Heparin-induced Thrombocytopenia And Thrombosis Syndrome Research Articles

Heparin-Induced Thrombocytopenia in Chinese Patients: 240 Patients Study in One Center

The study was conducted in order to analyze the incidence of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) in 240 patients from the Department of Vascular Surgery in China, to evaluate the current laboratory detection technique, and to explore the feasibility for the technique to be developed in China. 240 patients receiving unfractionated heparin (UFH) were studied in one center. Before and after the UFH treatment, platelet count, HIT-antibody ELISA test, and heparin-induced platelet aggregation (HIPA) were tested. Among 240 patients, HIT was diagnosed in 36 cases. The incidence was 15%. HITTS occurred in 6 cases (2.5%). The median time of thrombocytopenia was the 8th day. Platelet counts recovered to normal level in 3 - 6 days after heparin withdrawal The incidence of HIT is higher; however, the incidence of HITTS is lower. Monitoring platelet count, which is simple and easy to do and available in hospitals at different levels (township hospital included), is a reliable method to diagnose HIT early. The HIT-antibody ELISA test could be introduced in specific hospitals to prescreen HIT. In view of the higher sensitivity and specificity of HIPA, it can be used in larger diagnostic centers in all the big cities of China.

Allograft Coronary Artery Thrombosis: A Case Report of Early Cardiac Allograft Left Ventricular Myocardial Infarction

Cardiac allograft dysfunction is a major cause of morbidity and mortality in the early post-transplantation period. This is a critical condition that requires prompt diagnosis and management. We present the case of a 57-year-old man with ischemic cardiomyopathy who underwent cardiac transplantation and developed a rare case of coronary artery thrombosis in the setting of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) within the first 2 postoperative weeks. Transmural myocardial infarction (MI) was initially noted on cardiac magnetic resonance (CMR) imaging as regional left ventricular wall motion abnormalities and transmural hyperenhancement after gadolinium administration, prompting further evaluation of the coronary circulation with angiography.

Argatroban in the management of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an immunoglobulin-mediated serious complication of heparin therapy characterized by thrombocytopenia and high risk for venous and arterial thrombosis: HIT and thrombosis syndrome (HITTS). Argatroban, a direct thrombin inhibitor, is indicated as the anticoagulant for the treatment and prophylaxis of thrombosis in patients with HIT and in patients undergoing percutaneous coronary intervention (PCI) who have HIT. The aim of this review is to examine the pharmacological characteristics and the clinical efficacy and safety of this drug in adults with HIT, including those undergoing PCI. Briefly, 2 prospective multicenter, nonrandomized, open-label studies evaluated the efficacy and safety of argatroban as an anticoagulant in patients with HIT or HITTS. Both studies showed that the incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced in argatroban-treated patients vs control subjects with HIT or HITTS. In both studies, bleeding rates were similar between the groups. Argatroban was evaluated as the anticoagulant therapy in 3 prospective, multicenter, open-label studies in HIT patients who underwent PCI. The studies were similar in design with respect to patient inclusion and exclusion criteria, the argatroban dosing regimen, and primary efficacy outcomes. The investigators performed a pooled analysis of these studies, which showed that most (≥95%) patients achieved a satisfactory outcome from the procedure and adequate anticoagulation (coprimary end points).

Oversulfated Chondroitin Sulfate Does Not Cause Augmentation in HIT Antibody Mediated Heparin-Induced Platelet Aggregation (HIPA).

Abstract 2417Poster Board II-394Heparin is one of the widely used anticoagulants for the prophylaxis and treatment of thrombotic disorders. Heparin, a linear polysaccharide belonging to a family of glycosaminoglycans (GAGS) consists of repeating disaccharide units of 1-4 linked iduronic acid and glucosamine residues. Heparin is a mixture of low, medium and high molecular fractions and is heterogeneous not only in terms of molecular weight but also sites and degree of sulfation. Oversulfated chondroitin sulfate, one of the important toxic contaminants in certain batches of heparins manufactured during 2007 to 2008 resulted in deaths of some patients following intravenous administration that led to the recall of these heparins by the FDA. An increased incidence of heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS) was reported as a result of contaminated heparins. It was hypothesized that OSCS interacts with heparins and other LMWHs increasing their HIT/HITTS potential. In order to validate this hypothesis blood was drawn from healthy volunteers (n=5) and mixed with 3.2% sodium citrate solution (9 parts of whole blood to 1 part of citrate). The citrated blood samples were centrifuged at 800 rpm to obtain platelet rich plasma (PRP) and further centrifuged at 3000 rpm to obtain platelet poor plasma (PPP). Apheresis fluid was collected from confirmed cases of HIT and pooled. The platelet aggregometers (Biodata) were blanked with individual PPP. The PRP (300ml) was mixed with HIT positive pooled apheresis fluid (200ml) and platelet aggregation was recorded using Gentium Heparin, Enoxaparin, and Bemiparin at a final concentration of 10mg/ml, either alone or in mixtures of 10%, 20% and 30% OSCS. The Heparin-induced platelet aggregations (HIPA) were run for a period of 30 minutes and the tracings obtained. While OSCS alone at a final concentration of 10 mg/ml caused an average of 29.5% platelet aggregation, it did not cause an augmentation of platelet aggregation in 10%, 20% and 30% mixtures with Heparin, Enoxaparin, Bemiparin and AVE 5026 (see table). This data suggests that drugs like heparin, and low molecular weight heparins such as Enoxaparin, and Bemiparin did not augment HIT/HITTS response when combined in various proportions with OSCS. Based on HIPA the reported increase in HIT response may therefore be due to in vivo interactions of the OSCS with platelets and endothelial cells. Corroborative evidence from clinical studies are warranted to validate these preliminary results.Drugs (FC10mg/ml)Drug Alone10%OSCS mixture20%OSCS mixture30%OSCS mixtureOSCS aloneSalineHeparin52.3%60%58.3%58.6%21.6%8.3%Enoxaparin56%58%60.5%60.5%31%7%Bemiparin60%59.6%63%60%37.6%9.3% Disclosures:No relevant conflicts of interest to declare.

P948 A case report of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) post uterine fibroid embolisation at University College Hospital Galway, Ireland, December 2008

P948 A case report of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) post uterine fibroid embolisation at University College Hospital Galway, Ireland, December 2008

Homonymous Hemianopia Caused by Occipital Lobe Infarction in Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

A 73-year-old woman developed mental confusion and finger pain after treatment with enoxaparin following arthroplasty. A platelet count was 163,000/microL. Because digital embolism was suspected, she was emergently treated with heparin and recombinant tissue plasminogen activator (rTPA). During rTPA infusion, she reported sudden hemifield loss, so the infusion was aborted. Brain CT disclosed a non-hemorrhagic occipital infarct. Platelets had fallen to 63,000 over eight days, and antibodies against a complex of heparin and platelet factor 4 were detected. These findings led to the diagnosis of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), an immune-mediated disorder in which venous and arterial thromboses occur. Right lower extremity deep venous thromboses were later diagnosed, and an MRI disclosed multiple cerebral infarcts of recent onset but different ages. Previous reports have documented brain arterial strokes in HITTS, mostly in the distribution of the middle cerebral artery, but clinical documentation is sparse, and there have been no imaging reports. This is the first report to document the clinical and imaging features of a HITTS stroke and the first to describe a stroke presumptively caused by a low molecular weight heparin. It emphasizes that HITTS may cause stroke even when the platelet count is normal. Diagnosis of HITTS should prompt immediate cessation of heparin treatment and substitution of a direct thrombin inhibitor or fondaparinux.

Direct thrombin inhibitors in the treatment of immune-mediated heparin-induced thrombocytopenia.

Heparin was first discovered in 1916 and at present is used in more than 12 million patients a year. In the 1950s, several physicians noticed an uncommon paradoxical phenomenon in which heparin appeared to function as a procoagulant instead of an anticoagulant. This phenomenon is now known as the immune-mediated heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS). Our understanding of this syndrome has evolved over the last 2 to 3 decades, and therapeutic options are arising. This article will focus on the most extensively studied therapy for HIT, which is the class of drugs known as the direct thrombin inhibitors. Specifically, we will focus on the mechanisms by which direct thrombin inhibitors may be useful in this syndrome, the evidence for their use, and the unique characteristics of the two FDA-approved agents in this class, lepirudin and argatroban.

Heparin-induced CVA

Surgeons commonly use heparin as prophylaxis against post-operative venous thromboembolism. Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is a rare but potentially fatal complication of heparin therapy. We describe a case of HITTS in a 49-year-old woman, after elective cholecystectomy, which resulted in a CVA. The purpose of this case report is to increase the awareness of this phenomenon among health care professionals involved in day-care surgery and to discuss its management.

Heparin-induced thrombocytopenia and thrombosis syndrome after cardiac surgery

A case report of multisystem organ failure and limb loss associated with coronary artery bypass is reported. Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) occurs in 1% to 2% of patients suffering from thrombocytopenia associated with heparin or heparinoid use, which amounts to less than 1.4% of the cardiac surgical population. It carries a risk of significant comorbidity and mortality. Providers involved in the care of such patients should be well versed in the etiology and potential complications of HITTS, the treatment options, and alternative modalities of anticoagulation available for use.

Heparin‐induced thrombocytopenia and thrombosis syndrome: in vivo cross‐reactivity with danaparoid and successful treatment with r‐Hirudin

Heparin‐induced thrombocytopenia and thrombosis syndrome (HITTS) is an immune‐mediated drug reaction that occurs 5–14 d after initiation of heparin therapy and is a potentially life‐threatening thrombotic complication. The antibody–heparin–PF4 complexes cause platelet activation and generation of platelet microparticles. The need for anticoagulant treatment in asymptomatic thrombocytopenia is uncertain. However, treatment is warranted in HITTS, as illustrated in the case reported here. Danaparoid, r‐Hirudin and argatroban are effective drugs. Danaparoid has a 10–50% in vitro cross‐reactivity rate with the HIT antibodies, but has been proven to be clinically efficacious even in these cases. Here, we report a case of in vivo cross‐reactivity with danaparoid, the patient showed an excellent recovery with r‐Hirudin.

Emerging anticoagulant and thrombolytic drugs

Since its discovery, heparin has been used intensely as an anticoagulant for several medical and surgical indications. However, efforts are in progress to replace heparin because of its serious complications, such as intraoperative and postoperative bleeding, osteoporosis, alopecia, heparin resistance, heparin rebound, heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS), and other disadvantages. Significant developments in the field of new anticoagulants have resulted in the evaluation and introduction of low molecular weight heparins (LMWHs) and heparinoids, hirudin, ancrod, synthetic peptides and peptidomimetics. However, despite significant progress in the development of these new anticoagulants, a better or an ideal anticoagulant for cardiovascular patients is not yet available and heparin still continues to amaze both basic scientists and the clinicians. To minimise the adverse effects of heparin, newer approaches to optimise its use in combination with the new anticoagulants may provide better clinical outcome. In our experience, the off-label use of argatroban at a dose of 300 microg/kg iv. bolus followed by 10 microg/kg/minute infusion in combination with aggrastat (a glycoprotein [GP] IIb/IIIa inhibitor) at a dose of 10 microg/kg iv. bolus followed by an infusion of 0.15 microg/kg/minute in patients with HIT undergoing percutaneous coronary interventions resulted in elevation of celite activated clotting time (ACT) to 300 seconds followed by a gradual decline and the ACT remained above 200 seconds even after 200 min of drug administration. A bewildering array of newer anticoagulants now exist, such as LMWHs and heparinoids, indirect or direct thrombin inhibitors, oral thrombin inhibitors, such as melagatran (AstraZeneca) and HC-977 (Mitsubishi Pharmaceuticals), Factor IXa inhibitors, indirect or direct Factor Xa inhibitors, Factor VIIa/tissue factor (TF) pathway inhibitor, newer antiplatelet agents, such as GPIIb/IIIa inhibitors, fibrin specific thrombolytic agent, such as tenecteplase and modulation of the endogenous fibrinolytic activity by thrombin activatable fibrinolytic inhibitor (TAFI), Factor XIIIa inhibitors and PAI-1 inhibitors. The quest for newer anticoagulant, antiplatelet and fibrinolytic agents will continue until ideal agents are found.

Heparin-induced thrombocytopenia and thrombosis syndrome.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is an immune-mediated response to the administration of heparin that results in life-threatening thrombosis. The pathophysiology of HITTS remains controversial. The onset of clinical symptoms and laboratory changes is usually delayed 1-2 weeks after exposure to heparin. Thrombosis occurs in both the arterial and venous circulation with significant morbidity and mortality. Complications include deep venous thrombosis, pulmonary embolus, stroke, myocardial infarction, chronic venous insufficiency, extremity ischemia, gangrene, and death. Diagnostic criteria for HITTS include thrombocytopenia during heparin exposure, exclusion of other causes such as sepsis or medications, resolution of thrombocytopenia after withdrawal of heparin, demonstration of in vitro heparin-dependent platelet antibodies, and development of vascular thrombosis. Despite having several disadvantages, the carbon-14-serotonin release assay is the most sensitive and specific test for HITTS. Angiography as an adjunct to other imaging modalities can document the presence, location, and extent of thrombus. Optimal treatment has not yet been defined but should include immediate discontinuation of use of all heparin products and heparin-coated catheters. In addition, alternate methods of antithrombotic therapy should be considered. In severe cases, thrombolysis or thrombectomy may be warranted. Familiarity with the pathophysiology, clinical manifestations, complications, diagnostic criteria, and treatment options associated with HITTS will enable timely recognition and facilitate prompt and effective treatment.

Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor.

Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have focused on direct, or site-directed, thrombin inhibitors. Argatroban is a small-molecule, reversible, direct thrombin inhibitor selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose response, and rapid restoration of the hemostatic systems to baseline on termination of intravenous infusion. The intravenous agent Novastan (brand of argatroban) is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. Novastan is in advanced clinical development in North and South America for several indications, including (1) anticoagulant/antithrombotic therapy in heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia, and thrombosis syndrome (HITTS); and (2) adjunctive therapy to thrombolytic agents in acute myocardial infarction. Results from these trials are projected to be available by early 1997.

Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC)

Thrombotic occlusion is frequently a complication of central venous catheters (CVCs). The original designers and producers of CVCs recommended heparin flush regimens to prevent thrombosis and maintain patency. This has become standard practice although no studies have demonstrated a relationship between heparin flushing and reduction of catheter thrombosis. Many consider the routine use of heparin flushing innocuous. However, serious complications including drug interactions and heparin induced thrombocytopenia and thrombosis syndrome (HITS) have been reported in association with heparin flushing. Numerous studies comparing heparin to saline flushing in peripheral devices suggest equal rates of thrombotic occlusions. The purpose of this study was to examine the incidence of thrombotic occlusions in CVCs using heparin compared to saline flushing. The study involved 78 cancer patients undergoing apheresis collection for peripheral blood stem cells; 29 received saline flushes and 49 received heparin (100 U/ml of saline) flushes. Study endpoints included slow apheresis flow rate (< 50 ml/min), urokinase use for thrombolysis, and radiographic evidence of catheter thrombosis. No significant differences were found for any endpoint between the two groups. These findings suggest saline may be as effective as heparin for maintaining patency of CVCs.

Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC)

Thrombotic occlusion is frequently a complication of central venous catheters (CVCs). The original designers and producers of CVCs recommended heparin flush regimens to prevent thrombosis and maintain patency. This has become standard practice although no studies have demonstrated a relationship between heparin flushing and reduction of catheter thrombosis. Many consider the routine use of heparin flushing innocuous. However, serious complications including drug interactions and heparin induced thrombocytopenia and thrombosis syndrome (HITS) have been reported in association with heparin flushing. Numerous studies comparing heparin to saline flushing in peripheral devices suggest equal rates of thrombotic occlusions. The purpose of this study was to examine the incidence of thrombotic occlusions in CVCs using heparin compared to saline flushing. The study involved 78 cancer patients undergoing apheresis collection for peripheral blood stem cells; 29 received saline flushes and 49 received heparin (100 U/ml of saline) flushes. Study endpoints included slow apheresis flow rate (< 50 ml/min), urokinase use for thrombolysis, and radiographic evidence of catheter thrombosis. No significant differences were found for any endpoint between the two groups. These findings suggest saline may be as effective as heparin for maintaining patency of CVCs.

Report of successful use of argatroban as an alternative anticoagulant during coronary stent implantation in a patient with heparin‐induced thrombocytopenia and thrombosis syndrome

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is a severe complication of heparin caused by an anti-body response to the heparin-platelet factor 4 complex which results in severe thrombosis. Heparin rechallenge in HITTS patients carries a high risk of inducing thrombosis. Antithrombin agents represent treatment alternatives in HITTS patients who require anticoagulation. We report successful coronary stent implantation in a HITTS patient using the antithrombin agent argatroban. © 1996 Wiley-Liss, Inc.