Informa Healthcare has developed various series of beautifully produced books in different branches of medicine. These series have facilitated the integration of rapidly advancing information for both the clinical specialist and the researcher.

My goal as editor-in-chief of the Fundamental and Clinical Cardiology Series is to assemble the talents of world-renowned authorities to discuss virtually every area of cardiovascular medicine. I feel we have achieved this objective with Heparin-Induced Thrombocytopenia, Fourth Edition.

Theodore Warkentin, MD, PhD, and Andreas Greinacher, MD, have written and edited a much-needed practical and timely book. These world-renowned investigators have assembled a multidisciplinary and global team of key opinion leaders to assist them in creating one of the best written and most highly successful efforts in the history of our Fundamental and Clinical Cardiology Series. In the current edition, the editors hone in on the hot topics and controversies. These include assessment of the clinical likelihood of heparin-induced thrombocy-topenia (HIT), the increasing problem of excessive diagnosis of HIT, and new strategies to manage suspected and proven HIT.

HIT with thrombosis can lead to gangrene, amputation, and death. It is one of the most feared catastrophes in cardiovascular medicine. The optimal approach requires a multidisciplinary team. Drs. Warkentin and Greinacher have chosen experts from many continents and academic backgrounds to provide comprehensive data and guidelines in this informative and carefully edited book.

HIT is a rapidly changing field. I will take this book with me on the wards when I am confronted with new cases of this deadly disease. I especially appreciate the clear explanations of pathophysiology and therapy that the authors provide. Their coverage of direct thrombin inhibitors (lepirudin, argatroban, bivalirudin), danaparoid, pentasaccharides, and other therapeutic alternatives is superior to any resource available on the Internet or elsewhere.

Future contributions to the Fundamental and Clinical Cardiology Series will include books on molecular biology, interventional cardiology, and clinical management of such problems as coronary artery disease, venous thromboembolism, peripheral vascular disease, and cardiac arrhythmias.

Samuel Z. Goldhaber, MD Professor of Medicine Harvard Medical School Senior Staff Cardiologist Brigham and Women's Hospital Boston, Massachusetts, U.S.A.

Editor-in-Chief Fundamental and Clinical Cardiology Series

This fourth edition of Heparin-lnduced Thrombocytopenia continues to expound on the themes enunciated in the Preface to the First Edition (2000): heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome; HIT pathogenesis melds both platelet and coagulation activation—a key to comprehending its prothrombo-tic nature; and HIT exhibits a strikingly variable frequency in different clinical situations.


We have a better understanding of the diagnostic approach to HIT. The combination of a clinical assessment of pretest probability, together with the results of laboratory testing for the pathogenic HIT antibodies, enables the clinician to stratify patients into risk categories for HIT-associated complications. Clinical scoring systems, such as the 4 T's, are now available and evaluated, which help to standardize this approach. A major achievement is the high negative predictive value of this scoring system, i.e., a low score effectively "rules out" HIT. Further, the diagnostic value of the magnitude of a positive test result for "HIT antibodies" is increasingly appreciated. As well, the high sensitivity of the platelet factor 4 (PF4)-dependent enzyme-immunoassays (EIAs) and washed platelet activation assays (when performed by experienced laboratories) is increasingly accepted. New test concepts, such as the rapid assays, and novel methods for detecting antibodies against several heparin-binding proteins simultaneously by EIA are being introduced. But caution is required: there is growing recognition that HIT may be overdiagnosed, at least when low probability clinical situations and weak-positive EIAs are misinterpreted as indicating clinical HIT. Our selection of the "iceberg model" of HIT for the book's cover is meant to highlight the reality that only a minority of heparin-dependent antibodies have the potential to cause HIT, and that the various laboratory assays differ regarding their usefulness in detecting these pathologic "HIT antibodies."

The pathogenesis of HIT is now better understood, especially the biophysical nature of the PF4/heparin immune complexes. Ultrastructural studies have helped to clarify the basis of the greater immunogenic potential of unfractionated heparin [vis-à-vis low molecular weight heparin (LMWH) and fondaparinux], and have also provided a glimpse into the basis of the paradox of immunization induced by the sulfated pentasaccharide, fondaparinux, while at the same time its inability to form well the conformational changes leading to autoepitope formation on PF4. Still, the future of HIT research remains the unraveling of its unusual immunobiology.

Important new concepts in HIT treatment have evolved. There is emerging consensus that the "package insert" dosing for the direct thrombin inhibitors— particularly lepirudin—is too high. That the dangers of coumarin (warfarin, phenprocoumon, acenocoumarol) use during the acute phase of HIT include not only its potential to induce protein C depletion (thereby predisposing to microthrombosis syndromes such as coumarin-induced venous limb gangrene), but also to predispose to underdosing of direct thrombin inhibitor therapy (through prolongation of the partial thromboplastin time by coumarin). Also new to the fourth edition is the approval of bivalirudin for anticoagulation in percutaneous coronary intervention in patients with acute or previous HIT, an indication previously held only by argatroban. New data on the efficacies of the standard HIT therapies—danaparoid, lepirudin, and argatroban—are also discussed.

The growing use of LMWH results in a shift of patient populations affected by HIT, from post-major surgery to the intensive care setting, where unfraction-ated heparin (UFH) use still predominates. But, among critically-ill patients, HIT explains only a minority of platelet count declines, reflecting the high frequency of numerous thrombocytopenia-inducing comorbidities. How should such thrombo-cytopenic patients be managed in whom the diagnosis of HIT is raised, but where the probability is judged to be only low or intermediate? What anticoagulant options are available—and in what doses? An evolving concept in countries in which danaparoid is available is to use this agent in prophylactic doses in this setting of low (or even moderate) probability of HIT (when thrombosis is not present), pending clarification of the diagnosis. This approach could reduce the risk of bleeding associated with therapeutic-dose regimens. And, this edition includes a new chapter describing novel anticoagulants, such as fondaparinux, that could have future roles either for prevention or management of HIT.

HIT comprises a myriad of complexities and counter-intuitions. The new chapter on "paradoxes, myths, and realities" of HIT highlights some of the potential sources of error that can lead to catastrophic outcomes in affected patients and is a fitting conclusion to a topic with paradoxes aplenty.

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