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Semin Thromb Hemost 2012; 38(01): 01-04
DOI: 10.1055/s-0031-1300944
Preface
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hot Topics III

Emmanuel J. Favaloro
1   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, NSW, Australia
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Publication History

Publication Date:
07 February 2012 (online)

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Welcome to the first issue of Seminars in Thrombosis & Hemostasis for 2012, and the third issue compilation entitled “Hot Topics.” Seminars in Thrombosis & Hemostasis last published “Hot Topics” issues in late 2007[1] and early 2008.[2] Those issues were very popular with our readers, as identified in subsequent analyses.[3] [4] Although Seminars in Thrombosis & Hemostasis is a theme-driven publication, the occasional opportunity will be taken to publish a composite issue of articles of current interest and controversy as the need arises. This opportunity has presented itself as a result of the most recent (2010) Eberhard Mammen Young Investigator Awards.[5] [6] Accordingly, as current Editor in Chief of this journal, I am very pleased to present the latest “Hot Topics” issue, including articles from five of our Young Investigator Award winners. The remaining seven articles are from various contributors, including editorial members of this journal.

We begin this issue with several articles devoted to the new oral anticoagulants. In the first article,[7] Schulman and Majeed discuss the strengths and weaknesses of the new oral thrombin inhibitor dabigatran. The search for a replacement for warfarin began several decades ago and many new compounds have been brought forward to clinical trials.[8] The concept of an ideal anticoagulant has been previously noted in several publications,[9–11] and in this issue Schulman and Majeed review the strengths and weaknesses of dabigatran in terms of pharmacokinetics and clinical data. They propose that dabigatran does not accomplish the concept of an ideal anticoagulant for all characteristics, but they conclude that it reaches well above warfarin for most.

Laboratory testing for dabigatran is the focus of the second article of this issue.[12] According to Harenberg and colleagues, dabigatran has been shown to effectively prevent arterial and venous thromboembolism using fixed doses, without any need for adjustment according to laboratory monitoring. It may be however necessary to assess the in vitro anticoagulant effect of dabigatran in special patient populations such as in the elderly and patients with renal impairment, before surgery, to monitor self-compliance and following bleeding or thrombotic episodes in select individuals. Several clotting and thrombin-specific chromogenic substrate assays are available to assess the biological activity of dabigatran. All these tests are prolonged in the presence of dabigatran. This article reports the effects of dabigatran on clinical routine assays as well as their potential usefulness for measuring its activity.

The third article by Salmela and coworkers[13] presents an assessment of the potential issues related to the use of the new oral anticoagulants. Dr. Salmela, the lead author of this article, is one of our Young Investigator Award winners for 2011.[5] The authors advise that clinicians prescribing the new oral anticoagulants (including dabigatran, rivaroxaban, and apixaban) should be aware of the exclusion criteria related to bleeding risks defined in published clinical studies. Notably, at least one-quarter of patients currently using warfarin have an exclusion criterion that may prevent easy transition to the new oral anticoagulants. For example, the target populations appear generalized in the summary of product characteristics for dabigatran. Although routine laboratory monitoring of new oral anticoagulants is deemed unnecessary due to fixed dosing and predictable pharmacology, understanding the extent of thrombin or factor Xa inhibition may aid in special circumstances including evaluating compliance and handling emergency interventions, bleeding complications, or overdoses. Although commonly available, global coagulation time assessments (prothrombin time and activated partial thromboplastin time) are insensitive in their standard format. Nevertheless, they may still assist clinical management by indicating a severe accumulation of anticoagulants. Moreover, a normal thrombin time would exclude a thrombin inhibitor effect. In particular circumstances, specific assays (diluted thrombin time, Ecarin clotting time, antifactor IIa, or antifactor Xa activity) may quantify the anticoagulant effect, but therapeutic ranges for dose adjustment are not yet established. Laboratory results are also influenced by additional clinical considerations such as bleeding (consumption of coagulation factors) or in a postoperative state (activation of coagulation). Without specific antidotes and evidence-based treatment strategies, the new anticoagulants are also clinically concerning in patients with impairment of renal or liver functions. Future postmarketing surveillance and recording of bleeding complications will therefore be of major importance.

In the fourth article of this issue, another of our recent Young Investigator Award winners,[5] Dr. Cuker reviews heparin-induced thrombocytopenia (HIT),[14] which is a devastating complication of heparin therapy. No effective agents were available to treat this devastating and potentially fatal disease until about a decade ago. The management of HIT has undergone a revolution since then, driven by an increased understanding of its pathogenesis. Accordingly, several effective agents for the treatment and prevention of HIT-associated thrombosis are now available, which were proven effective to substantially reduce the incidence of thrombosis, amputation, and death. Nevertheless, the available therapies remain far from ideal, being expensive, complex to manage, and carrying a significant bleeding risk, and so a pipeline of new forthcoming agents are being progressed that hold the promise of greater safety, convenience, and cost-effectiveness.

The next three articles focus largely on the plasma protein von Willebrand factor (VWF). Turner and colleagues[15] first explore the generation and breakdown of soluble ultralarge von Willebrand factor (ULVWF) multimers. ULVWF multimeric strings are rapidly secreted by, and anchored to, stimulated endothelial cells (EC), and are hyperadhesive to platelets until cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13). In ADAMTS-13-deficient familial and autoantibody-mediated thrombotic thrombocytopenic purpura (TTP), there is severely restricted cleavage of EC-anchored ULVWF-platelet strings. The small amount of active enzyme released from their EC cleaves ULVWF strings minimally just above EC surfaces, leading to generation of soluble ULVWF multimers that are 2.5 to 50 times longer than normal plasma VWF forms. Soluble ULVWF multimers are hyperadhesive to platelets and can cause excessive platelet adhesion/aggregation. Soluble ULVWF multimers cannot be cleaved by ADAMTS-13 without exogenous chemicals or extreme shear stress, but can be de-assembled (reduced) in vitro by a free thiol-containing molecule (>30 kD) present in the cryosupernatant fraction of plasma. This molecule has been shown to not be ADAMTS-13, thrombospondin-1, albumin, cysteine, or glutathione. This reduction may help prevent occlusion of the microvasculature by embolic soluble ULVWF multimers (± adherent/aggregated platelets). New inhibitors of platelet adhesion to EC-anchored ULVWF multimeric strings and soluble ULVWF include an aptamer (ARC 1779), a nanobody (ALX-0081), and N-acetylcysteine (NAC).

These concepts are in part continued in the next article by Chapman and colleagues,[16] who review the relationship between ADAMTS-13 and thrombotic microangiopathies, including TTP. Thrombotic microangiopathy (TMA) is a term used to describe a group of disorders characterized by hemolytic anemia, thrombocytopenia, and microvasculature thrombosis. The term may be used when describing patients with TTP, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, as well as a myriad of other disorders. Although limited information exists as to the exact cause of microthrombosis in many TMA, recent advances have been made in the understanding of TTP and its pathophysiology. This progress can be attributed to the discovery of the VWF cleaving protease ADAMTS-13, whose absence in TTP has given the disorder a distinct molecular identity. The discovery of this metalloprotease has prompted a significant amount of research relating to its role in TTP as well as its general function in hemostasis. The exact mechanisms by which this metalloprotease achieves its role are slowly being understood, and these now provide other avenues to explore how TMA may occur and be treated.

The next article by Szántó et al[17] continues the theme of VWF, but this time from the perspective of von Willebrand disease (VWD). These authors also discuss platelet function. Dr. Szántó is another of our recent Young Investigator awardees.[5] Regulation of binding between VWF and its platelet receptor (glycoprotein [GP] Iba) is one of the key steps in controlling hemostasis and thrombosis. Upon vascular injury at sites of high shear rates, the GPIba interaction with subendothelial-bound VWF will initiate the tethering of circulating platelets to the vessel wall. Tethered platelets subsequently roll on the damaged vessel wall, a process that is amplified by the activation of the platelet integrin αIIbβ3 (GPIIb/IIIa). This process is rapidly followed by platelet binding to collagen through other specific platelet receptors, leading to firm adhesion, activation, and stabilization of bonding mediated by αIIbβ3. These interactions may result in two distinct processes depending on the prevailing circumstances: physiologic hemostasis or pathologic thrombosis. Furthermore, VWF carries coagulation factor VIII, which is involved in thrombin formation that in addition to activating platelets mediates fibrin formation and has several other actions. In addition to considering VWD and its many heterogeneous forms, polymorphisms of platelet receptors have also been associated with increased bleeding in VWD. Furthermore, thrombin- and platelet-procoagulant activity may be additional important counter players for determining the severity of bleeding complications associated with VWD.

The next two articles focus on hemophilia A. The first of these is by Jayandharan et al[18] who discuss the role of molecular genetics in hemophilia from the perspective of both diagnosis and therapy. Dr. Jayandharan is another of our most recent Young Investigator Award winners.[5] Despite significant advancements in the field, state-of-the-art care remains inaccessible to many patients with hemophilia, particularly those from developing countries. Thus, innovative approaches in the management of this condition are needed to improve patients’ quality of life. In this context, genetic studies in hemophilia have contributed to the better understanding of its biology, the detection of carriers, and prenatal diagnosis, and even fostering newer therapeutic strategies. This article reviews the applications of molecular genetics in hemophilia and how these techniques can be useful for optimizing patient care.

The second article related to hemophilia, by Coppola and coworkers,[19] discusses the evidence-based achievements, and the many past and ongoing challenges to prophylaxis in children with hemophilia. Recurrent joint bleeding leading to progressive musculoskeletal damage (hemophilic arthropathy), in spite of on-demand replacement with deficient factor concentrates, is the clinical hallmark of severe hemophilia A and B (i.e., the congenital deficiencies of coagulation factors VIII and IX, with circulating levels typically <1 IU/dL). Clinical experience of 50 years, which started in Northern Europe and then progressed to other European countries and North America, including recent randomized clinical trials, has provided definitive evidence that preventing bleeding from an early age through long-term regular prophylactic concentrate infusions limits the adverse clinical consequences of arthropathy and its consequences on the quality of life of hemophilic children. Primary prophylaxis begun after the first joint bleed and/or before the age of 2 years is now the evidence-based, first-choice treatment in severe hemophilia. Recent data also suggest a role for early prophylaxis in preventing inhibitor development, the most serious complication of replacement therapy. Secondary prophylaxis also aims to avoid (or delay) the progression of arthropathy. The earlier the treatment is started, the better the outcomes in joint status and quality of life. Although prophylaxis has radically transformed the natural history of severe hemophilia, several barriers to its implementation and general diffusion remain, including the obvious economic constraints, problems with venous access, as well as long-term adherence and uncertainties regarding the optimal prophylaxis regimen.

The mutual association between thrombin and cancer is then explored by Franchini and Mannucci.[20] This is a relationship that has been recognized for nearly 150 years and which has also been previously explored within Seminars in Thrombosis & Hemostasis.[21] [22] Despite this, the mechanisms underlying this association are not completely understood. This review focuses on the most important pathways by which thrombin may affect cancer growth and dissemination. The potential role of congenital (i.e., hemophilia) and pharmaceutical (i.e., antithrombotic agents) anticoagulation in cancer incidence and survival is also discussed through the analysis of published experimental and clinical studies.

The subsequent review is on platelet-derived microvesicles (PMVs), and is contributed by Aatonen et al.[23] A coauthor of this article, Dr. Siljander, is another of our most recent Young Investigator Award winners,[5] and the last to be lauded in this issue of Seminars in Thrombosis & Hemostasis. Platelets can release a heterogeneous pool of vesicles, which include the plasma membrane-derived microparticles (PMPs) and the multivesicular body-derived exosomes. As both vesicle types are generated upon activation and their distinction is complicated due to an overlap in their molecular properties and sizes, the authors discuss them as an entity, namely the PMVs. Several induction pathways can lead to the formation of PMPs, but these will differentially determine specific molecular profiles and facilitate tailor-made participation in intercellular communication. This dynamic variability may lie behind the multifaceted and sometimes very different observations of the PMPs in physiological and pathological settings. Currently, little is known of platelet-derived exosomes. Overall, PMVs participate in several homeostatic multicellular processes, including hemostasis, maintenance of vascular health and immunity, and also play a role in thrombotic and inflammatory diseases as well as cancer progression. In this review, the differential activation pathways and the molecular and functional properties of PMVs are discussed in context with their (sometimes) paradoxical role in health and in disease. Methodological issues of PMV detection and analysis are also discussed according to the recent advances within the field.

The final article in this issue investigates the potential role of vitamin D in thrombosis and hemostasis and concludes that this relationship is “more than skin deep.” Deficiency of vitamin D3 is a highly prevalent condition worldwide. Clinically, vitamin D3 has a key role in calcium homeostasis and bone mineralization and has recently been implicated in the pathogenesis and/or progression of several acute and chronic illnesses, including cardiovascular disease (CVD). Accumulating evidence from observational studies, Targher and colleagues[24] report that prospective studies suggest that low levels of serum 25-hydroxyvitamin D3 are independently associated with an increased risk of CVD events and death, although the molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a cardiovascular role for the active metabolite of vitamin D3. 1-α,25-dihydroxyvitamin D3 regulates the renin–angiotensin system, suppresses proliferation of vascular cell smooth muscle, improves insulin resistance and endothelial cell-dependent vasodilation, inhibits myocardial cell hypertrophy, exerts anticoagulant and antifibrotic activity, and modulates macrophage activity and cytokine generation. Overall, the high prevalence of vitamin D3 deficiency and plausible biological mechanisms linking this to CVD risk suggest that the prevention or treatment of vitamin D3 deficiency remains a promising field to explore in CVD. Nevertheless, whether vitamin D supplementation could have any potential benefit in reducing future CVD events and mortality risk remains to be determined.

I would like to sincerely thank all authors for their interesting contributions, and I sincerely hope that our readers enjoy this collation of articles. I would also like to make a special wish of gratitude to our most recent Young Investigators Award winners[5] for their contributions, and wish them the best of luck for their careers in this field. Finally, a note of special thanks to Giuseppe Lippi, one of our Associate Editors, for assisting in the manuscript review process.