M.J. Weston

CHARCOAL HÆMOPERFUSION IN THE TREATMENT OF FULMINANT HEPATIC FAILURE

Abstract Twenty-two patients with fulminant hepatic failure who deteriorated to grade-IV coma despite full supportive therapy were treated by repeated periods of haemoperfusion through columns containing activated charcoal. The procedure was well tolerated clinically. Eleven of the patients regained consciousness and ten left hospital. Follow-up liver biopsies in the first three patients at around six months after discharge from hospital showed restitution of the normal lobular architecture. Of the eleven treatment failures, haemorrhage was responsible for death in three, and in six brain herniation secondary to cerebral œdema was an important contributory factor. The column extracted most aminoacids from plasma, and during perfusion arterial concentrations of phenylalanine, tyrosine, and methionine-aminoacids known to be involved in the pathogenesis of the encephalopathy—fell significantly. The charcoal was coated with a biocompatible polymer, and there was no evidence for removal of coagulation factors. The extraction of platelets was below 30% in most instances, and in only two patients was there evidence that bleeding may have been precipitated by the haemoperfusion. These survival figures are to be compared with a previous survival figure of 10% in a series of ninety-two cases with fulminant hepatic failure and grade III or IV encephalopathy treated by full supportive measures.

PLATELET PROTECTION AND HEPARIN SPARING WITH PROSTACYCLIN DURING REGULAR DIALYSIS THERAPY

When prostacyclin (5 ng kg-1 min-1) was given during dialysis it enhanced the biological activity of heparin and prevented the activation and consumption of platelets. No adverse effects were observed. The reduction in heparin requirements produced by prostacyclin should make dialysis, safer, particularly for patients at risk of bleeding, while preserving the biocompatibility of the dialysis circuit. It remains to be established whether prevention of platelet activation will confer long-term benefit by inhibiting the prothrombotic state induced by haemodialysis, thereby reducing the risk of atherosclerosis in uraemic patients.

PROSTACYCLIN CAN REPLACE HEPARIN IN HÆMODIALYSIS IN DOGS

Despite the use of heparin, activation of platelets on the artificial surface of dialyser membranes results in thrombus formation, microembolisation, and thrombocytopenia. To assess the effects on these events of prostacyclin, the most potent inhibitor of platelet aggregation yet discovered, three groups of healthy greyhounds were dialysed with heparin, heparin plus prostacyclin, or prostacyclin alone. Prostacyclin, either alone or with heparin, abolished microembolisation from the dialyser (as estimated by whole-blood screen filtration pressure) and prevented thrombocytopenia. With prostacyclin, dialysis could be carried out without heparin, and there was no clotting of blood within the extracorporeal circuit nor any change in tests of coagulation.

PROSTACYCLIN TO PREVENT PLATELET ACTIVATION DURING CHARCOAL HÆMOPERFUSION IN FULMINANT HEPATIC FAILURE

Adverse effects associated with hypotension and the appearance of platelet aggregates in the circulation complicate charcoal haemoperfusion of patients with fulminant hepatic failure. In an attempt to avoid these difficulties the platelet protective effect of prostacyclin (PGI2) given intravenously before and continuously during haemoperfusion was evaluated with an improved charcoal column design. Two of the six patients who underwent haemoperfusion without PGI2 had hypotension, which in one was associated with a striking rise in Swank screen filtration pressure necessitating discontinuation of haemoperfusion after an hour. No platelet losses were observed in the six patients treated with haemoperfusion and PGI2 infusion, and there was significant protection from platelet activation, as assessed by the prevention of release into plasma of the platelet-specific protein beta-thromboglobulin.

Fish Oil Modifies Lipids and Reduces Platelet Aggregability in Haemodialysis Patients

Haemodialysis patients have an exceptionally high incidence of death from cardiovascular causes, related in part to abnormalities of lipids and platelets. Eskimos, however, have a low incidence of myocardial infarction and have a high dietary intake of fish, rich in omega-3 polyunsaturated fatty acids. We have, therefore, studied the effect of a fish oil MaxEPA, containing 3.6 g of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid on lipids and platelet function in haemodialysis patients. Following 8 weeks of therapy there was a 35% fall in triglycerides, a 10% rise of high-density lipoprotein (HDL) cholesterol, a 36% rise of HDL2 cholesterol fraction and a 54% rise of the HDL2:HDL3 cholesterol ratio. The platelet aggregation to adenosine diphosphate and collagen was significantly reduced. The activated whole-blood clotting time was prolonged from 141 to 153 s, and 69% of patients showed a reduction of factor VIII related antigen which is usually elevated in haemodialysis patients and is thought to be a marker of endothelial damage. The blood pressure fell from 147/82 to 124/74. We have thus shown that a dietary supplement of eicosapentaenoic acid produces potentially beneficial effects on lipids, platelets, and blood pressure and may help to protect against atheroma and thus cardiovascular mortality in high-risk haemodialysis patients.

Platelet function in chronic liver disease

Abnormalities of platelet aggregation in response to adenosine diphosphate in 56 patients with chronic liver disease correlated with impairment of hepatocellular function but not with the etiology of the liver disease. Platelet-poor plasma from some patients appeared to contain an inhibitor since, in cross-over studies, it reduced the degree of aggregation of control subjects. However, platelet-poor plasma from some other patients enhanced aggregation in controls, and this was thought to be due to the presence of fibrin monomer. In the majority of patients with severe liver disease, platelet function still appeared defective, even after exclusion of the effects of plasma, and was independent of the platelet count in peripheral venous blood. Since patient platelet volumes were smaller than those of controls, these findings might be explained by deficiency of the larger hemostatically active type of platelet as a consequence of either bone marrow failure or splenic sequestration.

Platelet function in fulminant hepatic failure and effect of charcoal haemoperfusion.

In 34 patients with fulminant hepatic failure, platelets, in addition to being reduced in numbers, were smaller than those of healthy controls. In keeping with this, capillary bleeding times were significantly longer than could be accounted for by reduction in numbers alone. In a small group of these patients use of charcoal haemoperfusion for temporary liver support produced a doubling of the capillary bleeding time despite only a small drop in arterial platelet counts. This disproportionate prolongation of bleeding time was almost certainly caused by the loss of larger platelets in the charcoal columns during perfusion, as the mean median volume also fell during perfusion. Rises in screen filtration pressure of blood leaving the columns were found during some perfusions and thought to be indicative of platelet aggregates. Release of vasoactive substances from platelets could account for the hypotension often found at this time.

Effects of haemoperfusion through charcoal or XAD-2 resin on an animal model of fulminant liver failure

In a group of dogs in whom fulminant liver failure had been induced, perfusion of blood through activated charcoal resulted in a significantly longer survival than that of a similar group of dogs whose blood was not so treated. An otherwise progressive rise in blood ammonia concentration was halted in the treatment group. In another group of dogs with fulminant liver failure perfusion of blood through the resin Amberlite XAD-2 was associated with a fall in the serum bilirubin concentration and complete clearance from the blood of 14C-labelled sodium glycocholate. Survival in this group of animals was not significantly prolonged. This was due at least in part to the occurrence of haemorrhage due to thrombocytopenia. Platelets adhere to the resin but do not adhere to the same degree to charcoal coated with a thin layer of polymer.

An assessment of whole blood impedance aggregometry using blood from normal subjects and haemodialysis patients

Impedance aggregometry allows the measurement of platelet responses in whole blood as well as in PRP. The variability of haematocrit values encountered when applying this technique to haemodialysis patients prompted an investigation of the effects of red cells on platelet aggregation in whole blood. Collagen induced aggregation was measured in both PRP and whole blood from haemodialysis patients and healthy controls. Platelets from haemodialysis patients were less aggregable than those from the controls when tested in PRP, but more aggregable when tested in whole blood. Blood samples with a range of haematocrit values were prepared by mixing PRP and autologous red cells, and used to study the effect of haematocrit on platelet aggregation. In blood from control subjects aggregation rate was reduced by rising haematocrit but no reduction of maximum aggregation occurred until haematocrit exceeded 40%. In contrast uraemic platelets showed increased responses in the presence of red cells. In a limited cross over study no significant difference was found in the effect on platelet aggregation of washed erythrocytes from uraemic and non-uraemic donors. It is concluded that red cell presence influences platelet aggregation by complex mechanisms during impedance aggregometry and that this effect must be considered when interpreting results.

Effects of sulphinpyrazone and dipyridamole on capillary bleeding time in man.

Abstract In a double blind cross-over study of sulphinpyrazone versus placebo, capillary bleeding times were prolonged in each subject (1.86 minutes, p = 0.033). In a similar study with dipyridamole, bleeding times became prolonged in eight of the 10 subjects (0.92 minutes, p = 0.065). Five days after stopping the drugs, bleeding times returned to baseline values in most cases. Changes in platelet numbers and volumes during each trial were not significant.