Microvascular thrombosis is a frequent finding in severe obstructive jaundice (OJ). We have previously demonstrated a very marked increase in plasma PAI activity in patients with OJ and hypothesized that this could lead to impaired fibribnolysis and thus contribute to fibrin accumulation within the microvasculature. To better define the effect of these plasma changes on the fibrinolytic process we tested the in vitro lysability of blood clots exposed to t-PA in 21 patients with OJ (serum bilirubin > 8mg/dl) and in 19 control patients matched for age and type of disease. 125I-fibrin labelled clots were prepared from freshly collected blood and submersed in 1 ml autologous citrated plasma containing 500 ng/ml of recombinant t-PA (rt-PA). The degree of lysis was determined after 3 hours at 37°C and corrected for the spontaneous lysis recorded in the absence of exogenous activator. Clots from jaundiced patients lysed markedly less than clots from controls (MeanlSD: 28.8±9.6 vs 43.7±8.0 %, p<0.0001) and in 30% of the cases the degree of lysis was below the lowest value recorded in control patients. Jaundiced patients also had significantly increased levels of PAI1 antigen (70.5±30 vs 34.0±12.9 ng/ml) and t-PA antigen (45.1 ±24.6 vs 9.4±13.6 ng/ml) with a net increase in PAI-1 activity (18.3±6.5 vs 11.8±3.5 U/ml). Plasminogen and fibrinogen levels, instead, were not significantly different in the two groups. Addition of anti-PAI-1 antibodies (100 ng/ml, final concentration) to the blood used for clot lysis, while reducing PAI-1 activity by more than 85%, had little effect on the response to rt-PA both in jaundiced patients and in controls, indicating that elevation of free PAI-1 is not the (only) cause of the in vitro resistance to thrombolysis. Addition to normal blood of bile (0.6% vol/vol), but not of purified bile salts (up to 150 nM). reduced the response to rt-PA significantly (32.5±11.5 vs 40.7±15.7, n=4, p<0.05), suggesting that bile components might have a direct effect on in vitro thrombolysis. It is concluded that OJ is associated with an enhanced resistance to t-PA-induced fibrinolysis which may be only partially explained by the alteration of the plasma t-PA/PAI-1 balance In vitro clot lysis by t-PA or other PAs might represent a useful screening test to identify patients with impaired fibrinolysis.
Resistance to fibrinolysis in patients with obstructive jaundice
Altomare D. F.;Rinaldi M.
1996-01-01
Abstract
Microvascular thrombosis is a frequent finding in severe obstructive jaundice (OJ). We have previously demonstrated a very marked increase in plasma PAI activity in patients with OJ and hypothesized that this could lead to impaired fibribnolysis and thus contribute to fibrin accumulation within the microvasculature. To better define the effect of these plasma changes on the fibrinolytic process we tested the in vitro lysability of blood clots exposed to t-PA in 21 patients with OJ (serum bilirubin > 8mg/dl) and in 19 control patients matched for age and type of disease. 125I-fibrin labelled clots were prepared from freshly collected blood and submersed in 1 ml autologous citrated plasma containing 500 ng/ml of recombinant t-PA (rt-PA). The degree of lysis was determined after 3 hours at 37°C and corrected for the spontaneous lysis recorded in the absence of exogenous activator. Clots from jaundiced patients lysed markedly less than clots from controls (MeanlSD: 28.8±9.6 vs 43.7±8.0 %, p<0.0001) and in 30% of the cases the degree of lysis was below the lowest value recorded in control patients. Jaundiced patients also had significantly increased levels of PAI1 antigen (70.5±30 vs 34.0±12.9 ng/ml) and t-PA antigen (45.1 ±24.6 vs 9.4±13.6 ng/ml) with a net increase in PAI-1 activity (18.3±6.5 vs 11.8±3.5 U/ml). Plasminogen and fibrinogen levels, instead, were not significantly different in the two groups. Addition of anti-PAI-1 antibodies (100 ng/ml, final concentration) to the blood used for clot lysis, while reducing PAI-1 activity by more than 85%, had little effect on the response to rt-PA both in jaundiced patients and in controls, indicating that elevation of free PAI-1 is not the (only) cause of the in vitro resistance to thrombolysis. Addition to normal blood of bile (0.6% vol/vol), but not of purified bile salts (up to 150 nM). reduced the response to rt-PA significantly (32.5±11.5 vs 40.7±15.7, n=4, p<0.05), suggesting that bile components might have a direct effect on in vitro thrombolysis. It is concluded that OJ is associated with an enhanced resistance to t-PA-induced fibrinolysis which may be only partially explained by the alteration of the plasma t-PA/PAI-1 balance In vitro clot lysis by t-PA or other PAs might represent a useful screening test to identify patients with impaired fibrinolysis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
