iloprost and Thromboembolism

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

Topics: Administration, Inhalation; Critical Care; Diuretics; Furosemide; Heart Failure; Humans; Hydrazones; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pyridazines; Simendan; Thromboembolism; Vasodilator Agents; Ventricular Dysfunction, Right

The treatment of pulmonary arterial hypertension (PAH) in pregnancy is reviewed.. PAH is a disease characterized by narrowing of the pulmonary arteries and increased vascular resistance. Women with PAH should avoid becoming pregnant, as the physiological, cardiovascular, and pulmonary changes that occur during pregnancy can exacerbate the condition. However, several viable treatment options are available to improve the outcomes in this patient population, including inhaled nitric oxide, calcium-channel blockers, targeted pulmonary vasodilators, and sildenafil. Epoprostenol, a naturally occurring prostaglandin and vasodilator, is a pregnancy category B drug. Reproductive studies in rats and rabbits have found no impaired fertility or fetal harm at 2.5-4.8 times the recommended human dosage of epoprostenol. Most of the published case reports describe initiating epoprostenol 2-4 ng/kg/min i.v. several weeks before or near the time of delivery. Iloprost is a pregnancy category C drug but has demonstrated benefit in pregnant patients with PAH, with no congenital abnormalities and no postpartum maternal or infant mortality reported. Sildenafil causes vasodilation of the pulmonary vascular bed and vasodilation in the systemic circulation. Two case reports have described the successful treatment with sildenafil, a pregnancy category B drug, of pregnant patients with PAH. Patients with idiopathic PAH or chronic thromboembolic PAH should receive full-dose subcutaneous low-molecular-weight heparin therapy instead of warfarin for bleeding prophylaxis during pregnancy.. Targeted pulmonary vasodilators are viable treatment options for pregnant patients with PAH. Early recognition and management of worsening symptoms are essential to improve outcomes for both the mother and infant.

Topics: Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Purines; Sildenafil Citrate; Sulfones; Thromboembolism; Vasodilator Agents

Polymorphonuclear neutrophils (PMN) have been implicated in various vascular inflammatory processes. We isolated PMN from venous blood samples of 10 patients with severe primary pulmonary arterial hypertension (PPH), 7 patients with pulmonary hypertension secondary to chronic thromboembolism (CTEPH), and 12 healthy controls. When stimulated with the calcium-ionophore A23187, platelet activating factor (PAF) or the microbial agent n-formyl-Methionyl-Leucyl-Phenylalanine (fMLP), significantly increased release of elastase and superoxide anion was noted in both groups with pulmonary hypertension. Moreover, the neutrophils of CTEPH patients responded with an enhanced liberation of leukotriene (LT) B(4) and 5-hydroxyeicosatetraenoic acid (5-HETE). Inhalation of aerosolized iloprost (5 microg) caused a rapid decline in pulmonary vascular resistance, in both PPH and CTEPH. This hemodynamic response was paralleled by a significant suppression of ionophore- and ligand-induced elastase and superoxide release, as well as LTB(4) and 5-HETE formation. The neutrophil inhibitory effect of the inhalation maneuver was fully reproduced by in vitro incubation of neutrophils with 1-10 pg/ml iloprost for 2 hours. This is the first study to demonstrate that circulating neutrophils from patients with PPH and CTEPH possess an enhanced readiness to respond with inflammatory mediator generation to different stimulatory agents ex-vivo, and that PMN respiratory burst, elastase secretion and leukotriene generation are promptly reduced by an iloprost inhalation maneuver. Neutrophils might participate in the inflammatory processes in pulmonary arterial hypertension.

Topics: Administration, Inhalation; Case-Control Studies; Humans; Hydroxyeicosatetraenoic Acids; Hypertension, Pulmonary; Iloprost; Inflammation Mediators; Leukocyte Elastase; Leukotrienes; Neutrophils; Pulmonary Circulation; Respiratory Burst; Superoxides; Thromboembolism; Vascular Resistance

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: Humans; Iloprost; Platelet Aggregation; Thromboembolism

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