This year's Editor's Choice highlights the 2021 manuscripts published in Thrombosis and Haemostasis and its open access companion journal TH Open that found most resonance within our academic community. As in the precedent year,
the 2021 COVID-19 pandemic situation has dictated the pace and direction of our research
and clinical management efforts which, although not exclusively, is well reflected
by this years' Editor's Choice contents.[1]
[2]
[3]
[4]
At the end of 2020, we published a Theme Issue dedicated to COVID-19 as a guide to
better comprehend newly identified vascular and inflammatory mechanistic aspects of
the disease,[5] its hypercoagulation state,[6] and clinical implications for vascular patients with COVID-19.[7]
[8] To address the rapidly evolving situation and following a first consensus paper,[9] we were pleased to publish an interesting discussion manuscript by the VAS investigators
on the need for a more integrated and global strategy to COVID-19, providing a useful
overview of public health approaches consideration and the next steps necessary to
best manage the pandemic.[10] While research efforts throughout 2020 focused on characterizing the coagulation
abnormalities observed in COVID19 patients giving cues to the next clinical approaches
to adopt, the results from such strategies mostly came out in the following year 2021.
Understanding and Managing COVID-19
Understanding and Managing COVID-19
Anticoagulation for COVID-19
Among the first published anticoagulation results in COVID-19, the cohort study from
Billett et al found that patients with moderate or severe disease benefited from anticoagulation
and that apixaban had similar efficacy to enoxaparin in decreasing mortality.[11] The large real-life observational CORIST Collaboration study could confirm that
heparin lowered in-hospital mortality, particularly in severely ill COVID-19 patients
and in those with strong coagulation activation.[12]
The first randomized controlled trial with antithrombotic sulodexide in COVID-19 by
Gonzalez-Ochoa et al[13] suggested a benefit of sulodexide in COVID-19 early stage with less frequent hospitalization.
Current societal and international recommendations of standard dose thromboprophylaxis
in hospitalized patients with COVID-19 were confirmed by the large pooled analysis
study from Patell et al.[14] Similarly, the 90-day follow-up of the INSPIRATION Trial[15] supported the routine use of standard dose over intermediate dose prophylactic anticoagulation
in intensive care unit patients with COVID-19. Likewise, the multicenter retrospective
study of venous thromboembolism (VTE) in COVID-19 patients by Cohen et al[16] endorsed standard prophylactic-dose anticoagulation in hospitalized patients with
COVID-19 while individual clinical and laboratory parameters may be instrumental for
tailoring thromboprophylaxis strategies in high-risk subgroups. Such high-risk hospitalized
COVID-19 patients may indeed benefit from treatment-dose instead of prophylactic-
or intermediate-dose low-molecular-weight heparin (LMWH) as demonstrated by the results
from the recent multicenter HEP-COVID randomized trial.[17]
[18] The multicenter observational GeroCovid study, presented convincing data on the
role of direct oral anticoagulants (DOACs) in reducing the risk of death in COVID-19
older patients.[19] While the beneficial anticoagulation effects of heparin on the thrombotic arm of
COVID-19 is easily explicable, intriguing data from Mycroft-West et al suggested that
heparin may also prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
from infecting cells,[20] opening options for repurposing heparin and its derivatives as antiviral agents.
Importantly, the precise identification of patients, who will best benefit from such
prophylactic anticoagulation strategies, is key to their efficacy. Efforts in (re)defining
risk biomarkers has therefore been the subject of several studies published last year.
As mentioned in last year's Editorial, elevated D-dimer levels were associated with
poor prognosis including severity and mortality with COVID-19 infection,[21] making it a biomarker of choice for COVID-19 severity diagnosis. The small retrospective,
one center study from Valerio et al[22] further identified specific dynamics associated with D-dimer as well as C-reactive
protein levels during COVID-19 which may refine monitoring disease activity. Sjöström
et al also proposed a 7-day trend to assess the changing rate of D-dimer and platelet
count for dose adjustment in relation to disease severity.[23] Interestingly, Bauer et al pointed out a subtle nature of coagulation changes early
in disease progression, highlighting the importance of monitoring coagulation parameters
throughout disease progression.[24] Since D-dimer has relatively low specificity and detects only late hemostatic stage,
Chaudhary et al laid out the rationale for a study to detect whole blood viscoelastic
analysis by thromboelastography or rotational thromboelastometry which may be useful
to guide antithrombotic therapy in COVID-19 patients.[25] Several authors[26]
[27] also systematically analyzed the viscoelastic changes in the clotting system and
acknowledged its use for predicting thromboembolic complications and to monitor the
efficacy of anticoagulation and fibrinolytic treatment in COVID-19 patients. In a
small pilot study, Hardy et al investigated daily monitoring of fibrin-related markers
to better detect thrombotic events in COVID-19 patients, and suggested these could
be used as further transient warning signals as D-dimers stay constantly elevated
in critical patients.[28] In a retrospective study of COVID-19 hospitalized patients, Sweeney et al demonstrated
an association of low ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13) activity on admission with increased risk of mortality, providing
a further maker to detect patients who may benefit from more aggressive anticoagulation
treatment.[29] While clinical efforts to limit COVID-19-induced coagulopathy were and are imminently
required in the actual situation, we also welcomed some less sought after strategies
which may open new horizons for understanding and treating the hypercoagulation state
of the disease. In this respect, Léopold et al shed light on the contribution of platelets
to thromboembolic complications encountered in COVID-19 patients as they characterized
the platelet phenotype and reactivity to collagen on SARS-CoV-2 infected hospitalized
patients.[30] The role of platelets in COVID-19 was also highlighted by Ghirardello et al in a
flow-chamber system suggesting impaired platelet activity and thrombus formation in
the early phase of COVID-19.[31] Such findings may open new avenues for antiplatelet drugs in COVID-19. Violi et
al reported on a case series study of COVID-19 patients with hypoalbuminemia and intravenous
administration of human albumin,[32] thereby suggesting an innovative approach to dampen hypercoagulability worth considering.
Hemoperfusion devices mimicking the endothelial glycocalyx may represent another option
to treat SARS-CoV-2 as shown by a case report from Pape et al.[33] Through electrostatic attraction, such systems are able to capture viruses, bacteria,
and cytokines and may potentially reduce viral antigen and cytokine load in the setting
of a cytokine storm.
While a great part of our scientific and clinical community has been fully engaged
in identifying and refining anticoagulation management strategies for COVID-19, the
virology and immunology scientists have been extremely fast in delivering the first
efficient vaccines against SARS-CoV-2, creating a blow of hope throughout the world.
As it appeared that some rare but severe cases of thrombotic events occurred after
inoculation with adenoviral vector-based vaccines, it was crucial that such events
should be better understood and treated by the thrombosis community. Although suspended
or restricted in many countries, at least 1 billion doses of the adenoviral ChAdOx1
nCov-19 vaccine (AstraZeneca) are currently being released to low- and middle-income
countries, making identification and treatment of vaccine-associated thrombosis crucial,
as vaccination currently appears to be our sole pandemic exit strategy.
Understanding and Treating Vaccine Complications
In late February last year, rare but severe thrombotic events concomitant with thrombocytopenia,
were reported in otherwise healthy individuals shortly after vaccination with the
adenoviral vector-based vaccine ChAdOx1 nCov-19 and later with another adenoviral
vector-based vaccine (Ad26.COV2.S Janssen; Johnson & Johnson). Risks versus benefits
were carefully assessed in a timely consensus paper from experts in the field,[34] who proposed a tracking algorithm for vaccinated patients based on 10-point guideline
for safe decision-making. In this novel disorder, termed “vaccine-induced immune thrombotic
thrombocytopenia” (VITT), vaccine components appear to form complexes with platelet
factor 4 (PF4) on platelet surface triggering formation of high-avidity anti-PF4 antibodies
able to activate platelets in VITT patients[35] strongly mimicking immune heparin-induced thrombocytopenia (HIT). In this context,
the recently developed humanized monoclonal antibodies tools by Vayne et al[36] to study the antibody response in autoimmune HIT may also help understanding VITT
pathophysiology. While similar, HIT and VITT are however not identical[37] and “rapid” PF4/heparin assays have been shown unsuitable to diagnose VITT in contrast
to enzyme-linked immunosorbent assay-based PF4/heparin immunoassays.[38] Because these immune complexes bind and activate platelets via Fc gamma receptor
IIA, von Hundelshausen et al[39] interestingly advocated for considering off-label use of Bruton tyrosine kinase
(Btk) inhibitors (approved for B cell malignancies) in VITT, as they are expected
to target Fc gamma RIIA-mediated activation of platelet aggregation. A proof-of-concept
could be indeed provided in a subsequent study showing that Btk inhibitors inhibit
platelet aggregation in whole blood induced by VITT serum from patients treated with
or without intravenous immunoglobulins.[40]
In addition to thrombosis, other immunological reactions to SARS-CoV-2 vaccines have
suggested that autoantibodies against the spike protein S1 of SARS-CoV-2 may be responsible
for conditions such as immune thrombocytopenia, vasculitis, Schönlein-Henoch purpura,
autoimmune hepatitis, and Guillain–Barré syndrome.[41] Case reports such as that from Farley et al describing[42] a case of acquired hemophilia after SARS-CoV-2 vaccination should therefore be considered
carefully. Importantly, all cases reported recovered after adequate treatment, and
should not hamper but rather help towards our vaccination efforts by providing transparent
communication and defining appropriate treatment.
Refining Anticoagulation Management
Refining Anticoagulation Management
Informing the 2020 European Society of Cardiology (ESC) guidelines on atrial fibrillation
(AF), the proposal for characterization and evaluation by Potpara et al[43] described the multidimensional aspects of AF requiring moving from classification
toward a structured characterization addressing specific domains with treatment and
prognostic implications, the 4S-AF scheme: Stroke risk; Symptom severity; Severity
of AF burden; and Substrate. Our journal also published the Executive Summary of the
2021 Focused Update Consensus Guidelines of the Asia Pacific Heart Rhythm Society
(APHRS) on Stroke Prevention in AF, with a state of the art discussion of the evidence
and management recommendations for this common arrhythmia.[44] The APHRS guidelines, in line with the ESC AF guidelines, recommends use of an integrated
care or holistic management approach, based on the Atrial fibrillation Better Care
(ABC) pathway[45] to improve outcome in the Asian AF population. The components of the ABC pathway
are as follows: “A”: Avoid stroke with anticoagulation, that is, well-managed warfarin
(time in therapeutic range [TTR] > 65–70%) or non-vitamin K antagonist oral anticoagulant;
“B”: Better symptom management with patient-centered symptom-directed decisions for
rate or rhythm control; and “C”: Cardiovascular risk and comorbidity management as
well as lifestyle changes. The APHRS guidelines noted evidence from a systematic review
and meta-analysis of > 285,000 patients from different regions of the world (including
Asia), showing how adherence to the ABC pathway is associated with a markedly lower
risk of all-cause death, cardiovascular death, stroke, and major bleeding, as well
as hospitalizations.[46] Of note the integrated care approach can be applied to other clinical scenarios
(e.g., stroke, aortovascular disease) given the need to manage the “whole” patient,
and not just one aspect of the patient.[47]
[48] Before characterization and treatment of AF, it is important to detect the arrhythmia
given the potential impact on clinical outcomes.[49]
[50] Indeed, even asymptomatic AF is not benign, as shown in a nice study of the risk
of ischemic stroke in asymptomatic AF patients incidentally detected in primary care.[51]
[52] Kitsiou et at[53] put forward the importance of continuous cardiac monitoring for detecting AF after
a stroke, enabling clinicians to promptly switch to oral anticoagulation and prevent
new strokes. Nelson et al addressed the existing literature on different anticoagulation
strategies efficacy for critical care patients with AF, pointing out to our urgent
need for randomized trials with standardized outcomes for such patients.[54] Machine-learning approaches which account for risk factors' dynamic nature and multimorbidity
may improve clinical stroke risk assessment over clinical scores, as demonstrated
by a comparative study based on a large real-world data set.[55] Jones et al investigated the economic aspects of service interventions and put into
light the cost-effectiveness of anticoagulation clinics, in particular targeting patients
at high-risk and/or with suboptimal treatment,[56] a subject less often studied but nonetheless crucial in improving management praxis.
While we require to acknowledge the dynamics of stroke risks and implement management
flexibility accordingly, identifying specific groups of patients whose risks and benefits
need to be weighted, also determines the success of anticoagulation strategies. Indeed,
a balance between simplicity, practicality, and clinical application is needed. Biomarker-based
scores can be nonspecific (predicting adverse events beyond stroke and bleeding),
and more complex clinical scores are not necessarily the answer given that statistical
significance is not the same as clinical significance.[57]
[58]
In our last Editor's Choice, we mentioned the difficulty in assessing risk–benefit
tradeoff of antithrombotic therapies in East Asians patients who are more prone to
bleeding. An interesting analysis by de Vries et al showed why event rates are higher
in clinical practice than randomized trials of stroke prevention in AF.[59] Also, Pandey et al published a systematic review and meta-analysis comparing lower
versus standard international normalized ratio (INR) targets in AF, showing evidence
that low INR targets may be associated with lower bleeding but has more adverse outcomes.[60]
[61] This work informed the 2021 APHRS guidelines on AF, and highlights the importance
of standard targets and good quality anticoagulation control, with high TTR. The consensus
document from Kim et al on the safety and efficacy of different antithrombotic agents
in Asians compared with Caucasian patients was welcomed by the clinical community
as reflected by its high citation score.[62] How AF patients with intermediate risk can benefit from anticoagulation is an important
issue, which was addressed in a nationwide population-based study by Choi et al[63] who observed benefits appear to have an age threshold. Also, some “real-world” evidence
on the timing of starting oral anticoagulation, after an acute ischemic stroke with
AF was provided by Chang et al, who showed the potential for more bleeding if anticoagulation
was started early.[64] Although risks associated with anticoagulation treatment in high body weight and
obese patients is uncertain, the International Society of Thrombosis and Haemostasis
guidance requires routinely checking DOAC concentrations in these patients which was
challenged by two studies published last year[65]
[66]
[67] that confirmed that almost all high body weight patients achieve expected drug levels
with the use of apixaban, edoxaban, and rivaroxaban with no compromise in efficacy.
Patients who suffered from major hemorrhage represent another group for whom the benefits
and tradeoffs of anticoagulation remain uncertain.[68] Although it seems natural to fear bleeding more than thrombosis in patients after
major hemorrhage, Milling et al challenged this bias as they observed net benefit
with restarting anticoagulation in a post hoc analysis on the DOAC reversal study
ANNEXA-4, highlighting the need for randomized clinical trials in major bleeding scenarios.[69] The well relayed consensus document from Douxfils et al[70] also provided useful updated International Council for Standardization in Haematology
guidance for laboratories regarding timing and modalities of monitoring DOACs, now
including the newly Food and Drug Administration-approved DOAC betrixaban, and the
specific DOAC reversal agent andexanet alfa. In our 2020 Editor's Choice we also highlighted
reassuring evidence on the safety of DOACs in cancer patients,[67]
[71]
[72]
[73] an issue again discussed by Falanga et al last year.[74] The Swedish Patient register cohort study confirmed current AF guidelines on DOACs
originally aimed for the general AF population.[75] Supporting evidence also came from a study from Cohen et al[76] among patients with VTE and active cancer prescribed apixaban, LMWH, or warfarin.
In a post hoc analysis of the Caravaggio study, a large trial on the treatment of
VTE in patients with cancer comparing apixaban with dalteparin, Ageno et al[77] reported additional data on bleeding events which supports administering apixaban
to an even larger population of cancer patients than previously recommended by guidelines,
also including patients with gastrointestinal cancer, and should help clinicians translate
the findings of the CARAVAGGIO study into clinical practice. Pregnancy and the postpartal
phase are also associated with increasing VTE risk making it a leading cause of maternal
mortality. We therefore very much welcomed the insights from the Global Anticoagulant
Registry in the FIELD (GARFIELD)-VTE into the clinical characteristics, diagnostic
strategies, treatment patterns, and outcomes of women with pregnancy-associated VTE.[78] To refine bleeding risk for VTE patients under anticoagulant therapy, a valuable
study compared the “classic” Registro Informatizado de Enfermedad TromboEmbólica (RIETE)
score to the more recently developed VTE-BLEED score at different times after VTE
diagnosis, with similar results for the prediction of early and late bleeds, and only
small differences depending on the time since VTE diagnosis and the site of hemorrhage.[79] As autoimmune hemolytic anemia is increasingly recognized as a strong risk factor
for venous thrombosis but there are not yet any guidelines on thromboembolism prevention
and management in this context, case report studies such as that of from Solari et
al should prove very useful to the clinical community.[80] Cirrhosis represents another disorder often associated with splanchnic vein thrombosis
for which the meta-analysis from Valeriani et al reviewed useful clinical information
on the value of anticoagulation therapy to lower the thrombotic burden without increasing
overall bleeding risk.[81] The efforts from Sokou et al[82] to develop an easy-to-use risk score for critically ill neonates based on bed-side
assessment of global coagulation and routinely available parameters was most welcome
as these subjects have a high bleeding risk difficult to predict with conventional
coagulation assays.
Following the ESC guidelines on acute coronary syndrome, the state-of-the-art review
by Guedeney and Collet provided a comprehensive overview of current evidence on the
pharmacological management of patients with acute coronary syndrome, particularly
on the use of modern and more potent antiplatelet agents.[83] The risk–benefit tradeoff of antithrombotic therapies in East Asian patients was
informed by the pharmacodynamic randomized trial A-MATCH which evaluated a prasugrel
deescalation strategy in East Asian patients with acute coronary syndrome and showed
a higher chance within the therapeutic window with reduced bleeding episodes.[84]
Bleeding Risks and the Management of Bleeding Complications
Bleeding Risks and the Management of Bleeding Complications
Hemophilia A patients whose lack of coagulation factor VIII (FVIII), put them at risk
of prolonged bleeding are conventionally treated with FVIII infusion which is unfortunately
limited by the development of neutralizing antibodies. The fourth generation rFVIII
product simoctocog alfa (Nuwiq; Octapharma) replicating the native human FVIII protein
without incorporation of potentially immunogenic elements of animal cell origin may
represent a promising candidate to overcome this issue as reflected by the final data
of the NuProtect study.[85] The recently approved bispecific monoclonal antibody emicizumab represents another
very attractive approach for treating hemophilia A patients bypassing FVIII activation.
We highlighted last year the published promising clinical trials and preliminary reports
with emicizumab[86] as well as its cost-effectiveness and budget.[87] We were pleased to publish new data from the Haven 1 study concerning pharmacokinetic
and pharmacodynamic of emicizumab effects[88] which should help the increasing number of clinicians using this new therapy. Severe
bleeding is also one of the most common complications for cirrhosis patients with
low fibrinogen for whom it is common practice to transfuse blood products such as
cryoprecipitate. Budnick et al demonstrated the inefficacy of such treatment in improving
survival or bleeding complications, seriously questioning routine management.[89]
Identifying New Targets and Mechanisms
Identifying New Targets and Mechanisms
Refining our understanding of platelet procoagulant physiology and pathophysiology
has been an active subject of investigation in the context of COVID-19[30]
[31]
[35] but also in a more general context as portrayed by further very welcomed investigations
last year. Aliotta et al[90] elegantly investigated ion fluxes in collagen and thrombin activated human platelets
providing novel insights into the dichotomous role of the sodium–calcium exchanger
in procoagulant platelet formation. Ya et al have addressed the counteracting effects
of protocatechuic acid on the apoptotic PI3K/Akt/GSK3β signaling pathways in human
platelets,[91] thereby highlighting a potentially important protective role in the progression
of cardiovascular disease. The role of lipid rafts in cyclic adenosine monophosphate
signaling homoeostasis in platelet was confirmed by Belleville-Rolland et al[92] who further pointed out to the role of transporter multidrug resistance protein
4 in particular, and thus a new potential target for antithrombotic agents. The importance
of the platelet–neutrophil feedback loop was evidence by a case–control study[93] that put forward the importance of combining biomarkers of NETosis and platelet
activation to predict the risk of major adverse events in a cohort of postmyocardial
infarction patients. NETosis markers may also predict placenta-mediated complications
in pregnancy as suggested by a pilot study, derived from the GrossPath study, demonstrating
distinct circulating nucleosome-bound histones were increased in complicated pregnancy.[94] Further shedding light on the effect of neutrophil extracellular traps on coagulation,
Locke and Longstaff[95] published an interesting manuscript demonstrating the inhibitory effects of histones
on fibrinolysis, suggesting new therapeutic targets for preventing thrombosis. Increasing
evidence suggests that circulating micro-ribonucleic acids (miRNAs) could be used
as diagnostic biomarkers and may even represent therapeutic targets for cardiovascular
diseases. The study from Stojkovic et al assessing the relationship between different
circulating miRNAs and monocyte-platelet aggregate formation in patients with acute
coronary syndrome on dual antiplatelet therapy is an example of such new interest.[96] Garcia et al identified an important role of a specific miRNA, miR-204–5p, on in
vitro platelet production and function,[97] suggesting genetic control of platelet production and function by miR-204–5p which
may thus be considered as a new biomarker for high platelet reactivity in the context
of personalized antiplatelet therapy.[98] The comprehensive overview of currently available techniques for studying miRNA
function with a focus on platelet reactivity regulation by Garcia et al,[99] also attracted much interest among our author community seeking to overcome the
current methodological limitations in this field.
We are thereby delighted to publish an ever more diverse panel of scientific advances
and clinical pictures reflecting the multifaceted aspects of Thrombosis and Haemostasis. This past year has brought its share of much needed investigations in understanding
and treating the cardiovascular complications associated with COVID-19 in particular,
but also in refining current clinical management in thrombosis in a more general context,
opening new avenues for targeting and biomarker strategies as well as understanding
underlying cardiovascular mechanisms. We are pleased that manuscripts are being increasingly
submitted from all over the world: China now holds the record of submissions, followed
by the United States, Italy, and Germany ([Fig. 1]).
Fig. 1 Worldwide author distribution of original manuscripts submitted in 2021. Circle size
is proportional to the total number of original manuscripts submitted in each country.
Map created with Datawrapper.
