Effects of acute liver injury on blood coagulation

Abstract

Summary. The mechanisms leading to the hemostatic changes of acute liver injury are poorly understood. To study these further we have assessed coagulation and immune changes in patients with acute paracetamol overdose and compared the results to patients with chronic cirrhosis and normal healthy controls. The results demonstrate that in paracetamol overdose coagulation factors (F)II, V, VII and X were reduced to a similar degree and were signi®cantly lower than FIX and FXI (mean levels 0.28, 0.16, 0.13, 0.19, 0.51 and 0.72 IU mL À1 , respectively). In cirrhosis, by contrast, FII, FV, FVII, FIX and FX were equally reduced whilst FXI was lower than the other factors (mean levels 0.64, 0.69, 0.62, 0.60, 0.66 and 0.40 IU mL À1 , respectively). FVIII was raised in paracetamol overdose patients but normal in those with cirrhosis (mean levels 1.95 and 1.01 IU mL À1 , respectively). Interleukin-6 and tumor necrosis factor-a levels were raised in both patient groups, but higher levels were found in paracetamol overdose, compared to cirrhosis. Thrombin-antithrombin and soluble tissue factor levels were higher in those with acute liver injury but normal in cirrhosis. Antithrombin levels were reduced in both acute liver injury and cirrhosis. From these data we put forward a novel mechanism for the coagulation changes in acute paracetamol induced liver injury. We propose that immune activation leads to tissue factor-initiated consumption of FII, FV, FVII and FX, but that levels of FIX and FXI are better preserved because antithrombin inhibits the thrombin induced positive feedback loop that activates these latter factors.

Urinary trypsin inhibitor protects against liver injury and coagulation pathway dysregulation induced by lipopolysaccharide/D-galactosamine in mice

“…In particular, liver injury reportedly leads to the tissue factorinitiated consumption of Factor II, V, VII, and X. 15 In this study, UTI (À/À) mice showed a significant prolongation of PT and APTT, and significant decreases in fibrinogen and platelet counts as compared with WT mice in the presence of LPS/D-GalN. These results suggest that UTI can protect against coagulatory disturbance in fulminant hepatic failure that can result in DIC.…”

“…12,13 Furthermore, severe liver injury develops both impaired productive and consumptive coagulatory disturbance resulting in DIC and fatal outcomes. 14,15 In this study, we explored the role of UTI in severe liver injury induced by the intraperitoneal injection of LPS/Dgalactosamine (D-GalN) using UTI (À/À) mice and the corresponding wild-type (WT) mice. We also determined the effects of UTI on coagulatory disturbance during lethal liver injury.…”

Hepatocyte tissue factor activates the coagulation cascade in mice

“…APAP overdose causes acute HPC injury in mice and humans in conjunction with an increase in plasma TAT levels. [13][14][15] Of importance, peak TAT levels were dramatically lower in APAP-treated HPC ΔTF mice compared with APAPtreated control mice. In fact, levels were similar to APAP-treated low TF mice, indicating that HPCs are the primary cellular source of procoagulant TF in vivo in this model of liver injury.…”

“…13 Similarly, patients presenting with APAP overdose have an increase in plasma TAT levels and a decrease in circulating coagulation factors, suggesting that this type of liver injury leads to a consumptive coagulopathy. 14,15 We previously have shown that thrombin generation associated with APAP-induced liver injury is significantly reduced in low TF mice (mTF 2/2 hTF 1 mice), which express ;1% of wild-type TF levels in all tissues compared with APAP-treated control mice expressing 50% of wild-type levels of TF (mTF 1/2 hTF 1 mice). 13,16 However, whether HPCs are the primary cellular source of procoagulant TF in this model is not known.…”

Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy

“…Furthermore, hFIX lentivirus treatment of hemophilia B mice resulted in sufficient hFIX:C (0.50-1.25 U/mL) to approach or enter the normal range (0.72-1.30 U/mL). 24,32 Levels of hFIX:Ag varied in MF1 mice over a 20-fold range but to a lesser degree in the hemophilia B mice. This may be due to increased variability in virus transduction and gene expression in the former compared with the latter strain.…”