Inflammation is in the background of every single major illness.
— Julie Daniluk, Author and Registered Holistic Nutritionist
The term inflammation appeared in the context of pathology first in the early 15th
century, meaning excessive redness or swelling in a body part. The word “inflammation”
reached a peak occurrence in English books ∼1830, followed by a steady decrease to
a nadir around 1970, and thereafter increasing progressively again.[1] There is now increasing interest in the interplay between inflammation and coagulation,
and when the two present simultaneously we often see the term thrombo-inflammations,
probably originating in 2004 in a description of interactions between platelets and
leukocytes.[2]
This theme issue includes two articles on the prominent role of inflammation. The
first contribution by Kruger et al is a review of the vascular pathogenesis in long
coronavirus disease 2019 (COVID-19), also called post-acute sequelae of COVID-19 (PASC).[3] The authors discuss data on thrombotic endothelialitis, which results in endothelial
dysfunction and is associated with the symptoms of PASC. Diagnostic techniques to
diagnose endothelial dysfunction are described, as well as some potential agents to
ameliorate the effects of PASC.
The second article explored the association between 91 inflammation-related proteins
and portal vein thrombosis.[4] After using multivariable Mendelian randomization, Zhang et al could confirm an
independent inverse association between the eukaryotic translation initiation factor
4E-binding protein 1 and risk for portal vein thrombosis, both in the initially used
database and in a replication study with another dataset. In other words, this protein
appears to have a protective effect against portal vein thrombosis. However, the mediating
mechanisms remain unclear.
The next contribution is also a Mendelian randomization study, here investigating
the effects of smoking on the risk of venous thromboembolism (VTE), and on deep vein
thrombosis and pulmonary embolism separately.[5] Of the different phenotypes of smoking, “lifetime smoking” showed the strongest
association with VTE and with pulmonary embolism, and there was also a suggested association
between total pack-years of smoking in adulthood or number of cigarettes smoked per
day and risk of VTE. The authors used rigorous statistical techniques to minimize
the chance of bias in their analyses, but the results are only based on data from
people of European ancestry. Obviously, in addition to any genetic susceptibility,
social and environmental factors also play an important role for the development of
smoking habits.
Pharmacological prophylaxis against VTE for patients after hip or knee arthroplasty
is recommended by all guidelines, whether it is with aspirin, low-molecular-weight
heparin (LMWH), or oral anticoagulants. In a network meta-analysis of 70 randomized
clinical trials, Yong et al compared unfractionated heparin, LMWH, fondaparinux, warfarin
factor Xa inhibitors, and factor IIa inhibitor (dabigatran).[6] Factor Xa inhibitors were identified as the most effective prophylactic agents and
possibly also providing the best balance between risk of VTE and risk of bleeding.
However, none of the agents reduced mortality.
Whereas prophylaxis against VTE after hip or knee arthroplasty generally continues
for some time after discharge from hospital, this is not commonly ordered for other
surgical patients or for medical patients. Furthermore, not all patients receive VTE
prophylaxis even during the hospitalization. In an analysis of time trends in usage
and outcomes, Brenner et al used registry data on more than 16,000 patients, who had
been hospitalized within 2 months before the index VTE between the years 2003 and
2022, inclusive.[7] The use of prophylaxis increased during this period for medical patients but decreased
for surgical patients. Maybe the latter observation could be influenced by more frequent
laparoscopic and other procedures with discharge the same or the following day? As
for the 90-day follow-up after the VTE, the authors found that the composite of recurrent
VTE and fatal pulmonary embolism decreased, but in medical patients there was an increase
in incidence of major bleeding.
Catastrophic thrombosis often involves unusual anatomical sites, presents with an
aggressive course, and is challenging to treat. Franchini et al review here the different
types of catastrophic thrombosis, the various triggering factors, and finally provide
a structure for diagnostic work-up and initial treatment.[8]
Steven Grover, recipient of one of our Young Investigator Awards,[9] reviews here data on the role of congenital C1-deficiency, caused by SERPING1 gene mutations, and hypercoagulability.[10] There is some epidemiological evidence linking this deficiency with increased risk
for VTE, and thus we could now have a new type of hereditary thrombophilia, albeit
rare. We are also informed about the potential effects of C1 inhibitor concentrates
to not only eliminate episodes of submucosal and subcutaneous swelling but also to
mitigate the risk of thrombosis.
Intravenous direct thrombin inhibitors (bivalirudin, argatroban, lepirudin) are often
used to treat heparin-induced thrombocytopenia, but there is an increase in application
of these agents for the treatment of acute VTE in the pediatric population. Kiskaddon
et al have performed a systematic review of indications for such treatment, dose regimens,
and outcomes.[11] From 16 published studies and case reports, it appeared that bivalirudin was the
most frequently used agent and it was associated with a resolution of the thrombus
in 62% of the patients.
The same research group has also contributed with a study on recurrent thromboembolism
in children with congenital heart disease.[12] Approximately 1% of children born in the United States are affected by vitium organicum cordis and the risk of thrombotic complications has increased. In a prospective study over
11 years at a single institution, 40 children with congenital heart disease developed
thromboembolism and one-third of those had a recurrent event. The risk factors for
recurrence included immobility and presence of a central venous catheter.
Still on the topic of pediatric thrombosis, we have a Letter to the Editor describing
13 patients who received secondary anticoagulation—mainly prophylactic—after completing
the anticoagulant treatment for an index VTE that was the subject of a large multicenter
randomized trial on duration of anticoagulation.[13]
[14] Secondary anticoagulation was more likely to occur in children with arm vein thrombosis,
which in turn was frequently associated with a central venous catheter.
Another Letter to the Editor summarizes the results of a Mendelian randomization study
on association between type 2 diabetes and VTE in East Asians and African Americans.
Lu and Wang confirmed results from studies in other population ethnicities that there
does not seem to be an association in any direction between the two diseases.[15]
A third Letter to the Editor by Chen et al is a case report on a 68-year-old female
with a reduced protein C activity, a point mutation in the PROC gene, deep vein thrombosis with multiple pulmonary emboli, and a family history of
mainly arterial thromboembolism.[16] There was recurrent swelling of the leg and thrombophlebitis while on full-dose
rivaroxaban, prompting exchange to warfarin with good effect.
Finally, we have two commentaries—the first by Hirsh et al discussing why lower doses
of anticoagulants are used for prevention of VTE than for treatment of VTE or for
stroke prevention in atrial fibrillation.[17] The authors propose two main deciding factors—the degree of thrombogenicity and
the severity of the consequences without anticoagulation.
And last but not least, a commentary by our Editor in Chief and colleagues, reviewing
the debated existence of sticky platelet syndrome, its history, three distinct patterns
in platelet aggregation studies, and the potential contribution of other factors to
the hyperreactivity.[18] The authors tie the narrative nicely into the 50-year anniversary of our journal.
Surely, the reader will find interesting reading all these 14 contributions that span
from pathogenesis and risk factors to diagnosis and treatment of various aspects of
thrombosis, mainly on the venous side.
