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Semin Thromb Hemost 2012; 38(02): 125-128
DOI: 10.1055/s-0032-1301409
Preface
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations, Part VI

Giuseppe Lippi
1   U.O. di Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
,
Emmanuel J. Favaloro
2   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
15 March 2012 (online)

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Welcome to the sixth issue of the opportune saga of Seminars in Thrombosis & Hemostasis issues devoted to the topic “Coagulopathies and Thrombosis: Usual and Unusual Causes and Associations.”[1] [2] [3] [4] [5] In the previous issues, we have comprehensively covered the typical as well as the atypical causes of venous and arterial thrombosis, highlighting or even unmasking often unappreciated biological or epidemiological associations with thrombosis, providing also information about prevention and therapy of a variety of thrombotic disorders and prothrombotic coagulopathies. It is thereby reasonable that some of our readers might be surprised to discover that we have continued further with this topic, organizing another issue and, even plausibly, to plan additional issues in forthcoming years. Epidemiological data and projections for the near future confirm that thrombosis is the leading pathology worldwide, arterial thrombosis being the leading cause of death worldwide, and venous thrombosis representing the leading cause of inpatient death.[6] [7] As such, it is not at all difficult to find new and interesting arguments, and to renew the interest of our readers on these topics. Some of the articles contained in the previous five issues have been among the most downloaded articles from the Website of the journal, and have also contributed to the respectable impact factor that Seminars in Thrombosis & Hemostasis enjoys. We anticipate that the articles contained in this issue will contribute further to these excellent results, and this has also encouraged us to continue the saga!

In the first article of this issue, Adams provides interesting updates and intriguing insights into tissue factor pathway inhibitor (TFPI),[8] a well-known but often underestimated inhibitor of blood coagulation. TFPI is the most important inhibitor of the activation of the blood cascade, as developing through the tissue factor (TF) pathway. TFPI is a Kunitz-type inhibitor that basically inhibits the TF-factor VIIa complex in a factor Xa-dependent manner. The consequence of this inhibitory activity in the further steps of the coagulation cascade reasonably culminates in a reduced thrombin generation and thereby in a reduced cleavage of fibrinogen into fibrin.[9] Most of the biological effects of this natural coagulation inhibitor have been broadly described since the beginning of the last century, although the real physiology of this protein has only been described in the past 25 years. In this article Adams reviews most of the biological function of TFPI, its metabolism, physiology, association with health and disease as well as its potential use as a therapeutic anticoagulant agent.

The following two articles of this issue are devoted to therapy and prevention of thrombosis.[10] [11]

Heparin-induced thrombocytopenia, most typically known by its abbreviation “HIT,” is a life-threatening disorder that occurs after exposure to heparin therapy in predisposed individuals. The global prevalence of this disorder is low (i.e., from 0.5 to 5%, varying depending on the clinical setting), but its catastrophic clinical manifestations in term of generalized, disseminated, and refractory arterial and venous thrombosis make it probably the thrombotic disease with the overall worst outcome.[12] [13] The clinical history of HIT can be, however, radically modified with an early diagnosis, which would lead to immediate suspension of heparin therapy, replacement with suitable surrogates accompanied by life-support treatments.[14] The article by Tan et al provides thereby essential information on pretest clinical scoring systems, as well as on the different laboratory techniques that allow us to screen or diagnoses HIT.[10] These include immunoassays, which can only identify anti-heparin-platelet factor (PF4) complexes but are characterized by a high negative predictive value when combined with pretest probability, and functional tests, which are essential for confirming the presence anti-heparin-PF4 antibodies but are cumbersome and do not provide definitive information for the clinical decision-making. Additional information contained in the article is focused on synthesizing recent efforts to ameliorate the analytical performance of these tests and to better integrate test results with the clinical scoring.

In an ideal progression from the previous article, Bikdeli and Kashani describe a further problem, frequently encounter and uncomfortably overlooked by the medical community, which represents a sort of “great divide” between medical theory and practice.[11] A wide armamentarium of both pharmacological and mechanical methods exists for prophylaxis and treatment of venous thromboembolism,[15] [16] but recent evidence attests that this disease is still the leading preventable cause of in-hospital death, at least in part attributable to a low adherence to practice guidelines recommendations by attending clinicians. This unfavorable trend recognizes several causes, including the user-unfriendly and repetitious formats of several documents, which dramatically limit their readability and applicability by practicing physicians, the significant heterogeneity in practice of prophylaxis as well as caveats between different countries. Besides the scarce compliance with the guidelines, which is considered to be a rather common problem in other medical fields, Bikdeli and Kashani[11] emphasize the other side of the coin in thromboprophylaxis—overprophylaxis—mainly as inappropriate use of pharmacological agents or mechanical devices in low-risk patients.

The description of atypical, unusual causes of thrombosis has been a hallmark of all the previous issues,[1] [2] [3] [4] [5] embracing even unpredictable associations such as sneezing and coughing attacks, eating, migraine, sexual intercourse, strenuous physical exercise, drug abuse, defecation,[17] as well as holiday vacation[18] and long-distance flights.[19] In the next article of this issue of Seminars in Thrombosis & Hemostasis, Gupta and Ashraf debate the topic of high altitude thrombosis,[20] an argument that they, as Indian scientists, might be particularly familiar with considering the highest mountains reside in the Himalayan chain. Although this peculiar event shares some features with thrombosis during long haul flight, there are however, several distinct and even peculiar characteristics, which would make it a rather unique condition. Basically, ascension of high mountains has been associated with the development of a hypercoagulable state due to a complex or multifactorial trait, which would significantly increase the risk of thrombosis. Although the exact pathogenetic mechanisms still remain poorly understood, hypoxia, dehydration, hemoconcentration, low temperature, use of constrictive clothing as well as enforced stasis from severe weather conditions are listed among the various aspects deemed responsible for the predisposition of a prothrombotic milieu resulting in high altitude thrombosis. All these factors probably interplay and support the traditional Virchow hypothesis according to which thrombosis develops through venous stasis, hypercoagulability, and vessel-wall injury.[21]

Following the very popular article on the association between moderate red wine consumption and cardiovascular disease risk,[22] we present in this issue a new article that further explores the intriguing relationship between diet and cardiovascular disease,[23] and namely the relationship between coffee consumption and heart disease.[24] The somewhat provocative title (i.e., “Virtue Does Not Take Center Stage”) clearly highlights that this association is not simple or straightforward, but rather develops through a complicated dose-effect “U-shaped” relationship, where the lowest risk is found for less than one cup or for more than four cups of coffee per day, whereas the highest risk is described for a modest consumption, of between two and four cups per day. It is also emphasized that the benefits are heterogeneous according to several specific aspects such as the type of coffee (e.g., Italian vs. American, decaffeinated vs. caffeinated, filtered vs. nonfiltered), the habit of consumption (e.g., the time of the day) as well as peculiar genetic characteristics (e.g., the metabolizer genotype and the baseline cardiovascular risk of the subject). In synthesis, the kaleidoscope of compounds contained in the different brands of coffee produces a wide spectrum of biological effects, some of which (e.g., chlorogenic acids and caffeine) are thought to be beneficial for the cardiovascular risk.

Rivaroxaban is an oxazolidinone derivative optimized for a highly selective inhibition of coagulation factor Xa, either free or bound in the prothrombinase complex. The drug has predictable pharmacokinetics across a wide spectrum of patients and can be administered in a fixed dose with little need for dose adjustments and routine coagulation monitoring,[25] [26] [27] [28] and in theory would pose less problems than standard vitamin K antagonist therapy, which is complicated by a plethora of issues.[29] Nevertheless, the evidence of a significant role played by the renal clearance in metabolism of rivaroxaban makes laboratory assessment of the anticoagulant effect/concentration of this drug advisable especially in the elderly patient, as well as in those with acute diseases and concurrent dehydration, before surgery, during bleeding or thrombotic episodes, or to monitor compliance with therapy. Consequently, in the next article by Harenberg et al the leading issues of rivaroxaban biology, metabolism, and monitoring are comprehensively presented and discussed.[30] Although this drug has been proven to prolong most first- and second-line clotting assays traditionally employed for routine assessment of other anticoagulants, the ideal assay for rivaroxaban monitoring has not been identified so far. It is also concluded that additional clinical investigations might be needed to establish a reliable and genuine association between test results and bleeding or thrombotic outcomes.

In the next article by Franchini and Coppola the challenging and still debated relationship between cardiovascular disease and von Willebrand disease (VWD) is discussed.[31] VWD, caused by deficiencies in von Willebrand factor (VWF), is the most frequent congenital bleeding disorder, displaying a prevalence between 1 and 2% in the general population.[32] [33] One of the most conflicting evidences related to VWF biology is that patients with VWD can still develop atherosclerotic disease and thrombosis despite the negative imbalance of the hemostatic system. This relationship has substantially raised considerable interest over recent years, due to significant therapeutic advances that have contributed to enhance the number of VWD patients who can reach an elderly age and thereby be exposed to or develop age-related disorders, including cardiovascular disease. Nevertheless, data on cardiovascular disease in VWD patients are limited, and even more incomplete when considering clinical management. These aspects have led Franchini and Coppola to conclude that this association is indeed underestimated and represents a potential explanation for the onset of bleeding complications in patients on antithrombotic treatment or undergoing invasive cardiovascular procedures.[31]

Antiplatelet therapy “resistance” is a frequently encountered problem in clinical management (e.g., it might develop in as much as half of all patients undergoing therapy with either aspirin, clopidogrel, or both). Such “resistance” is better referred to as treatment failure or high on-treatment platelet reactivity, as “resistance” more correctly refers to situations where it is demonstrated that the drug is unable to affect its therapeutic target (i.e., in this case a lack of desired pharmacologic effect of an antiplatelet medication). High on-treatment platelet reactivity represents a major problem in patients with cardiovascular disorders, and its diagnosis and management are crucial components of the medical regimen. In the article of Linden et al, the issue of antiplatelet therapy and high on-treatment platelet reactivity related to acute atherothrombosis is extensively reviewed.[34]

In the next article, Lippi et al introduce a relatively original concept in aberrant hemostasis, that is, lymphatic thrombosis.[35] Although this occurrence exhibits a much lower prevalence than arterial or venous thrombosis, it is however a serious clinical condition that mainly involves the thoracic duct, axillary, and inguinal lymphatics. The generation of fibrin is strongly inhibited in the lymph, but a factor VIIa-tissue factor-catalyzed activation of factor X is still possible, due to release of thromboplastin substances from the lymphatic endothelium in combination with chronic obstruction of lymph flow and a hypercoagulable milieu. Most frequently lymphatic thrombosis develop as a complication of primary pathologies such as cancer, infections, congestive heart failure, edema or inflammation of distal lower limb, central venous catheterization, coronary artery bypass grafting, thoracic outlet syndrome, and amyloidosis. Due to the unusual pathogenetic mechanism, the therapeutic approach to lymphatic thrombosis is still uncertain.

The next article of this issue is a technical one, focused on a hot-topic issue in diagnostics of acute coronary syndrome and acute myocardial infarction, that is, the degradation of the cardio-specific troponins in serum or plasma and the different reactivity of fragments with the current immunoassays.[36] The assessment of cardio-specific troponins is currently considered the mainstay in the diagnostic approach to a variety of myocardial injuries,[37] but especially for the fast triage of patients with suspected non-ST elevation myocardial infarction (NSTEM),[38] so that their accurate and reproducible assessment is essential for providing useful diagnostic information. The current immunoassays for detecting cardiac troponin I (cTnI), including the most innovative and “highly sensitive,” (HS) are characterized by a different cocktail of anti-TnI antibodies, which recognize different combinations of epitopes at the surface of the molecule. It is thereby understandable that the broad spectrum of cTnI isoforms present in serum or plasma, and derived from either the heterogeneous macrocomplexes released from the injured myocardium or from the enzymatic cleavage catalyzed by several proteases such as calpains, caspases, catepsin L, and gelatinase A, might complicate or even jeopardize harmonization as well as standardization among immunoassays. In the article of Lippi et al, the mechanisms of release from the injured myocardium as well as the enzymatic degradation by cardiac and extracardiac proteases are presented and discussed, with special focus on the potential bias generated by these two aspects on the current cTnI immunoassays.[36]

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share several risk factors, it is still unclear whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of VTE. Inherited thrombophilia has been reported in as high as 40% of patients with DVT, whereas conflicting data have been provided for PE. In the last article of this issue, Grifoni et al[39] present an interesting clinical study which shows that at least one thrombophilic abnormality is detectable in 73% of patients with DVT, whereas this prevalence is lower in those with DVT/PE (66%) and isolated PE (60%). Even more interestingly a high prevalence of hyperhomocysteinemia and hyperlipoproteinemia(a) has been identified in all patients with no significant differences among the three groups, although increased levels of lipoprotein(a) is the only marker significantly associated with isolated PE. Prothrombin G20210A polymorphism and elevated factor VIII levels were also more prevalent in patients with DVT and DVT/PE than in controls, but not in those with isolated PE. Conversely, factor V Leiden polymorphism was found to be associated with isolated DVT but not with DVT/PE or isolated PE.

As always, we thank our contributors for their interesting contributions, and hope that our readers enjoy the many treasures within this issue of Seminars in Thrombosis & Hemostasis.