Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both - the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

Clinic of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Hematology and Transfusion Medicine Jessenius Faculty of Medicine in Martin Comenius University in Bratislava 03601 Martin Slovakia

Department of Histology and Embryology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Natural Drugs Faculty of Pharmacy Masaryk University 61200 Brno Czech Republic

Department of Pathological Physiology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Physiology and Biophysics Weill Cornell Medicine Qatar Qatar Foundation Education City 24144 Doha Qatar

Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn 53127 Bonn Germany

Lambda Life JSC 85101 Bratislava Slovakia

Predictive Preventive and Personalised Medicine Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn 53127 Bonn Germany

Zobrazit více v PubMed

Hiller E. Basic Principles of Hemostasis. In: Munker R, editor. Modern hematology: biology and clinical management. Totowa, NJ: Humana Press; 2007. p. 327–345. 10.1007/978-1-59745-149-9_19.

Setyawan J, Mu F, Yarur A, Zichlin ML, Yang H, Fernan C, et al. Risk of thromboembolic events and associated risk factors, including treatments, in patients with immune-mediated diseases. Clin Ther. 2021;43:1392–1407.e1. doi: 10.1016/j.clinthera.2021.06.008. PubMed DOI

Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. The Lancet. 2016;388:3060–3073. doi: 10.1016/S0140-6736(16)30514-1. PubMed DOI

Vaqar S, Graber M. StatPearls: thromboembolic event. Treasure Island (FL); 2022. PubMed

Lyman GH, Culakova E, Poniewierski MS, Kuderer NM. Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer. Thromb Res. 2018;164:S112–S118. doi: 10.1016/j.thromres.2018.01.028. PubMed DOI

Al-Hameed F, Al-Dorzi H, Qadhi A, Shaker A, Al-Gahtani F, Al-Jassir F, et al. Thromboprophylaxis and mortality among patients who developed venous thromboembolism in seven major hospitals in Saudi Arabia. Ann Thorac Med. 2017;12:282. doi: 10.4103/atm.ATM_101_17. PubMed DOI PMC

Amin A, Deitelzweig S, Bucior I, Lin J, Lingohr-Smith M, Menges B, Neuman WR. Frequency of hospital readmissions for venous thromboembolism and associated hospital costs and length of stay among acute medically ill patients in the US. J Med Econ. 2019;22:1119–1125. doi: 10.1080/13696998.2019.1618862. PubMed DOI

Monreal M, Agnelli G, Chuang LH, Cohen AT, Gumbs PD, Bauersachs R, et al. Deep vein thrombosis in Europe—health-related quality of life and mortality. Clin Appl Thromb Hemost. 2019;25:107602961988394. doi: 10.1177/1076029619883946. PubMed DOI PMC

Chan NC, Weitz JI. Antithrombotic agents. Circ Res. 2019;124:426–436. doi: 10.1161/CIRCRESAHA.118.313155. PubMed DOI

Chu DK, Hillis CM, Leong DP, Anand SS, Siegal DM. Benefits and risks of antithrombotic therapy in essential thrombocythemia. Ann Intern Med. 2017;167:170. doi: 10.7326/M17-0284. PubMed DOI

Gupta R, Majumdar M, Imran R, Yi J. A comprehensive review on antithrombotic therapy for peripheral artery disease. Semin Vasc Surg. 2022;35:124–131. doi: 10.1053/j.semvascsurg.2022.04.004. PubMed DOI

Bojić M, Maleš Ž, Antolić A, Babić I, Tomičić M. Antithrombotic activity of flavonoids and polyphenols rich plant species. Acta Pharm. 2019;69:483–495. doi: 10.2478/acph-2019-0050. PubMed DOI

Subramani B, Sathiyarajeswaran P. Current update on herbal sources of antithrombotic activity—a comprehensive review. Egypt J Intern Med. 2022;34:e56. doi: 10.1186/s43162-021-00090-9. PubMed DOI PMC

Jones VC, Birrell MA, Maher SA, Griffiths M, Grace M, O'Donnell VB, et al. Role of EP 2 and EP 4 receptors in airway microvascular leak induced by prostaglandin E 2. Br J Pharmacol. 2016;173:992–1004. doi: 10.1111/bph.13400. PubMed DOI PMC

Sinegre T, Teissandier D, Milenkovic D, Morand C, Lebreton A. Epicatechin influences primary hemostasis, coagulation and fibrinolysis. Food Funct. 2019;10:7291–7298. doi: 10.1039/C9FO00816K. PubMed DOI

Golubnitschaja O, Baban B, Boniolo G, Wang W, Bubnov R, Kapalla M, et al. Medicine in the early twenty-first century: paradigm and anticipation - EPMA position paper 2016. EPMA Journal. 2016;7:77. doi: 10.1186/s13167-016-0072-4. PubMed DOI PMC

Wang W, Yan Y, Guo Z, Hou H, Garcia M, Tan X, et al. All around suboptimal health — a joint position paper of the Suboptimal Health Study Consortium and European Association for Predictive, Preventive and Personalised Medicine. EPMA J. 2021;12:403–433. doi: 10.1007/s13167-021-00253-2. PubMed DOI PMC

Koklesova L, Liskova A, Samec M, Qaradakhi T, Zulli A, Smejkal K, et al. Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine. EPMA Journal. 2020;11:261–287. doi: 10.1007/s13167-020-00210-5. PubMed DOI PMC

Kubatka P, Mazurakova A, Samec M, Koklesova L, Zhai K, AL-Ishaq R, et al. Flavonoids against non-physiologic inflammation attributed to cancer initiation, development, and progression—3PM pathways. EPMA J. 2021;12:559–87. 10.1007/s13167-021-00257-y. PubMed PMC

Tamer F, Tullemans BME, Kuijpers MJE, Claushuis TAM, Heemskerk JWM. Nutrition phytochemicals affecting platelet signaling and responsiveness: implications for thrombosis and hemostasis. Thromb Haemost. 2022;122:879–894. doi: 10.1055/a-1683-5599. PubMed DOI

Fuentes E, Wehinger S, Trostchansky A. Regulation of key antiplatelet pathways by bioactive compounds with minimal bleeding risk. IJMS. 2021;22:12380. doi: 10.3390/ijms222212380. PubMed DOI PMC

Navarro-Núñez L, Lozano ML, Palomo M, Martínez C, Vicente V, Castillo J, et al. Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway. J Agric Food Chem. 2008;56:2970–2976. doi: 10.1021/jf0723209. PubMed DOI

Badimon L, Vilahur G, Rocca B, Patrono C. The key contribution of platelet and vascular arachidonic acid metabolism to the pathophysiology of atherothrombosis. Cardiovasc Res. 2021;117:2001–2015. doi: 10.1093/cvr/cvab003. PubMed DOI

Irfan M, Kwon H-W, Lee D-H, Shin J-H, Yuk HJ, Kim D-S, et al. Ulmus parvifolia modulates platelet functions and inhibits thrombus formation by regulating integrin αIIbβ3 and cAMP signaling. Front Pharmacol. 2020;11:2007. doi: 10.3389/fphar.2020.00698. PubMed DOI PMC

Bijak M, Szelenberger R, Dziedzic A, Saluk-Bijak J. Inhibitory effect of flavonolignans on the P2Y12 pathway in blood platelets. Molecules. 2018;23:374. doi: 10.3390/molecules23020374. PubMed DOI PMC

Fuentes E, Palomo I. Relationship between platelet PPARs, cAMP levels, and P-selectin expression: antiplatelet activity of natural products. Evid Based Complementary Altern Med. 2013;2013:1–10. doi: 10.1155/2013/861786. PubMed DOI PMC

Adam F, Kauskot A, Nurden P, Sulpice E, Hoylaerts MF, Davis RJ, et al. Platelet JNK1 is involved in secretion and thrombus formation. Blood. 2010;115:4083–4092. doi: 10.1182/blood-2009-07-233932. PubMed DOI

Wang L, Liu G, Wu N, Dai B, Han S, Liu Q, et al. mTOR regulates GPVI-mediated platelet activation. J Transl Med. 2021;19:449. doi: 10.1186/s12967-021-02756-y. PubMed DOI PMC

Zhang S, Gui X, Ding Y, Tong H, Ju W, Li Y, et al. Matrine impairs platelet function and thrombosis and inhibits ROS production. Front Pharmacol. 2021;12:e14024. doi: 10.3389/fphar.2021.717725. PubMed DOI PMC

Cho J, Furie BC, Coughlin SR, Furie B. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J Clin Invest. 2008 doi: 10.1172/JCI34134. PubMed DOI PMC

Wu H, Su M, Jin H, Li X, Wang P, Chen J, Chen J. Rutin-loaded silver nanoparticles with antithrombotic function. Front Bioeng Biotechnol. 2020;8:160S. doi: 10.3389/fbioe.2020.598977. PubMed DOI PMC

Chiu J, Passam F, Butera D, Hogg P. Protein disulfide isomerase in thrombosis. Semin Thromb Hemost. 2015;41:765–773. doi: 10.1055/s-0035-1564047. PubMed DOI

Smolenski A. Novel roles of cAMP/cGMP-dependent signaling in platelets. J Thromb Haemost. 2012;10:167–176. doi: 10.1111/j.1538-7836.2011.04576.x. PubMed DOI

Freedman JE, Loscalzo J. Nitric oxide and its relationship to thrombotic disorders. J Thromb Haemost. 2003;1:1183–1188. doi: 10.1046/j.1538-7836.2003.00180.x. PubMed DOI

Ikemura M, Sasaki Y, Giddings JC, Yamamoto J. Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother Res. 2012;26:1272–1277. doi: 10.1002/ptr.3724. PubMed DOI

Gutmann C, Siow R, Gwozdz AM, Saha P, Smith A. Reactive oxygen species in venous thrombosis. IJMS. 2020;21:1918. doi: 10.3390/ijms21061918. PubMed DOI PMC

Wu Y-H, Chuang L-P, Yu C-L, Wang S-W, Chen H-Y, Chang Y-L. Anticoagulant effect of wogonin against tissue factor expression. Eur J Pharmacol. 2019;859:172517. doi: 10.1016/j.ejphar.2019.172517. PubMed DOI

Barbieri R, Coppo E, Marchese A, Daglia M, Sobarzo-Sánchez E, Nabavi SF, Nabavi SM. Phytochemicals for human disease: an update on plant-derived compounds antibacterial activity. Microbiol Res. 2017;196:44–68. doi: 10.1016/j.micres.2016.12.003. PubMed DOI

Hano C, Tungmunnithum D. Plant polyphenols, more than just simple natural antioxidants: oxidative stress, aging and age-related diseases. Medicines. 2020;7:26. doi: 10.3390/medicines7050026. PubMed DOI PMC

Truzzi F, Tibaldi C, Zhang Y, Dinelli G, D′Amen E. An overview on dietary polyphenols and their biopharmaceutical classification system (BCS). IJMS. 2021;22:5514. 10.3390/ijms22115514. PubMed PMC

Meccariello R, D’Angelo S. Impact of polyphenolic-food on longevity: an elixir of life. An overview. Antioxidants. 2021;10:507. doi: 10.3390/antiox10040507. PubMed DOI PMC

Dias MC, Pinto DCGA, Silva AMS. Plant flavonoids: chemical characteristics and biological activity. molecules. 2021;26:5377. 10.3390/molecules26175377. PubMed PMC

Liskova A, Koklesova L, Samec M, Smejkal K, Samuel SM, Varghese E, et al. Flavonoids in cancer metastasis. Cancers. 2020;12:1498. doi: 10.3390/cancers12061498. PubMed DOI PMC

Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG, et al. Important flavonoids and their role as a therapeutic agent. Molecules. 2020;25:5243. doi: 10.3390/molecules25225243. PubMed DOI PMC

Abotaleb M, Samuel S, Varghese E, Varghese S, Kubatka P, Liskova A, Büsselberg D. Flavonoids in cancer and apoptosis. Cancers. 2019;11:28. doi: 10.3390/cancers11010028. PubMed DOI PMC

Ahn-Jarvis J, Parihar A, Doseff A. Dietary flavonoids for immunoregulation and cancer: food design for targeting disease. Antioxidants. 2019;8:202. doi: 10.3390/antiox8070202. PubMed DOI PMC

Vazhappilly CG, Ansari SA, Al-Jaleeli R, Al-Azawi AM, Ramadan WS, Menon V, et al. Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases. Inflammopharmacol. 2019;27:863–869. doi: 10.1007/s10787-019-00612-6. PubMed DOI

Vallance TM, Ravishankar D, Albadawi DAI, Osborn HMI, Vaiyapuri S. Synthetic flavonoids as novel modulators of platelet function and thrombosis. IJMS. 2019;20:3106. doi: 10.3390/ijms20123106. PubMed DOI PMC

Oh TW, Do HJ, Jeon J-H, Kim K. Quercitrin inhibits platelet activation in arterial thrombosis. Phytomedicine. 2021;80:153363. doi: 10.1016/j.phymed.2020.153363. PubMed DOI

Stainer AR, Sasikumar P, Bye AP, Unsworth AJ, Holbrook LM, Tindall M, et al. The metabolites of the dietary flavonoid quercetin possess potent antithrombotic activity, and interact with aspirin to enhance antiplatelet effects. TH Open. 2019;03:e244–e258. doi: 10.1055/s-0039-1694028. PubMed DOI PMC

Guglielmone HA, Agnese AM, Nuñez-Montoya SC, Cabrera JL, Cuadra GR. Antithrombotic “in vivo” effects of quercetin 3,7,3’,4’-tetrasulfate isolated from Flaveria bidentis in an experimental thrombosis model in mice. Thromb Res. 2020;195:190–192. doi: 10.1016/j.thromres.2020.07.040. PubMed DOI

Choi J-H, Park S-E, Kim S-J, Kim S. Kaempferol inhibits thrombosis and platelet activation. Biochimie. 2015;115:177–186. doi: 10.1016/j.biochi.2015.06.001. PubMed DOI

Choi J-H, Kim D-W, Park S-E, Lee H-J, Kim K-M, Kim K-J, et al. Anti-thrombotic effect of rutin isolated from Dendropanax morbifera Leveille. J Biosci Bioeng. 2015;120:181–186. doi: 10.1016/j.jbiosc.2014.12.012. PubMed DOI

Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:598. doi: 10.1017/jns.2016.41. PubMed DOI PMC

Haggag YA, El-Ashmawy NE, Okasha KM. Is hesperidin essential for prophylaxis and treatment of COVID-19 infection? Med Hypotheses. 2020;144:109957. doi: 10.1016/j.mehy.2020.109957. PubMed DOI PMC

Guerrero JA, Navarro-Nuñez L, Lozano ML, Martínez C, Vicente V, Gibbins JM, Rivera J. Flavonoids inhibit the platelet TxA 2 signalling pathway and antagonize TxA 2 receptors (TP) in platelets and smooth muscle cells. Br J Clin Pharmacol. 2007;64:133–144. doi: 10.1111/j.1365-2125.2007.02881.x. PubMed DOI PMC

Guerrero JA, Lozano ML, Castillo J, Benavente-Garcia O, Vicente V, Rivera J. Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor. J Thromb Haemost. 2005;3:369–376. doi: 10.1111/j.1538-7836.2004.01099.x. PubMed DOI

Ku S-K, Bae J-S. Antithrombotic activities of wogonin and wogonoside via inhibiting platelet aggregation. Fitoterapia. 2014;98:27–35. doi: 10.1016/j.fitote.2014.07.006. PubMed DOI

Kang W-S, Lim I-H, Yuk D-Y, Chung K-H, Park J-B, Yoo H-S, Yun Y-P. Antithrombotic activities of green tea catechins and (−)-epigallocatechin gallate. Thromb Res. 1999;96:229–237. doi: 10.1016/S0049-3848(99)00104-8. PubMed DOI

Montagnana M, Danese E, Angelino D, Mena P, Rosi A, Benati M, et al. Dark chocolate modulates platelet function with a mechanism mediated by flavan-3-ol metabolites. Medicine. 2018;97:e13432. doi: 10.1097/MD.0000000000013432. PubMed DOI PMC

Känel Rv, Meister R, Stutz M, Kummer P, Arpagaus A, Huber S, et al. Effects of dark chocolate consumption on the prothrombotic response to acute psychosocial stress in healthy men. Thromb Haemost. 2014;112:1151–8. 10.1160/th14-05-0450. PubMed

Rinde FB, Fronas SG, Ghanima W, Vik A, Hansen J-B, Brækkan SK. D-dimer as a stand-alone test to rule out deep vein thrombosis. Thromb Res. 2020;191:134–139. doi: 10.1016/j.thromres.2020.04.026. PubMed DOI

Zwicker JI, Schlechter BL, Stopa JD, Liebman HA, Aggarwal A, Puligandla M, et al. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight. 2019;4:637. doi: 10.1172/jci.insight.125851. PubMed DOI PMC

Kumar N, Goel N. Phenolic acids: natural versatile molecules with promising therapeutic applications. Biotechnology Reports. 2019;24:e00370. doi: 10.1016/j.btre.2019.e00370. PubMed DOI PMC

Paluszczak J, Baer-Dubowska W. DNA Methylation as a target of cancer chemoprevention by dietary polyphenols. In: Polyphenols in Human Health and Disease: Elsevier; 2014. p. 1385–1392. 10.1016/B978-0-12-398456-2.00105-5.

Espíndola KMM, Ferreira RG, Narvaez LEM, Silva Rosario ACR, da Silva AHM, Silva AGB, et al. Chemical and pharmacological aspects of caffeic acid and its activity in hepatocarcinoma. Front Oncol. 2019;9:541. doi: 10.3389/fonc.2019.00541. PubMed DOI PMC

Genaro-Mattos TC, Maurício ÂQ, Rettori D, Alonso A, Hermes-Lima M. Antioxidant activity of caffeic acid against iron-induced free radical generation—a chemical approach. PLoS ONE. 2015;10:e0129963. 10.1371/journal.pone.0129963. PubMed PMC

Liang N, Kitts D. Antioxidant property of coffee components: assessment of methods that define mechanisms of action. Molecules. 2014;19:19180–19208. doi: 10.3390/molecules191119180. PubMed DOI PMC

Choi HG, Tran PT, Lee J-H, Min BS, Kim JA. Anti-inflammatory activity of caffeic acid derivatives isolated from the roots of Salvia miltiorrhiza Bunge. Arch Pharm Res. 2018;41:64–70. doi: 10.1007/s12272-017-0983-1. PubMed DOI

Khan FA, Maalik A, Murtaza G. Inhibitory mechanism against oxidative stress of caffeic acid. J Food Drug Anal. 2016;24:695–702. doi: 10.1016/j.jfda.2016.05.003. PubMed DOI PMC

Lu Y, Li Q, Liu Y-Y, Sun K, Fan J-Y, Wang C-S, Han J-Y. Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases. Sci Rep. 2015;5:255. doi: 10.1038/srep13824. PubMed DOI PMC

Nam GS, Park H-J, Nam K-S. The antithrombotic effect of caffeic acid is associated with a cAMP-dependent pathway and clot retraction in human platelets. Thromb Res. 2020;195:87–94. doi: 10.1016/j.thromres.2020.07.024. PubMed DOI

Lee D-H, Kim H-H, Cho H-J, Bae J-S, Yu Y-B, Park H-J. Antiplatelet effects of caffeic acid due to Ca2+ mobilization inhibition via cAMP-dependent inositol-1, 4, 5-trisphosphate receptor phosphorylation. JAT. 2014:23–37. 10.5551/jat.18994. PubMed

Daily JW, Yang M, Park S. Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint arthritis: a systematic review and meta-analysis of randomized clinical trials. J Med Food. 2016;19:717–729. doi: 10.1089/jmf.2016.3705. PubMed DOI PMC

Kim D-C, Ku S-K, Bae J-S. Anticoagulant activities of curcumin and its derivative. BMB Rep. 2012;45:221–226. doi: 10.5483/BMBRep.2012.45.4.221. PubMed DOI

Wang K-H, Li S-F, Zhao Y, Li H-X, Zhang L-W. In vitro anticoagulant activity and active components of safflower injection. Molecules. 2018;23:170. doi: 10.3390/molecules23010170. PubMed DOI PMC

Choi J-H, Park J-K, Kim K-M, Lee H-J, Kim S. In vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid. J Biochem Mol Toxicol. 2018;32:e22004. doi: 10.1002/jbt.22004. PubMed DOI

Hong Q, Ma Z-C, Huang H, Wang Y-G, Tan H-L, Xiao C-R, et al. Antithrombotic activities of ferulic acid via intracellular cyclic nucleotide signaling. Eur J Pharmacol. 2016;777:1–8. doi: 10.1016/j.ejphar.2016.01.005. PubMed DOI

Merrill-Skoloff G, Dubois C, Atkinson B, Furie B, Furie B. Real time in vivo imaging of platelets during thrombus formation. In: Platelets: Elsevier; 2013. p. 635–649. 10.1016/B978-0-12-387837-3.00031-6.

Wang S, Gao Z, Chen X, Lian X, Zhu H, Zheng J, Sun L. The anticoagulant ability of ferulic acid and its applications for improving the blood compatibility of silk fibroin. Biomed Mater. 2008;3:44106. doi: 10.1088/1748-6041/3/4/044106. PubMed DOI

Kottke RH. Furan derivatives. In: John Wiley & Sons I, editor. Kirk-Othmer Encyclopedia of Chemical Technology: Wiley; 2000. p. 693. 10.1002/0471238961.0621180111152020.a01.

Graening T, Thrun F. Furans and their benzo derivatives: synthesis. In: Comprehensive Heterocyclic Chemistry III: Elsevier; 2008. p. 497–569. 10.1016/B978-008044992-0.00307-2.

Hansen S, Wood DK, Higgins JM. 5-(Hydroxymethyl)furfural restores low-oxygen rheology of sickle trait blood in vitro. Br J Haematol. 2020;188:985–993. doi: 10.1111/bjh.16251. PubMed DOI PMC

Cheng T-F, Zhao J, Wu Q-L, Zeng H-W, Sun Y-T, Zhang Y-H, et al. Compound Dan Zhi tablet attenuates experimental ischemic stroke via inhibiting platelet activation and thrombus formation. Phytomedicine. 2020;79:153330. doi: 10.1016/j.phymed.2020.153330. PubMed DOI

Sirerol JA, Rodríguez ML, Mena S, Asensi MA, Estrela JM, Ortega AL. Role of natural stilbenes in the prevention of cancer. Oxid Med Cell Longev. 2016;2016:1–15. doi: 10.1155/2016/3128951. PubMed DOI PMC

Vijayan N, Haridas M, Abdulhameed S. Stilbenes and their derivatives in traditional medicine. In: Sugathan S, Pradeep NS, Abdulhameed S, editors. Bioresources and bioprocess in biotechnology. Singapore: Springer; 2017. p. 407–418. 10.1007/978-981-10-4284-3_17.

Pecyna P, Wargula J, Murias M, Kucinska M. More than resveratrol: new insights into stilbene-based compounds. Biomolecules. 2020;10:1111. doi: 10.3390/biom10081111. PubMed DOI PMC

Huang T-Y, Yu C-P, Hsieh Y-W, Lin S-P, Hou Y-C. Resveratrol stereoselectively affected (±)warfarin pharmacokinetics and enhanced the anticoagulation effect. Sci Rep. 2020;10:1633. doi: 10.1038/s41598-020-72694-0. PubMed DOI PMC

Chiba T, Kimura Y, Suzuki S, Tatefuji T, Umegaki K. Trans-resveratrol enhances the anticoagulant activity of warfarin in a mouse model. J Atheroscler Thromb. 2016;23:1099–1110. doi: 10.5551/jat.31765. PubMed DOI PMC

Shahidi M, Parhizkary F, Sharifi R, Ghotaslou A, Barati M. Effects of resveratrol on coagulative, fibrinolytic, and inflammatory marker expression and secretion by endothelial cells (human umbilical vein endothelial cells) Blood Coag Fibrinol. 2020;31:207–212. doi: 10.1097/MBC.0000000000000900. PubMed DOI

Xu M, Xue W, Ma Z, Bai J, Wu S. Resveratrol reduces the incidence of portal vein system thrombosis after splenectomy in a rat fibrosis model. Oxid Med Cell Longev. 2016;2016:1–7. doi: 10.1155/2016/7453849. PubMed DOI PMC

Önder A. Anticancer activity of natural coumarins for biological targets. In: Bioactive Natural Products: Elsevier; 2020. p. 85–109. 10.1016/B978-0-12-817903-1.00003-6.

Qu SY, Jiang XL, Zhao XH, Pan DB, Wang XR, Chen YL, et al. Antithrombotic effect of daphnetin in the rat. Yao Xue Xue Bao. 1986;21:498–501. PubMed

Suttie JW. Warfarin and Vitamin K. Clinical Cardiology. 1990;13:VI-16-VI-18. 10.1002/clc.1990.13.s6.16. PubMed

Zimmermann R, Barth P, Masche R. Die antithrombotische Wirkung von Acetylsalicylsäure, Heparin und Phenprocoumon auf die Entstehung von experimentellen Gerinnungsthromben [Antithrombotic effect of acetylsalicylic acid, heparin and phenprocoumon on the formation of experimental coagulation thrombi] Verh Dtsch Ges Inn Med. 1974;80:1446–1448. PubMed

Hsia C-W, Lin K-C, Lee T-Y, Hsia C-H, Chou D-S, Jayakumar T, et al. Esculetin, a coumarin derivative, prevents thrombosis: inhibitory signaling on PLCγ2–PKC–AKT activation in human platelets. IJMS. 2019;20:2731. doi: 10.3390/ijms20112731. PubMed DOI PMC

Jain M, Surin WR, Misra A, Prakash P, Singh V, Khanna V, et al. Antithrombotic activity of a newly synthesized coumarin derivative 3-(5-Hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide. Chem Biol Drug Des. 2013;81:499–508. doi: 10.1111/cbdd.12000. PubMed DOI

Bhambhani S, Kondhare KR, Giri AP. Diversity in chemical structures and biological properties of plant alkaloids. Molecules. 2021;26:3374. doi: 10.3390/molecules26113374. PubMed DOI PMC

Hesse M. Alkaloids: nature’s curse or blessing? Weinheim: Wiley-VCH; op; 2002.

Huang C-J, Huang W-C, Lin W-T, Shu L-H, Sheu J-R, Tran O-T, et al. Rutaecarpine, an alkaloid from evodia rutaecarpa, can prevent platelet activation in humans and reduce microvascular thrombosis in mice: crucial role of the PI3K/Akt/GSK3β signal axis through a cyclic nucleotides/VASP—independent mechanism. IJMS. 2021;22:11109. doi: 10.3390/ijms222011109. PubMed DOI PMC

Roach REJ, Siegerink B, Le Cessie S, Rosendaal FR, Cannegieter SC, Lijfering WM. Coffee consumption is associated with a reduced risk of venous thrombosis that is mediated through hemostatic factor levels. J Thromb Haemost. 2012;10:2519–2525. doi: 10.1111/jth.12034. PubMed DOI

Kam T-S. Alkaloids from Malaysian Flora. In: : Elsevier; 1999. p. 285–435. 10.1016/S0735-8210(99)80005-3.

Zhang Q, Chen C, Wang F-Q, Li C-H, Zhang Q-H, Hu Y-J, et al. Simultaneous screening and analysis of antiplatelet aggregation active alkaloids from Rhizoma Corydalis. Pharm Biol. 2016;54:3113–3120. doi: 10.1080/13880209.2016.1211714. PubMed DOI

Ashour AS, El Aziz MMA, Gomha Melad AS. A review on saponins from medicinal plants: chemistry, isolation, and determination. JNMR. 2019;7:282–8. 10.15406/jnmr.2019.07.00199.

Zhai K-f, Zheng J-r, Tang Y-m, Li F, Lv Y-n, Zhang Y-y, et al. The saponin D39 blocks dissociation of non-muscular myosin heavy chain IIA from TNF receptor 2, suppressing tissue factor expression and venous thrombosis. British Journal of Pharmacology. 2017;174:2818–31. 10.1111/bph.13885. PubMed PMC

Zhang R, Huang B, Du D, Guo X, Xin G, Xing Z, et al. Anti-thrombosis effect of diosgenyl saponins in vitro and in vivo. Steroids. 2013;78:1064–1070. doi: 10.1016/j.steroids.2013.07.003. PubMed DOI

Qi H, Huang Y, Yang Y, Dou G, Wan F, Zhang W, et al. Anti-platelet activity of panaxatriol saponins is mediated by suppression of intracellular calcium mobilization and ERK2/p38 activation. BMC Complement Altern Med. 2016;16:97. doi: 10.1186/s12906-016-1160-7. PubMed DOI PMC

Wang C, Gong X, Bo A, Zhang L, Zhang M, Zang E, et al. Iridoids: research advances in their phytochemistry, biological activities, and pharmacokinetics. Molecules. 2020;25:287. doi: 10.3390/molecules25020287. PubMed DOI PMC

Yamane H, Konno K, Sabelis M, Takabayashi J, Sassa T, Oikawa H. Chemical defence and toxins of plants. In: Comprehensive Natural Products II: Elsevier; 2010. p. 339–385. 10.1016/B978-008045382-8.00099-X.

Liu H, Chen Y-F, Li F, Zhang H-Y. Fructus Gardenia (Gardenia jasminoides J. Ellis) phytochemistry, pharmacology of cardiovascular, and safety with the perspective of new drugs development. J Asian Nat Prod Res. 2013;15:94–110. 10.1080/10286020.2012.723203. PubMed

Suzuki Y, Kondo K, Ikeda Y, Umemura K. Antithrombotic effect of geniposide and genipin in the mouse thrombosis model. Planta Med. 2001;67:807–810. doi: 10.1055/s-2001-18842. PubMed DOI

Wang P, Wang Q, Luo C, Tan C, Yuan X. Iridoid glycosides extracted from Zhizi (Fructus Gardeniae) decrease collagen-induced platelet aggregation and reduce carotid artery thrombosis in an in vivo rat model. J Tradit Chin Med. 2013;33:531–534. doi: 10.1016/S0254-6272(13)60160-0. PubMed DOI

Awouafack MD, Tane P, Kuete V, Eloff JN. Sesquiterpenes from the medicinal plants of Africa. In: Medicinal Plant Research in Africa: Elsevier; 2013. p. 33–103. 10.1016/B978-0-12-405927-6.00002-3.

Lee MH, Son YK, Han YN. Tissue factor inhibitory sesquiterpene glycoside from Eriobotrya japonica. Arch Pharm Res. 2004;27:168. doi: 10.1007/BF02980160. PubMed DOI

Fang H, Gao B, Zhao Y, Fang X, Bian M, Xia Q. Curdione inhibits thrombin-induced platelet aggregation via regulating the AMP-activated protein kinase-vinculin/talin-integrin αIIbβ3 sign pathway. Phytomedicine. 2019;61:152859. doi: 10.1016/j.phymed.2019.152859. PubMed DOI

Nemmar A, Al-Salam S, Beegam S, Yuvaraju P, Ali BH. Thrombosis and systemic and cardiac oxidative stress and DNA damage induced by pulmonary exposure to diesel exhaust particles and the effect of nootkatone thereon. Am J Physiol Heart Circ Physiol. 2018;314:H917–H927. doi: 10.1152/ajpheart.00313.2017. PubMed DOI

Ciancia M, Fernández PV, Leliaert F. Diversity of sulfated polysaccharides from cell walls of coenocytic green algae and their structural relationships in view of green algal evolution. Front Plant Sci. 2020;11:554585. doi: 10.3389/fpls.2020.554585. PubMed DOI PMC

Quinderé A-LG, Santos GRC, Oliveira S-NMCG, Glauser BF, Fontes BP, Queiroz INL, et al. Is the antithrombotic effect of sulfated galactans independent of serpin? J Thromb Haemost. 2014;12:43–53. 10.1111/jth.12448. PubMed

Farias WR, Nazareth RA, Mourão PA. Dual effects of sulfated D-galactans from the red algae Botryocladia occidentalis preventing thrombosis and inducing platelet aggregation. Thromb Haemost. 2001;86:1540–1546. doi: 10.1055/s-0037-1616760. PubMed DOI

Fernández PV, Quintana I, Cerezo AS, Caramelo JJ, Pol-Fachin L, Verli H, et al. Anticoagulant activity of a unique sulfated pyranosic (1→3)-β-l-Arabinan through direct interaction with thrombin. J Biol Chem. 2013;288:223–233. doi: 10.1074/jbc.M112.386441. PubMed DOI PMC

Noor-E-Tabassum, Das R, Lami MS, Chakraborty AJ, Mitra S, Tallei TE, et al. Ginkgo biloba: a treasure of functional phytochemicals with multimedicinal applications. Evid Based Complementary Alternat Med. 2022;2022:1–30. 10.1155/2022/8288818. PubMed PMC

Chen T-R, Wei L-H, Guan X-Q, Huang C, Liu Z-Y, Wang F-J, et al. Biflavones from Ginkgo biloba as inhibitors of human thrombin. Bioorg Chem. 2019;92:103199. doi: 10.1016/j.bioorg.2019.103199. PubMed DOI

Ke J, Li M-T, Huo Y-J, Cheng Y-Q, Guo S-F, Wu Y, et al. The synergistic effect of Ginkgo biloba extract 50 and aspirin against platelet aggregation. DDDT. 2021;15:3543–3560. doi: 10.2147/DDDT.S318515. PubMed DOI PMC

Chiu Y-L, Tsai W-C, Wu C-H, Wu C-H, Cheng C-C, Lin W-S, et al. Ginkgo biloba induces thrombomodulin expression and tissue-type plasminogen activator secretion via the activation of Krüppel-like factor 2 within endothelial cells. Am J Chin Med. 2020;48:357–372. doi: 10.1142/S0192415X20500184. PubMed DOI

Lamponi S. Bioactive natural compounds with antiplatelet and anticoagulant activity and their potential role in the treatment of thrombotic disorders. Life. 2021;11:1095. doi: 10.3390/life11101095. PubMed DOI PMC

Pierre S, Crosbie L, Duttaroy AK. Inhibitory effect of aqueous extracts of some herbs on human platelet aggregation in vitro. Platelets. 2005;16:469–473. doi: 10.1080/09537100500129540. PubMed DOI

Bijak M, Saluk J, Tsirigotis-Maniecka M, Komorowska H, Wachowicz B, Zaczyńska E, et al. The influence of conjugates isolated from Matricaria chamomilla L. on platelets activity and cytotoxicity. Int J Biol Macromol. 2013;61:218–29. 10.1016/j.ijbiomac.2013.06.046. PubMed

Țigu AB, Moldovan CS, Toma V-A, Farcaș AD, Moț AC, Jurj A, et al. Phytochemical analysis and in vitro effects of Allium fistulosum L. and Allium sativum L. extracts on human normal and tumor cell lines: a comparative study. Molecules. 2021;26:574. 10.3390/molecules26030574. PubMed PMC

Bhandari J, Muhammad B, Thapa P, Shrestha BG. Study of phytochemical, anti-microbial, anti-oxidant, and anti-cancer properties of Allium wallichii. BMC Complement Altern Med. 2017;17:125. doi: 10.1186/s12906-017-1622-6. PubMed DOI PMC

Deka B, Manna P, Borah JC, Talukdar NC. A review on phytochemical, pharmacological attributes and therapeutic uses of Allium hookeri. Phytomedicine Plus. 2022;2:100262. doi: 10.1016/j.phyplu.2022.100262. DOI

Bhandari SR, Yoon MK, Kwak J-H. Contents of phytochemical constituents and antioxidant activity of 19 garlic (Allium sativum L.) parental lines and cultivars. Hortic. Environ. Biotechnol. 2014;55:138–47. 10.1007/s13580-014-0155-x.

Sobenin IA, Myasoedova VA, Iltchuk MI, ZHANG D-W, Orekhov AN. Therapeutic effects of garlic in cardiovascular atherosclerotic disease. Chin J Nat Med. 2019;17:721–8. 10.1016/S1875-5364(19)30088-3. PubMed

Mikaili P, Maadirad S, Moloudizargari M, Aghajanshakeri S, Sarahroodi S. Therapeutic uses and pharmacological properties of garlic, shallot, and their biologically active compounds. Iran J Basic Med Sci. 2013;16:1031–1048. PubMed PMC

Sadeghi M, Safaeian L, Ghazvini M, Ramezani M. Evaluation of fibrinolytic and antioxidant effects of Allium affine hydroalcoholic extract. Res Pharma Sci. 2017;12:299. doi: 10.4103/1735-5362.212047. PubMed DOI PMC

Hiyasat B, Sabha D, Grötzinger K, Kempfert J, Rauwald J-W, Mohr F-W, Dhein S. Antiplatelet activity of Allium ursinum and Allium sativum. Pharmacology. 2009;83:197–204. doi: 10.1159/000196811. PubMed DOI

Lorigooini Z, Ayatollahi SA, Amidi S, Kobarfard F. Evaluation of anti-platelet aggregation effect of some allium species. Iran J Pharm Res. 2015;14:1225–1231. PubMed PMC

Shafiekhani M, Faridi P, Kojuri J, Namazi S. Comparison of antiplatelet activity of garlic tablets with cardio-protective dose of aspirin in healthy volunteers: a randomized clinical trial. Avicenna J Phytomed. 2016;6:550–557. PubMed PMC

Alzoubi HK, Khabour FO, Alkofahi SA, Mhaidat MN, Abu-Siniyeh AA. Anticancer and antimutagenic activity of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. against skin cancer induced by DMBA: in vitro and in vivo models. Pak J Pharm Sci. 2021;34:987–93. PubMed

Aghazadeh S, Amini R, Yazdanparast R, Ghaffari SH. Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. Exp Toxicol Pathol. 2011;63:569–574. doi: 10.1016/j.etp.2010.04.009. PubMed DOI

Bijak M, Szelenberger R, Saluk J, Nowak P. Flavonolignans inhibit ADP induced blood platelets activation and aggregation in whole blood. Int J Biol Macromol. 2017;95:682–688. doi: 10.1016/j.ijbiomac.2016.12.002. PubMed DOI

Bijak M, Saluk-Bijak J. Flavonolignans inhibit the arachidonic acid pathway in blood platelets. BMC Complement Altern Med. 2017;17:561. doi: 10.1186/s12906-017-1897-7. PubMed DOI PMC

Pourová J, Applová L, Macáková K, Vopršalová M, Migkos T, Bentanachs R, et al. The effect of silymarin flavonolignans and their sulfated conjugates on platelet aggregation and blood vessels ex vivo. nutrients. 2019;11:2286. 10.3390/nu11102286. PubMed PMC

Goshua G, Pine AB, Meizlish ML, Chang C-H, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7:e575–e582. doi: 10.1016/S2352-3026(20)30216-7. PubMed DOI PMC

Kumar A, Narayan RK, Kumari C, Faiq MA, Kulandhasamy M, Kant K, Pareek V. SARS-CoV-2 cell entry receptor ACE2 mediated endothelial dysfunction leads to vascular thrombosis in COVID-19 patients. Med Hypotheses. 2020;145:110320. doi: 10.1016/j.mehy.2020.110320. PubMed DOI PMC

Singh AK, Khunti K. Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: a narrative review. Diabetes Res Clin Pract. 2020;165:108266. doi: 10.1016/j.diabres.2020.108266. PubMed DOI PMC

Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. The Lancet. 2020;395:1417–1418. doi: 10.1016/S0140-6736(20)30937-5. PubMed DOI PMC

Samuel SM, Varghese E, Büsselberg D. Therapeutic potential of metformin in COVID-19: reasoning for its protective role. Trends Microbiol. 2021;29:894–907. doi: 10.1016/j.tim.2021.03.004. PubMed DOI PMC

Varghese E, Samuel SM, Liskova A, Kubatka P, Büsselberg D. Diabetes and coronavirus (SARS-CoV-2): molecular mechanism of metformin intervention and the scientific basis of drug repurposing. PLoS Pathog. 2021;17:e1009634. doi: 10.1371/journal.ppat.1009634. PubMed DOI PMC

He L, Mäe MA, Muhl L, Sun Y, Pietilä R, Nahar K, et al. Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19; 2020.

Ward A, Sarraju A, Lee D, Bhasin K, Gad S, Beetel R, et al. COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: insights from a large US cohort; 2021. PubMed PMC

Stefan A, Petkovic M, König A, Koch J, Hagemann F, Wuerstlein R, et al. Increased risk for thromboembolic events from combination of a gynecologic malignancy with severe acute respiratory syndrome coronavirus 2 infection: a case report. J Med Case Reports. 2022;16:1004. doi: 10.1186/s13256-022-03340-8. PubMed DOI PMC

Tufano A, Rendina D, Abate V, Casoria A, Marra A, Buonanno P, et al. Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: a systematic review with meta-analysis. JCM. 2021;10:4925. doi: 10.3390/jcm10214925. PubMed DOI PMC

Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–847. doi: 10.1111/jth.14768. PubMed DOI PMC

Ribes A, Vardon-Bounes F, Mémier V, Poette M, Au-Duong J, Garcia C, et al. Thromboembolic events and Covid-19. Adv Biol Regul. 2020;77:100735. doi: 10.1016/j.jbior.2020.100735. PubMed DOI PMC

Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 2020;8:782–792. doi: 10.1016/S2213-8587(20)30238-2. PubMed DOI PMC

Gavriilaki E, Anyfanti P, Gavriilaki M, Lazaridis A, Douma S, Gkaliagkousi E. Endothelial dysfunction in COVID-19: lessons learned from coronaviruses. Curr Hypertens Rep. 2020;22:1417. doi: 10.1007/s11906-020-01078-6. PubMed DOI PMC

Jin Y, Ji W, Yang H, Chen S, Zhang W, Duan G. Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches. Sig Transduct Target Ther. 2020;5:270. doi: 10.1038/s41392-020-00454-7. PubMed DOI PMC

Elbadawi A, Elgendy IY, Sahai A, Bhandari R, McCarthy M, Gomes M, et al. Incidence and outcomes of thrombotic events in symptomatic patients with COVID-19. ATVB. 2020;75:2950. doi: 10.1161/ATVBAHA.120.315304. PubMed DOI PMC

Huertas A, Montani D, Savale L, Pichon J, Tu L, Parent F, et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J. 2020;56:2001634. doi: 10.1183/13993003.01634-2020. PubMed DOI PMC

Triggle CR, Ding H, Marei I, Anderson TJ, Hollenberg MD. Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease. Can J Physiol Pharmacol. 2020;98:415–430. doi: 10.1139/cjpp-2019-0677. PubMed DOI

Bonaventura A, Vecchié A, Dagna L, Martinod K, Dixon DL, van Tassell BW, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol. 2021;21:319–329. doi: 10.1038/s41577-021-00536-9. PubMed DOI PMC

Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol. 2021;18:194–209. doi: 10.1038/s41569-020-00469-1. PubMed DOI PMC

Nägele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: current findings and therapeutic implications. Atherosclerosis. 2020;314:58–62. doi: 10.1016/j.atherosclerosis.2020.10.014. PubMed DOI PMC

Kyriakoulis KG, Kollias A, Kyriakoulis IG, Kyprianou IA, Papachrysostomou C, Makaronis P, et al. Thromboprophylaxis in Patients with COVID-19: systematic review of national and international clinical guidance reports. CVP. 2022;20:96–110. doi: 10.2174/1570161119666210824160332. PubMed DOI

Helms J, Severac F, Merdji H, Schenck M, Clere-Jehl R, Baldacini M, et al. Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study. Ann Intensive Care. 2021;11:1559. doi: 10.1186/s13613-021-00809-5. PubMed DOI PMC

Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action. Br J Haematol. 2020;189:846–847. doi: 10.1111/bjh.16727. PubMed DOI PMC

Beura SK, Panigrahi AR, Yadav P, Singh SK. Phytochemicals as potential therapeutics for SARS-CoV-2–induced cardiovascular complications: thrombosis and platelet perspective. Front Pharmacol. 2021;12:1443. doi: 10.3389/fphar.2021.658273. PubMed DOI PMC

Kraft P, de Meyer SF, Kleinschnitz C. Next-generation antithrombotics in ischemic stroke: preclinical perspective on ‘bleeding-free antithrombosis’. J Cereb Blood Flow Metab. 2012;32:1831–1840. doi: 10.1038/jcbfm.2012.108. PubMed DOI PMC

Payne AB, Adamski A, Abe K, Reyes NL, Richardson LC, Hooper WC, Schieve LA. Epidemiology of cerebral venous sinus thrombosis and cerebral venous sinus thrombosis with thrombocytopenia in the United States, 2018 and 2019. Res Pract Thromb Haemost. 2022;6:e12682. doi: 10.1002/rth2.12682. PubMed DOI PMC

Camargo EC, Singhal AB. Stroke in pregnancy: a multidisciplinary approach. Obstet Gynecol Clin North Am. 2021;48:75–96. doi: 10.1016/j.ogc.2020.11.004. PubMed DOI PMC

Roeder HJ, Lopez JR, Miller EC. Ischemic stroke and cerebral venous sinus thrombosis in pregnancy. Handb Clin Neurol. 2020;172:3–31. doi: 10.1016/B978-0-444-64240-0.00001-5. PubMed DOI PMC

Zambrano MD, Miller EC. Maternal stroke: an update. Curr Atheroscler Rep. 2019;21:33. doi: 10.1007/s11883-019-0798-2. PubMed DOI PMC

Mszar R, Gopal DJ, Chowdary R, Smith CL, Dolin CD, Irwin ML, et al. Racial/ethnic disparities in screening for and awareness of high cholesterol among pregnant women receiving prenatal care. J Am Heart Assoc. 2021;10:e017415. doi: 10.1161/JAHA.120.017415. PubMed DOI PMC

Pétursdóttir Maack H, Larsson A, Axelsson O, Olovsson M, Wikström A-K, Sundström PI. Pregnancy in metabolic healthy and unhealthy obese women. Acta Obstet Gynecol Scand. 2020;99:1640–1648. doi: 10.1111/aogs.13929. PubMed DOI

Evsevieva M, Sergeeva O, Mazurakova A, Koklesova L, Prokhorenko-Kolomoytseva I, Shchetinin E, et al. Pre-pregnancy check-up of maternal vascular status and associated phenotype is crucial for the health of mother and offspring. EPMA J. 2022;13. 10.1007/s13167-022-00294-1. PubMed PMC

Lee NT, Ong LK, Gyawali P, Nassir CMNCM, Mustapha M, Nandurkar HH, Sashindranath M. Role of purinergic signalling in endothelial dysfunction and thrombo-inflammation in ischaemic stroke and cerebral small vessel disease. Biomolecules 2021. 10.3390/biom11070994. PubMed PMC

Mukai M, Oka T. Mechanism and management of cancer-associated thrombosis. J Cardiol. 2018;72:89–93. doi: 10.1016/j.jjcc.2018.02.011. PubMed DOI

Hsu P-Y, Mammadova A, Benkirane-Jessel N, Désaubry L, Nebigil CG. Updates on anticancer therapy-mediated vascular toxicity and new horizons in therapeutic strategies. Front Cardiovasc Med. 2021;8:694711. doi: 10.3389/fcvm.2021.694711. PubMed DOI PMC

Mazurakova A, Koklesova L, Samec M, Kudela E, Kajo K, Skuciova V, et al. Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care. EPMA J. 2022;13:315–334. doi: 10.1007/s13167-022-00277-2. PubMed DOI PMC

Koklesova L, Mazurakova A, Samec M, Biringer K, Samuel SM, Büsselberg D, et al. Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person. EPMA J. 2021;12:477–505. doi: 10.1007/s13167-021-00263-0. PubMed DOI PMC

Torres Crigna A, Link B, Samec M, Giordano FA, Kubatka P, Golubnitschaja O. Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine. EPMA J. 2021;12:265–305. doi: 10.1007/s13167-021-00248-z. PubMed DOI PMC

Nannoni S, de Groot R, Bell S, Markus HS. Stroke in COVID-19: a systematic review and meta-analysis. Int J Stroke. 2021;16:137–149. doi: 10.1177/1747493020972922. PubMed DOI PMC

Berkman SA, Song SS. Ischemic stroke in the young. Clin Appl Thromb Hemost. 2021;27:10760296211002274. doi: 10.1177/10760296211002274. PubMed DOI PMC

Liskova A, Koklesova L, Samec M, Abdellatif B, Zhai K, Siddiqui M, et al. Targeting phytoprotection in the COVID-19-induced lung damage and associated systemic effects-the evidence-based 3PM proposition to mitigate individual risks. EPMA J. 2021;12:325–347. doi: 10.1007/s13167-021-00249-y. PubMed DOI PMC

Ischemic stroke of unclear aetiology: a case-by-case analysis and call for a multi-professional predictive, preventive and personalised approach