Welcome to the latest issue of Seminars in Thrombosis and Hemostasis (STH) published under the “banner” of “Editorial Compilation,” this being the seventh such
issue. Although STH is primarily a theme-driven publication, ongoing opportunities arise to publish some
issues containing more wide-ranging contributions of current interest and controversy,
which do not quite match a current-themed issue in progress. We also require a medium
to enable publication of contributions from our Eberhard F. Mammen Young Investigator
Award winners.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8] As now standard for this compilation series, the current issue has a mixture of
content that comprises such elements, as well as broadly fitting within the separate
themes of “thrombosis” and “bleeding.”
This issue begins with several contributions related to the arena of preanalytical
variables, or laboratory or potentially point-of-care diagnostics.[9]
[10]
[11] The first article provides some guidance around preanalytical variables, which may
affect the results of many routine coagulation and also diagnostic hemostasis assays.[12] While advances in laboratory instrumentation have partially addressed the laboratory's
ability to recognize some of these variables, there remains increased reliance on
laboratory personnel to recognize the three potential areas where coagulation testing
preanalytical issues may emerge, these being (1) specimen collection (including patient
selection), (2) specimen transportation and stability, and (3) specimen processing
and storage. The purpose of this article is to identify the preanalytical variables
associated with hemostasis testing and provide laboratory practice recommendations
in an effort to improve quality of such testing and accuracy of result reporting.[9]
Next is a contribution around the topic of thromboelastography/thromboelastometry
(TEG/TEM), in particular its application in the neonatal population. Hemostasis is
a dynamic age-related process, which gradually evolves from fetal life, throughout
childhood until adulthood.[13] Although at birth a hemostatic deficit of most coagulation factors is commonplace,
some studies have shown that this “hemostatic immaturity” is functionally counterbalanced
in healthy term or preterm newborns. Age-related effects around platelet function
have also been reported.[14] The delicate hemostatic balance, however, may be deranged in sick neonates, thus
resulting in enhanced risk of hemorrhage and/or thrombosis. In critically ill neonates,
conventional coagulation tests may not provide reliable information or indications
regarding the functional status of platelets or fibrinolysis, especially in real time.
In contrast, viscoelastic tests, namely TEG/TEM, hold promise for rapid assessment
of the whole hemostatic potential, allowing immediate intervention should this be
required. However, neonatal data are limited due to lack of reference values, especially
in premature neonates. In this narrative review, the authors provide some insights
around current knowledge regarding TEG/TEM applications in healthy and sick newborns.
Overall, the use of viscoelastic tests in the diagnosis and management of coagulation
disorders in neonates is worthy of further exploration. The authors further propose
that consideration should be made to include these tests in the routine laboratory
investigation of neonates, and specific transfusion algorithms should also be developed
to avoid treatment pitfalls.[10]
This issue of STH continues the exploration of laboratory testing with a third contribution,
by Ames and colleagues, on coagulation activation markers in antiphospholipid syndrome
(APS).[11] In particular, prothrombin fragment F1 + 2 (F1 + 2) and thrombin–antithrombin (TAT)
have been assessed in APS, but without evaluating a direct relationship with antiphospholipid
(aPL) antibody titers. The authors of this hybrid report, comprising a systematic
review and meta-analysis combined with a short report of original data, aimed to investigate
whether a direct relationship between aPL and F1 + 2 could be identified, as well
as to perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. The
authors performed a systematic search of several databases from January 1982 to December
2018, and then undertook a random effects meta-analysis for continuous outcomes. They
also performed an ex vivo study as a cross-sectional case–control evaluation of immunoglobulin
G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-β2-glycoprotein-I (aβ2GPI), antiprothrombin (aPT) antibodies, F1 + 2 and lupus anticoagulants (LA), as measured
in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls.
For the meta-analysis, the significant effect size (ES) for F1 + 2 between aPL +ve
and aPL −ve SLE and between aPL +ve SLE and control displayed high heterogeneity.
The significant ES for F1 + 2 between aPL −ve SLE and controls displayed no heterogeneity.
The ES for TAT between aPL +ve and aPL −ve SLE patients and between aPL −ve SLE and
controls were low, without heterogeneity. For the original study, mean F1 + 2 was
greater in PAPS (p ≤ 0.0001), inversely correlating with IgG aCL, IgM aPT, and LA (p = 0.001, 0.03, and 0.01, respectively), though only IgG aCL negatively predicted
F1 + 2 (p = 0.01). The authors concluded that (1) IgG aCL inversely predicts F1 + 2; (2) IgG
aCL positivity introduces heterogeneity in the F1 + 2 ES; and (3) the lack of heterogeneity
in the ES for TAT may indicate poor TAT formation in aPL +ve group. Thus, F1 + 2 measurements
may be unfounded as already demonstrated for TAT in the 1990s.[11]
Continuing the exploration of APS, Tufano et al[15] review its cardiac manifestations, including clinical presentation, role of cardiac
imaging, and treatment strategies. As noted earlier, APS is an autoimmune disorder
characterized by the presence of aPL, but also vascular thrombosis (venous, arterial,
or small vessels) and/or pregnancy morbidity. Diagnosis of APS is based on the presence
of at least one clinical criterion (thrombotic events or pregnancy morbidity) and
at least one of the laboratory criteria (persistently medium/high titer IgG/IgM aCL,
and/or medium/high titer IgG/IgM aβ2GPI, and/or a LA test, confirmed after repetition at least 12 weeks apart. The clinical
spectrum of APS encompasses additional (extracriteria) clinical manifestations, including
cardiac diseases. Heart involvement may manifest as a consequence of direct (autoimmune-mediated)
or indirect (thrombosis) mechanisms, and include heart valve disease (vegetations
and/or thickening associated with functional abnormalities) and intracardiac thrombosis,
coronary and vascular-accelerated atherosclerosis, along with ischemic heart disease.
APS can also cause pulmonary arterial hypertension, left ventricular dysfunction,
and heart failure. This review is thus aimed at describing the major cardiac manifestations
of APS and illustrating the important role of cardiac imaging for diagnosing subclinical
and overt heart involvement and addressing management of these patients. The possible
role of therapeutic strategies in cardiac manifestations of APS is also discussed.[15]
The “prothrombosis” theme continues, with several contributions around therapy.[16]
[17]
[18] First, Christiansen and colleagues report a systematic review and meta-analysis
around the topic of primary prevention of cardiovascular events with aspirin, essentially
concluding that such treatment is heading toward more harm than benefit.[16] The authors begin by reminding readers that primary prevention of cardiovascular
events using aspirin remains controversial, as the risk of bleeding might outweigh
the benefits.[17] New evidence has recently emerged from ARRIVE (Aspirin to Reduce Risk of Initial
Vascular Events), ASCEND (A Study of Cardiovascular Events in Diabetes), and ASPREE
(Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly) trials.
The aims of this report are to provide a systematic review and meta-analysis of aspirin's
efficacy and safety in the primary prevention of cardiovascular events in healthy
individuals and in those with cardiovascular risk factors, and separately in diabetic
patients. The authors searched the Medline database, without time restrictions, for
relevant human trials published in English up to December 10, 2018, and additional
trials were also identified from reference lists. Data on efficacy (cardiovascular
death and nonfatal myocardial infarction) and safety (major bleeding) were extracted
for analysis. In total, 20 randomized trials were identified. Separate meta-analyses
were performed on 10 trials including 144,930 individuals, who were healthy or had
cardiovascular risk factors, and on 4 trials including 20,326 individuals with diabetes.
In healthy individuals and individuals with cardiovascular risk factors, aspirin reduced
the risk of nonfatal myocardial infarction by 21% (p < 0.001), but had no effect on cardiovascular death (p = 0.52), and increased the risk of major bleeding by 48% (p < 0.001). In individuals with diabetes, aspirin had no effect on nonfatal myocardial
infarction (p = 0.93) or cardiovascular death (p = 0.92), and enhanced the risk of bleeding by 49% (p = 0.13). This meta-analysis thus suggests that the use of aspirin on routine basis
in primary prevention of cardiovascular events seems unadvisable, especially in individuals
with diabetes.
A second exploration on thrombosis treatment/prevention is provided by Lippi and colleagues,[18] who provide a state-of-the-art review on current and emerging direct oral anticoagulants
(DOACs). As would be recognized by the readership of this journal, anticoagulant drugs
comprise a specific subcategory of antithrombotic agents that act to inhibit blood
coagulation at various stages, reducing clot development and ultimately lowering the
risk of developing new onset or recurrent thrombosis. Although the long history of
anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives,[19]
[20]
[21] DOACs represent a new generation of anticoagulants, recently emerged, and that specifically
inhibit thrombin or activated factor X. These DOACs combine many advantages of their
progenitor drugs, and are therefore prepotently revolutionizing the landscape of antithrombotic
therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766],
rivaroxaban [BAY 59–7939]) have already received widespread approval by national or
supranational medicinal agencies.[22]
[23] However, this narrative review primarily explores several other DOACs at different
stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, and nokxaban),
and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717,
odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from the authors'
analysis is that DOACs sharing very similar mechanisms of action are still characterized
by different efficacy and safety profiles. This not only depends on biochemical, biological,
and pharmacokinetics characteristics but also on lack of standardization between different
clinical trials in terms of targeted disease, patient recruitment, sample size, duration
and endpoints, as well as lack of harmonization around procedures used for drug licensing.
These factors contribute to challenging the minds of physicians, who may find difficulty
navigating their way through multiple indications, different pharmacological profiles,
various side effects, and specific drug-to-drug interactions. Such considerations
also burden laboratory professionals, who may face organizational and economic challenges
in developing and/or implementing multiple assays to assess the pharmacodynamics (effect
on coagulation) or pharmacokinetics (drug levels) of DOACs.
DeLoughery and colleagues also discuss emerging treatments for thrombosis.[24] The authors begin by reminding readers of STH that although anticoagulation without
hemorrhage is a primary aim of thrombosis prevention/treatment, this vision has remained
as yet out of reach. Despite the superior safety profile of DOACs, hemorrhage remains
a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation,
specifically coagulation factors XI and/or factor XII, has now substantial epidemiologic
and preclinical data supporting the notion that these factors contribute to pathologic
thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way,
targeting factors XI and XII may revolutionize the future anticoagulation landscape.
Several drugs are under development for this purpose, including ISIS 416858, a factor
XI antisense oligonucleotide which impairs hepatic synthesis of factor XI; MAA868,
a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and
activated factor XI; BAY 1213790, a monoclonal antibody that binds the procoagulant
enzymatic site of activated factor XI only; and AB023, a monoclonal antibody that
inhibits activated factor XII-mediated activation of factor XI, along with two small
molecules in clinical trials. Each of these drugs demonstrated favorable safety profiles
in their phase 1 and 2 studies to date, with preclinical data also supporting efficacy
of abrogating thrombosis in various animal models. Other benefits of some of these
drugs include once-monthly dosing and safety in patients with renal or hepatic impairment,
while others offer quickly metabolized parenteral options, thus providing more convenient
and widely available anticoagulation options. Though still far from the marketplace,
drugs targeting factor XI and factor XII have the potential to usher in a new era
of anticoagulation therapy.
We move this issue of STH from purely prothrombotic considerations to other considerations
in hemostasis.[25]
[26]
[27] First, the article by Horstman and colleagues describes the putative role of tissue
factor–negative cell-derived microparticles in hemostasis.[25] Circulating cell-derived microparticles exhibit procoagulant activity and have been
investigated for a possible role in some human pathologies. However, their potential
role in hemostasis has been neglected and often denied. This review brings to attention
a specific body of direct clinical evidence supporting an important but distinctive
role of microparticles in hemostasis. Evidence for a role of microparticles in hemostasis
includes (1) two congenital bleeding disorders, attributed to impaired release of
microparticles; (2) two recent studies of trauma patients, relating to naturally elevated
endogenous microparticles at admission with reduced transfusion requirements and better
outcomes; (3) a study of coronary surgery patients, showing that elevated microparticles
before surgery reduces transfusion requirements during surgery; and (4) a clinical
study of patients with immune thrombocytopenia, demonstrating that patients with high
circulating microparticles have reduced bleeding compared with those with similar
platelet counts but lower microparticle levels. Mechanisms involving potentiating
the contact factor pathway are thought to play a key role and are probably synergistic
with polyphosphate released from activated platelets at sites of endothelial injury.
The authors conclude that hemostatic defects of patients with deficient microparticle-mediated
coagulation resembles deficiency of FXI (i.e., also sometimes known as hemophilia
C), distinct from hemophilia A or B; so, it can be termed “type C hemostasis.” A better
understanding of this proposed hemostatic pathway may lead to improved methods for
controlling excessive bleeding in surgery, trauma, and other clinical settings.
Next, de Mello and colleagues performed a systematic review and meta-analysis of hemostatic
abnormalities in dementia.[26] Alzheimer's disease is considered the most frequent cause of dementia. It is known
that vascular risk factors play an important role in the development and progression
of this condition. Alterations in vascular walls represent documented findings in
patients with Alzheimer's disease and other dementias affecting elderly people. The
authors aimed to synthesize observational studies that evaluated how the hemostatic
system may contribute to cognitive decline in the elderly, using articles published
until April 2018 and as indexed in several databases. Among 5,278 studies identified,
33 were included in the final synthesis, and these included 485 patients with mild
cognitive impairment (MCI), 588 with vascular dementia, 1,781 with Alzheimer's disease,
and 2,895 participants without dementia. Patients with Alzheimer's disease had increased
plasma von Willebrand Factor (VWF), plasminogen activator inhibitor-1 (PAI-1), and
homocysteine levels. In contrast, the vascular dementia group showed increased fibrinogen
levels, activated factor VII, factor VIII, VWF, D-dimer, and homocysteine. The authors
conclude by stating that Alzheimer's disease patients show an elevation in some markers
of endothelial dysfunction, whereas patients with vascular dementia present mostly
an involvement of coagulation cascade components.
The final full-length article in this issue of the journal is by Tabibian and coworkers,
who provide a comprehensive overview of coagulation factor V (FV) and congenital FV
deficiency.[27] Coagulation FV is a glycoprotein with an essential role in the formation of the
prothrombinase complex, in turn critical for progressing clot formation. FV deficiency
is a rare bleeding disorder with an estimated incidence of 1 per 1 million in the
general population. The disorder is manifested with a wide array of clinical bleeding
events. The most common bleeding features of FV deficiency are mucosal bleedings.
Life-threatening manifestations are rarely seen in this disorder. FV deficiency is
diagnosed using routine coagulation tests and FV activity assays, supplemented with
FV antigen if available. A wide spectrum of mutations including missense, nonsense,
and frameshift is observed throughout the F5 gene. Although fresh frozen plasma (FFP) is the dominant therapeutic choice, a newly
introduced plasma-derived FV concentrate was found effective in in vitro correction
of prothrombin time, activated partial thromboplastin time, and thrombin generation
parameters in severe FV deficiency, and should provide more targeted treatment for
patients with FV deficiency in the future.
As usual for these nonthematic issues of STH, this issue also contains some correspondence
and associated commentaries.[28]
[29]
[30]
[31]
[32] We again thank all the authors to this latest issue of “Editorial Compilations”
for their original and comprehensive contributions, and we hope our readers enjoy
this new installment in this series.
