Special Thanks

A multi-author book depends on many contributors. For us, as editors, it was a great pleasure to produce this 4th edition together with our contributing colleagues throughout the world, many of whom became our friends, all dedicated to research and resulting improved clinical management of HIT. We would also like to acknowledge the help of many individuals in this project. Paula Garber was superb in managing this edition on behalf of the publisher. In Hamilton, we wish to thank in particular Maria Adamek, Jo-Ann Sheppard, Jim Smith, Jane Moore, Carol Smith, Di Moffatt, Junior Santos, Rumi Clare, and Dr. Greg Lo; in Greifswald, gratitude is owed to Uta Alpen, Norbert Lubenow, Petra Eichler, Kathleen Selleng, David Juhl, Birgitt Furll, Ulrike Strobel, Ricarda Raschke, and Carmen Blumentritt, for their invaluable technical and administrative support, for ideas and discussions, and especially for being part of the team dedicated to research in HIT.

Theodore E. Warkentin Andreas Greinacher

Since the appearance of the second edition of Heparin-lnduced Thrombocytopenia over three years ago, new and important advances in the understanding and treatment of this paradoxical adverse reaction to heparin have continued to emerge.

For example, mapping of the target epitopes recognized by HIT antibodies to platelet factor 4 (a "self protein" found within platelets) rather than on heparin itself helps to explain some of the "autoimmune" features of HIT, such as its potential to present as thrombocytopenia and thrombosis several days after stopping heparin ("delayed-onset HIT"), as well as the increased risk of thrombosis that can persist for several days or weeks even after HIT is recognized and the inciting agent, heparin, stopped. A new double-transgenic animal model of HIT (with mice engineered to produce both human platelet factor 4 and human platelet Fcg receptors provides direct evidence that platelet Fc receptor-mediated platelet activation by HIT antibodies indeed helps to explain thrombocytopenia and the associated risk of thrombosis in HIT.

There is increasing recognition of the danger of microvascular thrombosis in HIT, particularly when warfarin or other coumarin anticoagulants are given when HIT remains active. This can lead to a variant of coumarin-induced necrosis, with a predisposition to involve the extremities, i.e., warfarin-induced venous limb gangrene complicating HIT-associated deep-vein thrombosis. The recognition of this syndrome underscores the importance of continuing therapy with a direct thrombin inhibitor or danaparoid (where available), and postponing warfarin therapy until substantial resolution of the thrombocytopenia of HIT has occurred.

In 2002, danaparoid was withdrawn from the United States, leaving the direct thrombin inhibitors, lepirudin and argatroban, as the two main agents in that market for managing the difficult clinical situation of HIT complicated by thrombosis. (Danaparoid remains available in Canada, the European Union and elsewhere.) Another recent clinical development is the recognition that lepirudin bolus infusion can (rarely) trigger life threatening anaphylaxis, perhaps because of antibodies that have been formed against this foreign protein (although lepirudin is manufactured using recombinant biotechnology, its blueprint is drawn from the medicinal leech).

Perhaps most important, there is increasing agreement that patients suspected as having HIT should not merely have their heparin stopped, but should additionally have an alternative anticoagulant given, so as to reduce the risk of subsequent thrombosis. Indeed, argatroban has FDA approval for this novel indication of prophylaxis against thrombosis in HIT. Post-marketing studies indicate that lepirudin is also effective in this situation. Thus, physicians need to consider carefully the possibility of HIT in many hospitalized patients who develop thrombocytopenia during heparin therapy, or even in patients who return to the emergency room with thrombosis and thrombocytopenia following a recent hospitalization in which heparin was given (delayed-onset HIT). If HIT is strongly suspected, alternative anticoagulation is indicated.

All 20 chapters from the second edition have been revised, and two new chapters added. One reviews pediatric HIT, and the other discusses use of a new direct thrombin inhibitor, bivalirudin, in the context of preventing and, possibly, treating HIT. Of course, for their generosity of time in updating and adding to this book, we thank the contributors. And, for their invaluable efforts, we thank (in Canada) Jo-Ann I. Sheppard, Aurelio Santos, Jr., James W. Smith, and Maria Adamek, and (in Germany) Uta Alpen, Petra Eichler, Norbert Lubenow, Lena Carlsson, and Theresia Lietz.

Despite the lower risk of HIT with low molecular weight heparin and the novel factor Xa-inhibiting pentasaccharide (fondaparinux), compared with unfrac-tionated heparin, HIT does not seem to be going away. It remains an issue particularly in cardiac surgery patients, where unfractionated heparin remains the prevailing drug for providing anticoagulation during the cardiac surgery itself, as well as in the postoperative period in many centers. Further, the increasing awareness of HIT, and the increasing availability of laboratory testing for HIT antibodies, means that more cases of HIT continue to be recognized, even if, perhaps, the overall frequency of this reaction is in decline (due to increasing use of low molecular weight heparin). Further, the common concurrence of thrombo-cytopenia and heparin therapy in hospitalized patients, and the medicolegal consequences of a missed diagnosis of HIT, mean that this diagnosis continues to be considered and discussed daily around the world. We hope that this compilation of information and practical guidelines on HIT diagnosis and treatment will assist the health care professional in managing this challenging and fascinating disorder.

Theodore E. Warkentin Andreas Greinacher

Since the first edition of Heparin-lnduced Thrombocytopenia appeared, there is much new on this topic. In particular, there is growing awareness of the intense "thrombin storm" characteristic of heparin-induced thrombocytopenia (HIT), especially after heparin has been stopped. Recently, another therapeutic option became available to manage this situation, namely, argatroban, a synthetic, small-molecule, direct thrombin inhibitor. Significantly, the indication approved by the Food and Drug Administration for this novel anticoagulant was "for prophylaxis or treatment of thrombosis in patients with HIT."

This approval of argatroban for prevention of thrombosis in HIT parallels the growing recognition that even "isolated HIT" (i.e., HIT recognized on the basis of thrombocytopenia alone, rather than because of a new thrombotic complication) is associated with an unacceptably high risk of life- and limb-threatening thrombosis, even when heparin has been promptly discontinued because of a falling platelet count. Indeed, this view that isolated HIT itself is an indication for prescribing an alternative anticoagulant in most patients has been accepted by the 2000 Consensus Conference on Antithrombotic Therapy of the American College of Chest Physicians.

Thus, there now exist three anticoagulant agents for which there is consensus regarding efficacy treatment for HIT: danaparoid sodium, recombinant hirudin (lepirudin), and argatroban (listed in order of availability). Approval status of the three drugs with respect to HIT varies in different countries, but even if unap-proved they may be available for "off-label" use, or on a "compassionate-use" basis. Important differences in pharmacokinetics, particularly in half-life, metabolism, and monitoring, mean that each of these three agents will be appropriate in some of the complex clinical settings in which HIT occurs.

Other developments in HIT include new understanding of the molecular structure of the target antigen, a proposed role for activation of monocytes in thrombin generation, and new animal models for studying this fascinating syndrome. Even the clinical syndrome itself is now better understood: The influence of previous heparin exposure on the timing of onset of HIT has been clarified, and the peculiar transience of HIT antibodies has been shown. These clinical and laboratory insights provide a firmer basis for estimating pretest probabilities of HIT in various clinical settings, and also give a scientific rationale for considering re-exposure to heparin in a patient with previous HIT but whose antibodies are no longer detectable.

Ironically, improvements in a laboratory testing also mean that not all detectable HIT antibodies are truly pathogenic. Thus, physicians need to interpret results of diagnostic assays in the clinical context, so as to estimate accurately the posttest probability of HIT. A major aim of this book is to provide the relevant information for understanding such a "clinipathologic" framework of HIT.

More and more, it seems, HIT is an issue in cases of alleged medical malpractice. This is because HIT often occurs in patients who received heparin for prophylaxis of thrombosis. So it can seem evident even to a nonmedical person that something fundamentally went wrong if the patient ended up with severe pulmonary embolism or even limb loss.

To address these new developments, and others, all chapters of the first edition have been updated. In addition, two new chapters have been added, one discussing the use of argatroban for management of HIT and the other dealing with U.S. perspectives on medicolegal aspects of HIT.

Theodore E. Warkentin Andreas Greinacher

An anticoagulant turns procoagulant; an antithrombotic causes thrombosis. This is the fundamental paradox of heparin-induced thrombocytopenia (HIT), an antibody-mediated prothrombotic drug reaction without parallel in clinical medicine.

Heparin justifiably is listed as an "essential" drug by the World Health Organization (1997): with a rapid onset of action, simple laboratory monitoring, and a low cost, heparin has benefited countless patients. And yet, beginning some 40 years ago, a few physicians asserted that heparin caused unusual and sometimes catastrophic thrombi in some of their patients who received the drug for a week or more. Subsequently, two landmark studies led by a vascular surgeon, Donald Silver, identified the key elements of the HIT syndrome: thrombocytope-nia, thrombosis, and heparin-dependent antibodies in the patient's blood (Rhodes et al., 1973,1977; see Chap. 1). But key questions remained: how can heparin cause thrombosis? What is the frequency of this event? How should these patients be treated? This book summarizes a quarter-century of observation and study that has begun to provide answers to these questions.

The reader will observe several "themes" in this book. One is that HIT should be considered a clinicopathologic syndrome. This means that HIT should be diagnosed only when 1) one or more unexpected clinical events occur during heparin treatment (most commonly, thrombocytopenia with or without thrombosis), and 2) heparin-dependent antibodies can be demonstrated in the laboratory. A corollary is that the inability to demonstrate the antibodies using reliable assays means that an alternative diagnosis must be considered. Both editors view HIT through this "filter" of confirmatory laboratory testing. For us, the laboratory has been crucial to defining the HIT syndrome, by making it possible to distinguish patients who really have HIT from those affected by the numerous other causes of thrombocytopenia encountered in clinical medicine. Indeed, our own first studies on HIT, presented at the XIIIth Congress of the International Society on Thrombosis and Hemostasis in Amsterdam, focused on improvements and innovations in diagnostic testing using platelet activation assays (Greinacher et al., 1991; Warkentin et al., 1991). Coincidentally, this was the same time scientific meeting at which Jean Amiral and colleagues (1991) announced the identity of the protein coantigen of HIT (platelet factor 4; PF4), providing another diagnostic avenue (enzyme immunoassay). Thus, when we stepped onto the patient wards, we increasingly relied on the laboratory to confirm or refute the diagnosis of HIT. Through mutually reinforcing experiences of clinic and laboratory, the nature of the HIT syndrome was unfolded. And, over time, the wide spectrum of complications of HIT, and its high frequency in certain clinical settings, became apparent.

Our focus on HIT as a clinicopathologic syndrome has implications for the terminology we have used in this book. Because the causative role of heparin can generally be established—in the appropriate clinical context—by the demonstration of pathogenic, heparin-induced thrombocytopenia to describe this syndrome (i.e., heparin can be shown convincingly to have "induced" the platelet count fall in a particular patient). In contrast, we use the term nonimmune heparin-associated thrombocytopenia (nonimmune HAT) to describe patients who have developed thrombocytopenia during heparin treatment and in whom a pathogenic role for HIT antibodies cannot be shown. In our view, this term unambiguously denotes that HIT antibodies are not responsible for the thrombo-cytopenia, while leaving open the possibility that heparin may have played a role in the causation of the platelet count fall by nonimmune mechanisms (although coinciding thrombocytopenia from another cause is probably the most frequent explanation for this event). We have also introduced the term pseudo-HIT to indicate those patients with nonimmune HAT that, by virtue of associated thrombosis or the timing of onset of thrombocytopenia, closely mimics HIT (see Chap. 11).

A second theme of this book is the importance of in vivo thrombin generation in the pathogenesis of HIT. By virtue of antibody-mediated activation of platelets and endothelium, and the neutralization of heparin by PF4 released from activated platelets, the HIT syndrome can be understood as a prothrombotic disorder characterized by activation of the coagulation system. This concept of HIT helps explain its association with venous as well as arterial thrombosis (by analogy with other hypercoagulable states, such as congenital deficiency of natural anticoagulant factors), and also the occasional HIT patient with decompensated, disseminated intravascular coagulation (DIC).

Marked thrombin generation in HIT also helps explain its association with coumarin-induced venous limb gangrene, an unusual syndrome now recognized as a potential complication of coumarin treatment of HIT-associated deep venous thrombosis (see Chap. 2). This iatrogenic disorder represents perhaps the most striking of all the HIT treatment paradoxes (see Chap. 12): two antithrombotic agents with distinct adverse event profiles that interact to produce a profound disturbance in procoagulant-anticoagulant balance, i.e., increased thrombin generation (secondary to HIT) together with acquired, severe protein C deficiency (secondary to coumarin treatment). Finally, the concept of HIT as a hypercoagul-able state with in vivo thrombin generation provides a rationale for understanding the efficacy of new therapies that either reduce thrombin generation by inhibition of factor Xa (e.g., danaparoid) or directly inactive thrombin (e.g., lepirudin).

A third theme of this book is the peculiarly inconstant nature of HIT, in particular, its variable frequency and clinical presentation among different patient populations treated with heparin. Figure 1 depicts HIT as an iceberg within which a variety of clinical and laboratory factors interact to influence antibody formation, development of thrombocytopenia, and, finally, resulting clinical complications, such as thrombosis. A recent, novel concept is that the size and buoyancy of the HIT icebergs can vary among different patient populations who receive heparin. This concept of multiple icebergs of HIT is shown in Chapter 3, Figs. 3 and 5. Unraveling the clinical and laboratory determinants for these differences in the icebergs among patient populations is a major challenge of current and future investigation.

Why should HIT be the subject of a book? First and foremost, HIT is common, and nonimmune HAT is very common. According to the Council for International Organization of Medical Sciences (CIOMS III), adverse drug reactions can be classified as common if they occur in 1—10% of patients, and very common if they occur in 10% or more of patients. There is convincing evidence that HIT occurs in as many as 5% of certain patient populations, such as postoperative orthopedic patients receiving unfractionated heparin. The clinical

• Endothelial cell activation by HIT antibodies (Chap. 9) DIC with natural anticoagulant failure (Chap. 2) Autoreactive platelet-activating IgG (?) (Chap. 2)

• Concomitant clinical factors, including Atherosclerosis (Chap. 3)

Vascular trauma (e.g., intravascular catheters; Chap. 2) Postoperative immobility (Chap. 3) Severity of thrombocytopenia (Chap. 2) Venous limb gangrene: coumarin treatment (Chaps. 2,11,12) Prevent thrombosis by treating 'Isolated HIT' (Chap. 12)

• Risk of thrombocytopenia depends on Clinical setting (e.g., post-orthopedic surgery; Chap. 3) Heparin dose (Chap. 3)

Platelet Fc receptor number or genotype (Chap. 8) Definition of thrombocytopenia used (Chaps. 2, 3) Inflammatory responses (Chap. 5)

• Frequency of HIT antibody formation depends on Heparin chain length and degree of sulfation (Chaps.3, 6, 7) Clinical setting (e.g., cardiac>orthopedic patients; Chap. 3) Perioperative platelet factor 4 levels (Chaps.3, 4, 5) Nonimmune platelet activation (Chaps. 4, 11)

FIGURE 1 The iceberg model of heparin-induced thrombocytopenia as an index for this book.

influence of HIT is substantial: about half of these patients develop HIT-associated thrombosis. Nonimmune HAT occurs in as many as 30% of certain patient populations. Thus, physicians need to be able to reliably distinguish among the various thrombocytopenic disorders that occur during heparin treatment. This will minimize the risk of inappropriate treatments, such as failing to stop heparin administration in a patient with probable HIT, or deciding to stop heparin in a patient with nonimmune HAT or pseudo-HIT. Because HIT is a life- and limb-threatening iatrogenic illness with many diagnostic and treatment pitfalls, medicolegal consequences of caregiver's action or inaction can be significant (see Chap. 21).

A second reason for the compilation of this book is that most of the pieces of the HIT puzzle are now firmly in place. Consensus has emerged on several key aspects of the syndrome, including the nature of its target antigen, the participation of platelet and endothelial cell activation in the pathogenesis of thrombosis, the frequency of HIT, and optimal laboratory testing. The publication of this book reflects this coherence in our understanding of the HIT syndrome. Yet there remain important unresolved issues: for example, what is the fundamental nature of the "autoimmune" response to the PF4-heparin neoepitope? Why is the immune response to the HIT antigen so transient? Why do only a subset of patients who form HIT antibodies develop clinical HIT?

Heparin has been, and will continue to be, one of the most important agents for the prophylaxis and treatment of venous and arterial thromboembolism. Consequently, HIT will continue to be an important management problem for some time to come. Both of us have spent a decade of our scientific careers providing, in the context of other investigators' work, a rational management approach aimed at minimizing morbidity and mortality among the many patients who develop the most common immune-mediated adverse drug reaction in clinical medicine. The importance of controlling thrombin generation in HIT is now widely appreciated. The book should help guide clinicians through the often paradoxical clinical and management problems posed by patients with HIT (see Chaps. 12-19).

The book is a tribute to our scientific mentors, John G. Kelton and Christian Mueller-Eckhardt, and the close cooperation of many of our scientific colleagues and personal friends whose efforts made this project possible.

We would also like to acknowledge the help of many individuals in this project. In North America, we thank Jo-Ann Sheppard for technical support over the years, and also for preparing many of the figures in this book; Aurelio Santos, Jr., for preparing the key Fig. 12.1; James W. Smith, for help with vexing computer problems; Katherine Bean and Maria Adamek, for able secretarial assistance; and Erica Warkentin, for checking references and manuscripts. In Germany, we thank Uta Alpen for excellent secretarial assistance and Petra Eichler, Norbert Lubenow, Lena Carlsson, and Oliver Ranze for valuable discussion and review of manuscripts.

Theodore E. Warkentin Andreas Greinacher

0 0

Post a comment