Fructose-1,6-bisphosphate inhibits in vitro and ex vivo platelet aggregation induced by ADP and ameliorates coagulation alterations in experimental sepsis in rats.
Sepsis is a systemic response to an infection that leads to a generalized inflammatory reaction. There is an intimate relationship between procoagulant and proinflammatory activities, and coagulation abnormalities are common in septic patients. Pharmaceutical studies have focused to the development of substances that act on coagulation abnormalities and on the link between coagulation and inflammation. Fructose-1,6-bisphosphate (FBP) is a high-energy glycolitic metabolite that in the past two decades has been shown therapeutic effects in great number of pathological situations, including sepsis. The aims of this study were to assess the effects of FBP on platelet aggregation in vitro and ex vivo in healthy and septic rats and evaluate the use of FBP as a treatment for thrombocytopenia and coagulation abnormalities in abdominal sepsis in rat. FBP inhibited platelet aggregation (P < 0.001) in vitro in healthy rats from the smallest dose tested, 2.5 mM, in a dose-dependent manner. The mean effective dose calculated was 10.6 mM. The highest dose tested, 40 mM, completely inhibited platelet aggregation (P < 0.001) induced by ADP. Platelet aggregation in plasma from septic rats was inhibited only with higher doses of FBP, starting from 20 mM (P < 0.001). The calculated mean effective dose was 19.3 mM. Ex vivo platelet aggregation in septic rats was significantly lower (P < 0.05) than healthy rats and the treatment with FBP, at the dose of 2 g/kg, diminished the platelet aggregation at the extension of 27% (P < 0.001), suggesting that FBP is a potent platelet aggregation inhibitor in vivo. Moreover, treatment with FBP 2 g/kg prevented thrombocytopenia (P < 0.001), prolongation of prothrombin and partial thromboplastin time (P < 0.001), but not fibrinogen, in septic rats. The most important findings in this study are that FBP is a potent platelet aggregation inhibitor, in vitro and ex vivo. It presents protective effects on coagulation abnormalities, which can represent a treatment against DIC. The mechanisms for these effects remain under investigation.
de Oliveira
Luciana M
LM
Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, Porto Alegre, RS, Brazil. oliveiralm@gmail.com
Pires
Melissa G Simões
MG
Magrisso
Alessandra B
AB
Munhoz
Terezinha P
TP
Roesler
Rafael
R
de Oliveira
Jarbas R
JR
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000818:Animals; D001778:Blood Coagulation Disorders / Q000188:drug therapy / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005635:Fructosediphosphates / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008297:Male; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011517:Prothrombin Time; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D013921:Thrombocytopenia / Q000188:drug therapy / Q000378:metabolism
D005635:Fructosediphosphates; D007155:Immunologic Factors; D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; C029063:fructose-1,6-diphosphate
Pharmacol Res. 2004 May;49(5):449-53
14998554
Crit Care Med. 2006 Mar;34(3):807-14
16521276
Crit Care Med. 2001 Jul;29(7):1303-10
11445675
Hepatology. 1992 Jun;15(6):1147-53
1317340
Am J Med Sci. 1985 Jul;290(1):3-10
4036992
Am J Med Sci. 2004 Oct;328(4):196-204
15486534
Crit Care Med. 2006 Feb;34(2):285-92
16424704
Crit Care Med. 2002 Sep;30(9):2069-74
12352043
Biochem Biophys Res Commun. 1998 Feb 24;243(3):683-7
9500992
J Antimicrob Chemother. 1998 Jan;41 Suppl A:17-24
9511082
Naunyn Schmiedebergs Arch Pharmacol. 2000 Sep;362(3):208-12
10997722
Chest. 1997 Jul;112(1):235-43
9228382
Blood. 1998 Jul 1;92(1):152-9
9639511
Shock. 2005 Dec;24 Suppl 1:52-7
16374373
Clin Infect Dis. 2003 May 15;36(10):1259-65
12746771
Nature. 1962 Jun 9;194:927-9
13871375
Crit Care Med. 2000 Feb;28(2):451-7
10708182
Res Commun Mol Pathol Pharmacol. 1995 Jul;89(1):17-26
7582858
Thromb Res. 2000 Dec 15;100(6):511-8
11152931
Hematology. 2005;10 Suppl 1:129-31
16188653
Crit Care Med. 2005 Oct;33(10):2266-77
16215381
Pharmacol Res. 2003 Jan;47(1):35-41
12526859
Intensive Care Med. 2004 Jun;30(6):1032-40
15148567
Crit Care Med. 2001 Jul;29(7 Suppl):S99-106
11445742
J Thromb Thrombolysis. 2003 Aug-Oct;16(1-2):43-7
14760211
Blood. 1972 Feb;39(2):187-96
5009024
Gastroenterology. 1990 Jan;98(1):117-26
2293570
Scand J Infect Dis. 2003;35(9):545-54
14620133
Toxicol Lett. 2003 Jun 5;143(1):73-81
12697383
Intensive Care Med. 1996 Jul;22(7):707-10
8844239
Nat Protoc. 2009;4(1):31-6
19131954
Crit Care Med. 2002 May;30(5 Suppl):S313-7
12004253
Pharmacol Res. 2004 Mar;49(3):245-8
14726219
Int Immunopharmacol. 2003 Feb;3(2):267-72
12586607
Mol Cell Biochem. 2001 May;221(1-2):33-40
11506184
Biochem Pharmacol. 1992 Apr 1;43(7):1539-44
1314605
J Thorac Cardiovasc Surg. 1998 Aug;116(2):335-43
9699588