Top

Journal of Thrombosis and Thrombolysis

Published in:

Open Access 06-11-2023

Reduced fibrin clot permeability on admission and elevated E-selectin at 3 months as novel risk factors of residual pulmonary vascular obstruction in patients with acute pulmonary embolism

Authors: Konrad Stępień, Michał Ząbczyk, Magdalena Kopytek, Joanna Natorska, Jarosław Zalewski, Anetta Undas

Published in: Journal of Thrombosis and Thrombolysis | Issue 2/2024

Abstract

Background

Residual pulmonary vascular obstruction (RPVO) is common following pulmonary embolism (PE) but its association with fibrin clot properties is poorly understood. We investigated whether prothrombotic state and hypofibrinolysis markers can identify patients with RPVO.

Methods

In 79 normotensive noncancer patients (aged 56 ± 13.3 years) with acute PE, we determined fibrin clot permeability (K_s), clot lysis time (CLT), endogenous thrombin potential (ETP), fibrinolysis proteins, oxidative stress markers, and E-selectin on admission before initiation of anticoagulant therapy, after 5–7 days, and 3 months of anticoagulation. RPVO was diagnosed using computed tomography angiography 3–6 months since PE.

Results

Patients with RPVO (n = 23, 29.1%) had at baseline higher simplified Pulmonary Embolism Severity Index (sPESI) (P = 0.004), higher N-terminal brain natriuretic propeptide (P = 0.006) and higher D-dimer (P = 0.044). Patients with versus without RPVO had lower K_s (P < 0.001) and longer CLT (P < 0.05), both at baseline and 5–7 days since admission, but not at 3 months. Patients with RPVO showed 40.6% higher E-selectin (P < 0.001) solely at 3 months. By multivariable logistic regression, baseline K_s (odds ratio [OR] 0.010, 95% confidence interval [CI] 0.001–0.837, P = 0.042, per 10^− 9 cm²), baseline D-dimer (OR 1.105, 95% CI 1.000-1.221, P = 0.049, per 100 ng/ml), and E-selectin levels after 3 months (OR 3.874, 95% CI 1.239–12.116, P = 0.020, per 1 ng/ml) were associated with RPVO.

Conclusions

RPVO patients despite anticoagulation characterize with the formation of denser fibrin clots on admission and higher E-selectin at 3 months. Those parameters could be the potential novel RPVO risk factors that warrant further evaluation in an independent cohort.

Graphical Abstract

Available only for authorised users

Lami D, Cellai AP, Antonucci E et al (2014) Residual perfusion defects in patients with pulmonary embolism are related to impaired fibrinolytic capacity. Thromb Res 134:737–741. https://doi.org/10.1016/j.thromres.2014.07.013CrossRefPubMed

Planquette B, Ferré A, Peron J et al (2016) Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism. A single center cohort study. Thromb Res 148:70–75. https://doi.org/10.1016/j.thromres.2016.10.030CrossRefPubMed

Sista AK, Klok FA (2018) Late outcomes of pulmonary embolism: the post-PE syndrome. Thromb Res 164:157–162. https://doi.org/10.1016/j.thromres.2017.06.017CrossRefPubMed

Picart G, Robin P, Tromeur C et al (2020) Predictors of residual pulmonary vascular obstruction after pulmonary embolism: results from a prospective cohort study. Thromb Res 194:1–7. https://doi.org/10.1016/j.thromres.2020.06.004CrossRefPubMed

Undas A (2017) Prothrombotic Fibrin Clot Phenotype in Patients with Deep Vein Thrombosis and Pulmonary Embolism: A New Risk Factor for Recurrence. Biomed Res Int. ; 2017: 8196256. https://doi.org/10.1155/2017/8196256

Undas A, Zawilska K, Ciesla-Dul M et al (2009) Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 114:4272–4278. https://doi.org/10.1182/blood-2009-05-222380CrossRefPubMed

Zabczyk M, Plens K, Wojtowicz W et al (2017) Prothrombotic fibrin clot phenotype is Associated with Recurrent Pulmonary Embolism after discontinuation of anticoagulant therapy. Arterioscler Thromb Vasc Biol 37:365–373. https://doi.org/10.1161/ATVBAHA.116.308253CrossRefPubMed

Undas A, Cieśla-Dul M, Drążkiewicz T et al (2012) Altered fibrin clot properties are associated with residual vein obstruction: effects of lipoprotein(a) and apolipoprotein(a) isoform. Thromb Res 130:e184–187. https://doi.org/10.1016/j.thromres.2012.06.005CrossRefPubMed

Ząbczyk M, Natorska J, Janion-Sadowska A et al (2022) Isoprostane-8 and GDF-15 as novel markers of post-PE syndrome: relation with prothrombotic factors. Eur J Clin Invest 52:e13660. https://doi.org/10.1111/eci.13660CrossRefPubMed

10.

Planquette B, Sanchez O, Marsh JJ et al (2018) Fibrinogen and the prediction of residual obstruction manifested after pulmonary embolism treatment. Eur Respir J 52:1801467. https://doi.org/10.1183/13993003.01467-2018CrossRefPubMedPubMedCentral

11.

Purdy M, Obi A, Myers D et al (2022) P- and E- selectin in venous thrombosis and non-venous pathologies. J Thromb Haemost 20:1056–1066. https://doi.org/10.1111/jth.15689CrossRefPubMedPubMedCentral

12.

Sullivan VV, Hawley AE, Farris DM et al (2003) Decrease in fibrin content of venous thrombi in selectin-deficient mice. J Surg Res 109:1–7. https://doi.org/10.1016/s0022-4804(02)00041-0CrossRefPubMed

13.

Myers D Jr, Farris D, Hawley A et al (2002) Selectins influence thrombosis in a mouse model of experimental deep venous thrombosis. J Surg Res 108:212–221. https://doi.org/10.1006/jsre.2002.6552CrossRefPubMed

14.

Xie Y, Duan Q, Wang L et al (2012) Genomic characteristics of adhesion molecules in patients with symptomatic pulmonary embolism. Mol Med Rep 6:585–590. https://doi.org/10.3892/mmr.2012.940CrossRefPubMed

15.

Darwish I, Fareed J, Brailovsky Y et al (2022) Dysregulation of biomarkers of hemostatic activation and inflammatory processes are Associated with adverse outcomes in Pulmonary Embolism. Clin Appl Thromb Hemost 28:10760296211064898. https://doi.org/10.1177/10760296211064898CrossRefPubMedPubMedCentral

16.

Kansas GS (1996) Selectins and their ligands: current concepts and controversies. Blood 88:3259–3287CrossRefPubMed

17.

Bittar LF, Silva LQD, Orsi FLA et al (2020) Increased inflammation and endothelial markers in patients with late severe post-thrombotic syndrome. PLoS ONE 15:e0227150. https://doi.org/10.1371/journal.pone.0227150CrossRefPubMedPubMedCentral

18.

Ząbczyk M, Natorska J, Janion-Sadowska A et al (2020) Prothrombotic fibrin clot properties associated with NETs formation characterize acute pulmonary embolism patients with higher mortality risk. Sci Rep 10:11433. https://doi.org/10.1038/s41598-020-68375-7CrossRefPubMedPubMedCentral

19.

Pruszczyk P, Skowrońska M, Ciurzyński M et al (2021) Assessment of pulmonary embolism severity and the risk of early death. Pol Arch Intern Med 131:16134. https://doi.org/10.20452/pamw.16134CrossRefPubMed

20.

Ciurzyński M, Kurzyna M, Kopeć G et al (2022) An expert opinion of the polish Cardiac Society Working Group on Pulmonary circulation on screening for chronic thromboembolic pulmonary hypertension patients after acute pulmonary embolism: update. Kardiol Pol 80:723–732. https://doi.org/10.33963/KP.a2022.0141CrossRefPubMed

21.

Stepien K, Nowak K, Szlosarczyk B et al (2022) Clinical characteristics and long-term outcomes of MINOCA accompanied by active Cancer: a retrospective insight into a Cardio-Oncology Center Registry. Front Cardiovasc Med 9:785246. https://doi.org/10.3389/fcvm.2022.785246CrossRefPubMedPubMedCentral

22.

Stepien K, Nowak K, Zalewski J et al (2019) Extended treatment with non-vitamin K antagonist oral anticoagulants versus low-molecular-weight heparins in cancer patients following venous thromboembolism. A pilot study. Vascul Pharmacol 120:106567. https://doi.org/10.1016/j.vph.2019.106567CrossRefPubMed

23.

Stępień K, Siudut J, Konieczyńska M et al (2023) Effect of high-dose statin therapy on coagulation factors: lowering of factor XI as a modifier of fibrin clot properties in coronary artery disease. Vascul Pharmacol 149:107153. https://doi.org/10.1016/j.vph.2023.107153CrossRefPubMed

24.

Pieters M, Philippou H, Undas A et al (2018) An international study on the feasibility of a standardized combined plasma clot turbidity and lysis assay: communication from the SSC of the ISTH. J Thromb Haemost 16:1007–1012. https://doi.org/10.1111/jth.14002CrossRefPubMed

25.

Zalewski J, Stepien K, Nowak K et al (2020) Delayed Thrombin Generation is Associated with minor bleedings in venous thromboembolism patients on Rivaroxaban: usefulness of calibrated Automated Thrombography. J Clin Med 9:2018. https://doi.org/10.3390/jcm9072018CrossRefPubMedPubMedCentral

26.

Bonnefoy PB, Margelidon-Cozzolino V, Catella-Chatron J et al (2019) What’s next after the clot? Residual pulmonary vascular obstruction after pulmonary embolism: from imaging finding to clinical consequences. Thromb Res 184:67–76. https://doi.org/10.1016/j.thromres.2019.09.038CrossRefPubMed

27.

Chang Y, Moon JY, Park JH et al (2021) Predictors of residual pulmonary vascular obstruction after anticoagulation monotherapy in patients with intermediate-risk pulmonary embolism. J Thorac Dis 13:4217–4227. https://doi.org/10.21037/jtd-21-403CrossRefPubMedPubMedCentral

28.

Pietrasik A, Gąsecka A, Smyk JM et al (2022) Acute-on-chronic pulmonary embolism and concomitant paradoxical embolism: two diseases, one intervention. Pol Arch Intern Med 132:16155. https://doi.org/10.20452/pamw.16155CrossRefPubMed

29.

Chopard R, Genet B, Ecarnot F et al (2017) Detection of residual pulmonary vascular obstruction by ventilation-perfusion lung scan late after a First Pulmonary Embolism. Am J Cardiol 119:1883–1889. https://doi.org/10.1016/j.amjcard.2017.03.002CrossRefPubMed

30.

Meneveau N, Ider O, Seronde MF et al (2013) Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate- to high-risk pulmonary embolism. Eur Heart J 34:693–701. https://doi.org/10.1093/eurheartj/ehs365CrossRefPubMed

31.

Undas KW, Siudut J, Ząbczyk M (2022) Unfavorably altered fibrin clot properties are associated with recurrent venous thromboembolism in patients following postdischarge events. Pol Arch Intern Med 132:16326. https://doi.org/10.20452/pamw.16326CrossRefPubMed

32.

Scott EM, Ariëns RA, Grant PJ (2004) Genetic and environmental determinants of fibrin structure and function: relevance to clinical disease. Arterioscler Thromb Vasc Biol 24:1558–1566. https://doi.org/10.1161/01.ATV.0000136649.83297.bfCrossRefPubMed

33.

de Vries JJ, Snoek CJM, Rijken DC et al (2020) Effects of post-translational modifications of fibrinogen on clot formation, clot structure, and Fibrinolysis: a systematic review. Arterioscler Thromb Vasc Biol 40:554–569. https://doi.org/10.1161/ATVBAHA.119.313626CrossRefPubMedPubMedCentral

34.

Ząbczyk M, Stachowicz A, Natorska J et al (2019) Plasma fibrin clot proteomics in healthy subjects: relation to clot permeability and lysis time. J Proteom 208:103487. https://doi.org/10.1016/j.jprot.2019.103487CrossRef

35.

Stachowicz A, Siudut J, Suski M et al (2017) Optimization of quantitative proteomic analysis of clots generated from plasma of patients with venous thromboembolism. Clin Proteom 14:38. https://doi.org/10.1186/s12014-017-9173-xCrossRef

36.

Watany MM, Abdou S, Elkolaly R et al (2022) Evaluation of admission levels of P, E and L selectins as predictors for thrombosis in hospitalized COVID-19 patients. Clin Exp Med 22:567–575. https://doi.org/10.1007/s10238-021-00787-9CrossRefPubMedPubMedCentral

37.

Culmer DL, Dunbar ML, Hawley AE et al (2017) E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model. Thromb Haemost 117:1171–1181. https://doi.org/10.1160/TH16-04-0323CrossRefPubMed

38.

Myers DD Jr, Ning J, Lester P et al (2022) E-selectin inhibitor is superior to low-molecular-weight heparin for the treatment of experimental venous thrombosis. J Vasc Surg Venous Lymphat Disord 10:211–220. https://doi.org/10.1016/j.jvsv.2020.12.086CrossRefPubMed

39.

Ortel TL, Neumann I, Ageno W et al (2020) American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 4:4693–4738. https://doi.org/10.1182/bloodadvances.2020001830CrossRefPubMedPubMedCentral

40.

Bruinstroop E, Klok FA, Van De Ree MA et al (2009) Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost 7:611–618. https://doi.org/10.1111/j.1538-7836.2009.03293.xCrossRefPubMed

41.

Kaczyńska A, Kostrubiec M, Pacho R et al (2008) Elevated D-dimer concentration identifies patients with incomplete recanalization of pulmonary artery thromboemboli despite 6 months anticoagulation after the first episode of acute pulmonary embolism. Thromb Res 122:21–25. https://doi.org/10.1016/j.thromres.2007.08.020CrossRefPubMed

42.

Aranda C, Peralta L, Gagliardi L et al (2021) A significant decrease in D-dimer concentration within one month of anticoagulation therapy as a predictor of both complete recanalization and risk of recurrence after initial pulmonary embolism. Thromb Res 202:31–35. https://doi.org/10.1016/j.thromres.2021.02.033CrossRefPubMed

43.

Wiliński J, Skwarek A, Borek R et al (2022) Right ventricular wall thickness indexed to body surface area as an echocardiographic predictor of acute pulmonary embolism in high-risk patients. Kardiol Pol 80:205–207. https://doi.org/10.33963/KP.a2021.0180CrossRefPubMed

44.

Delluc A, Wang TF (2021) How to treat incidental pulmonary embolism in cancer patients? Recent advances. Kardiol Pol 79:1305–1310. https://doi.org/10.33963/KP.a2021.0164CrossRefPubMed

Title: Reduced fibrin clot permeability on admission and elevated E-selectin at 3 months as novel risk factors of residual pulmonary vascular obstruction in patients with acute pulmonary embolism
Authors: Konrad Stępień
Michał Ząbczyk
Magdalena Kopytek
Joanna Natorska
Jarosław Zalewski
Anetta Undas
Publication date: 06-11-2023
Publisher: Springer US
Published in: Journal of Thrombosis and Thrombolysis / Issue 2/2024
Print ISSN: 0929-5305
Electronic ISSN: 1573-742X
DOI: https://doi.org/10.1007/s11239-023-02901-y

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Please log in to get access to this content

Other articles of this Issue 2/2024

Characterization of an andexanet alfa administration protocol guided by drug-specific quantitative anti-Xa assays

Incidence and risk factors of venous thromboembolism in kidney transplantation patients: a prospective cohort study

Real-world effectiveness and safety of evolocumab in very high-risk atherosclerotic cardiovascular disease patients with acute ischemic stroke

Short-term antiplatelet versus anticoagulant therapy after left atrial appendage closure: a systematic review and meta-analysis

Mesoglycan for the secondary prevention of superficial vein thrombosis: a randomized, controlled, double-blind study (METRO Study)—rationale and protocol

In-Hospital and readmission outcomes of patients with myeloproliferative neoplasms and atrial fibrillation: insights from the National Readmissions Database

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials