Anti-C5a Ameliorates Coagulation/Fibrinolytic Protein Changes in a Rat Model of Sepsis

Laudes, Ines J.; Chu, Jeffrey C.; Sikranth, Sujata; Huber‐Lang, Markus; Guo, Ruocheng; Riedemann, Niels C.; Sarma, J. Vidya; Schmaier, Alvin H.; Ward, Peter A.

doi:10.1016/s0002-9440(10)61133-9

Cited by 150 publications

(100 citation statements)

References 45 publications

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“…The evel of plasminogen activity in rats changes with age and sex of the animal, but it is much lower than those in humans. The parameters we measured in this study are comparable with those in the literature [26][27][28][29] . Plasminogen binds to fibrin as soon as a fibrin clot forms.…”

Section: Discussionsupporting

confidence: 88%

Diagnostic value of plasminogen activity level in acute mesenteric ischemia

Günerhan¹,

Köksal²,

Kayahan³

et al. 2008

WJG

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AIM:To investigate the changes in plasminogen activity level during mesenteric ischemia. METHODS:We performed laparotomy in 90 female Wistar-Albino rats (average weight 230 g). In sham groups (SL) (GroupsⅠand Ⅱ) the superior mesenteric artery (SMA) and vein (SMV) were explored, but not tied. In SMA groups (Groups Ⅲ and Ⅳ) the SMA was ligated, and in SMV groups (Groups Ⅴ and Ⅵ) the SMV was ligated. On re-laparotomy 2 mL of blood was drawn at 1 h in groupsⅠ, Ⅲ and Ⅴ, and at 3 h in groups Ⅱ, Ⅳ and Ⅵ. Plasminogen levels were assessed and comparisons were made between groups and within each group.

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Section: Discussionsupporting

confidence: 88%

Diagnostic value of plasminogen activity level in acute mesenteric ischemia

Günerhan¹,

Köksal²,

Kayahan³

et al. 2008

WJG

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“…There are several lines of evidence supporting a role for C5a and its receptor, C5aR, in the coagulation process: Recent studies have implicated C5a in the procoagulant response associated with severe sepsis and remote organ injury in a rat cecal ligation and puncture model of sepsis (6). In vivo blockade using anti-C5a IgG results in amelioration of several fibrinolytic/coagulation protein changes occurring in sepsis.…”

Section: Discussionmentioning

confidence: 99%

“…Both are considered among the earliest innate immune effectors that sense incoming inflammatory signals and are rapidly recruited to sites of injury and inflammation (3). Earlier studies have indicated a role for complement in procoagulant pathways by showing that interception of C5a and its receptor C5aR results in distinct changes in pro-/antifibrinolytic proteins (3,6) and in the induction of tissue factor (TF) in endothelial cells (7) and monocytes (8). Furthermore, studies in rodent models of APS-induced thrombophilia have indicated that activation of complement components C3 and C5 is required for the induction of thrombus formation (9 -11).…”

mentioning

confidence: 99%

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Ritis

Doumas

Mastellos

et al. 2006

The Journal of Immunology

425

338

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Neutrophils and complement are key sentinels of innate immunity and mediators of acute inflammation. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways. To date, the potential cross-talk between innate immunity and thrombosis and the precise molecular pathway by which complement and neutrophils trigger the coagulation process have remained elusive. In this study, we demonstrate that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the induction of tissue factor (TF), a key initiating component of the blood coagulation cascade. TF expression by neutrophils was associated with an enhanced procoagulant activity, as verified by a modified prothrombin time assay inhibited by anti-TF mAb. Inhibition studies using the complement inhibitor compstatin revealed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF-dependent coagulant activity. Blockade studies using a selective C5a receptor antagonist and stimulation of neutrophils with recombinant human C5a demonstrated that C5a, and its receptor C5aR, mediate the expression of TF in neutrophils and thereby significantly enhance the procoagulant activity of neutrophils exposed to APS serum. These results identify a novel cross-talk between the complement and coagulation cascades that can potentially be exploited therapeutically in the treatment of APS and other complement-associated thrombotic diseases.

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“…The abnormal vitamin K-dependent factors are detected in rats by measuring coagulation time using the Kurata, Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan thrombotest [4, 6, 14, 18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21].…”

Section: Abstract: a Battery Of Simple Tests For Profiling Abnormalitmentioning

confidence: 99%

“…One of the causes of this is decreased activity of vitamin K-dependent coagulation factors due to the generation of the inactive des-carboxyl form of coagulation factors, also known as "protein induced by vitamin K absence or antagonists (PIVKA)" [7,12]. Many chemicals are known to cause such abnormalities [8,20].The abnormal vitamin K-dependent factors are detected in rats by measuring coagulation time using the Kurata, Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan thrombotest [4, 6, 14, 18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21].…”

mentioning

confidence: 99%

Battery of Tests for Profiling Abnormalities of Vitamin K-Dependent Coagulation Factors in Drug-Toxicity Studies in Rats

et al. 2005

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A battery of simple tests for profiling abnormalities of vitamin K-dependent coagulation factors encountered in drug-toxicity studies was verified in rats treated with warfarin (3 and 10 mg/kg, p.o). The thrombotest, or hepaplastin-test, is useful as a followup test after routine screening tests for coagulation abnormalities based on PT and APTTThe rat is the species most commonly used to assess the general toxicity of compounds under development for clinical use. We sometimes observe prolongation of the routine screening parameters, prothrombin time (PT) and activated partial thromboplastin time (APTT) in general toxicity studies in rats. One of the causes of this is decreased activity of vitamin K-dependent coagulation factors due to the generation of the inactive des-carboxyl form of coagulation factors, also known as "protein induced by vitamin K absence or antagonists (PIVKA)" [7,12]. Many chemicals are known to cause such abnormalities [8,20].The abnormal vitamin K-dependent factors are detected in rats by measuring coagulation time using the Kurata, Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan thrombotest [4, 6, 14, 18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21]. Among them, the thrombotest and hepaplastin-test are the least specific, since these show a prolongation of coagulation time when the activity of either factor II, VII or X has declined, regardless of whether vitamin K abnormality is involved or not. The activity of individual coagulation factors is insufficient to confirm the patho-mechanism of coagulation abnormalities, because it is impossible to detect the inactive form of coagulation factors (e.g., PIVKA-II). PIVKA-II, if measured alone, is also insufficient

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Anti-C5a Ameliorates Coagulation/Fibrinolytic Protein Changes in a Rat Model of Sepsis

Cited by 150 publications

References 45 publications

Diagnostic value of plasminogen activity level in acute mesenteric ischemia

Diagnostic value of plasminogen activity level in acute mesenteric ischemia

A Novel C5a Receptor-Tissue Factor Cross-Talk in Neutrophils Links Innate Immunity to Coagulation Pathways

Battery of Tests for Profiling Abnormalities of Vitamin K-Dependent Coagulation Factors in Drug-Toxicity Studies in Rats

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