Thrombus formed distal to the arterial anastomosis of the second flap and recurred when the anastomosis was redone. The flap was perfused with urokinase and then iloprost. After this, iloprost was given intravenously peroperatively and for 12 hours postoperatively. Postoperatively, the patient also received aspirin, ticlopidine and heparin. The flap survived without any late complications. A literature review offers confirmation of the advantages of using iloprost if microvascular anastomoses thrombose and during the reperfusion of flaps after prolonged ischaemia.

Topics: Anastomosis, Surgical; Blood Platelets; Carcinoma, Basal Cell; Female; Humans; Iloprost; Microcirculation; Microsurgery; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Skin Neoplasms; Surgical Flaps; Thrombolytic Therapy; Thrombosis

Topics: Adult; Arm; Brachial Artery; Female; Forearm; Humans; Iloprost; Infusions, Intra-Arterial; Ischemia; Platelet Aggregation Inhibitors; Radial Artery; Thrombosis; Ulnar Artery; Vasodilator Agents

Aspirin has been used for the prevention of platelet thrombi, both prophylactically and therapeutically, in a wide variety of conditions. Although the dosage used has also varied, it is now suggested that lower doses are as efficacious and probably safer than higher doses. Part of the problem in determining the amount to be used is that aspirin not only inhibits the formation of the proaggregatory thromboxane A2 in the platelet, at any dose, but also that it interferes with the production of prostacyclin (antiaggregatory) by the endothelial cells in a dose-dependent manner. Previously, utilizing a hamster cheek pouch preparation, we demonstrated that platelets would adhere to intact endothelium, in vivo, after an otherwise ineffectual dose of thrombin if the glycosaminoglycans of endothelial cells that produce antithrombin activity were first neutralized by protamine. Reported here is the effect of aspirin on the platelet thrombi produced by thrombin in this manner. Aspirin was found to inhibit platelet thrombosis by thrombin in low doses (optimum dose 2.5 mg/kg body weight), but at higher doses the aspirin was less effective. Actually, the higher doses of aspirin promoted platelet thrombus formation by thrombin even in the absence of protamine. Infusion of iloprost, an analog of prostacyclin, also prevented platelet thrombus formation by protamine and thrombin with or without the administration of aspirin, and this infusion overcame the thrombogenicity of the higher doses of aspirin. The results of these experiments in the hamster suggest that the optimum dosage of aspirin in the clinical treatment of prophylaxis of thrombosis in human patients would be 160 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Cricetinae; Endothelium, Vascular; Iloprost; Male; Mesocricetus; Platelet Adhesiveness; Protamines; Thrombin; Thrombosis

A new method is introduced admitting of direct quantification of collagen-induced platelet trapping in the rat lung. The synthetic PG1(2)-mimetics, Iloprost and Cicaprost, are capable of inhibiting the trapping of platelets induced by collagen. The described method has proved to be suited for performing both pharmacodynamic and effectkinetic investigations with inhibitors of collagen-induced platelet trapping.

Topics: Administration, Oral; Animals; Blood Platelets; Collagen; Epoprostenol; Female; Iloprost; Lung; Male; Platelet Aggregation; Rats; Rats, Wistar; Thrombosis

Topics: Animals; Arginine; Aspirin; Blood Pressure; Cats; Epoprostenol; Extracorporeal Circulation; Fibrinolysis; Heparitin Sulfate; Iloprost; Infusions, Intravenous; Injections, Intravenous; Molsidomine; Nitric Oxide; Nitroarginine; Platelet Aggregation; Streptokinase; Thrombosis; Vasodilator Agents

Arteriotomy/intimectomy and venotomy/intimectomy were performed in the ears of 43 rabbits. Twenty were treated with iloprost given as intravenous doses of 10 micrograms/kg body weight (bw) administered shortly before reperfusion followed by hourly infusions (3 micrograms/kg b w) until 12 hrs after reperfusion. At reperfusion venous and arterial bleeding times were noted. Patency was determined at 15-min intervals until 2 hrs after reperfusion and at 1 and 2 weeks postoperatively. As controls, 23 rabbits were given a single infusion of saline. Compared to controls, iloprost significantly prolonged arterial and venous bleeding times and significantly improved patency 2 hrs after reperfusion. One and two weeks later, however, virtually all vessels were occluded. Administered in this fashion, iloprost does not improve long-term patency in highly traumatized small veins and arteries.

Topics: Animals; Arteries; Blood Pressure; Ear, External; Female; Hemorrhage; Iloprost; Injections, Intravenous; Male; Platelet Aggregation; Rabbits; Regional Blood Flow; Reperfusion; Thrombosis; Time Factors; Tunica Intima; Vascular Patency; Veins

To test the thrombosis resistance of a vascular prosthesis coated with antithrombogenic agents, we evaluated a small vessel prosthesis of expanded polytetrafluoroethylene (ePTFE) implanted in the rat aorta and removed 1 week following surgery. Control grafts consisted of 1 mm internal diameter ePTFE. Experimental grafts consisted of 1 mm internal diameter ePTFE noncovalently bonded to tissue plasminogen activator (tPA) and iloprost using the surfactant tridodecylmethylammonium chloride. After 1 week the grafts were harvested, patency was determined, and histologic specimens were prepared for electron microscopy. Six of 10 control grafts were thrombosed, whereas 9 of 10 tPA-iloprost-bonded grafts were patent (p < 0.03). Of concern, there was an unexpectedly high mortality rate in the tPA-iloprost group compared to the control group among animals that died before completion of the study. Evaluation of the safety of these drugs must, therefore, be an early component of future experiments. Nevertheless, these studies indicate that a small vessel prosthesis bonded to tPA and iloprost may ameliorate some of the complications associated with early graft failure.

Topics: Animals; Aorta, Abdominal; Blood Vessel Prosthesis; Graft Occlusion, Vascular; Iloprost; Male; Microscopy, Electron, Scanning Transmission; Polytetrafluoroethylene; Prosthesis Failure; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Surface-Active Agents; Thrombosis; Tissue Plasminogen Activator; Vascular Patency

Topics: Antibodies, Antiphospholipid; Diagnosis, Differential; Female; Heart Atria; Heart Diseases; Heart Neoplasms; Heparin; Humans; Iloprost; Middle Aged; Myxoma; Thrombocytopenia; Thrombosis

Adhesion molecules mediate the interaction between endothelium and platelets as well as other blood cells and the endothelium. The structure and function of some of these molecules will be reviewed and discussed. The expression of these molecules is largely affected by disease states such as hypertension, diabetes, and cardiac failure. Determination of adhesion molecules expressed on the surface of endothelial cells and platelets by cytoflowmetry enables a new approach to estimate the activity state of these cells and might be helpful to identify patients with an increased thrombotic risk.

Topics: Blood Platelets; Cell Adhesion Molecules; Endothelium, Vascular; Humans; Iloprost; Membrane Glycoproteins; P-Selectin; Platelet Membrane Glycoproteins; Risk Factors; Thrombosis; Thrombospondins; Vasculitis

Drugs can be encapsulated within blood platelets by reversible electroporation and can be haemostatically targeted to vessel wall injury sites. Initial studies with iloprost-loaded pig platelets and pig aorta tunica media in perfusion circuits are presented. After autologous reconstitution into blood, no significant difference was observed in the deposition of 111Indium labelled sham-loaded and untreated platelets onto the tunica media during perfusion under low and high shear conditions. In paired experiments (n = 10 pairs), the deposition of iloprost-loaded platelets was significantly lower (mean 61%) after 5 min perfusion than the deposition from blood containing sham-loaded (control) platelets. A similar significant reduction (mean 54%) was seen after 10 min perfusion. Pre-perfusion of iloprost-loaded platelets for 10 min under low shear conditions (212/s), followed by 5 min perfusion of 111Indium labelled normal platelets, significantly reduced the secondary platelet deposition (p < 0.01) when compared with the deposition seen when control untreated platelets were preperfused. Significant differences (p < 0.001) in secondary deposition were also observed when primary and secondary platelet perfusions were made under high shear (1690/s). Histology of the tunica media segments post perfusion, supported the inhibitory effect of predeposited iloprost-loaded platelets on secondary platelet recruitment. By exploiting their natural haemostatic propensity, drug-loaded platelets can be targeted to vessel wall injury sites. Appropriate drugs could be packaged that may passivate the carrier platelets at the lesion inhibiting thrombus formation or they may act as a depot for sustained drug release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta, Thoracic; Blood Platelets; Drug Compounding; Elastic Tissue; Electroporation; Endothelium, Vascular; Iloprost; Muscle, Smooth, Vascular; Platelet Adhesiveness; Platelet Aggregation; Swine; Thrombosis

An existing arterio-venous shunt thrombosis model in the rat has been modified to increase its usefulness for the testing of anti-thrombotic agents and characterised using morphological and radiometric techniques. The thrombus formed on the cotton thread held in the shunt was found to be composed of platelet aggregates surrounded by red thrombus. After 30 min of blood flow there was a 15-fold increase in the platelet content of the thrombus and a 4-fold increase in the fibrin(ogen) content compared with an equivalent weight of whole blood. Use of the anticoagulants recombinant desulphatohirudin (CGP 39393, 4 mg/kg, s.c.) and unfractionated heparin (800 IU/kg, s.c.) showed that approx. 90% inhibition of thrombus weight and approx. 80% inhibition of fibrin(ogen) content could be achieved without significant effect on the platelet content. Conversely, using the platelet inhibitor Iloprost (1 microgram kg-1 min-1), a reduction in thrombus weight of 50% was associated with 75% inhibition of platelet content and only 20% inhibition of fibrin(ogen). These observations suggest that the growth of this type of thrombus is largely the result of continued fibrin formation rather than continued platelet recruitment and activation.

Topics: Animals; Arteriovenous Shunt, Surgical; Disease Models, Animal; Fibrinolytic Agents; Hematologic Tests; Heparin; Hirudin Therapy; Hirudins; Iloprost; Male; Radiometry; Rats; Rats, Inbred Strains; Recombinant Proteins; Thrombosis

This study examined the effects of laser-generated tissue debris from thrombus, atheroma, and normal aorta on platelet aggregation. Debris supernatant and suspension from lased thrombus induced dose-related aggregation, maximal at 48 +/- 12% and 65 +/- 2%, respectively. Debris suspension from normal aorta induced maximal aggregation of 35 +/- 12%, but the debris from atheromatous aorta surprisingly had no effect on platelet aggregation. The debris particle count was in the range of 10(10) to 10(12) per liter. Aspirin, 0.2 and 2.0 mmol/L, only weakly inhibited the debris-induced aggregation, and heparin up to 10 U/ml was ineffective. However, iloprost reduced aggregation to 40 +/- 11% of control at 0.3 ng/ml, and totally abolished it at 3 ng/ml. Soluble and particulate laser-generated debris from vascular tissue and thrombus may cause platelet aggregation in vitro. This may have implications for laser coronary angioplasty.

Topics: Aged; Angioplasty, Laser; Animals; Aorta; Aortic Diseases; Arteriosclerosis; Aspirin; Blood Coagulation; Heparin; Humans; Iloprost; In Vitro Techniques; Middle Aged; Platelet Aggregation; Swine; Thrombosis

Heparin-associated thrombocytopenia and thrombosis is a severe complication of systemic heparin therapy. Its treatment is mainly based upon discontinuation of heparin therapy. However in some patients requiring emergency cardiac or vascular surgery, reexposure to heparin may be unavoidable. We report the management of two such patients by use of antiplatelet drugs for a vascular procedure. In the two cases, a combination of iloprost, a stable prostacyclin analogue (1 to 2 ng/kg/mn) with aspirin and dipyridamole was shown to inhibit ex vivo the heparin-induced platelet aggregation. These antiplatelet agents were continued during the perioperative period. A successful vascular procedure was achieved with full heparinization without subsequent thrombocytopenia or thrombotic or hemorrhagic complications. This experience supports the hypothesis that heparin can be readministered early to patients with heparin-associated thrombocytopenia and thrombosis, provided antiplatelet therapy is given.

Topics: Aged; Aorta, Abdominal; Aspirin; Dipyridamole; Female; Femoral Vein; Heparin; Humans; Iliac Artery; Iliac Vein; Iloprost; Ischemia; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombocytopenia; Thrombosis; Vena Cava, Inferior

Evidence for chronic in vivo platelet activation and hyperaggregability has been assessed in 21 renal allograft recipients. All patients received long term immunosuppression with cyclosporin (CS) and low dose prednisolone and were studied serially for 1 year post-transplantation. Spontaneous platelet aggregation in PRP was observed on 10 occasions in 5 patients. Platelet aggregation responses in PRP to low doses of ADP (0.5 and 1.0 microM) were significantly increased up to 1 year post-transplantation (p less than 0.02-less than 0.002). Total platelet nucleotide (ATP and ADP) content and release to 20 micrograms/ml of collagen were significantly decreased for 2 months post-transplantation, indicative of in vivo platelet activation (p less than 0.05-less than 0.002), and plasma PF4 levels were increased up to 1 year post-transplantation suggesting continued platelet activation of a lesser degree. Platelet sensitivity to the prostacyclin analogue Iloprost decreased after 1 month (p less than 0.05) and this persisted up to 1 year (p less than 0.01) compared with sensitivity at 1 week post-transplantation. These prothrombotic changes persisted when trough whole blood CS levels were within the therapeutic range and plasma creatinine levels were approaching or were in the normal range. These data indicate that CS-treated renal allograft recipients exhibit chronic platelet hyperactivity.

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adult; Blood Platelets; Cyclosporins; Epoprostenol; Female; Humans; Iloprost; In Vitro Techniques; Kidney Transplantation; Male; Middle Aged; Platelet Aggregation; Thrombosis; Time Factors

Pretreatment of rats by the cyclooxygenase inhibitors diclofenac, phenylbutazone, and aminophenazone did not influence kappa-carrageenin (KC) rat tail thrombosis (RTT) whereas pretreatment by aspirin, at high doses, and particularly sulfinpyrazone decreased RTT frequency, PGI2 or iloprost i.v. injection showed strong RTT preventing effects as it was also seen by thromboxane synthesis inhibitors (benzydamine, imidazole) at high doses. The PAF antagonist BN 52020 weakly protected. Lipoxygenase inhibitors (quercetin, oxphaman a.o.) proved ineffective. Therefore, thromboxane/PGI2 balance and partly PAF seem to be involved in the mechanism of KC RTT.

Topics: Aminopyrine; Animals; Aspirin; Benzydamine; Cardiovascular Agents; Carrageenan; Diclofenac; Epoprostenol; Female; Iloprost; Imidazoles; Phenylbutazone; Rats; Rats, Inbred Strains; Thrombosis; Thromboxanes; Trapidil

Heparin-induced platelet activation (HIPA) is a syndrome associated with thrombocytopenia, intravascular thrombosis, and arterial emboli. We have evaluated 16 patients for presumed HIPA because of the occurrence of thrombocytopenia or a new thrombotic complication during heparin therapy. In this group, 16 thrombotic events occurred in 10 patients with a mortality rate of 18.8%. Diagnosis was confirmed in vitro by the demonstration of at least 20% platelet aggregation and/or 6% 14C-serotonin release after heparin (0.1 to 3 U/ml) was added to a mixture of patient platelet-poor plasma (PPP, two parts) and aspirin-free donor platelet-rich plasma (PRP, three parts). After heparin was discontinued, seven patients continued to have HIPA in their own PRP although it could no longer be observed in donor PRP. Iloprost, a potent prostacyclin analog that reversibly inhibits platelet activation, completely prevented HIPA and release in all of nine patients. Aspirin, an irreversible cyclooxygenase inhibitor, failed to prevent HIPA in four of these nine patients. In conclusion, HIPA is associated with an extremely high morbidity and mortality rate. Evaluation of the patients' PRP in response to heparin may improve the diagnostic sensitivity of this assay. Aspirin does not reliably prevent HIPA, which suggests participation of thromboxane-independent pathways. Thus, if further exposure to heparin is unavoidable, a more effective platelet inhibitor such as iloprost is required to reliably prevent in vivo HIPA.

Topics: Adult; Aged; Aspirin; Epoprostenol; Female; Heparin; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation; Platelet Count; Thrombocytopenia; Thrombosis

Patients with heparin-induced platelet activation who are reexposed to heparin may have recurrent thrombocytopenia, intravascular thrombosis, arterial emboli, or sudden death. To permit carotid endarterectomy in two patients with confirmed heparin-induced platelet activation, we compared the efficacies of aspirin and iloprost, a stable analogue of prostacyclin, in preventing heparin-induced platelet activation. In the first patient, although aspirin prevented both in vitro heparin-induced platelet aggregation (70% without and 7.5% with aspirin) and 14C serotonin release (48% without and 0% with aspirin), intraoperative administration of heparin resulted in an increase in plasma levels of platelet factor 4 from 8 to 260 ng/ml and beta-thromboglobulin levels from 29 to 39 ng/ml. In addition, the circulating platelet count decreased from 221,000 to 174,000 microliters, and 15% spontaneous platelet aggregation was observed. Fortunately, fibrinopeptide A levels remained less than 10 ng/ml intraoperatively, and no thrombotic complications occurred. In the second patient, aspirin did not prevent heparin-induced platelet aggregation in vitro (65% without and 41% with aspirin); however, iloprost (0.01 mumol/L) prevented both in vitro heparin-induced platelet aggregation (59.5% without and 0.0% with iloprost) and 14C serotonin release (56.7% without and 0.0% with iloprost). Therefore, a continuous infusion of iloprost was begun before administration of heparin and was continued until 20 minutes after reversal of heparin with protamine. After intraoperative administration of heparin, plasma levels of platelet factor 4 increased from 19 to 200 ng/ml, and beta-thromboglobulin levels increased from 56 to 76 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aspirin; beta-Thromboglobulin; Cardiovascular Agents; Carotid Arteries; Drug Evaluation; Endarterectomy; Epoprostenol; Fibrinopeptide A; Heparin; Humans; Iloprost; Male; Platelet Activating Factor; Platelet Aggregation; Platelet Count; Platelet Factor 4; Preoperative Care; Thrombosis

The influence of red blood cells on spontaneous platelet aggregation (SPA) has been studied ex vivo. Platelet aggregation was quantified by measuring the fall in single platelet count using a new whole blood platelet counter. When aliquots of whole blood and autologous platelet rich plasma (PRP) were roller-mixed at 37 degrees C, a marked fall in platelet count occurred in whole blood due to SPA but platelet count remained almost unchanged in PRP. When blood from healthy young controls, aged 20-35 years, was compared with healthy old controls, aged 48-80 years, and patients with thrombotic complications, the extent of SPA was in the order: thrombotic patients greater than old controls greater than young controls. Prostacyclin and the new stable prostacyclin analogue Iloprost, at 8 nM effectively inhibited SPA. 2-Chloroadenosine (10 microM) which is an inhibitor of ADP-induced platelet aggregation was also an effective inhibitor of SPA. Acetylsalicylic acid (56 microM) and the thromboxane A2 receptor blocker BM13.177 (0.5 microM) only partially inhibited SPA. ADP from red blood cells is suspected to mediate red cell-induced SPA. However, the possibility that the red cells have an important physical role in SPA cannot be ruled out.

Topics: 2-Chloroadenosine; Adenosine; Adult; Aged; Aspirin; Epoprostenol; Erythrocytes; Humans; Iloprost; In Vitro Techniques; Middle Aged; Platelet Aggregation; Platelet Count; Sulfonamides; Thrombosis

Topics: Animals; Bleeding Time; Epoprostenol; Guinea Pigs; Iloprost; Mice; Platelet Aggregation; Rats; Thrombophlebitis; Thrombosis