Recent Advances in Thrombosis and Hemostasis—Part XI

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.

Publication History

Article published online:
20 December 2024

• References

• 1 Google Books Ngram Viewer. Accessed November 27, 2024 at: https://books.google.com/ngrams/
• 2 Tanguay JF, Geoffroy P, Sirois MG. et al. Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions with recombinant P-selectin glycoprotein ligand-1. Thromb Haemost 2004; 91 (06) 1186-1193
• 3 Kruger A, Joffe D, Lloyd-Jones G. et al. Vascular pathogenesis in acute and long COVID: current insights and therapeutic outlook. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 4 Zhang B, Yao Z, Li P. et al. Causal relationships of circulating inflammatory proteins and portal vein thrombosis: a Mendelian randomization study. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 5 Li Y, Tong L, Zhang Y, Huang B, Zhu L. Comprehensive Mendelian randomization analysis of smoking and its effects on venous thromboembolism. . Semin Thromb Hemost 2025;51(03: (e-pub ahead of print)
• 6 Yong BSJ, Ling RR, Li R. et al. Pharmacotherapy for venous thromboprophylaxis following total hip or knee arthroplasty: a systematic review and network meta-analysis. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 7 Brenner B, Tzoran I, Bikdeli B. et al; RIETE Investigators. Venous thromboembolism after hospital discharge: temporal trends in baseline characteristics, prevention, treatment, and 90-day outcomes. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print).
• 8 Franchini M, Focosi D, Pezzo MP, Mannucci PM. Catastrophic thrombosis: a narrative review. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 9 Favaloro EJ. 2023 Eberhard F. Mammen Award Announcements: Part II-Young Investigator Awards. Semin Thromb Hemost 2024; 50 (08) 1049-1057
• 10 Grover SP. Hereditary angioedema and venous thromboembolism: where there's smoke, there's fire. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 11 Kiskaddon AL, Branstetter J, Williams P. et al. Intravenous direct thrombin inhibitors for acute venous thromboembolism or heparin-induced thrombocytopenia with thrombosis in children: a systematic review of the literature. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 12 Kiskaddon A, Giglia TM, Betensky M. et al. Recurrent thromboembolism in pediatric congenital heart disease: cumulative incidence and prognostic factors. . Semin Thromb Hemost 2025;51(03 (e-pub ahead of print)
• 13 Wilson HP, Mosha M, Miller A. et al. Secondary anticoagulation use in patients <21 years old following a primary anticoagulant treatment for provoked venous thromboembolism: findings from the Kids-DOTT trial. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print).
• 14 Goldenberg NA, Kittelson JM, Abshire TC. et al; Kids-DOTT Trial Investigators and the ATLAS Group. Effect of Anticoagulant therapy for 6 weeks vs 3 months on recurrence and bleeding events in patients younger than 21 years of age with provoked venous thromboembolism: the Kids-DOTT randomized clinical trial. JAMA 2022; 327 (02) 129-137
• 15 Lu J, Wang Z. Mendelian randomization provides no evidence for the bidirectional relationship between type 2 diabetes and venous thromboembolism in East Asians and African Americans. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 16 Chen Z, Wu H, Xu Y, Gu T, Liu D, Lan M. Hereditary thrombophilia: a case of subacute pulmonary embolism in a 68-year-old female with a mutation in the PROC gene. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 17 Hirsh J, Godoy A, Chan NC. Dosing intensity of anticoagulants for prevention and treatment of venous thromboembolism and prevention of stroke in atrial fibrillation: why is there a difference?. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)
• 18 Favaloro EJ, Pasalic L, Fan BE, Lippi G. Sticky platelet syndrome revisited?. Semin Thromb Hemost 2024; 51 (03) (e-pub ahead of print)