The digestive system involvement of antiphospholipid syndrome: pathophysiology, clinical characteristics, and treatment strategies

Figures & data

Table 1. Pathophysiological mechanisms mediated by aPL.

Thrombotic mechanisms:

Increased monocyte tissue factor expression [13]

Platelet activation [14,15]

Endothelial cell dysfuction [14,15]

aPL-mediated eNOS inhibition [14,15]

Increased production of endothelin-1 and tissue factor [14,15]

Release of neutrophil ectracellular traps [16]

Complement system activation [17]

Increased thromboxane A2 production [18]

Disturbances of anticoagulant mechanisms [18]

Immune mechanisms:

Interference by lupus anticoagulants [9]

Immune complex deposition [19]

Immune cross-reactions [20]

The production of neoantigens in cell membrane rupture [20]

The direct action of antiphospholipid antibodies [22,23,25]

aPL:antiphospholipid antibodies; eNOS: endothelial nitric oxide synthase.

Figure 1. Thrombotic mechanisms mediated by aPL. Thrombus formation can be promoted in the different ways [1]: aPL interacts with endothelial cells [2]; aPL activates mononuclear cells, induces expression of tissue factors, proteinase activated receptors and proinflammatory cytokines [3]; aPL interacts with platelets [4]; aPL inhibit fibrinolysis.aPL:antiphospholipid antibodies; β2-GPI:β2-glycoprotein I.

Table 2. Summary of digestive system manifestations associated with APS.

Gastrointestinal Organ	Manifestations
Esophagus	Oesophageal necrosis [25,27]
	Oesophageal rupture [26]
Stomach	Gastric ulcer [28]
	Gastric gangrene [29]
Intestine	Intestinal infarction [32–35]
	Inflammatory bowel disease [38,40]
Liver	Budd-Chiari syndrome [44–54]
	Hepatic infarction [57–61,63–65]
	Hepatic venous-occlusive disease [68–74]
	Nodular regenerative hyperplasia [22,77–81]
	Portal hypertension [82–87]
	Autoimmune liver disease(Autoimune hepatitis [92,93]
	Primary biliary cirrhosis [89,90]
	Primary sclerosing cholangitis [91,94]
Spleen	Splenic infarction [95–98]
	Autosplenectomy or functional asplenia [100–102]
Pancreas	Pancreatitis [24,103–106,108–110]
	Pancreatic duct injury [107,111]

Figure 2. Drug treatment strategies for thrombotic APS. APS: antiphospholipid syndrome; LMWH: low molecular weight heparin; DOAC: direct oral anticoagulants.

Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;379(13):1290.

 PubMed Web of Science ®Google Scholar

Zhang W, Gao F, Lu D, et al. Anti-β2 glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two receptors: apolipoprotein E receptor 2' and glycoprotein I bα. Front Med. 2016;10(1):76–84.

 PubMed Web of Science ®Google Scholar

Bontadi A, Ruffatti A, Falcinelli E, et al. Platelet and endothelial activation in catastrophic and quiescent antiphospholipid syndrome. Thromb Haemost. 2013;109(5):901–908.

 PubMed Web of Science ®Google Scholar

Sule G, Kelley W, Gockman K, et al. Increased adhesive potential of antiphospholipid syndrome neutrophils mediated by β2 integrin mac-1. Arthritis Rheumatol. 2020;72(1):114–124.

 PubMed Web of Science ®Google Scholar

Pierangeli S, Girardi G, Vega-Ostertag M, et al. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 2005;52(7):2120–2124.

 PubMed Web of Science ®Google Scholar

Bae S, Lee Y. Association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and circulating PAI-1 level in systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. Z Rheumatol. 2020;79(3):312–318.

 PubMed Web of Science ®Google Scholar

Fawzy M, Edrees A, Okasha H, et al. Gastrointestinal manifestations in systemic lupus erythematosus. Lupus. 2016;25(13):1456–1462.

 PubMed Web of Science ®Google Scholar

Kolitz T, Shiber S, Sharabi I, et al. Cardiac manifestations of antiphospholipid syndrome with focus on its primary form. Front Immunol. 2019;10:941.

 PubMed Web of Science ®Google Scholar

La Rosa L, Covini G, Galperin C, et al. Anti-mitochondrial M5 type antibody represents one of the serological markers for anti-phospholipid syndrome distinct from anti-cardiolipin and anti-beta2-glycoprotein I antibodies. Clin Exp Immunol. 1998;112(1):144–151.

 PubMed Web of Science ®Google Scholar

Klein R, Goller S, Bianchi L. Nodular regenerative hyperplasia (NRH) of the liver–a manifestation of organ-specific antiphospholipid syndrome? Immunobiology. 2003;207(1):51–57.

 PubMed Web of Science ®Google Scholar

Sipeki N, Davida L, Palyu E, et al. Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease. WJG. 2015;21(22):6952–6964.

 PubMed Web of Science ®Google Scholar

Cappell MS. Esophageal necrosis and perforation associated with the anticardiolipin antibody syndrome. Am J Gastroenterol. 1994;89(8):1241–1245.

 PubMed Web of Science ®Google Scholar

Petri M. Antiphospholipid syndrome. Transl Res. 2020;225:70–81.

 PubMed Web of Science ®Google Scholar

McIntyre J, Wagenknecht D, Faulk W. Antiphospholipid antibodies: discovery, definitions, detection and disease. Prog Lipid Res. 2003;42(3):176–237.

 PubMed Web of Science ®Google Scholar

Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.

 PubMed Web of Science ®Google Scholar

Gomez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun. 2014;48-49:20–25.

 PubMed Web of Science ®Google Scholar

Padda A, Mandalia A, Sawalha AH. Clinical images: black esophagus in antiphospholipid syndrome. Arthritis Rheumatol. 2017;69(7):1460.

 PubMed Web of Science ®Google Scholar

Naitoh H, Fukuchi M, Kiriyama S, et al. Recurrent, spontaneous esophageal ruptures associated with antiphospholipid antibody syndrome: report of a case. Int Surg. 2014;99(6):842–845.

 PubMed Web of Science ®Google Scholar

Kalman DR, Khan A, Romain PL, et al. Giant gastric ulceration associated with antiphospholipid antibody syndrome. Am J Gastroenterol. 1996;91(6):1244–1247.

 PubMed Web of Science ®Google Scholar

Srivastava V, Basu S, Ansari M, et al. Massive gangrene of the stomach due to primary antiphospholipid syndrome: report of two cases. Surg Today. 2010;40(2):167–170.

 PubMed Web of Science ®Google Scholar

Vianna JL, D'Cruz DP, Khamashta MA, et al. Anticardiolipin antibodies in a patient with Crohn's disease and thrombosis. Clin Exp Rheumatol. 1992;10(2):165–168.

 PubMed Web of Science ®Google Scholar

Ates Y, Aslan M, Tuzun A, et al. Ulcerative colitis case beginning during pregnancy in a patient with antiphospholipid antibody syndrome. Turk J Gastroenterol. 2004;15(4):263–265.

 PubMedGoogle Scholar

Rossi FW, Lobasso A, Selleri C, et al. Autoimmune tautology in a complex case of polyautoimmunity: systemic sclerosis, autoimmune liver involvement, antiphospholipid syndrome and hashimoto's thyroiditis. Isr Med Assoc J. 2017;19(3):193–195.

 PubMed Web of Science ®Google Scholar

Fedorchenko SV, Klimenko ZB, Martynovich TL. Antiphospholipid syndrome at the onset of clinical manifestations of chronic autoimmune hepatitis of type I. Ter Arkh. 2009;81(11):14–16.

 PubMed Web of Science ®Google Scholar

Targonska-Stepniak B, Majdan M, Suszek D, et al. Overlap syndrome autoimmune hepatitis and primary biliary cirrhosis associated with antiphospholipid syndrome. Pol Merkur Lekarski. 2006;21(125):480–483. [PMID] [17345845]

 PubMedGoogle Scholar

Pamfil C, Candrea E, Berki E, et al. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome associated with dermatomyositis, autoimmune thyroiditis and antiphospholipid syndrome. J Gastrointestin Liver Dis. 2015;24(1):101–104.

 PubMed Web of Science ®Google Scholar

Hua R, Wu H, Zhang XW, et al. Probable catastrophic antiphospholipid syndrome complicated with primary sclerosing cholangitis. J Dig Dis. 2012;13(11):601–603.

 PubMed Web of Science ®Google Scholar

Romdhane H, Karoui S, Serghini M, et al. Crohn's disease, primary sclerosing cholangitis and antiphospholipid syndrome: an uncommon association. Tunis Med. 2009;87(5):349–351.

 PubMedGoogle Scholar

Nguyen HC, Dimou A, Govil A, et al. Primary antiphospholipid syndrome and necrotizing pancreatitis: a diagnostic challenge. J Clin Rheumatol. 2013;19(6):348–350.

 PubMed Web of Science ®Google Scholar

Chang LH, Francoeur L, Schweiger F. Pancreaticoportal fistula in association with antiphospholipid syndrome presenting as ascites and portal system thrombosis. Can J Gastroenterol. 2002;16(9):601–605.

 PubMed Web of Science ®Google Scholar

Savey L, Piette JC, Bellanger J, et al. Catastrophic antiphospholipid syndrome (CAPS)-induced ischemic pancreatic ducts injury mimicking intraductal papillary mucinous neoplasm (IPMN). Semin Arthritis Rheum. 2018;47(4):565–568.

 PubMed Web of Science ®Google Scholar

Data availability statement

The data that support the findings of this study are available in [Pubmed] at [DOI:10.1016/s0163-7827(02)00048-6,DOI:10.1002/art.10187,DOI:10.1038/nrrheum.2017.124, DOI:10.1002/art.40901], reference number [2,6,10,11].