Diseases Journal » Heart Disease

Iloprost

admin — Mon, 06 Sep 2010 18:14:06 +0000

Iloprost, a stable prostacyclin analogue with a circulating half-life of 15 to 30 min, consistently blocks heparin-dependent platelet activation and aggregation in vitro. Intraoperative infusion of Iloprost has permitted the uneventful administration of heparin to patients with a history of HIT undergoing both vascular and cardiac surgery. At higher doses the drug may cause hypotension requiring coadministration of vasopressor support. Although, from the reports cited earlier, this agent showed considerable promise in this setting, it is unfortunately not currently available in the United States. The monoclonal antibody to the platelet glycoprotein IIb/IIIa 7E3 (Reopro) has been shown to prevent heparin-mediated platelet aggregation induced by HIT plasma in vitro. Furthermore, recent in vitro studies have demonstrated that Reopro can significantly reduce thrombin generation initiated by tissue factor. Although preliminary studies from our laboratory and others suggest Reopro is able to block the heparin-dependent antibodyinduced platelet release reactions, platelets from patients with Glanzmann’s thrombasthenia lacking the glycoprotein IIb/IIIa receptor can be activated by HIT IgG, suggesting that inhibition of this receptor will not give complete protection against the prothrombotic manifestations of the syndrome.
Other therapies. Surgical intervention such as thrombectomy or embolectomy may be indicated for limb salvage. Insertion of an inferior vena cava filter in patients with proximal deep venous thrombosis or embolism may reduce the risk of further emboli, but has been associated with thrombosis of the inferior vena cava up to the level of the filter. There have been isolated case reports of the administration of fibrinolytic agents (streptokinase, urokinase) without bleeding complications to patients with HIT with deep venous thrombosis, pulmonary emboli and arterial thrombosis. Small numbers of patients have received plasma exchange therapy in an attempt to remove the heparin-associated IgG. After relatively few treatments (ranging from one to six, generally in association with antiplatelet agents, plasmapheresis has been followed by reversal of the heparin-associated platelet aggregation abnormality, resolution of thrombocytopenia and stabilization of thrombotic phenomena. Some preparations of high dose Ig can prevent heparinassociated platelet activation by HIT sera, presumably by competitively inhibiting binding of the HIT-IgG to the platelet Fc receptor. Correction of thrombocytopenia after administration of intravenous Ig has been reported in several patients with HIT. Mexican hgh – cheap medications online.
Readministration of heparin. In patients with heparindependent antibodies, as detected by in vitro aggregation studies, reexposure to heparin is associated with a high risk of thrombocytopenia and thrombosis. In the majority of patients, the heparin-induced aggregation will disappear within several weeks, although persistence for over 2 years has been documented. In some clinical situations, such as cardiopulmonary bypass surgery, where anticoagulation is deemed essential and the safety and efficacy of heparin are well established, some investigators have advocated awaiting disappearance of the heparin-dependent antibody, as monitored by in vitro aggregation studies, and then performing the operation or procedure with full heparinization but without postoperative heparin administration. Although anecdotal, this approach has been successful. However, it may prove dangerous in those patients for whom the available in vitro assay is not sufficiently sensitive to detect a pathophysiologically potent antibody or for the occasional patient in whom severe HIT can be provoked by reexposure to heparin. HIT with thrombosis can recur years after a previous episode, even when a negative platelet aggregation test has been confirmed after the initial event. In general, patients with a history of HIT should therefore be advised to avoid further heparin exposure for life.

Conclusions
HIT is encountered more frequently in the practice of cardiology as the application of anticoagulant therapy becomes more generalized. The thrombotic complications of HIT are associated with significant morbidity and mortality and can only be prevented by early recognition of the condition. It is therefore imperative that cardiologists maintain a high index of suspicion and perform frequent platelet counts in all patients receiving heparin therapy. Once HIT is diagnosed, heparin must be stopped immediately and eliminated from all infusion lines and flushes. In most cases, alternative anticoagulant therapy should be initiated—a task made difficult at present by the absence of a readily available alternative anticoagulant agent with proven efficacy in patients with acute coronary disease. Several direct thrombin inhibitors are being evaluated in patients with HIT, and it is hoped that the margin of benefit will be sufficient to encourage the manufacturers to make this drug available for the management of this potentially lifethreatening complication of heparin therapy.

LMW heparinoid, Ancrod and Antiplatelet agents

admin — Thu, 02 Sep 2010 18:14:42 +0000

LMW heparinoid. Although it belongs to the same family of drugs as heparin and LMW heparin, the LMW heparinoid Orgaran, which is presently available for compassionate use in the United States, differs from the LMW heparins in a number of ways. It is a mixture of sulfated glycosaminoglycans derived from porcine intestinal mucosa and consists of 84% heparan sulfate, 12% dermatan sulfate and 4% chondroitin sulfate. In contrast to LMW heparin, each component of Orgaran is structurally distinct from unfractionated heparin. As a consequence, it has relatively low cross reactivity (10% to 20%) with the heparin-dependent antibody, as determined by aggregation, serotonin release or HIPA assays. In an overview of 230 patients with HIT treated with Orgaran, 93% of patients were considered to have responded adequately to the drug during the treatment period. Approximately 26% of the patients died, but in only 7 patients (3%) was the death deemed directly attributable to Orgaran. The use of Orgaran in patients undergoing open heart surgery is potentially limited by the fact that its anticoagulant effect cannot be neutralized by protamine sulfate. Consistent with this, of 19 patients undergoing cardiopulmonary bypass surgery with Orgaran in place of heparin, 11 bled more than expected. Although Orgaran has been demonstrated to be effective in the prevention and treatment of venous thrombosis, experience in patients with acute coronary disease or in those requiring coronary or vascular surgery outside the contexts cited earlier is limited. Nevertheless, in Canada and Australia, where the drug has been licensed for clinical use for some years, most authorities currently regard Orgaran as the treatment of choice for patients with HIT (T. Warkentin, personal communication, 1997).
Ancrod. This is a rapidly acting defibrinogenating agent derived from the Malayan pit viper; it is immunologically distinct from heparin and does not cause thrombocytopenia. It acts by cleaving fibrinopeptide A from fibrinogen, producing an unstable product that is rapidly removed from the circulation. It may be administered intravenously or subcutaneously and is monitored by measuring the fibrinogen concentration. Although ancrod has been used successfully in a number of patients with thrombotic complications of HIT, it is not readily available in the United States. Furthermore, it does not suppress thrombosis in all cases (T. Warkentin, personal communication, 1997) and should therefore be considered a less favorable alternative in these patients.
Antiplatelet agents. In the absence of controlled, prospective data, antiplatelet agents such as aspirin, dipyridamole or dextran have been recommended empirically as adjunctive therapy after cessation of heparin in patients with HIT, both in the presence and absence of thrombosis. Antiplatelet agents have also been given with continued administration of heparin in patients in whom cessation of the anticoagulant agent was believed to be undesirable. In a series of 12 patients with HIT requiring urgent open heart surgery with intraoperative heparin, the preoperative administration of aspirin and dipyridamole resulted in no postoperative thromboembolic events and bleeding in only three patients. In another small study of 9 patients, however, it was found that although this strategy protected patients from thromboembolic complications, it did not prevent the thrombocytopenia associated with limited heparin reexposure. Aspirin is not consistently effective in inhibiting the heparin-dependent antibody in vitro, presumably reflecting the fact that it has an impact on only one of several pathways of platelet activation and aggregation. Furthermore, even when aspirin does prevent heparin-induced platelet activation in vitro, this does not necessarily predict its efficacy in viv.

Clinical Presentation of HIT. Part 5

admin — Fri, 27 Aug 2010 22:42:51 +0000

Of the alternative anticoagulant therapies that have been tried in patients requiring early management for the thromboembolic manifestations of HIT, LMW heparin, the LMW heparinoid Orgaran and the defibrinogenating agent ancrod have been used most extensively. In the setting of acute coronary disease, however, the most promising therapy is direct thrombin inhibition.
Direct thrombin inhibitors. After anecdotal reports of the successful use of the prototypic direct thrombin inhibitor hirudin in the management of patients with HIT, a prospective, open-label evaluation of this drug in achieving therapeutic levels of anticoagulation in patients with HIT is under way in Europe. In a recent preliminary report on the first 82 patients enrolled in this study, effective anticoagulation was achieved in the majority. Five patients (6%) had new thromboembolic complications, 7 (8%) had major bleeding events and 3 (4%) had to undergo limb amputation.
Six patients died, but all fatal events were due to aggravation of underlying medical problems; none were causally related to hirudin. In the United States, the cost of hirudin, together with a general perception that it performed less well than expected in two recent large-scale trials in patients with acute coronary syndromes, has discouraged manufacturers from pursuing its further development for management of patients with acute coronary disease. However, these studies did confirm the safety and antithrombotic efficacy of direct thrombin inhibition, features which, together with the lack of cross reactivity with the heparin-dependent antibody, render the direct thrombin inhibitors potentially ideal alternatives for HIT. The synthetic thrombin inhibitor argatroban has been successfully used in patients with HIT. One center recently reported a reduction in mortality from 32% in untreated historical control subjects to 18% in argatroban-treated patients with HIT (107). Open-label, prospective studies evaluating argatroban in patients with a history or current evidence of HIT undergoing percutaneous coronary intervention or peripheral vascular procedures are nearing completion in the United States, and it is hoped that the margin of benefit will be sufficient to encourage the further development and marketing of this agent for the management of this condition.
LMW heparins. Several retrospective reports have shown that LMW heparin administered to patients with HIT in the absence of cross reactivity, as detected by in vitro platelet ggregation assay, results in a favorable outcome, whereas if cross reactivity is demonstrated, there is a significant likelihood of further thrombotic events. However, when sera from patients with HIT are tested for reactivity with LMW heparin using the sensitive serotonin release or HIPA assays, cross reactivity with unfractionated heparin approaches 100%. For this reason, LMW heparin therapy should be avoided in patients with HIT. However, in the absence of readily available alternatives, if the in vitro platelet aggregation assay does not demonstrate cross reactivity with LMW heparin, it is currently common practice to administer LMW heparin to these patients and monitor them closely for further thrombotic events, persisting thrombocytopenia or the development of a LMW heparin-dependent antiplatelet antibody.

Clinical Presentation of HIT. Part 4

admin — Tue, 24 Aug 2010 12:05:06 +0000

A number of investigators have adapted the enzyme-linked immunosorbent assay (ELISA) technique to devise diagnostic tests for HIT. The most recent of these uses immobilized PF4 bound to heparin as a target for the HIT antibody. Initial studies reported PF4 ELISA to be at least as sensitive as both the 14C-serotonin release and HIPA assays, although discrepant results occur in up to 25% of patients, indicating that the different assays recognize different patient cohorts. Two recent studies evaluating this assay in patients after cardiopulmonary bypass surgery have reported the heparin-associated antibody to be detectable in .50% of patients by the time of hospital discharge. The presence of antibody was not predictive of either thrombocytopenia or thromboembolic complications, suggesting that the increased sensitivity may be of limited clinical utility in this setting. Further evaluation of this assay will be required before its integration into routine clinical practice.

Prevention

The most important principle of prevention is to minimize the exposure to heparin. In patients with established venous thrombosis, early commencement of warfarin shortens the duration of heparin therapy, thus minimizing the likelihood of developing thrombocytopenia without affecting efficacy. Most investigators stress the importance of maintaining a high index of suspicion and performing regular platelet counts in all patients receiving heparin therapy. This has been predicated on the retrospective observation that prompt diagnosis of the condition with abrupt withdrawal of the drug can substantially reduce the complication and mortality rates. However, in a more recent retrospective analysis, patients with a diagnosis of HIT had a subsequent 30-day risk of thrombosis .50%, despite cessation of heparin therapy with or without institution of warfarin therapy, suggesting that additional alternative anticoagulant therapy may be necessary in this patient group.

Treatment

HIT type I. Asymptomatic patients developing mild thrombocytopenia in the absence of the heparin-dependent antibody do not require specific treatment. However, it may be difficult to distinguish this condition from early type II; these patients should be closely monitored, and if there is any doubt, heparin should be discontinued.
HIT type II. In patients who develop thrombocytopenia with a positive laboratory test for the heparin-dependent antibody, the cornerstone of therapy is the absolute discontinuation of heparin. It is imperative that all potential sources of heparin be avoided, a task that can be difficult given the ubiquity of the drug in the hospital setting. Platelet transfusions are not recommended, both because bleeding complications are uncommon and thrombotic events can follow the transfusions. Once heparin is discontinued, the platelet count should begin to increase within 24 to 48 h and reach normal levels by 4 to 5 days. For patients with confirmed venous or arterial thrombosis, the selection of substitute anticoagulant therapy is particularly problematic in the United States at present, as there is currently no readily available, effective, alternative antithrombotic drug. If long-term anticoagulation is required, treatment with warfarin should be commenced. However, warfarin may precipitate venous limb gangrene in patients with deep venous thrombosis complicating HIT by producing protein C deficiency without simultaneous inhibition of thrombin generation, so it should not be administered without concomitant use of a rapidly acting anticoagulant agent.

Clinical Presentation of HIT. Part 3

admin — Fri, 20 Aug 2010 15:32:53 +0000

HIT should be suspected in any patient who develops thrombocytopenia (,150,000/ml) or a 50% or greater fall in the platelet count after 5 days of heparin therapy. The platelet count should be repeated and the blood film examined to exclude platelet clumping causing pseudothrombocytopenia. After confirmation of the low platelet count, the diagnosis of HIT may be made according to the following criteria:
1) occurrence of thrombocytopenia during heparin administration;
2) exclusion of other causes of thrombocytopenia such as infection, drugs and autoimmune thrombocytopenia;
3) resolution of thrombocytopenia after cessation of heparin therapy;
4) demonstration of a heparin-dependent platelet antibody by an in vitro test.
Criteria 1 and 2 only are required for the diagnosis of HIT type I. As in most hospitals, in vitro confirmation requires analysis of samples in a reference laboratory (see later discussion); the initial diagnosis of HIT is often made on clinical grounds (criteria 1, 2 and 3). In the absence of thrombocytopenia, HIT should also be considered if a patient receiving heparin experiences a new thrombosis or develops heparin resistance or (rarely) skin necrosis at sites of heparin administration.

Laboratory Studies for the Heparin-Dependent Platelet Antibody

A variety of laboratory tests for the detection of heparindependent platelet antibodies have been described. The most widely used is the platelet aggregation test, which measures the aggregation of normal donor platelets by patient serum or plasma in the presence of heparin. This test is popular because it is simple, inexpensive and based on a technique that is already in use in most hemostatic laboratories and can provide a result within 2 to 3 h. Although it has a specificity of ;90%, the sensitivity is reported to be between 30% and 50%, which, in the view of some investigators, limits its clinical usefulness. However, when performed under optimal conditions, with appropriate positive and negative controls, using donor platelets from individuals known to be highly reactive to the antibody, the sensitivity of the test is reported to exceed 80%. Using washed platelets (prepared as for the two-point 14C-serotonin release assay [see later discussion]) in place of platelet-rich plasma for the aggregation assay may increase its sensitivity and specificity (heparin-induced platelet aggregation [HIPA] test) The currently accepted reference standard for the laboratory diagnosis of HIT is the two point 14C-serotonin release assay. In this assay, radiolabeled, washed platelets from reactive donors are incubated with heat-treated patient serum in the presence of heparin. The test is positive if 14C-serotonin release occurs at therapeutic (0.1 U/ml) but not high (100 U/ml) heparin concentrations. It is technically demanding, uses radioactivity and is timing consuming, and therefore usually performed in a reference laboratory and used to confirm rather than to make the diagnosis of HIT.

Smokers paradox

admin — Wed, 04 Aug 2010 09:31:31 +0000

Fonarow et al. have explored the ‘smoker’s paradox’ in a novel inception cohort of hospitalized heart failure patients included in the OPTIMIZE-HF registry, by determining the impact of current or recent smoking on outcomes during hospitalization and in the first 60–90 day period following hospital discharge.
Adjustments for known important potential confounders were performed. Smokers were more likely to have left ventricular systolic dysfunction (59 vs. 51%), were more likely to be male (61 vs. 46%), and had higher B-type natriuretic peptide (BNP) levels (895 vs. 789 pg/mL). However, smokers were much younger (63 vs. 75 years of age), were less likely to have a previous history of heart failure admission (84 vs. 89%), and were less likely to have a diagnosis of diabetes requiring insulin therapy (14 vs. 17%). Despite this, when compared with non-smokers, the risk of in-hospital mortality was ∼30% lower for current or recent smokers, while the risk for re-hospitalization or post-discharge mortality was similar between the two groups.

How could this be? Assuming the authors appropriately assembled an inception cohort, correctly classified smokers, and appropriately adjusted for important potential confounders, only one of two conclusions can be drawn: either smoking is somehow ‘protective’ in heart failure patients; or a substantial component of the adverse effects of smoking in heart failure is reversible and has a short half-life (i.e. days) so that ‘enforced’ in-hospital smoking cessation led to an imbalance of beneficial therapies in the smokers (usual therapy plus smoking cessation) compared with their non-smoking cohorts (usual therapies only). The former hypothesis (that smoking is protective) can probably be refuted immediately. There is overwhelming evidence that smoking increases the incidence of heart failure, as well as heart failure morbidity and mortality (including sudden death) for those who have heart failure.

It can be argued that there is substantially more merit in the second argument. Constituents of inhaled tobacco damage the cardiovascular system in numerous ways: producing endothelial and platelet dysfunction; enhancing coagulation; increasing heart rate and blood pressure; increasing myocardial oxygen demand and consumption; and inducing vasoconstriction. Cigarette smoking also significantly increases carboxyhaemoglobin production, impairing oxygen carriage and release, which has a negative inotropic effect, increasing left ventricular end-diastolic pressure. Thus the abrupt removal of these deleterious effects of cigarette smoking following hospital admission and enforced smoking cessation, in addition to the provision of the usual heart failure therapies in smokers, might well be expected to ‘outstrip’ the impact of usual therapies alone in non-smokers.