Welcome to the sixth issue compilation of Seminars in Thrombosis and Hemostasis entitled “Hot Topics.”[1]
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[5] The previous issues have been very popular with our readership, as identified in
subsequent analyses.[6]
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[11] Although Seminars in Thrombosis & Hemostasis is primarily a theme-driven publication, the occasional opportunity arises to publish
composite issues containing more wide-ranging articles of current interest and controversy.
This opportunity presents itself once again as a result of several events, including
the most recent (2014) Eberhard F. Mammen Young Investigator Awards.[12] Accordingly, I am very pleased to present the latest “Hot Topics” issue (Part VI),
including contributions from three of six of our 2014 Eberhard F. Mammen Young Investigator
Award winners.[12] The other award winners will provide contributions that will be published in a subsequent
issue of this journal. The remaining articles from this Hot Topics issue derive from
various other contributors, and we have a very interesting potpourri of material to
share with our readership.
The issue begins with a seminal contribution from the International Society on Thrombosis
and Hemostasis Steering Committee for World Thrombosis Day, and on thrombosis as a
major contributor to global disease burden.[13] This contribution is being published jointly within several leading hemostasis/thrombosis
journals to celebrate the inaugural “World Thrombosis Day” on October 13, 2014, and
indeed, we have delayed publication of this issue of the journal specifically to coincide
with this date. Seminars in Thrombosis & Hemostasis is proud to be a part of this important initiative, and this article is also being
published online as an open access paper, entirely free for all to download. The writing
group of Raskob et al have performed a systematic review of the literature on the
global disease burden due to venous thromboembolism (VTE) in low-, middle-, and high-income
countries. Studies from Western Europe, North America, Australia, and Southern Latin
America (Argentina) yielded consistent results with annual incidences ranging from
0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between
2 and 7 per 1,000 among those aged 70 years or more. Of special note, and of special
relevance to our readership, is the fact that the increasing burden of thrombosis
with aging was recently highlighted in this journal.[14] Indeed, one of the guest editors to this previous issue of the journal[14] was also a contributor to the current thrombosis burden review.[13] The data presented in this review, as associated with age-related VTE, are summarized
in [Fig. 1]. Although the incidence of VTE is lower in individuals of Chinese and Korean ethnicity,
their total disease burden is not low because of their population aging.[13] VTE associated with hospitalization was, perhaps unsurprisingly, the leading cause
of disability-adjusted life years (DALYs) lost in low- and middle-income countries,
and the second leading cause in high-income countries. VTE associated with hospitalization
was responsible for more DALYs lost than nosocomial pneumonia, catheter-related bloodstream
infections, and adverse drug events. The authors conclude that VTE causes a major
burden of disease in all countries, denoting low-, middle-, and high-income countries.
In summary, thrombosis is a common pathology underlying ischemic heart disease, ischemic
stroke, and VTE. Providing detailed data on the global burden of VTE should enable
informed policy and resource allocation in health systems, and to assess if improved
utilization of preventive measures will reduce the burden.
Fig. 1 Venous thromboembolism (VTE) rates per 1,000 population per year. In general, rates
for males were higher than those for females, and rates for certain ethnicities (e.g.,
Asian, Chinese, Korean and American) were lower than those for whites and African
Americans. Finally, there was a strong and consistent association of increasing incidence
of VTE with increasing age. Data summarized from the article by Raskob GE, Angchaisuksiri
P, Blanco AN, et al; International Society on Thrombosis and Hemostasis (ISTH) Steering
Committee for World Thrombosis Day.[13]
This issue of the journal continues the topic of thrombosis and related disease burden
with an Australian-based contribution on the topic of VTE in tropical Australia and
in Indigenous Australians.[15] There is a paucity of data on the incidence VTE in this population of Australians,
and accordingly, the authors have conducted a retrospective review of all cases of
deep vein thrombosis and pulmonary embolism over a 24-month period in two major hospitals
of the Northern Territory. A total of 429 VTE diagnoses were recorded over this period
and 71 of 429 (17%) patients were Indigenous Australians. The overall incidence rate
was 0.9 per 1,000 person-year for the population of the Northern Territory with a
rate of 0.5 per 1,000 person-year for Indigenous Australians versus 1 per 1,000 person-year
for Non-indigenous Australians. Of 71, 39 (55%) of VTE cases in the indigenous group
occurred in patients younger than 50 years and almost half of these (n = 18) were younger than 29 years. Hospitalization was found to be a major risk factor
for VTE in 20 (38%) of 54 Indigenous Australians of whom 10 (26%) patients were younger
than 50 years. Although the rate of VTE in Indigenous Australians was low, its onset
was significantly earlier in life and it was often triggered by prolonged hospitalization.
VTE therefore should be added to the list of adverse outcomes of poor health and chronic
diseases, which cause disproportional high rates of hospitalization amongst Indigenous
Australians. The low number of VTE cases observed in older Indigenous patients in
this study possibly reflects on the lower life expectancy and ongoing wide gap in
life expectancy between Indigenous and Non-indigenous Australians. In summary, this
contribution adds to this issue's lead article by providing new data on VTE incidence
in Indigenous Australian people, which is furthermore consistent with lower VTE incidence
also observed in some (e.g., Asian) ethnicities,[13] as well as providing age-related information.
The third contribution in this issue of the journal continues the topic of thrombosis,
this time as related to the antiphospholipid (antibody) syndrome (APS).[16] Patients who are diagnosed with APS are identified to have a high risk of recurrent
thrombosis, which can occur despite anticoagulant therapy. APS is an acquired autoimmune
syndrome characterized by venous or arterial thrombosis and/or pregnancy morbidity
in patients with persistent presence of antiphospholipid antibodies (aPL). The optimal
type, intensity, and duration of anticoagulant therapy for the treatment of APS remain
controversial issues, particularly for arterial thrombosis and recurrent thrombosis.
Patients with persistently positive testing for lupus anticoagulant and elevated levels
of anticardiolipin antibodies and anti-β2 glycoprotein I antibodies—known as triple
positivity—appear to be at increased risk for thrombosis compared with patients who
test positive for a single aPL. Recognizing that patients with APS may potentially
have different thrombotic risk profiles may assist clinicians in assessing the risks,
benefits, and optimal duration of anticoagulation. Although this topic has been previously
and extensively covered in this journal,[17]
[18]
[19]
[20] the current review provides an excellent synopsis of the subject matter. Why different
aPL define different levels of risks for thrombosis has not been conclusively identified.
Various hypotheses have been proposed, including different sensitivities for clinically
relevant versus irrelevant antibodies, differences in the level of standardization
and harmonization of laboratory assays used to identify the different aPL, as well
as the distinct species of aPL defined by each aPL assay.[21] Whatever the reasons, the author of the current review concludes that future studies
that delineate thrombotic risk in APS and evaluate current and novel anticoagulants
as well as non-anticoagulant therapies are required. It is also worth noting that
this contribution comes from one of the 2014 Eberhard F. Mammen Young Investigator
Award winners.[12]
The next contribution by Pennings and Kritharides also continues the topic of thrombosis,
also adding the subject of cardiovascular disease, to explore the potential role of
CD147, together with its binding partners in platelets, in thrombosis, and arterial
disease.[22] The authors also assess mechanistic aspects of CD147 biology. CD147, also called
extracellular matrix metalloproteinase (abbreviated EMMPRIN) is a member of the immunoglobulin
superfamily that is expressed on many cell types including hematopoietic, endothelial
cells, leukocytes, keratinocytes, platelets, and others. The binding partners of CD147
are numerous and diverse and give some indication to the various roles that CD147
can play; these include homophilic interactions, integrins, cyclophilins (Cyps), glycoprotein
VI (GPVI), caveolin-1, and monocarboxylate transporters. Thrombotic and inflammatory
pathways play a key role in coronary artery disease (CAD) development. Recent evidence
suggests a role for CD147 in both thrombosis and inflammation, as well as involvement
in CAD and cancer.
The next contribution by Lippi et al[23] continues the thrombosis saga, this time focusing on therapeutic aspects defined
by the (newer/novel) direct oral anticoagulants (DOACs), as well as their potential
“monitoring,” or more appropriately termed laboratory “measurement.” The recent development
and marketing of these drugs represent a paradigm shift in the management of patients
requiring long-term anticoagulation. The advantages of these compounds over traditional
therapy with vitamin K antagonists include a reportedly lower risk of severe hemorrhages
and the limited need for laboratory testing. However, there are several scenarios
in which testing should be applied. The potential for drug-to-drug interaction is
one plausible but currently underrecognized indication for laboratory assessment of
their anticoagulant effect. In particular, substantial concern has been raised during
phase I studies regarding the potential interaction of these drugs with some antibiotics,
especially those that interplay with permeability glycoprotein (P-gp) and cytochrome
3A4 (CYP3A4). The authors performed a specific electronic search on clinical trials
to confirm that clarithromycin and rifampicin significantly impair the bioavailability
of dabigatran, whereas clarithromycin, erythromycin, fluconazole, and ketoconazole
alter the metabolism of rivaroxaban in vivo. Because of their more recent development,
no published data were found for apixaban and edoxaban, or for potential interactions
of DOACs with other and widely used antibiotics. It is noteworthy, however, that an
online resource based on Food and Drug Administration (FDA) and social media information,
reports several hemorrhagic and thrombotic events in patients simultaneously taking
dabigatran and some commonly used antibiotics such as amoxicillin, cephalosporin,
and metronidazole. According to these reports, the administration of antibiotics in
patients undergoing therapy with DOACs would seem to require accurate evaluation as
to whether dose adjustments (personalized or antibiotic class driven) of the anticoagulant
drug may be advisable. This might be facilitated by direct laboratory assessments
of their anticoagulant effect ex vivo. These DOACs have also been the subject of many
previous recent articles in Seminars in Thrombosis & Hemostasis.[24]
[25]
[26]
[27] Of additional interest, there are several guidelines and recommendations for laboratory
testing of the DOACs,[28] which may in time be updated with information such as that explored in this contribution,
and which suggests that despite manufacturer-driven dogma that monitoring is not required,
that measurements may instead be necessary in many clinical scenarios.
The next contribution begins our journey away from the specific topic of thrombosis
and toward the more general field of thrombosis/hemostasis. Danese et al discuss the
potential role of nucleic acids (NAs) as unconventional mediators of thrombus formation,
intervening in both hemostasis and thrombosis.[29] NAs constitute the backbone of cellular life, permitting conservation, transmission,
and execution of genetic information. In the last few years, new unexpected functions
for NAs, projecting them also beyond nuclear and cellular boundaries, have been recognized:
circulating cell-free NAs, histones, DNA-histone complexes, microRNAs may have a regulatory
role in physiological and pathological processes. Furthermore, in the last decade,
the possibility to detect and quantify these in plasma and/or in serum has led to
their ancillary use as potential markers in various medical conditions. The use of
these as markers within the fields of thrombosis and hemostasis looks especially promising:
the potential implications include the possibility to assess patients' risk profiles
for thrombotic events and the identification of more directed targets for pharmacologic
intervention. The major impediment is that, to date, the methods by which NAs are
explored, still largely differ between published studies and standardized procedures
remain elusive. The authors propose that future research should focus on the physiological
mechanisms underlying the activities of such mediators in specific thrombotic conditions
and on the definition of reliable methods for their quantification in biological fluids.
Rabbolini et al then continued the further exploration into hemostasis, this time
as related to primary hemostasis, and namely the group of inherited macrothrombocytopenias
that remain underrecognized and which are frequently misdiagnosed as immune thrombocytopenia
purpura.[30] Inherited macrothrombocytopenias represent a clinically heterogeneous group of disorders,
many of which cause moderate-to-severe bleeding tendencies in affected individuals.
Diagnostic strategies to date have included a predominant phenotypic approach. The
emergence of genetic testing and the implementation of next generation sequencing
strategies in the investigation and diagnosis of these disorders have broadened the
understanding of their pathogenesis, classification, and presentation. This review
describes the increasingly expanding group of recognized inherited macrothrombocytopenias
and highlights their pathophysiology and the role of phenotypic and genetic testing
in their description and diagnosis.
This issue of Seminars in Thrombosis & Hemostasis then turns our attention to the topic of other bleeding disorders, specifically for
the next three contributions as related to hemophilias. The first of these contributions
is from another of our Young Investigator Award winners.[12] Fernandes et al discuss the issue of prophylaxis as a treatment strategy for severe
hemophilia, particularly as prophylaxis started early in life is now well established
as the treatment of choice for children with severe hemophilia.[31] Although, there is no consensus among the hemophilia management community to either
stop or maintain prophylactic treatment in adulthood, experts, and centers advise
individualized prophylaxis according to clinical bleeding pattern, condition of joints,
pharmacokinetic profile, physical activity, type of employment, and patients' personal
preferences. The aim of the current report is to describe the impact of an individualized
prophylaxis approach on a small cohort of young adults with severe hemophilia, in
the setting of a Portuguese Haemophilia Comprehensive Care Centre. The authors explored
a tailored prophylaxis approach in this young adult cohort initiated on standard prophylactic
regimens in childhood, as based on clinical outcome. Patients were evaluated and prophylaxis
was adjusted (dose and/or frequency) to daily life activity and bleeding pattern.
After 12 months of follow-up, 9 of 10 patients maintained their new but lowered prophylaxis
approach, without increasing bleeding episodes. The authors concluded that with this
individualized approach, they observed no negative impact on clinical outcome in most
patients, with a proposed improvement in quality of life (given reduced dosing) and
a reduction of overall costs such that existing funding could then be utilized to
manage an increased number of patients with hemophilia. This contribution may be particularly
relevant to economically disadvantaged geographies and promote better utilization
of available resources.
The next contribution, by Witkop et al,[32] continues the theme of hemophilia, but this time from the perspective of emerging
therapies and the role of the interdisciplinary team in this new era. The authors
suggest that the introduction of new hemophilia management therapies, targeting extended
half-lives through bioengineering, ushers in an era of potential promise and increasing
complexity, more so for those with hemophilia B than hemophilia A. Questions arise
for patients, caregivers, and hemophilia treatment center staff about how to assess
and incorporate novel therapies and how to determine whether new therapies offer a
distinct advantage over established treatment routines. The authors propose that nurses
and other interdisciplinary hemophilia treatment center staff are well positioned
to assess, educate, and support patients and families in navigating this rapidly changing
landscape. To support these challenging efforts, this review offers a perspective
on issues affecting therapeutic transitions and provides tools to foster ongoing adherence.
The next contribution, by Tiede et al,[33] continues the exploration of hemophilia, but this time acquired hemophilia A, which
they counsel should be suspected in all patients with a new onset of bleeding and
an isolated prolongation of activated partial thromboplastin time (aPTT). About 10%
of acquired hemophilia A patients do not bleed at the time of diagnosis, but they
are at risk of future bleeding, in particular, during interventions or surgery. Diagnosis
of acquired hemophilia A is confirmed by demonstrating markedly reduced factor VIII
activity (FVIII:C) and neutralizing anti-FVIII antibodies, so-called inhibitors. Several
limitations and pitfalls exist with the assays used to diagnose acquired hemophilia
A, as also extensively explored previously in this journal.[34] Interference can result from anticoagulants or lupus anticoagulant.[35]
[36] The Bethesda assay used to measure inhibitor potency assumes a log–linear relationship
between inhibitor concentration and effect on residual FVIII:C activity to allow exact
quantification. However, this relationship is not present for the type 2 inhibitors
typically seen in acquired hemophilia A. Therefore, this assay only provides a rough
estimate of inhibitor potency. These limitations can explain, in part, why laboratory
data, such as inhibitor potency, failed to predict bleeding or response to treatment
in acquired hemophilia A. This article reviews the diagnostic approach to acquired
hemophilia A, discusses assay-specific limitations, including limitations of mixing
tests,[37] and addresses some of the challenges for future research.
The final contribution to this issue of Seminars in Thrombosis & Hemostasis is by Lippi et al,[38] and discusses the important topic of “defensive medicine,” otherwise largely unexplored
within the field of thrombosis and hemostasis. “Defensive medicine,” as a term, conventionally
defines the medical practice of ordering medically questionable diagnostic testing,
procedures, or visits, or to avoid high-risk patients or procedures, potentially as
aimed to reduce exposure to malpractice liability, to avoid patient criticism regarding
“medical inaction,” or to avoid “missing” some otherwise potential identifiable defect(s).
Although the precise impact of defensive medicine in the field of laboratory testing
is difficult to estimate from the current literature, the authors report that overuse
or inappropriate use of laboratory resources ranges from 23 to 67%, and a large part
of this can be attributed to medical liability concerns, with apparently little clinical
awareness of the adverse consequences that may be associated with this practice. Essentially,
performing inappropriate testing remarkably increases the risk of obtaining false-positive
results due to statistical, preanalytical, and analytical reasons, thus triggering
further and potentially even more invasive follow-up testing, inappropriate patient
management, along with incremental increases of expenditure due to misuse of health
care resources. Although one pragmatic example is the overuse of prostate-specific
antigen testing, as routine coagulation testing is commonly performed for the screening
of patients with bleeding or thrombotic disorders, either a false-negative or a false-positive
result in these basic procedures may also significantly impact on clinical outcomes
and health care resources. The primary aim of this article is to describe the leading
causes of physiological, pathological, therapeutic, and spurious variations of the
prothrombin time, aPTT, and D-dimer, as well as the potential clinical consequences
emerging from the generation of false-negative and false-positive results with these
tests. The authors plan to further explore these problems in subsequent issues of
this journal and as relating to more specialized “diagnostic” assays of hemostasis.
I thank all the authors to this issue of Seminars in Thrombosis & Haemostasis for their original and comprehensive contributions. However, I especially thank the
Eberhard F. Mammen Young Investigator Award winners for their submissions, as well
as again highlighting the lead article in this issue. Ultimately, however, I hope
that the readership of this journal finds the entire issue of considerable interest.
This will of course be determined in time, as measured and established for previous
issues of “hot topic” compilations.[1]
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