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Thromb Haemost 2020; 120(08): 1173-1181
DOI: 10.1055/s-0040-1713169
Coagulation and Fibrinolysis

Endothelial Damage of the Portal Vein is Associated with Heparin-Like Effect in Advanced Stages of Cirrhosis

Sarah Shalaby‡   *
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Paolo Simioni‡   *
2   Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), University of Padua Medical School, Padua, Italy
,
Elena Campello
2   Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), University of Padua Medical School, Padua, Italy
,
Luca Spiezia
2   Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), University of Padua Medical School, Padua, Italy
,
Sabrina Gavasso
2   Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), University of Padua Medical School, Padua, Italy
,
Debora Bizzaro
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Romilda Cardin
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Francesco D'Amico
3   Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Enrico Gringeri
3   Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Umberto Cillo
3   Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Giulio Barbiero
4   Institute of Radiology, Department of Medicine, Padua University Hospital, Padua, Italy
,
Michele Battistel
4   Institute of Radiology, Department of Medicine, Padua University Hospital, Padua, Italy
,
Alberto Zanetto
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Alessandro Ruzzarin
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Patrizia Burra
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
,
Marco Senzolo
1   Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
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Abstract

Background Portal vein thrombosis (PVT) is the most common thrombotic complication in cirrhosis; however, local risk factors involved in its pathogenesis are still not fully investigated. The aim of the study was to evaluate hemostasis and endothelial damage in the portal vein in patients with cirrhosis and portal hypertension.

Methods Adult cirrhotics undergoing transjugular intrahepatic portosystemic shunt were consecutively enrolled. Rotational thromboelastometry (ROTEM), dosage of total circulating glycosaminoglycans (GAGs), and endotoxemia levels (lipopolysaccharide [LPS]), along with evaluation of endothelial dysfunction by quantification of circulating endothelial microparticles (MPs), were performed on citrated peripheric and portal venous blood samples from each enrolled patient.

Results Forty-five cirrhotics were enrolled. ROTEM analysis revealed the presence of a significant heparin-like effect in portal blood (median ɑ angle NATEM 50° vs. HEPTEM 55°, p = 0.027; median coagulation time NATEM 665 s vs. HEPTEM 585 s, p = 0.006), which was not detected in peripheral blood, and was associated with a higher concentration of circulating GAGs. Even though total annexin V-MP circulating MPs were less concentrated in the splanchnic district, the proportion of MPs of endothelial origin, with respect to annexin V-MP, was significantly increased in the portal district (p = 0.036). LPS concentration was higher in portal (197 pg/mL) compared with peripheral blood (165 pg/mL) (p < 0.001).

Conclusion Evidences of a damage of glycocalyx along with increased concentration of endothelial MPs suggest the presence of a significant endothelial alteration in the portal vein with respect to peripheral veins. Portal site-specific endothelial damage could hamper its antithrombotic properties and may represent an important local risk factor in the pathogenesis of PVT.

Keywords

heparin-like effect - microparticles - glycosaminoglycans - endotoxemia - portal hypertension

* Equally contributed and share first authorship.


Supplementary Material



Publication History

Received: 27 January 2020

Accepted: 05 May 2020

Article published online:
30 June 2020

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52 (03) 355-361
    CrossrefPubMedGoogle Scholar
  • 2 Nery F, Chevret S, Condat B. , et al; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015; 61 (02) 660-667
    CrossrefPubMedGoogle Scholar
  • 3 Francoz C, Belghiti J, Vilgrain V. , et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 2005; 54 (05) 691-697
    CrossrefPubMedGoogle Scholar
  • 4 Zocco MA, Di Stasio E, De Cristofaro R. , et al. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 2009; 51 (04) 682-689
    CrossrefPubMedGoogle Scholar
  • 5 Maruyama H, Okugawa H, Takahashi M, Yokosuka O. De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes. Am J Gastroenterol 2013; 108 (04) 568-574
    CrossrefPubMedGoogle Scholar
  • 6 Villa E, Cammà C, Marietta M. , et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260
    CrossrefPubMedGoogle Scholar
  • 7 Lisman T, Bongers TN, Adelmeijer J. , et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (01) 53-61
    CrossrefPubMedGoogle Scholar
  • 8 Maisonneuve P, Sultan Y. Modification of factor VIII complex properties in patients with liver disease. J Clin Pathol 1977; 30 (03) 221-227
    CrossrefPubMedGoogle Scholar
  • 9 Webster GJ, Burroughs AK, Riordan SM. Review article: portal vein thrombosis -- new insights into aetiology and management. Aliment Pharmacol Ther 2005; 21 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 10 Amitrano L, Guardascione MA, Brancaccio V. , et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004; 40 (05) 736-741
    CrossrefPubMedGoogle Scholar
  • 11 Mangia A, Margaglione M, Cascavilla I. , et al. Anticardiolipin antibodies in patients with liver disease. Am J Gastroenterol 1999; 94 (10) 2983-2987
    CrossrefPubMedGoogle Scholar
  • 12 Gaiani S, Bolondi L, Li Bassi S, Zironi G, Siringo S, Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients. Gastroenterology 1991; 100 (01) 160-167
    CrossrefPubMedGoogle Scholar
  • 13 Tripodi A, Primignani M, Chantarangkul V. , et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009; 137 (06) 2105-2111
    CrossrefPubMedGoogle Scholar
  • 14 Englesbe MJ, Kubus J, Muhammad W. , et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl 2010; 16 (01) 83-90
    CrossrefPubMedGoogle Scholar
  • 15 Yerdel MA, Gunson B, Mirza D. , et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000; 69 (09) 1873-1881
    CrossrefPubMedGoogle Scholar
  • 16 Pan C, Shi Y, Zhang JJ. , et al. Single-center experience of 253 portal vein thrombosis patients undergoing liver transplantation in China. Transplant Proc 2009; 41 (09) 3761-3765
    CrossrefPubMedGoogle Scholar
  • 17 Zanetto A, Rodriguez-Kastro KI, Germani G. , et al. Mortality in liver transplant recipients with portal vein thrombosis - an updated meta-analysis. Transpl Int 2018; 31 (12) 1318-1329
    CrossrefPubMedGoogle Scholar
  • 18 Anderson Jr FA, Wheeler HB, Goldberg RJ. , et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (05) 933-938
    CrossrefPubMedGoogle Scholar
  • 19 Nonami T, Yokoyama I, Iwatsuki S, Starzl TE. The incidence of portal vein thrombosis at liver transplantation. Hepatology 1992; 16 (05) 1195-1198
    CrossrefPubMedGoogle Scholar
  • 20 Delahousse B, Labat-Debelleix V, Decalonne L, d'Alteroche L, Perarnau JM, Gruel Y. Comparative study of coagulation and thrombin generation in the portal and jugular plasma of patients with cirrhosis. Thromb Haemost 2010; 104 (04) 741-749
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Violi F, Ferro D, Basili S. , et al. Ongoing prothrombotic state in the portal circulation of cirrhotic patients. Thromb Haemost 1997; 77 (01) 44-47
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Violi F, Ferro D, Basili S. , et al. Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology 1995; 109 (02) 531-539
    CrossrefPubMedGoogle Scholar
  • 23 Semeraro N, Biondi A, Lorenzet R, Locati D, Mantovani A, Donati MB. Direct induction of tissue factor synthesis by endotoxin in human macrophages from diverse anatomical sites. Immunology 1983; 50 (04) 529-535
    PubMedGoogle Scholar
  • 24 van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76 (12) 2520-2526
    CrossrefPubMedGoogle Scholar
  • 25 Zanetto A, Campello E, Spiezia L, Burra P, Simioni P, Russo FP. Cancer-associated thrombosis in cirrhotic patients with hepatocellular carcinoma. Cancers (Basel) 2018; 10 (11) E450
    CrossrefPubMedGoogle Scholar
  • 26 Campello E, Zanetto A, Spiezia L. , et al. Hypercoagulability detected by circulating microparticles in patients with hepatocellular carcinoma and cirrhosis. Thromb Res 2016; 143: 118-121
    CrossrefPubMedGoogle Scholar
  • 27 Campello E, Spiezia L, Zabeo E, Maggiolo S, Vettor R, Simioni P. Hypercoagulability detected by whole blood thromboelastometry (ROTEM®) and impedance aggregometry (MULTIPLATE®) in obese patients. Thromb Res 2015; 135 (03) 548-553
    CrossrefPubMedGoogle Scholar
  • 28 Senzolo M, Cholongitas E, Thalheimer U. , et al. Heparin-like effect in liver disease and liver transplantation. Clin Liver Dis 2009; 13 (01) 43-53
    CrossrefPubMedGoogle Scholar
  • 29 Campello E, Spiezia L, Radu CM. , et al. Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. Thromb Res 2011; 127 (05) 473-477
    CrossrefPubMedGoogle Scholar
  • 30 Agarwal S, Senzolo M, Melikian C, Burroughs A, Mallett SV. The prevalence of a heparin-like effect shown on the thromboelastograph in patients undergoing liver transplantation. Liver Transpl 2008; 14 (06) 855-860
    CrossrefPubMedGoogle Scholar
  • 31 Chau TN, Chan YW, Patch D, Tokunaga S, Greenslade L, Burroughs AK. Thrombelastographic changes and early rebleeding in cirrhotic patients with variceal bleeding. Gut 1998; 43 (02) 267-271
    CrossrefPubMedGoogle Scholar
  • 32 Khoory MS, Nesheim ME, Bowie EJ, Mann KG. Circulating heparan sulfate proteoglycan anticoagulant from a patient with a plasma cell disorder. J Clin Invest 1980; 65 (03) 666-674
    CrossrefPubMedGoogle Scholar
  • 33 McKee RF, Hodson S, Dawes J, Garden OJ, Carter DC. Plasma concentrations of endogenous heparinoids in portal hypertension. Gut 1992; 33 (11) 1549-1552
    CrossrefPubMedGoogle Scholar
  • 34 Palmer RN, Rick ME, Rick PD, Zeller JA, Gralnick HR. Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder. N Engl J Med 1984; 310 (26) 1696-1699
    CrossrefPubMedGoogle Scholar
  • 35 Wages DS, Staprans I, Hambleton J, Bass NM, Corash L. Structural characterization and functional effects of a circulating heparan sulfate in a patient with hepatocellular carcinoma. Am J Hematol 1998; 58 (04) 285-292
    CrossrefPubMedGoogle Scholar
  • 36 Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 2007; 454 (03) 345-359
    CrossrefPubMedGoogle Scholar
  • 37 Nelson A, Berkestedt I, Bodelsson M. Circulating glycosaminoglycan species in septic shock. Acta Anaesthesiol Scand 2014; 58 (01) 36-43
    CrossrefPubMedGoogle Scholar
  • 38 Burke-Gaffney A, Evans TW. Lest we forget the endothelial glycocalyx in sepsis. Crit Care 2012; 16 (02) 121
    CrossrefPubMedGoogle Scholar
  • 39 Henrich M, Gruss M, Weigand MA. Sepsis-induced degradation of endothelial glycocalix. ScientificWorldJournal 2010; 10: 917-923
    CrossrefPubMedGoogle Scholar
  • 40 Praktiknjo M, Trebicka J, Carnevale R. , et al. Von Willebrand and factor VIII portosystemic circulation gradient in cirrhosis: implications for portal vein thrombosis. Clin Transl Gastroenterol 2020; 11 (02) e00123
    CrossrefPubMedGoogle Scholar
  • 41 Carnevale R, Raparelli V, Nocella C. , et al. Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis. J Hepatol 2017; 67 (05) 950-956
    CrossrefPubMedGoogle Scholar
  • 42 Kapiotis S, Besemer J, Bevec D. , et al. Interleukin-4 counteracts pyrogen-induced downregulation of thrombomodulin in cultured human vascular endothelial cells. Blood 1991; 78 (02) 410-415
    CrossrefPubMedGoogle Scholar
  • 43 Terada Y, Eguchi Y, Nosaka S, Toba T, Nakamura T, Shimizu Y. Capillary endothelial thrombomodulin expression and fibrin deposition in rats with continuous and bolus lipopolysaccharide administration. Lab Invest 2003; 83 (08) 1165-1173
    CrossrefPubMedGoogle Scholar
  • 44 Biró E, Akkerman JW, Hoek FJ. , et al. The phospholipid composition and cholesterol content of platelet-derived microparticles: a comparison with platelet membrane fractions. J Thromb Haemost 2005; 3 (12) 2754-2763
    CrossrefPubMedGoogle Scholar
  • 45 Simak J, Gelderman MP. Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers. Transfus Med Rev 2006; 20 (01) 1-26
    CrossrefPubMedGoogle Scholar
  • 46 Boilard E, Nigrovic PA, Larabee K. , et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327 (5965): 580-583
    CrossrefPubMedGoogle Scholar
  • 47 Campello E, Spiezia L, Radu CM, Simioni P. Microparticles as biomarkers of venous thromboembolic events. Biomarkers Med 2016; 10 (07) 743-755
    CrossrefPubMedGoogle Scholar
  • 48 Chirinos JA, Heresi GA, Velasquez H. , et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45 (09) 1467-1471
    CrossrefPubMedGoogle Scholar
  • 49 Huber J, Vales A, Mitulovic G. , et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol 2002; 22 (01) 101-107
    CrossrefPubMedGoogle Scholar
  • 50 Patel KD, Zimmerman GA, Prescott SM, McIntyre TM. Novel leukocyte agonists are released by endothelial cells exposed to peroxide. J Biol Chem 1992; 267 (21) 15168-15175
    CrossrefPubMedGoogle Scholar
  • 51 Zhou L, Qi XL, Xu MX, Mao Y, Liu ML, Song HM. Microparticles: new light shed on the understanding of venous thromboembolism. Acta Pharmacol Sin 2014; 35 (09) 1103-1110
    CrossrefPubMedGoogle Scholar
  • 52 Smith A, Quarmby JW, Collins M, Lockhart SM, Burnand KG. Changes in the levels of soluble adhesion molecules and coagulation factors in patients with deep vein thrombosis. Thromb Haemost 1999; 82 (06) 1593-1599
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Musolino C, Alonci A, Allegra A. , et al. Increased levels of the soluble adhesion molecule E-selectin in patients with chronic myeloproliferative disorders and thromboembolic complications. Am J Hematol 1998; 57 (02) 109-112
    CrossrefPubMedGoogle Scholar
  • 54 Basili S, Merli M, Ferro D. , et al. Clotting activation after transjugular intrahepatic portosystemic stent shunt. Thromb Haemost 1999; 81 (05) 711-714
    Article in Thieme ConnectPubMedGoogle Scholar