iloprost and Thrombocytopenia

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

Thrombocytopenia and platelet dysfunction are major mechanisms of cardiopulmonary bypass-induced postoperative hemorrhage. This study evaluated the effects of low amounts of nitric oxide, iloprost (prostacyclin analog), and their combination administered directly into the oxygenator on platelet function, platelet-leukocyte interactions, and postoperative blood loss in patients undergoing coronary artery bypass grafting.. Blood samples from 41 patients randomized to the control, nitric oxide (20 ppm), iloprost (2 ng x kg -1 x min -1 ), or nitric oxide plus iloprost groups were collected during cardiopulmonary bypass. Platelets and leukocytes were enumerated. Platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa, P-selectin, platelet-derived microparticles, leukocyte CD11b/CD18 (Mac-1), and platelet-leukocyte aggregate were quantified by means of flow cytometry. Collagen and thrombin receptor-activating peptide-induced platelet aggregation in whole blood was analyzed by means of aggregometry.. Both nitric oxide or iloprost attenuated cardiopulmonary bypass-induced thrombocytopenia, reduction of glycoprotein Ib and glycoprotein IIb levels, translocation of P-selectin, microparticle formation, Mac-1 upregulation, and suppression of collagen-induced aggregation. Nitric oxide plus iloprost was significantly more effective in preventing thrombocytopenia, microparticle formation, and P-selectin translocation. Moreover, this treatment preserved thrombin receptor-activating peptide-induced aggregation, which was not rescued by single treatments. Both nitric oxide and nitric oxide plus iloprost attenuated postoperative blood loss.. Nitric oxide plus iloprost reduced the deleterious effects of cardiopulmonary bypass, such as thrombocytopenia, platelet activation, platelet-leukocyte aggregate formation, and suppression of platelet aggregative responses. The reduced postoperative bleeding observed with this treatment suggests that this is a new and clinically feasible therapeutic option for patients subjected to cardiopulmonary bypass.

Topics: Aged; Blood Platelets; Cardiopulmonary Bypass; Coronary Artery Bypass; Drug Combinations; Free Radical Scavengers; Humans; Iloprost; Leukocytes; Macrophage-1 Antigen; Middle Aged; Nitric Oxide; Oxygenators; P-Selectin; Peptide Fragments; Pilot Projects; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Hemorrhage; Receptors, Cell Surface; Thrombocytopenia

Thrombocytopenia and thromboembolism(s) may develop in heparin immune-mediated thrombocytopenia (HIT) patients after reexposure to heparin. At the Onassis Cardiac Surgery Center, 530 out of 17,000 patients requiring heart surgery over an 11-year period underwent preoperative HIT assessment by ELISA and a three-point heparin-induced platelet aggregation assay (HIPAG). The screening identified 110 patients with HIT-reactive antibodies, out of which 46 were also thrombocytopenic (true HIT). Cardiac surgery was performed in HIT-positive patients under heparin anticoagulation and iloprost infusion. A control group of 118 HIT-negative patients received heparin but no iloprost during surgery. For the first 20 patients, the dose of iloprost diminishing the HIPAG test to ≤5% was determined prior to surgery by in vitro titration using the patients' own plasma and donor platelets. In parallel, the iloprost "target dose" was also established for each patient intraoperatively, but before heparin administration. Iloprost was infused initially at 3 ng/kg/mL and further adjusted intraoperatively, until ex vivo aggregation reached ≤5%. As a close correlation was observed between the "target dose" identified before surgery and that established intraoperatively, the remaining 90 patients were administered iloprost starting at the presurgery identified "target dose." This process significantly reduced the number of intraoperative HIPAG reassessments needed to determine the iloprost target dose, and reduced surgical time, while maintaining similar primary clinical outcomes to controls. Therefore, infusion of iloprost throughout surgery, under continuous titration, allows cardiac surgery to be undertaken safely using heparin, while avoiding life-threatening iloprost-induced hypotension in patients diagnosed with HIT-reactive antibodies or true HIT.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Anticoagulants; Aortic Aneurysm; Blood Platelets; Cardiac Valve Annuloplasty; Cardiovascular Agents; Coronary Artery Bypass; Drug Administration Schedule; Drug Monitoring; Female; Heparin; Humans; Iloprost; Male; Middle Aged; Perioperative Care; Platelet Aggregation; Platelet Count; Thrombocytopenia; Thromboembolism; Treatment Outcome

In vitro platelet aggregation in feline blood samples is a well-known phenomenon in veterinary clinical laboratories resulting in high numbers of pseudothrombocytopenia. Several attempts have been made to prevent or dissolve platelet aggregates in feline blood samples and to increase the reliability of feline platelet counts. Prostaglandin I2 (PGI2) is the most powerful endogenous inhibitor of platelet aggregation but unstable. Iloprost is a stable PGI2 analogue. The aims of the present study were (1) to evaluate the anti-aggregatory effect of Iloprost on feline platelet counts and to determine a useful concentration to inhibit platelet aggregation in EDTA samples from clinically healthy cats, (2) to investigate the effect of Iloprost on hematological blood parameters, and (3) to determine stability of Iloprost in K3-EDTA tubes for up to 16 weeks. From 20 clinically healthy cats blood was drawn from the jugular vein and immediately distributed in a 1.3 ml K3-EDTA tube, and two 1.3 ml K3-EDTA tubes containing 20 ng and 200 ng Iloprost, respectively. A complete blood cell count was performed on the Sysmex XT-2000iV and the Mythic 18 on eight consecutive time points after collection. Blood smears were evaluated for the presence of PLT aggregates.. In the absence of Iloprost, pseudothrombocytopenia was observed in 50% of the investigated samples that led to significantly decreased optical PLT counts by a mean of 105 x10(3)/μl, which could be prevented by the addition of 1 μL (20 ng) Iloprost leading to an increase in PLT counts by a mean of 108 x10(3)/μl.. This is the first study showing an anti-aggregatory effect of the PGI2-analogue Iloprost in feline EDTA blood. In all clinically healthy cats investigated, pseudothrombocytopenia was prevented by adding Iloprost to EDTA tubes prior to blood collection. Furthermore, Iloprost was very useful in preventing falsely increased WBC counts in samples with platelet aggregates analyzed on impedance-based hematological instruments. Iloprost is preferable to PGI2 or PGE1 due to its stability and easy and safe handling properties. Cytological evaluations of blood smears as well as other hematological parameters were not influenced to a clinically significant degree by the presence of Iloprost.

Topics: Animals; Cats; Iloprost; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Thrombocytopenia

A 63-year old, male patient presented with prosthetic valve endocarditis and developed heparin-induced thrombocytopaenia (HIT) following heparin administration for continuous veno-venous haemofiltration. Use of cardiopulmonary bypass in patients suffering from heparin-induced thrombocytopaenia is difficult and challenging. We report a novel method that allows heparin use in patients diagnosed with HIT using Multiplate platelet analyser and iloprost. Platelet function analysis is complex, poorly standardized and time consuming. Multiplate platelet analyser represents a convenient, safe, reliable and rapid system that allows the assessment of platelet dysfunction. It allows objective demonstration of platelet inhibition before administration of heparin, allowing safe establishment of cardiopulmonary bypass in patients suffering from HIT.

Topics: Anticoagulants; Cardiopulmonary Bypass; Endocarditis; Heart Valve Prosthesis Implantation; Heparin; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Function Tests; Reoperation; Thrombocytopenia; Treatment Outcome

Topics: Blood Platelets; Female; Heart Valve Prosthesis; Humans; Iloprost; Immunoglobulins; Middle Aged; Platelet Count; Pulmonary Artery; Receptors, Epoprostenol; Sleep Apnea Syndromes; Thrombocytopenia

Diverse anticoagulation protocols are used in patients after implantation of ventricular assist devices. No consensus exists, especially in patients with heparin-induced thrombocytopenia type II. In a patient with heparin-induced thrombocytopenia type II, we implanted a left ventricular assist device (HeartMate XVE; Thoratec, Pleasanton, CA). Thirteen months later the device had to be replaced due to mechanical failure with a HeartMate II left ventricular assist device. We report on our successful protocol of perioperative anticoagulation management using heparin and iloprost during surgery and argatroban thereafter.

Topics: Anticoagulants; Arginine; Cardiopulmonary Bypass; Drug Therapy, Combination; Heart-Assist Devices; Heparin; Humans; Iloprost; Length of Stay; Male; Middle Aged; Pipecolic Acids; Platelet Aggregation Inhibitors; Prosthesis Design; Prosthesis Implantation; Sulfonamides; Thrombocytopenia; Warfarin

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

Patients with preoperatively diagnosed type II heparin-induced thrombocytopenia (HIT) scheduled for cardiopulmonary bypass (CPB) present a challenge in their intraoperative anticoagulation management because re-exposure to heparin may result in profound thrombocytopenia, intravascular thromboses, bleeding, and even death. Iloprost, a prostacyclin analogue that reversibly inhibits platelet aggregation, has been suggested as a management approach in such cases. The purpose of this study was to assess and confirm the efficacy of a perioperative intravenous iloprost infusion in preventing thromboembolic complications in patients with type II HIT undergoing cardiac surgery and requiring the use of heparin and CPB.. During a one-and-a-half-year period, 22 patients with type II HIT presented at the Cardiac Surgery Service of the Onassis Cardiac Center in Athens. In these patients, platelet aggregation test results were found strongly positive at heparin serum concentrations corresponding to those achieved during CPB. Iloprost was used in a preoperatively, in vitro-determined, patient-specific concentration that was assessed and modified perioperatively depending on its in vivo effect on platelet aggregation as opposed to the conventional constant rate.. In the 22 patients, the preoperatively determined concentration of iloprost seemed to correlate well with the in vivo interruption of platelet aggregation, as tested by a perioperative heparin-induced platelet aggregation (HIPA) assay, and in only 3 cases (14%) was the rate of iloprost infusion increased. The patients' platelet counts, which were evaluated peri- and postoperatively, were preserved with no statistically significant fluctuations. Postoperative bleeding was within normal limits and no thrombotic episodes or other complications were reported.. Although a number of alternative anticoagulation methods, such as the use of another anticoagulant (danaparoid sodium and recombinant hirudin) or the preoperative use of a defibrinogenating agent (ancorod), have been suggested for patients with type II HIT requiring anticoagulation during CPB, the use of heparin associated with a potent platelet inhibitor such as the prostacyclin analog iloprost is, as this study confirmed, the only to-date safe and effective choice.

Topics: Aged; Anticoagulants; Cardiac Surgical Procedures; Dose-Response Relationship, Drug; Female; Heart Diseases; Heparin; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors; Preoperative Care; Retrospective Studies; Thrombocytopenia

Injection of lipopolysaccharide (LPS) (Salmonella W. Typhosa i.v. bolus) into conscious rats, induced a rapid drop of circulating platelets analogous to that induced by ADP. The animals showed a small fall in mean arterial blood pressure (MABP), an increase in heart rate and a significant increase in plasma nitrite and nitrate level. This result is consistent with the stimulation of an inducible NO synthase (i-NOS). The administration of the stable prostacyclin analogue, iloprost plus ADP or LPS, significantly protected against the decrease in free platelet number induced by ADP or LPS. The plasma nitrite and nitrate level stimulated by LPS was significantly reduced by iloprost and also by prostacyclin. These results are consistent with an inhibition of i-NOS by agents that increase the intracellular level of cAMP. The administration of the NO donor S-Nitroso-N-acyl-D-penicillamine (SNAP) plus ADP or LPS, significantly prevented thrombocytopenia induced by ADP and by LPS. SNAP did not decrease the plasma nitrite and nitrate level stimulated by LPS; furthermore it induced a significant increase of heart rate, without affecting MABP, suggesting a direct accelerating effect of NO on the sino-atrial node. The administration of S-nitroso-glutathione (GSNO), a stable nitrosothiol, plus ADP or LPS, significantly prevented thrombocytopenia induced by ADP but not by LPS. GSNO significantly reduced the plasma nitrite and nitrate level stimulated by LPS. These data demonstrate that the L-Arginine: NO pathway in vivo may be modulated by prostanoids and that compounds which increase cAMP, such as iloprost, are able to protect against LPS-induced early thrombocytopenia.

Topics: Adenosine Diphosphate; Animals; Blood Pressure; Enzyme Induction; Heart Rate; Iloprost; Lipopolysaccharides; Male; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Penicillamine; Platelet Activation; Platelet Count; Rats; Rats, Wistar; Thrombocytopenia

A patient with a Starr prosthetic heart valve for 13 years developed chronic idiopathic thrombocytopaenic purpura and a highly probable crossed allergy to heparin. As the valve needed to be replaced, cardiopulmonary bypass surgery was undertaken associating heparin with lioprost and Aprotinine. In this type of situation, aggregation of control platelets by the patient's plasma in the presence of unfractionated heparin and of low molecular weight heparin justifies the use of powerful antiplatelet agents such as lioprost which was associated with Aprotinine for its platelet protective effects. This original combination allowed successful cardiopulmonary bypass surgery under unfractionated heparin under excellent conditions with minimal blood loss. This case underlines the value of this approach for cardiopulmonary bypass surgery in patients with heparin-induced thrombocytopaenia.

Topics: Adult; Anticoagulants; Aprotinin; Cross Reactions; Drug Hypersensitivity; Extracorporeal Circulation; Female; Heart Valve Prosthesis; Hemostatics; Heparin; Humans; Iloprost; Intraoperative Care; Mitral Valve; Platelet Aggregation Inhibitors; Preoperative Care; Prosthesis Failure; Reoperation; Thrombocytopenia

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

Topics: Heparin; Humans; Iloprost; Thrombocytopenia

Topics: Adult; Female; Humans; Hypoxia; Iloprost; Infusions, Intravenous; Thrombocytopenia

A 73-year-old female patient was admitted for myocardial infarction. Conventional treatment with heparin was started, intraaortic balloon assistance was required for several days, together with heparin. The platelet counts decreased progressively, from 288 G.l-1 on admission to 41 G.l-1 on the 16th day, despite the use of low molecular weight heparin. The in vitro heparin platelet aggregation test remained positive. This aggregation ended on adding iloprost, an analogue of prostacyclin, to the platelet culture bath. A coronary aortic bypass graft was required. An infusion of iloprost was started just after induction of anaesthesia. The initial dose of 0.5 ng.kg-1 x min-1 was gradually increased to 20 ng.kg-1 x min-1. Heparin (400 IU.kg-1) was thereafter added. To maintain a mean blood pressure of a least 50 mmHg, an infusion of up to 10 micrograms.kg-1 x min-1 of phenylephrine was given. As it was insufficient, an infusion of up to 1 microgram.kg-1 x min-1 noradrenaline was required. The iloprost infusion was gradually stopped 15 min before the end of CPB, together with that of noradrenaline. Platelet aggregation tests were positive after protamine had been given, whereas they had been negative during the infusion of iloprost. There was no abnormal postoperative bleeding. An infusion of 2 ng.kg-1 x min-1 was started at the sixth postoperative hour for 48 h, until the coumarin-like agent had started taking its effects. It is concluded that iloprost might be useful for carrying out cardiac surgery in patients with heparin-induced thrombocytopaenia.

Topics: Aged; Coronary Artery Bypass; Extracorporeal Circulation; Female; Heparin; Humans; Iloprost; Platelet Aggregation; Thrombocytopenia

In patients who receive heparin for anticoagulation, there can be a mild, transient thrombocytopenia which is usually devoid of complications. However, 6% of these patients experience serious heparin-induced thrombocytopenia (HIT), which can result in coagulation problems or death. Iloprost, a recently developed drug, given in conjunction with heparin, can be used to manage the patient with HIT. Two cases reported are of patients diagnosed with HIT and their management with Iloprost.

Topics: Blood Coagulation Tests; Endarterectomy, Carotid; Heparin; Humans; Iloprost; Male; Middle Aged; Thrombocytopenia

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

The authors report a case of massive pulmonary embolism revealing thrombocytopenia induced by a low molecular weight heparin (LMWH) initially proposed for the treatment of superficial phlebitis. The diagnosis was confirmed by in vitro aggregation tests and a fall in the platelet count when the LMWH was reintroduced. The outcome was clinically, angiographically and hematologically satisfactory in response to in situ treatment with prostaglandin, subsequently replaced by Vitamin K antagonists.

Topics: Fibrinogen; Heparin, Low-Molecular-Weight; Humans; Iloprost; Male; Middle Aged; Phlebitis; Platelet Count; Pulmonary Embolism; Radiography; Thrombocytopenia

For 11 patients with confirmed heparin-induced thrombocytopenia, we used reversible platelet inhibition with iloprost, a stable prostacyclin analogue, to permit safe heparin administration for cardiac (n = 9) or vascular (n = 2) operations. In vitro, iloprost (0.01 mumol/L) prevented both heparin-induced platelet aggregation and 14C-serotonin release in all patients. Therefore, intraoperatively, a continuous infusion of iloprost was started before administration of heparin and was continued until 15 minutes after administration of protamine. For cardiac patients, after heparin administration, the whole blood platelet count did not change (171,000 +/- 29,000/microL versus 174,000 +/- 29,000/microL, mean +/- standard error of the mean); no spontaneous platelet aggregation was observed, and plasma levels of the alpha-granule constituents platelet factor 4 and beta-thromboglobulin increased from 38 +/- 14 and 140 +/- 18 ng/mL to 591 +/- 135 and 235 +/- 48 ng/mL, respectively. Fibrinopeptide A levels actually decreased from 287 +/- 150 to 27 +/- 6 ng/mL. Furthermore, adenosine diphosphate-induced platelet activation was preserved, postoperative bleeding times were unchanged, and no heparin-related deaths occurred. Similar results were obtained in both vascular patients. We conclude that temporary platelet inhibition with iloprost now permits safe heparin administration in all patients with heparin-induced thrombocytopenia who require a cardiac or vascular operation.

Topics: Adult; Aged; Aspirin; beta-Thromboglobulin; Bleeding Time; Epoprostenol; Fibrinopeptide A; Heparin; Humans; Iloprost; Intraoperative Period; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Platelet Factor 4; Thrombocytopenia; Thromboxane B2

A chemically stable prostacyclin analog, KP-10614 [(4z,16s)-4,5,18,18,19,19-hexadehydro-16,20-dimethyl-delta 6(9;alpha)-9(o)- methano-PGI1], has been compared with two other prostacyclin derivatives (Iloprost and TEI-7165) and one prostaglandin E1 derivative (OP-1206) with respect to ADP-induced in vitro aggregation of human platelets and ex vivo platelet aggregation in rats and dogs, given by bolus injection and i.v. infusion. These compounds were also tested on the systemic arterial blood pressure of rats and dogs. KP-10614 was the most potent inhibitor of in vitro platelet aggregation induced by ADP with IC50 of 1 nM among the compounds studied in this report, and it also showed ex vivo effectiveness at doses much lower than the other three compounds. KP-10614 was also orally active. At oral doses of 25, 50 and 100 micrograms/kg, this new compound caused a dose-dependent inhibition of ex vivo platelet aggregation in rats, whereas the other three compounds were effective only at 500 micrograms/kg or more. In addition, KP-10614 showed definite antithrombotic effects at a dose range of 0.1 to 1 microgram/kg i.v. in various thrombosis models in which platelet aggregation was mainly involved. These results indicate that KP-10614 possesses therapeutic potential in thrombotic diseases.

Topics: Administration, Oral; Alprostadil; Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Collagen; Dogs; Epoprostenol; Female; Fibrinolytic Agents; Heart Rate; Humans; Iloprost; Infusions, Intravenous; Injections, Intravenous; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Pulmonary Embolism; Rats; Rats, Inbred Strains; Thrombocytopenia; Vasodilator Agents

We report the vascular surgical strategies and results in 13 patients with heparin-associated thrombocytopenia and describe useful in vitro techniques for the evaluation of anticoagulant therapy. Thirteen of 40 patients with heparin-associated thrombocytopenia had 18 cardiovascular procedures done to save life or limb. Greenfield filters were placed in eight patients to prevent pulmonary embolism. Eight patients had 10 arterial procedures, with alternative anticoagulation that used dextran or warfarin in five cases. In three cases iloprost, a derivative of prostacyclin and a potent platelet inhibitor, was infused intraoperatively and heparin was given. Both the use of alternative anticoagulants and platelet suppression by iloprost were clinically effective strategies. The concurrent measurement of plasma levels of beta-thromboglobulin and fibrinopeptide A in two patients confirmed that both approaches can successfully prevent activation of platelets and plasma coagulation during arterial surgery. One operative death occurred; all vascular reconstructions remained patent at 3 to 6 months. In two patients who received heparin alone for arterial surgery, both procedures resulted in thrombosis and limb loss. When major venous thromboembolism is complicated by heparin-associated thrombocytopenia, insertion of a Greenfield vena cava filter should be considered if there is significant risk of pulmonary embolism. When necessary, arterial surgery is feasible in patients with heparin-associated thrombocytopenia if alternative anticoagulation or adequate suppression of platelet reactivity can be achieved.

Topics: Dextrans; Epoprostenol; Filtration; Heparin; Humans; Iloprost; Middle Aged; Pulmonary Embolism; Risk Factors; Thrombocytopenia; Thromboembolism; Vena Cava, Inferior; Warfarin

The stable PGI2-analogue iloprost and the TXA2-receptor antagonist sulotroban were investigated for possible cooperative effects on platelet function and experimental thrombus formation in guinea pigs and rats. Iloprost and sulotroban inhibit intravascular platelet aggregation in guinea pigs and rats induced by the stable endoperoxide U 46.619 and collagen, with iloprost being the more potent and (for collagen) more efficacious drug. Combinations of both compounds show synergistic or additive effects on in vivo platelet function. Thrombus formation in rats induced by vascular damage is strongly reduced by combining doses of iloprost and sulotroban (BM 13.177) which given alone are ineffective. These results suggest a cooperative enhancement of antiplatelet and antithrombotic effects for combinations of iloprost and sulotroban. In view of disadvantages of currently used platelet inhibitors this cooperativity may offer a new approach in antiplatelet therapy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cardiovascular Agents; Collagen; Drug Synergism; Epoprostenol; Fibrinolytic Agents; Guinea Pigs; Iloprost; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Rats; Sulfonamides; Thrombocytopenia; Thrombophlebitis; Thromboxanes

Topics: Aged; Drug Evaluation; Epoprostenol; Female; Heart Diseases; Heparin; Humans; Iloprost; Male; Middle Aged; Thrombocytopenia

Increased adherence of leucocytes to the vessel wall is thought to be a key event in potentially deleterious leucocyte-vessel wall interactions in a variety of diseases associated with microvasculatory dysfunction. As measured by videomicroscopy in mesenteric venules (phi 40 +/- 8 microns) of anaesthetized rats, an injury caused by one short electrical stimulus to the venule wall led to a prolonged increase of marginated (sticking and rolling) leucocytes from 228/mm2 to 797/mm2 without affecting red cell velocity and shear rate. Iloprost (0.1 micrograms/kg/min i.v.), PGE1 (2.0 micrograms/kg/min i.a.), BW 755 C (40 mg/kg s.c.), forskolin (0.3 mg/kg i.v.), and hirudin (500 IU/kg + 200 IU/kg/h i.v.) all significantly attenuated injury-induced leucocyte margination. Indomethacin (10 mg/kg s.c.) had no effect and sulotroban (0.5 mg/kg/min) showed borderline efficacy. Platelet depletion by rat antiplatelet serum completely inhibited increased leucocyte margination. PGI2 mimetics, drugs interfering with lipoxygenase metabolism, and thrombin inhibitors may therefore be useful to prevent exaggerated leucocyte-vessel wall interactions.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Alprostadil; Animals; Cell Adhesion; Colforsin; Electric Stimulation; Epoprostenol; Hirudins; Iloprost; Indomethacin; Leukocytes; Male; Mesenteric Veins; Rats; Rats, Inbred Strains; Sulfonamides; Thrombocytopenia; Venules

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

Recurrent thrombocytopenia, thrombosis, or sudden death may develop in patients with heparin-induced thrombocytopenia who are reexposed to heparin. Three patients came to us in whom a diagnosis of heparin-induced thrombocytopenia had been made on the basis of clinical and serologic evidence; these patients required reexposure to heparin because of urgent cardiac surgery. Therefore, we evaluated the ability of iloprost (ZK36374), a new analogue of prostacyclin, to prevent heparin-dependent activation of platelets and thereby permit obligatory heparinization for safe extracorporeal circulation. Before operation, we demonstrated that iloprost prevented both heparin-dependent platelet aggregation and tritiated (3H)-serotonin release in vitro. Therefore a continuous infusion of iloprost was begun 1 hour before heparinization and was continued throughout cardiopulmonary bypass and for an additional 15 minutes after protamine administration. The mean platelet count of 130,000/microliters before operation remained stable, and no spontaneous platelet aggregation was observed in samples of platelet-rich plasma obtained before cardiopulmonary bypass but after heparin administration. Similarly, after heparin administration but before bypass, platelet responsiveness to adenosine diphosphate remained unchanged when compared with preoperative values. Plasma levels of platelet factor 4 increased from 26 +/- 1 ng/ml (mean +/- standard error) to 843 +/- 383 ng/ml after heparin administration but actually decreased throughout cardiopulmonary bypass to 52 +/- 25 ng/ml. Beta-thromboglobulin levels increased from 103 +/- 16 to 244 +/- 94 ng/ml with heparinization. The mean bleeding time was 10.5 minutes preoperatively and 13.3 minutes postoperatively. The mean amount of postoperative chest tube drainage (duration: 12 hours) was 432 +/- 67 ml. Thus, despite the confirmed presence of heparin-dependent platelet-activating factor in the plasma of these three patients, iloprost prevented heparin-induced platelet activation during cardiopulmonary bypass while preserving platelet function, as would be desired for postoperative hemostasis.

Topics: Adult; Cardiopulmonary Bypass; Cardiovascular Agents; Epoprostenol; Fibrinopeptide A; Heparin; Humans; Iloprost; Middle Aged; Platelet Aggregation; Platelet Count; Platelet Factor 4; Thrombocytopenia; Thromboxane B2

Topics: Epoprostenol; Extracorporeal Circulation; Heparin; Humans; Iloprost; Thrombocytopenia

Thrombocytopenia and platelet dysfunction are commonly seen after cardiopulmonary bypass. In addition, the microvascular bed of ischemic myocardium is a potent stimulus for platelet deposition and microvascular plugging. Thus, it would appear theoretically advantageous to provide pharmacologic protection of platelets by inhibiting their response to activating agents and thereby preventing their loss into the extracorporeal circuit; this would further inhibit myocardial platelet deposition and the deleterious effects therein. Twenty-one mongrel dogs were placed on cardiopulmonary bypass with 30 minutes of normothermic global ischemia. They were randomly assigned to receive pretreatment with an infusion of saline (control, n = 8), a thromboxane synthetase inhibitor (RO-22-4679, n = 5), or a prostacyclin analogue that does not produce hypotension (ZK 36,374, n = 8). The platelet count in those animals treated with ZK 36,374 was significantly higher at the end of the experiment than in the control group (102.8 +/- 10.7 X 10(3) versus 69.7 +/- 10.6 X 10(3), p less than 0.01); the animals treated with RO-22-4679 had a platelet count between the other two groups (92.8 +/- 14.8 X 10(30)), which was not significantly different from either. Myocardial platelet deposition was measured with indium 111-labeled platelets. Those animals treated with ZK 36,374 had a much lower level of platelet deposition than the group of controls; again the RO-22-4679 group had values between the other two. Finally, myocardial blood flow after global ischemia and cardiopulmonary bypass, measured with radioactive microspheres, was significantly higher in the ZK 36,374 group than in the control group. We conclude that ZK 36,374 prevents platelet consumption during cardiopulmonary bypass over and above that seen with inhibition of thromboxane synthesis alone. It also prevents deposition of platelets into the myocardium after global ischemia and we presume by that mechanism increases myocardial blood flow.

Topics: Animals; Cardiopulmonary Bypass; Coronary Circulation; Dogs; Epoprostenol; Hematocrit; Hemodynamics; Iloprost; Imidazoles; Oxidoreductases; Platelet Aggregation; Thrombocytopenia; Thromboxane-A Synthase; Time Factors