Biomedical subjects

J M Walenga

Publications and source records attributed to J M Walenga.

At least 37 records · Page 2Linked to original sources

PubMed2000

Bleeding complications with glycoprotein IIb/IIIa inhibitors.

The new class of antiplatelet drugs, the GPIIb/IIIa inhibitors, has proven to be effective in acute coronary syndromes including unstable angina and myocardial infarction as well as adjunct therapy for coronary interventions for preventing morbidity and mortality. As these drugs inhibit the final common pathway of platelet activation, effectively blocking the platelet aggregation response, potential bleeding is a concern with their use. The risk of bleeding has been demonstrated to be higher in patients treated with combination drug therapy (heparin, aspirin, thienopyridines, thrombolytics, oral anticoagulants), when antithrombotic drugs are not given on an individual weight basis and with late removal of vascular access sheaths. The early clinical trials have defined modifications in patient management that have effectively reduced bleeding. Pooled data from the more recent clinical trials, mostly in coronary intervention enrolling over 27,000 patients, show a bleeding rate of 3.6% in the drug group and 2.3% in the placebo group. Although this is acceptable, several unresolved issues remain to be addressed regarding the GPIIb/IIIa inhibitors. Thrombocytopenia occurs infrequently with all GPIIb/IIIa inhibitors but can be severe. The use of these drugs by oral administration presents new challenges with determining optimal dosing, drug-drug interactions and long-term effects. Incorporating point-of-care monitoring may enable better titration of these drugs to avoid bleeding complications. GPIIb/IIIa inhibitors are destined to become a mainstay therapy for cardiovascular treatment and over time these issues should be resolved.

Journal Article↗

PubMed2000

Pathophysiology of heparin-induced thrombocytopenia. Clinical and diagnostic implications--a review.

OBJECTIVE: This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. DATA SOURCES AND STUDY SELECTION: Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin->platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a "superactive" heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. CONCLUSIONS: The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

Heparin↗

PubMed2000

Pharmacokinetics of argatroban in primates: evidence on endogenous uptake.

BACKGROUND: Antithrombin agent, argatroban, is currently undergoing several clinical trials for cardiovascular indications. Because of its solubility, this drug is usually administered via an intravenous bolus followed by infusion. The purpose of this study was to determine the pharmacokinetics of argatroban after intravenous bolus injection in primates. METHODS: Parallel in vitro studies in primate whole blood were carried out to simulate a one-compartment system. Argatroban (range 1.0-7.5 mg/kg) was administered to four groups of primates and blood samples were drawn at various time periods. Argatroban measurements were made in plasma using functional (aPTT, Heptest, TT) and HPLC methods. RESULTS: In vitro, argatroban primarily distributed in the plasma in proportionate amounts. Relative uptake of argatroban to the blood cells (leukocytes and erythrocytes) was minimum. However, in vivo, argatroban followed a complex pharmacokinetics. Within 5 min after the bolus administration, only <20% of argatroban was recovered. The recovered amount was proportionate to the dosage and followed the expected kinetics with a half-life of <20 min. Simultaneous quantitation of M1-metabolite of argatroban revealed only a fraction of recovered argatroban (approximately 25%) converted into M1 in these experimental settings. Results obtained from the functional and absolute methods correlated well. HPLC profile did not reveal the presence of any other metabolite(s). CONCLUSIONS: These observations suggest that argatroban may be endogenously taken up by the vascular or other sites and may exhibit a complex kinetics. In acute settings, the metabolic transformation of argatroban to M1 is relatively low. To further clarify the pharmacokinetics/pharmacodynamics of this drug, additional studies are warranted.

Animals↗

PubMed1999

Laboratory monitoring of pentasaccharide in a dog model of hemodialysis.

Varying dosages of pentasaccharide (400-800 nmol/kg) were compared to a 250-U/kg single bolus dosage of unfractionated heparin (UFH) in a dog model of hemodialysis. Several laboratory assays were used to monitor the effects of pentasaccharide and UFH. The pentasaccharide did not produce any anticoagulant effects as measured by the activated partial thromboplastin time. However, in the anti-Xa chromogenic assay and the Heptest assays, there was a dose-dependent prolongation after pentasaccharide administration. In the group of dogs administered 800 nmol/kg of pentasaccharide, there was a 50% decrease in the thrombin antithrombin (TAT) complex level after 60 minutes on dialysis. In the UFH-treated dogs, wide variations in assays were observed. There was a marked elevation in the activated partial thromboplastin time and Heptest assays up to 6 hours after UFH administration. Both anti-Xa and anti-IIa activity was measured up to 4 hours. In the TAT assay, UFH was found to have a stronger effect in suppressing the formation of TAT in comparison to the pentasaccharide. These results suggest that pentasaccharide can be used as a replacement for UFH in a dog model of hemodialysis to keep the dialysis circuit patent. In addition, the anti-Xa-based assays such as the Heptest and the chromogenic anti-Xa assays can be used to monitor the effects of pentasaccharide in this model.

Animals↗

PubMed1999

Hemostatic effects of 1 mg daily warfarin on post CABG patients. Post CABG Studies Investigators.

Although coronary bypass graft surgery has increased the survival and quality of life of many individuals, patients remain at risk of restenosis and thrombotic occlusion of the coronary arteries and bypass grafts. In the screening period for participation in the multicenter Post Coronary Artery Bypass Graft (Post CABG) trial, the effects of 1 mg daily warfarin were evaluated using paired patient samples collected prior to and after at least 21 days of treatment. In stable patients (n = 40; 39 males 1 female; 51-74 years old) who previously had undergone coronary artery revascularization (1-10 years), no alterations in prothrombin time, international normalized ratio (INR), prothrombin fragment 1.2, or the hemostatic risk factors factor VII antigen and coagulant activity, von Willebrand's factor, fibrinogen, tPA, or PAI-1 were associated with the 1 mg daily warfarin treatment. The observations reported here supported the Post CABG Studies Steering Committee decision to treat patients with 1-4 mg warfarin daily adjusted to achieve INRs not to exceed 2. 0 consistent with low-intensity therapy.

Aged↗

PubMed1999

Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood.

In an in vitro study, anticoagulant and antiplatelet effects of the synthetic, direct factor Xa inhibitor DX-9065a, (+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-a midino-2-naphthyl]propanoic acid hydrochloride pentahydrate, which shows a high affinity and selectivity towards the enzyme, were investigated. Anticoagulant actions of DX-9065a were studied in human plasma using global clotting assays [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest]. The effect on thrombin generation was measured in whole blood by determining the plasma concentration of prothrombin fragment F1.2. The influence on agonist-induced platelet activation in whole blood was studied using flow cytometric analysis. DX-9065a caused a concentration-dependent prolongation of clotting times in the PT and APTT assay, whereas Heptest was less affected and TT was not influenced. Furthermore, DX-9065a strongly inhibited the generation of thrombin without and after coagulation activation. The factor Xa inhibitor did not affect platelet activation mediated by either thrombin receptor activating peptide, arachidonic acid or y-thrombin, but prevented tissue factor- and factor Xa-induced activation of platelets in a concentration-dependent manner. Inactivation of factor Xa by a highly effective and selective inhibitor, and the resulting inhibition of thrombin generation leads to strong anticoagulant and antiplatelet actions. The interference with the coagulation system at the early level of factor Xa is expected to be an effective approach for a successful anticoagulant/antithrombotic therapy.

Anticoagulants↗

PubMed1999

Heparin-induced thrombocytopenia: clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors.

Heparin-induced thrombocytopenia (HIT), the most common complication of heparin therapy, is also the most common form of the drug-induced thrombocytopenias. HIT is classified as type I and type II, the first being benign and the latter severe. HIT type II is attributed to an immune response characterized by complexes of heparin and platelet factor (PF) 4. Enzyme-linked immunosorbent assays allow easy and simple determination of these antibody titers; however, because specificity and sensitivity is not optimal, there is concern that the clinical relevance may be low. In clinical trials many patients were shown to form HIT-IgG in response to heparin without developing manifestations of HIT type II. Therefore, routine screening of clinically asymptomatic patients for antiheparin/PF 4 antibodies is not recommended. HIT type II is a clinico-pathologic syndrome that ideally should be confirmed by laboratory testing. If any clinical suspicion arises, however, heparin and low molecular weight heparin therapy should be discontinued and an alternative anticoagulant therapy started. Alternative drugs have been evaluated in significant numbers of patients including danaparoid and thrombin inhibitors. In the case of danaparoid, it is highly recommended that an in vitro test for cross-reactivity be performed before the onset of therapy. If testing cannot be performed, immediate administration of a thrombin inhibitor is preferred.

Anticoagulants↗

PubMed1999

Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications.

Argatroban is a peptidomimetic inhibitor of thrombin that is currently undergoing extensive clinical trials as a heparin substitute for thrombotic complications. Argatroban is readily metabolized into a major derivative, M1, that has pharmacological characteristics distinct from its parent compound. The currently available clot-based assays measure the cumulative anticoagulant effect of argatroban and its metabolite(s). Available HPLC methods do not differentiate between argatroban and M1-metabolite. A modified method was developed to simultaneouly quantitate M1-metabolite and argatroban in biological fluids. Initial validation studies for the method included clinical trials of argatroban in patients with heparin-induced thrombocytopenia, (ARG 911 Study) and coronary interventional procedures (ARG 310 Study). Plasma samples were extracted with acetonitrile and reconstituted in a mobile phase. Calibration curves were prepared by running known standards of argatroban and M1-metabolite in normal human plasma. Ultraviolet detection was made at 320 nm. The retention times for argatroban and M1-metabolite peaks were found to be 10.5 +/- 0.3 minutes and 3.9 +/- 0.1 minutes, respectively. The extraction efficiency was > 95% (r2 = 0.99). In heparin-induced thrombocytopenia patients with major bleeding complications (n = 30), the relative increase in M1-metabolite compared to argatroban varied widely (two- to eight-fold). The mean concentration of argatroban during the steady infusion period was found to be 0.7 +/- 0.35 microgram/mL, and for M1-metabolite, it was 5.5 +/- 2.8 micrograms/mL. Proportionate results were not seen when higher dosages of argatroban were administered (coronary angioplasty studies). Argatroban and M1-metabolite levels also compared well with the results in global clotting assays. Owing to the simultaneous quantitation of argatroban and M1-metabolite, this method provides a rapid assessment of the pharmacokinetics and pharmacodynamics of argatroban. The differential quantitation may be useful in the assessment of relative metabolic turnover of argatroban that can be related to the hepatic and renal functions in a given patient.

Anticoagulants↗

PubMed1999

Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies.

A synthetic selective inhibitor of factor Xa, the pentasaccharide SR90107A/Org31540 is in clinical development for the prophylaxis of postsurgical deep vein thrombosis. Another synthetic pentasaccharide with even more sustained inhibition of factor Xa, SanOrg34006, has also been developed. Both of these agents were tested in comparison to unfractionated heparin and a low molecular weight heparin (enoxaparin) for their relative platelet activation potential in heparin-induced thrombocytopenia assays. Sera from patients (n = 30) with heparin-induced thrombocytopenia were pooled and validated for heparin-dependent aggregation responses. Using heparin-platelet factor 4 Sepharose columns, antibodies to heparin-platelet factor 4 were purified from the same pool. The effects of heparin, enoxaparin, SR90107A/Org31540, and San-Org34006 were evaluated in a platelet aggregation assay using platelet donors (n = 10). At comparable concentrations, heparin and enoxaparin consistently produced platelet activation, whereas both pentasaccharides failed to produce a response at a concentration up to 100 micrograms/mL (approximately 50 microM). Similarly, in the 14C-serotonin release and flow cytometric assays, heparin and enoxaparin produced positive responses (n = 30), whereas the two pentasaccharides consistently failed to produce any effect. These observations suggest that the two pentasaccharides with highly selective anti-Xa activity are devoid of generating antiheparin-platelet factor 4 antibody, do not produce heparin-induced thrombocytopenic responses and may inhibit active heparin-induced thrombocytopenia antibody platelet activation.

Antibodies↗

PubMed1999

Inadequacy of current prevention strategies for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia is one of the most difficult problems facing clinicians today. Despite recent understanding of the pathophysiology of this disorder, there are many unresolved issues about diagnosis, prevention, and treatment. In this article, difficulties physicians encounter when faced with a suspected heparin-induced thrombocytopenia patient will be reviewed as well as our experience in 113 patients with heparin-induced thrombocytopenia which highlights the failure of current preventive strategies for heparin-induced thrombocytopenia. The experience of using warfarin in 51 patients with heparin-induced thrombocytopenia will also be reviewed.

Fibrinolytic Agents↗

PubMed1999

Laboratory diagnosis of heparin-induced thrombocytopenia.

The characteristics of the currently available platelet function assays (platelet aggregation, serotonin release, and flow cytometry) and enzyme-linked immunosorbent assays that quantitate antiheparin-platelet factor 4 antibody titers were studied using sera collected from clinically diagnosed heparin-induced thrombocytopenia patients, patients without heparin-induced thrombocytopenia, patients with platelet immune disorders other than heparin-induced thrombocytopenia, and normal individuals. The platelet aggregation assay was less sensitive than the serotonin release assay, which was less sensitive than the enzyme-linked immunosorbent assay (p < 0.001). Yet heparin-induced thrombocytopenia was identified by platelet aggregation assay in cases where the serotonin release assay and/or the enzyme-linked immunosorbent assay were negative. Patients with heparin-induced thrombocytopenia and thrombosis were more often positive than heparin-induced thrombocytopenia patients without thrombosis (p < 0.05). Positive platelet aggregation assay and serotonin release assay results were generally associated with a higher antibody titer; however, a minimum critical titer could not be identified. Over a 30-day period the percentage of positive responses did not change significantly even though clinical symptoms corrected in most heparin-induced thrombocytopenia patients. Multiple testing over several days enhanced the chance of detecting a positive, and combined results of the three assays further enhanced the positive response (p < 0.005). In patients without heparin-induced thrombocytopenia, false-positive results were obtained with the enzyme-linked immunosorbent assay. These data demonstrate that there is no direct correlation between the positive responses of these assays, that clinically positive patients can be missed by all assays, and the presence of antibody alone does not determine clinical heparin-induced thrombocytopenia. With these limitations, the combination of aggregation, serotonin release, and enzyme-linked immunosorbent assay testing with multiple samples offers the best chance of identifying a positive heparin-induced thrombocytopenia patient. Caution is advised for all assays as none is optimal.

Anticoagulants↗

PubMed1999

Functional heterogeneity of antiheparin-platelet factor 4 antibodies: implications in the pathogenesis of the HIT syndrome.

Heparin-induced thrombocytopenia represents one of the most severe drug-induced disorders of platelets. This syndrome is believed to be mediated through antibodies generated against a heparin-platelet factor 4 complex. Complexation of a sulfated mucopolysaccharide chain of heparin with a platelet granular protein (platelet factor 4) produces an allosteric modification of platelet factor 4 resulting in neoepitope formation and the generation of antiheparin-platelet factor 4 antibodies. These antibodies are capable of activating platelets by binding to heparin, platelet factor 4 and the Fc receptor on platelets, resulting in a complex pathophysiology involving ischemic, thrombotic, and inflammatory processes. To characterize this antibody, IgG fractions were obtained from the serum of patients with heparin-induced thrombocytopenia using ammonium sulphate precipitation and heparin-platelet factor 4-sepharose 4B affinity chromatography methods. With the affinity purification, two major components, peaks I and II, with high antiheparin-platelet factor 4 antibody titers were eluted. The purity of all the fractionated immunoglobulins was established by sodium dodecylsulphate-polyacrylamide gel electrophoretic analyses. While peak I did not induce 14C-serotonin release from platelets in the heparin-dependent assay for heparin-induced thrombocytopenia antibodies (14C-serotonin release assay), peak II and the IgGs obtained with the ammonium sulphate precipitation method exhibited a strong and concentration-dependent activation in the presence and absence of heparin and low molecular weight heparin. These immunoglobulins were treated with heparinase, a cationic ion-exchange resin (Heparsorb), or dialyzed to remove traces of heparin, and when tested in the 14C-serotonin release assay, showed the same high degree of activity. These data are suggestive of the generation of heparin-induced thrombocytopenia antibodies capable of activating platelets directly in a nonheparin-dependent manner. These observations underscore the complex pathophysiology of heparin-induced thrombocytopenia syndrome and suggest that the severity of this syndrome in some patients may be due to the generation of "super-active" heparin-induced thrombocytopenia antibodies capable of activating platelets without the requirement of heparin. This could explain why the cessation of heparin in patients does not necessarily correct the symptoms of heparin-induced thrombocytopenia or associated thrombosis.

Antibodies↗

PubMed1999

Soluble adhesion molecules in the HIT syndrome: pathophysiologic role and therapeutic modulation.

Heparin-induced thrombocytopenia pathophysiology is now known to be a complex process that involves platelets, vascular endothelium, and leukocytes/lymphocytes. The activation products from these sites also contribute to the activation of coagulation and fibrinolytic deficit. While many of the markers of hemostatic activation processes have been found to be increased during the acute phase of heparin-induced thrombocytopenia syndromes, the circulating levels of soluble adhesion molecules such as the P, E, and L selectins, and intracellular and vascular cell adhesion molecules have not been reported. Since the pathophysiology of heparin-induced thrombocytopenia involves the activation of platelets, endothelium, and leukocytes, it is expected that the activation products related to these hemostatic systems including soluble selectins and cellular adhesion molecules will also be increased in circulating blood. These alterations may also provide an index of the pathophysiologic process. With the availability of highly sensitive enzyme-linked immunosorbent assays for soluble P, E, and L selectins, intracellular and vascular cell adhesion molecules, it is now possible to measure these adhesion molecules in biological fluids. This study reports on the circulating levels of various adhesion molecules in patients with heparin-induced thrombocytopenia and their modulation after therapeutic interventions by the use of direct thrombin inhibitors. With the availability of recombinant hirudin, it is now possible to treat these patients with alternate antithrombin agents. However, the immunoactivation of platelets and other cells as shown here indicates the possible need for additional adjunct therapeutic approaches to suppress their participation in the thrombotic process. The reported increase in the circulating levels of the soluble adhesion molecules during the heparin-induced thrombocytopenia and heparin-induced thrombocytopenia with thrombosis syndrome suggests that the antiheparin platelet factor 4 antibody is capable of modulating their regulation. The prognostic role of these mediators in the management of heparin-induced thrombocytopenia syndrome warrants further investigation.

Antithrombins↗

PubMed1999

Antithrombin agents: the new class of anticoagulant and antithrombotic drugs.

Antithrombin drugs represent a wide group of natural agents, recombinant agents equivalent to some of the naturally occurring proteins, and synthetic agents. This group of drugs is characterized by marked structural and functional heterogeneity. Several of these drugs are currently in various phases of development. Argatroban represents the first clinically approved antithrombin agent, which was made available in Japan several years ago. Two recombinant hirudin preparations, Revasc (Novartis) and Refludan (Aventis), are available for postsurgical DVT prophylaxis and alternate anticoagulant use in patients with heparin-induced thrombocytopenia. A synthetic antithrombin agent based on the combined structures of hirudin and antithrombin peptides, hirulog (Bivalirudin), is undergoing clinical trials in cardiovascular indications. Additional studies on the hirudins are being carried out to test their efficacy as surgical and interventional anticoagulants as replacements for heparin. However, the need for a proper antagonist is one of the limiting factors for the optimal development of hirudin in this indication. Several of the synthetic thrombin inhibitors are also being developed for oral use for the prophylaxis of DVT in surgical patients. Since the therapeutic index of thrombin inhibitors is narrower than that of heparin, this route may not be an optimal approach for the development of these agents. Despite several unresolved developmental issues, the thrombin inhibitors provide a useful alternative to heparin anticoagulation and may prove to be useful in validated clinical use.

Anticoagulants↗

PubMed1999

Heparin-induced thrombocytopenic potential of GAG and non-GAG-based antithrombotic agents.

We have undertaken these studies of the heparin-like, or glycosaminoglycan, and nonglycosaminoglycan-based antithrombotics in an effort to add to the understanding of the pathophysiologic mechanism of heparin-induced thrombocytopenia by investigations of how glycosaminoglycan-related agents interact with the heparin-induced thrombocytopenia antibodies. The low molecular weight heparins, originally thought to be useful alternatives to heparin because of their smaller size, show platelet activation and aggregation responses in platelet heparin-induced thrombocytopenia serum systems (P-selectin expression, microparticle formation, serotonin release, platelet aggregation). Although the molecular mass and sulfation of the heparinoid Lomoparan is similar to that of heparin and low molecular weight heparins, its chemical structure is different and probably is not recognized by the heparin-induced thrombocytopenia antibodies. The heparin-related pentasaccharide did not show a positive reaction in any system of platelet activation/aggregation. These studies have shown that the antibodies produced in patients with heparin-induced thrombocytopenia are reactive to highly sulfated glycosaminoglycans and nonglycosaminoglycan agents and less dependent on the molecular mass of these agents; whether the agent is a heparin or nonheparin compound was not critical. A combination of a moderate sulfation but low molecular mass in a heparin-like molecule was sufficient to prevent interaction with the heparin-induced thrombocytopenia antibodies. However, a chemical structure that is different from heparin (e.g., a heparinoid or a thrombin inhibitor) will also be nonreactive to platelet activation by heparin-induced thrombocytopenia antibodies.

Antibodies↗

PubMed1999

Pharmacology of argatroban.

Argatroban, a synthetic peptidomimetic antithrombin agent, is the first clinical anticoagulant solely to target thrombin. For some time, this drug has been used in Japan for the management of thromboembolic disorders. Recently, it has been approved in Japan for use in thrombotic and ischaemic stroke. Despite a large number of preclinical studies on the pharmacology of this agent, clinical trials in Europe and North America were only initiated in 1996. Argatroban produces anticoagulant effects comparable to therapeutic heparinisation at concentrations of approximately 1 microg/ml. At concentrations of 5-10 microg/ml, this agent produces adequate anticoagulation for inteventional cardiovascular procedures and prolongs the activated clotting time (ACT) to 400-600 s. The predictable anticoagulant effect of this agent is relatively short lasting, and may not warrant pharmacologic neutralisation in the majority of patients. However, patients with hepatic dysfunction may need some means of neutralisation. Unlike heparin, this drug produces its anticoagulant effects by direct inhibition of thrombin and thrombin-mediated processes. This agent is not influenced by endogenous factors such as platelet factor 4 and other proteins which bind heparin. Argatroban's use does not lead to the formation of antiplatelet antibodies. Thus, this drug is useful in the management of heparin induced thrombocytopenic (HIT) patients. Although argatroban was initially developed for the management of deep vein thrombosis (DVT), based on its pharmacologic properties, it can be developed for safer anticoagulation in such indications as acute coronary syndromes, as an adjunct to thrombolytics, thrombotic and ischaemic stroke and inflammatory diseases resulting in thrombotic complications.

Journal Article↗

PubMed1999

Failure of current strategies in the prevention of thrombosis in patients with heparin-induced thrombocytopenia: a clinician's perspective.

Heparin-induced thrombocytopenia (HIT), and heparin-induced thrombocytopenia with thrombosis syndrome (HITTS), are immune-mediated complications of heparin therapy associated with significant morbidity and mortality. Although much has been learned about the pathophysiology of this syndrome, there are many difficult issues remaining for physicians involved in the daily care of the patient about the diagnosis, prevention, and treatment. To determine whether the earliest detection of HIT and heparin cessation impacted outcome, 116 consecutive patients at a single institution, with HIT diagnosed by platelet aggregometry, were divided into groups by time to heparin cessation based on daily platelet counts. Thrombocytopenia was defined in two ways: as a 50% decline from baseline and an absolute platelet count of less than 100x10(9)/L. The overall thrombosis rate was 39% and was predominantly venous. The mortality rate of 27% was similar in patients with both HIT and HITTS. Despite heparin cessation at less than 48 h from the onset of thrombocytopenia (mean 0.5 days), there were no differences in thrombosis or mortality when compared to patients with later heparin cessation (mean 4.3 days). In summary, early detection of HIT with heparin cessation is insufficient therapy for the management and treatment of HITTS. An alternative to this strategy in the treatment of patients with HIT is indicated.

Anticoagulants↗

PubMed1999

Selectins in the HIT syndrome: pathophysiologic role and therapeutic modulation.

The pathophysiology of heparin-induced thrombocytopenia (HIT) is now known to be a complex process which involves platelets, vascular endothelium, and leukocytes. The activation products from these sites also contribute to the activation of coagulation and to the fibrinolytic deficit. While many of the markers of hemostatic activation processes have been found to be at increased levels during acute phases of the HIT syndromes, the circulating levels of soluble P-, E-, and L- selectins have not been reported. Since the pathophysiology of HIT involves the activation of platelets, endothelium, and leukocytes, it is expected that activation products related to these hemostatic systems, including soluble selectins, will also be increased in circulating blood. These alterations may provide an index of the pathophysiologic process. With the availability of highly sensitive ELISAs for soluble P-, E-, and L-selectins, it is now possible to measure these adhesion molecules in biological fluids. This study reports on the circulating levels of P-, E-, and L-selectins in HIT patients and their modulation after therapeutic intervention. With the availability of recombinant hirudin, it is now possible to provide alternate anticoagulants to HIT patients. However, the immunoactivation of platelets and other cells may require additional adjunct therapeutic approaches.

Anticoagulants↗