RETICULOENDOTHELIAL SYSTEM AND ANTICOAGULANT THERAPY

470 and in 1 for recurrent thrombosis in the lower extremities. We also studied 15 controls-patients with no lesion of heart or liver and in the same age-group as those treated with anticoagulants. The experimental procedure was as follows: The patient lay on his left side with knees drawn up; a leaden Colloidal gold (y3Au) shield was placed behind his buttocks. stabilised with gelatin (purchased from the Radiochemical Centre, Amersham, England) was injected into a cubital vein; a dose of 100 C was given. Radioactivity over the muscles of the right calf

RETICULOENDOTHELIAL SYSTEM AND

pectoris,

ANTICOAGULANT THERAPY STUDIES WITH RADIOACTIVE COLLOIDAL GOL]

ERIK ADLERCREUTZ M.D.

TOR PETTERSSON M.D.

From the Medical

Department, Maria Hospital, Helsingfors,

measured every second minute for sixteen to twenty minutes a scintillation counter coupled to a ratemeter. The readings were plotted on semilogarithmic paper and the half time (T;2) read from the linear portion of the clearance curve. The prothrombin content of samples of venous blood was estimated by the prothrombin and proconvertin method. was

with

Finland

PROTHROMBIN is now known to be synthesised in the cells of the reticuloendothelial system (R.E.s.) (Jurgens 1952a and b, Bajusz 1954, Slatis 1958). The Kupffer cells in the liver constitute 70-95% of these. As a rule, the synthesis of prothrombin is disturbed in severe liver disorders, but there is no strict correlation between the extent of hepatocellular injury and the functional disturbance of the R.E.s. The R.E.s. can be regarded as a state within a state, since its activity is largely independent of hepatocellular function. The phagocytic capacity of the R.E.s. has long been recognised, particles larger than one millimicron in diameter being taken up by the constituent cells. This function can be tested by administering colloidal substances -in particular, colloidal radioactive gold-and following their fate in the body. After intravenous injection, most of the gold is retained by the Kupffer cells in the liver. This forms the basis of a method of determining the hepatic blood-flow in liver-disease by measurement of the so-called Kupffer clearance (Vetter et al. 1954, Benhamou et al. 1958, Fauvert et al. 1958). Liver function during anticoagulant therapy has been extensively studied. The consensus of opinion now seems to be that, apart from the occasional case of toxic hepatitis caused by phenylindanedione, long-term treatment does not damage the liver. This conclusion, however, rests on the results of investigations of the functional state of the liver cells alone. In rats, a decrease in prothrombin and proconvertin activity has been observed when the R.E.s. is blocked withThorotrast’ (Slatis 1958). We therefore wondered whether the reverse might also be true-namely, whether the phagocytic activity of the

might be impaired during anticoagulant therapy. Prothrombin synthesis takes place in the cells of the R.E.s. and is blocked by anticoagulants. But how does the phagocytic function of the R.E.s. respond to these drugs ? R.E.s.

Patients and Methods Our series comprised 61 patients (51 men and 10 women) who were being treated with anticoagulants. The majority (87%) were between fifty and seventy years old. 20 were

being given phenylpropylhydroxycoumarin, while the

rest

were

on

phenylindanedione. No patients with cardiac failure and liver stasis were included in the series. In 59 patients

anticoagulant therapy was indiFig. 1-T/2 values in 17 patients treated with anticoagulants for up to 45 days.

cated for myocardial infarction, in 1 for severe angina

.

Results 1 shows values of T/2 in 17 patients who had been Fig. on anticoagulants for a short time (up to forty-five days). All these patients had had an episode of myocardial infarction, and treatment was begun immediately after their admission to hospital. In fig. 1 the area between the

UUf’B.-,",llun

values in 41 30 months.

Fig. 2-T/2

ur

patients

I nl;;."l"B.r"’ I

treated with

B IIIUlltoll.:J }I

anticoagulants for 2 to

continuous lines is the range of normal (mean i 2 x standard deviation) as found in the 15 controls; most of the results obtained in the patients lie within this range. In a few patients only was the decline in radioactivity abnormally slow, the longest half-time being observed in a patient who had been treated for as long as forty-five days. Fig. 2 shows T/2 values in patients who had been treated for over two months and it contrasts strikingly with fig. 1. Radiogold uptake was retarded in 29 of the 41 patients-in many to an extent comparable to that seen, for instance, in cirrhosis of the liver. Thus, in these patients, the phagocytic capacity of the R.E.S. was substantially impaired. Only in 12 of these patients did the results lie within the normal range, and in 1 of these, who had been treated for about two months, uptake was found to be abnormally slow when the test was repeated a few months later. In another 3 patients, 2 of whom had been treated for two years and eleven months and 1 for eight years, the results clearly differed from normal. (They are omitted from fig. 2 because of the time scale.) The difference between the results in figs. 1 and 2 is striking and statistically significant and shows that the full effect of anticoagulant therapy in blocking the phagocytic capacity of the R.E.S. is felt only after a certain period-some weeks, as a rule. In a few patients we performed a second clearance test two

471

later in the

course

COLLOIDAL-GOLD CLEARANCE ON SUCCESSIVE OCCASIONS DURING ANTICOAGULANT THERAPY

of

therapy (see table). Results in the first 3 patients provide additional evidence that the blocking of the R.E.s. takes time. In patients 6 and 8, uptake was found to be faster on the second occasion, although it was still abnormally slow. Pcssibly, therefore, the phagocytic capacity of the R.E.s. can recover during treatment; but 13 values in no definite conclusions patients Fig. 3-T/2 during and after anticoagulant can be drawn from treatment. only 2 instances. 3 in 13 after the comshows the results patients Fig. of after reduction of the gradual pletion treatment-i.e., Sudden of to zero. discontinuation anticoagulant dosage the have involved a risk to therapy might patient. Apparently, the R.E.s. resumes normal phagocytosis when anticoagulant treatment is discontinued; this was shown, in particular, by the results in 5 of 6 patients in whom tests were performed both during and after the treatment. We detected no difference between the results in patients treated with phenylpropylhydroxycoumarin and in those given phenylindanedione, nor was there any correlation with the prothrombin values or with the daily dose of anticoagulant. Discussion

Our results show

that, in most patients, long-term antireduces the capacity of the R.E.s. to take up colloidal radioactive gold. What are the implications of this observation-in particular, with regard to the liver ? In the first place, the resistance of the liver to infective and toxic agents may be reduced. The protective function of the R.E.S. is, as yet, incompletely understood, and opinions differ about the effect of blockade of the R.E.S. by colloidal substances. The blockade produced by anticoagulants is probably only partial and does not affect all the various functions of the R.E.s. (Popper and Schaffner 1961). Nevertheless, the possibility cannot be excluded that gross and protracted impairment of the phagocytic capacity of the R.E.s. involves a risk to the

coagulant therapy

n

i

barrier-the Kupffer cells-is impaired, hepatitis may result. When, therefore, anticoagulant therapy has largely blocked the phagocytic capacity of the R.E.s. the

patient may be in a critical situation which calls for special precautions. Only further study will determine whether this is true. In an outbreak of virus-A hepatitis, it would be particularly interesting to know whether such patients are more than usually prone to infection. Summary

anticoagulant therapy, the phagocytic of the reticuloendothelial system was assessed capacity of colloidal radioactive gold by measuring the clearance from the bloodstream. In 61

patients

on

Long-term treatment with anticoagulants led to impairment of the ability of the phagocytes of the system to take up colloidal radioactive gold. The full effect was produced after some weeks of treatment ; it was completely reversed when therapy was discontinued. As a result of the blockade of the reticuloendothelial system, patients on long-term anticoagulant therapy may be more than usually prone to infective hepatitis. We are indebted to Prof. G. Totterman for the opportunity to study patients in the medical department of the Maria Hospital, and to Dr. R. Grasbeck, of the central laboratory of the Maria Hospital, for technical aid in the performance of the colloidal-gold clearance tests. REFERENCES

Bajusz, E. (1954) Z. ges. exp. Med. 123, 6. Benhamou, J. P., Afifi, F., Loverdo, A., Fauvert, R. (1958) Rev. int. Hepat. 7, 451. Fauvert, R., Benhamou, J. P., Nicollo, S., Loverdo, A. (1958) ibid. p. 525. Fretland, A., Jacobsen, C. D. (1961) Nord. Med. 65, 324. Jürgens, R. (1952a) Schweiz. Med. Wschr. 82, 1119. (1952b) Acta Hœmat. 7, 143. Popper, H., Schaffner F. (1961) Die Leber. Struktur und Funktion; p. 112. Stutigart. Slätis, P. (1958) Scand. J. clin. Lab. Invest. suppl. 33. Vetter, H., Falkner, R., Neumayer, A. (1954) J. clin. Invest. 33, 1594. —

patient.

Jacobsen (1961) have reported 7 cases of hepatitis among 94 patients treated with anticoagulants; during the period of observation, no other cases of hepatitis occurred in the hospital or among its outpatients. The disease showed the features typical of infective hepatitis. Although the instructions of the World Health Organisation regarding the sterilisation of instruments had been followed in the hospital, Fretland and Jacobsen believed that the virus was transferred by inoculation. There is, however, another possible route of infection -namely, intestinal. In healthy subjects, bacteria have never been found in the portal vein, since the intestinal mucosa protects against bacterial invasion. On the other hand, in patients with some acute or chronic disorder of the alimentary tract and in those exposed to infection by hepatitis virus A, organisms may well enter the portal circulation. If this happens during anticoagulant therapy when the phagocytic capacity of the second protective Fretland and

A COMPARATIVE TRIAL OF TRIMEPRAZINE AND AMYLOBARBITONE IN PRURITUS F. F. HELLIER M.D. Lond., F.R.C.P. PHYSICIAN-IN-CHARGE OF THE DERMATOLOGICAL THE GENERAL INFIRMARY AT LEEDS

DEPARTMENT,

IT seems reasonable that a new drug should be put on the market only if it fulfils at least one of the following criteria: It is more effective than previously used drugs. It produces fewer or less serious side-effects. It is available in a more convenient form-e.g., oral penicillin and long-acting insulin. It is cheaper.

If this is drug has

then trials which merely show that a certain action, while necessary in its early

accepted, a