Hot Topics II: An Editorial Collection of Current Issues and Controversies in Thrombosis and Hemostasis

Welcome to another special issue of Seminars in Thrombosis and Hemostasis. Characteristically, each issue of Seminars in Thrombosis and Hemostasis is theme-driven, with each new issue devoted to a specific or particular theme of relevance to thrombosis and hemostasis. The theme of the current issue of Seminars in Thrombosis and Hemostasis is uncharacteristically less specific and rather represents a broader collection of articles related to thrombosis and hemostasis. This first issue for 2008 carries on from the last issue of 2007 in terms of it being the second consecutive issue devoted to the topic of current issues and controversies in thrombosis and hemostasis. However, the content for the current issue has derived primarily from members of the editorial team at Seminars in Thrombosis and Hemostasis. On this occasion, therefore, the current issue largely reflects our take on topics considered to be topical or potentially controversial. The issue has also been supplemented by selected articles contributed by other experts in the field of thrombosis and hemostasis. We hope once again that you enjoy this slight diversion from the norm.

The first article on offer was prepared fairly late in the process of composing this issue of Seminars in Thrombosis and Hemostasis and was written in response to recent interest in the impact factor, both from authors and journal editors alike. The impact factor is a measure of recent re-citation rates and is commonly used as a marker of both article and journal “quality.” Although the impact factor is of general interest to all fields and disciplines, this article should be of specific interest to readers of Seminars in Thrombosis and Hemostasis, as it includes an assessment of the pattern of past publications within this journal, in part to highlight several limitations to the use of the impact factor as the sole marker of article and journal utility. The author has also included other relevant examples, as well as a minireview of the uses and abuses of the impact factor.

The remainder of this issue of Seminars in Thrombosis and Hemostasis comprises a collection of articles that are primarily thrombosis-associated or primarily bleeding-associated. In keeping with our journal's name, the thrombosis-associated articles precede the bleeding-associated articles.

Accordingly, the second article of this issue of Seminars in Thrombosis and Hemostasis is from Levi and colleagues and looks at the metabolic modulation of inflammation-induced activation of coagulation. There is a bidirectional interaction between coagulation and inflammation, which is relevant in various disease states that are dominated by systemic inflammatory responses (including severe infection and chronic vascular disease), and which is modulated by metabolic factors. Glucose and insulin, and changes in the metabolism of lipoprotein, all seem to affect the inflammation-induced activation of coagulation, and this may have significant downstream effects, including organ dysfunction and survival. Specifically, hyperglycemia appears to affect the inflammation-induced and tissue factor-driven activation of coagulation, whereas hyperinsulinemia modulates the fibrinolytic response. Levi and colleagues report that the modulatory effect of metabolic factors on inflammation and coagulation may also have an impact on clinical outcome in various disease states.

The next article, from Wada and Sakuragawa, discusses the potential usefulness of fibrin-related markers for the diagnosis of thrombosis. These include D-dimer (as typically requested), but also those less typically requested, such as fibrinogen degradation products and soluble fibrin. Levels of fibrin-related markers are significantly elevated in patients with thrombosis, including deep vein thrombosis and disseminated intravascular coagulation. Interestingly, normal background population D-dimer levels may differ according to genetic or geographic considerations or depending on methodology. Thus, D-dimer assay levels might be 2-fold higher in Japan than those found in Europe and North America. The levels of soluble fibrin are significantly elevated in patients before the onset of thrombosis, suggesting that this marker is useful not only for the diagnosis of thrombosis but also for identifying a prethrombotic state. Overall, elevated levels of fibrin-related markers indicate a high risk for, and are considered to be useful for the diagnosis of, thrombosis.

The article by Harenberg and Wehling provides an extensive overview of the current and future prospects for anticoagulant therapy, with a focus on inhibitors of factor Xa and factor IIa. There are a large number of indirect and oral direct factor Xa and oral direct factor IIa inhibitors with improved pharmacologic profiles (compared with heparins and vitamin K antagonists) currently in clinical development. Their overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, these authors review the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, dose-finding studies for the treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of a large number of ongoing clinical trials.

Fareed and colleagues then present another extensive overview of heparins, oral anticoagulants, and aspirin, and ask the question: Will these survive after the year 2010? These compounds form the basis of current conventional management of thrombotic and cardiovascular disorders. The authors suggest that despite remarkable progress in life sciences, these drugs still remain a challenge and a mystery to us, and their use is far from optimized. For example, the development of low-molecular-weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. From this background, additional drugs will continue to develop; however, none of these drugs, they believe, will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as ADP receptor inhibitors, glycoprotein IIb/IIIa inhibitors, and other specific inhibitors have more limited effects and have been tested in patients who have already been treated with aspirin. Warfarin still provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. Accordingly, the optimized use of these “old” drugs still remains the approach of choice to generally manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa, and XIIIa), recombinant forms of serpins (antithrombin, heparin cofactor II, and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin, and site-specific serine protease inhibitor complexes have also been developed. There is also a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and anti-IIa agents), which are slated to replace oral anticoagulants. Several safety concerns related to liver enzyme elevations, thrombosis rebound, and bleeding have been reported with their use. The newer antiplatelet drugs have also added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated COX-1 and P2Y₁₂ receptors as targets for new drug development. Despite remarkable recent progress, however, Fareed and colleagues suggest that heparins, warfarin, and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond the year 2010. In addition to sorting out safety issues, none of the newer drugs can be expected to replace the conventional drugs in polytherapeutic approaches.

The article from Jeske and colleagues continues the theme of anticoagulant therapy and deals with the topic of differentiating low-molecular-weight heparins (LMWHs) based on their chemical, biological, and pharmacologic properties. This has significant implications for the development of generic versions of LMWHs. These compounds are polypharmacologic drugs that are used to treat thrombotic and cardiovascular disorders. Different versions of these drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. However, applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence, and pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities such as LMWHs and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. Various regulatory bodies are currently developing guidelines for the acceptance of biosimilar agents including LMWHs; but until such guidelines are complete, generic interchange of LMWHs may not be feasible.

The next article is by Prechel and Walenga, who discuss a significant complication of anticoagulant heparin therapy, namely heparin-induced thrombocytopenia (HIT), which can in some individuals progress to severe thrombosis, amputation, or death. HIT is an immune response in which antiheparin antibodies cause platelet activation, platelet aggregation, the generation of procoagulant platelet microparticles, and the activation of leukocytes and endothelial cells. Early diagnosis is based on a comprehensive interpretation of clinical and laboratory information and is important to improve clinical outcomes. However, limitations of the laboratory assays and atypical clinical presentations can make the diagnosis difficult. Clinical management of patients with HIT is with a non-heparin anticoagulant such as a direct thrombin inhibitor or danaparoid followed by a vitamin K antagonist for long-term treatment. Some new anti-factor Xa drugs and other non-heparin antithrombotic agents can also potentially be used for the treatment of HIT when clinically validated. Important drug-specific limitations and dosing and monitoring guidelines must be considered to optimize patient safety. There still remain many issues regarding the optimal clinical management of HIT.

The next article marks the beginning of the “bleeding-associated” articles for this special issue of Seminars in Thrombosis and Hemostasis, and Watson and Greaves pose the very pertinent question: Can we predict bleeding? No one would argue that the prior identification of subjects who are likely to bleed excessively when subjected to operative surgery and other invasive procedures is desirable. Frequently, however, undue reliance is placed on laboratory-based screening tests of blood coagulation for this purpose, potentially instead of the taking of clinical bleeding histories. They highlight the view that published evidence does not support this approach as the current laboratory tests are not fit for purpose and their sensitivity and specificity are low. Moreover, they argue, whereas some more global assays may have use in the diagnostic workup in subjects with hemorrhage, none has so far been established as an efficient method for prediction of bleeding in unselected populations. Accordingly, they report a strong renewed interest in the use of the clinical history for the prediction of bleeding. Recent reports suggest that, when a structured questionnaire is employed to derive a bleeding score, there is a high positive predictive value for the detection of bleeding disorders.

Franchini and colleagues then provide a critical systematic review on the use of recombinant factor VIIa (rFVIIa) in life-threatening obstetric postpartum hemorrhage. A total of 31 studies were found, incorporating 118 cases of massive postpartum hemorrhage treated with rFVIIa. The median age of the patients was 31.4 years, and cesarean section appeared to increase the risk of postpartum hemorrhage. At a median dose of 71.6 μg/kg, rFVIIa was reported to be effective in stopping or reducing bleeding in nearly 90% of the reported cases. Basing on the evidence from the literature, they give some recommendations on the use of rFVIIa in this setting. Nevertheless, although these reports suggest the potential role of rFVIIa in treating massive postpartum hemorrhage refractory to standard therapy, they advise particular caution in interpreting published findings, as they are derived from few and uncontrolled studies. They also indicate that further evidence is needed using well-designed clinical trials to better assess the optimal dose, the effectiveness, and the safety of rFVIIa in such critical bleeding conditions.

The next article by Favaloro was prepared in view of several recent publications showing renewed interest in the identification of platelet-type von Willebrand disease (PT-VWD, or pseudo-VWD) and its discrimination from type 2B VWD. This article, focused on phenotypic laboratory testing, to some extent compliments an article published in the past issue of Seminars in Thrombosis and Hemostasis that focused on genetic testing used to identify and discriminate the two disorders. PT-VWD and type 2B VWD have different etiologies although both present with a similar clinical bleeding and basic laboratory phenotype. Both represent gain-of-function mutations that lead to enhanced binding between plasma von Willebrand factor (VWF) and its platelet ligand, glycoprotein Ibα (GP1BA). However, type 2B VWD results from a functionally abnormal VWF molecule arising from mutations in the VWF gene, whereas PT-VWD is caused by hyperresponsive platelets resulting from mutations in the platelet GP1BA gene. A definitive diagnosis of PT-VWD versus type 2B VWD is critical for treatment decisions (as differential therapies might be respectively required) and also for family counseling. However, their discrimination by laboratory testing is problematic because simple phenotypic testing will not permit their differentiation, and the more complex testing approaches that might permit their differentiation are either rarely applied or are perhaps poorly applied. Although differential identification of PT-VWD versus type 2B VWD can most definitively be achieved by identifying the gene defect at either the VWF or GP1BA loci, such tests are not commonly available, not always successful, and even if available and successful might not be readily available to serve time-critical treatment decisions. Accordingly, simple laboratory tools to enable discrimination of the two disorders would be a valuable addition to the test repertoire of the hemostasis laboratory. This article provides a review of PT-VWD-related literature and an overview of a phenotypic laboratory test process that should enable the effective identification of PT-VWD and its discrimination from type 2B VWD.

Jayandharan and Srivastava then provide an overview on the phenotypic heterogeneity of severe hemophilia. They report that it has long been recognized that 10 to 15% of patients with “phenotypically characterized” severe hemophilia (< 1% clotting factor activity) have relatively mild disease clinically. Thus, not all these patients have frequent spontaneous bleeding, and even among those who bleed, the extent of joint damage tends to vary considerably. The basis for this difference has not been completely understood. Accordingly, this article reviews the literature on possible determinants of phenotypic variation in patients with severe hemophilia. Apart from the well-recognized associations of the level of residual clotting factor activity, pharmacokinetics of administered clotting factor concentrates, and presence of prothrombotic markers, there is evidence to suggest that variations in other coagulation proteins as assessed in tests of global hemostasis as well as the fibrinolytic system can affect the clinical severity of bleeding. They also hypothesize that mediators of the inflammatory response in the synovium are likely to affect the severity of joint damage in these patients. One of the major issues in the management of hemophilia today is to decide on ways in which therapy, particularly the initiation and intensity of prophylaxis, can be individualized. A detailed understanding of all factors that may contribute to joint damage in severe hemophilia could help, therefore, in tailoring therapy for these individuals.

I sincerely thank all the contributors to this special issue of Seminars in Thrombosis and Hemostasis for their excellent contributions, and each of us sincerely hopes that the reader will enjoy the collected articles.