Ann Rheum Dis: first published as 10.1136/ard.38.3.244 on 1 June 1979. Downloaded from

Annals of the Rheumatic Diseases, 38, 1979, 244-247

Thrombokinetics in giant , with special reference to corticosteroid therapy

ANNA-LISA BERGSTROM, BENGT-AKE BENGTSSON, LARS-BERTIL OLSSON, BO-ERIC MALMVALL, AND JACK KUTTI From the Departments of Internal Medicine and Infectious Diseases, Eastern Hospital, University of Gothenburg, S-416 85 Gothenburg, Sweden

SUMMARY Duplicate survival studies were carried out on 8 patients with (GCA), once before the institution of any therapy, and the second time when they were in a com- pletely asymptomatic phase after having received corticosteroid treatment. The time interval be- tween the studies ranged between 5 and 14 months. In the first study the mean peripheral platelet count was 486 ±25 x 109/1 and in the second 326 ±25 x 109/1. The difference between the means was highly significant (P<0 001). The mean life-span of the platelets was normal in the duplicate experiments (6 * 7 ±0 * 3 and 7 *3 ±0 *4 days, respectively). Platelet production rate was significantly (P<0 001) raised in the first experiment but became normal in response to corticosteroid therapy. It is concluded that the thrombocytosis seen in GCA is reactive to the present in this disease, and it seems reasonable to assume that the reduction in the peripheral platelet count which occurs in response to corticosteroid therapy accurately reflects the clinical improvement of the patient.

Thrombocytosis is frequently present in patients Table 1 Eight patients with GCA in whom duplicate platelet sutrvival studies were carried out with untreated giant cell arteritis (GCA) (Olhagen, http://ard.bmj.com/ 1963; Hamrin, 1972; Malmvall and Bengtsson, Patients Age Sex Time interval Maintenance. 1978). No information is available on platelet (years) between the 2 oral dose of production and platelet survival in this disease. platelet survival prednisolone stuidies (months) during the second It is well recognised that corticosteroid treatment is platelet survival highly effective in GCA. However, its effects on the study (mg per day) above mentioned parameters are unknown. In the 1 59 F 5 10 present report we therefore provide data on platelet 2 71 F 7 10 3 72 F 6 10 on October 4, 2021 by guest. Protected copyright. kinetics in a group of patients with GCA before 4 69 M 6 7-5 and after the institution of corticosteroid therapy. 5 72 F 6 2 5 6 56 M 7 12-5 7 76 F 14 10 Material and methods 8 80 F 12 10 Eight consecutive patients (2 males and 6 females) Mean 69 8 with GCA aged 56-80 (mean 69) years were selected for study (Table 1). Six patients had histologically verified arteritis on temporal , and the re- Platelet survival studies were carried out twice: maining 2 were included according to the criteria for once before the institution of treatment and the the diagnosis of GCA as recently described by MaIm- second time when the patients were in a completely vall and Bengtsson (1978). Two ofthe patients had the asymptomatic phase ofthe disease after corticosteroid clinical picture of temporal arteritis combined with therapy. The time interval between the two studies the syndrome, 2 had poly- ranged between 5 and 14 (mean 8) months. During myalgia rheumatica, 2 had only general symptoms, the second platelet survival study the patients and 2 had symptoms of localised temporal arteritis. received a maintenance dose of 2-5-12 5 mg pred- Accepted for publication 25 July, 1978. nisolone orally per day. The individual data for Correspondence to Dr J. Kutti. the patients are given in Table 1. The control group 244 Ann Rheum Dis: first published as 10.1136/ard.38.3.244 on 1 June 1979. Downloaded from

Thrombokinetics in giant cell arteritis with special reference to corticosteroid therapy 245 consisted of 8 healthy volunteers with a mean age 90 %/recovery % is the correction for splenic pooling of 56 years. of (Kutti and Weinfeld, 1971). All experiments were carried out with autologous The enumeration of platelets was carried out on platelets. The labelling technique has been described venous by means of phase microscopy elsewhere in detail (Kutti and Weinfeld, 1971; Kutti (Brecher et al., 1953). The platelet counts reported and Safai-Kutti, 1975). Only a brief summary of the are the values obtained on day zero. procedure is given below. Standard statistical methods were used. Unless Whole blood (approximately 250 ml) was collected otherwise stated mean values ± standard error (SE) by gravity in two plastic bags each containing 20 ml of the mean are reported. Within the group of GCA of acid ACD (Aster and Jandl, 1964). After centri- the statistical analyses were made with Student's fugation of the blood (at 260 g) the platelet-rich t test and calculated on differences between matched plasma (PRP) was transferred to another bag. PRP pairs. The difference between means was considered was then centrifuged (at 1600 g) to provide a platelet statistically significant if P<0 05). button, which was resuspended in 10 ml of platelet- poor plasma (PPP) and incubated with 400 FCi of Results 51Cr in the form of sodium chromate. Thereafter the incubated platelets were washed with PPP and Peripheral platelet count. The mean peripheral finally injected into the patient. Blood samples were platelet count at the first experiment was 486 ± 25 obtained 15, 30, 60, and 120 min after injection of x 109/l. The corresponding mean at the second labelled platelets. Subsequent samples were drawn study was 326 ± 25 x 109/l, and the difference at 24 h intervals during a period of 8 days. All blood between means was highly significant (P<0-001) sampling was in duplicate, and platelet-bound (Tables 2 and 3). In every patient the peripheral radioactivity (PBR) was extracted from 9 ml of platelet count decreased after prednisolone therapy. venous blood as previously reported (Kutti and Weinfeld, 1971). Table 2 Results ofplatelet survival studies in 8 Platelet recovery, that is the percentage of infused untreatedpatients with GCA PBR remaining in the peripheral blood shortly after Patients Peripheral Platelet MLS N Platelet infusion, was calculated from: PBR per ml of blood platelet recovery (days) (x 1010) production count % rate/day x BV x IOO/PBR infiused. BV denotes the blood (x 109/I) (x 1010) volume and was calculated from height and weight measurements (Nadler et al., 1962). 1 435 72 6-4 207 32 2 502 77 5-2 211 41 http://ard.bmj.com/ Platelet mean life-span (MLS) was obtained by 3 415 75 6-1 189 31 extra'polating the initial slope of the survival curve 4 532 73 7-4 308 42 5 568 53 6.3 338 54 to the time axis (Mills, 1946; Dornhorst, 1951). 6 388 73 7.0 225 32 This was achieved by fitting an arbitrary mathe- 7 577 82 6-9 215 31 matical function: 8 471 77 8-2 187 23 Mean 486 73 6.7 235 36 x 0a

246 Bergstrom, Bengtsson, Olsson, Malmvall, Kutti

Platelet recovery. Fig. 1 shows the circulating nisolone treatment significantly reduced the peri- PBR 2 h after infusion in the duplicate experiments. pheral platelet concentration. Platelet MLS was It is seen that the values for platelet recovery in the shown to be normal in untreated patients and was second experiment were considerably higher than in unaffected by corticosteroids. the first, and the difference was statistically signi- It is generally accepted that disorders associated ficant (P<0 005). with thrombocytosis may be designated as either The individual values for platelet recovery given reactive or autonomous (Harker and Finch, 1969). in Tables 2 and 3 denote the highest value obtained Reactive thrombocytosis may occur with, for example at 60 or 120 min. The mean platelet recovery in the inflammation, iron deficiency, or neoplasia not control group was 73 ± 4 %. arising from haemopoietic tissue (Harker and Finch, Platelet mean life-span (Tables 2 and 3). The 1969). Autonomous thlrombocytosis on the other hand average platelet MLS before treatment was 6 7 ± is the term applied to an increased peripheral 0 3 days. After corticosteroid therapy the corres- platelet count associated with neoplastic proliferation ponding value was slightly higher (7 3 ± 0 4), but of the as characteristically seen in there was no statistical difference between the means. the so-called myeloproliferative disorders, for The mean platelet MLS in the control group was example, primary thrombocythaemia, polycyth- 6 * 6 + 0 * 5 (range 4 * 5-8 * 7 days). aemia vera, myelofibrosis with myeloid metaplasia, Platelet production rate (Tables 2 and 3). In the and chronic granulocytic leukaemia (Harker and first study the mean for P was 36 ± 3 x 1010 Finch, 1969; Kutti and Weinfeld, 1971; Kutti et al., platelets per day. In response to prednisolone therapy 1973; Weinfeld et al., 1975). Hence, in accordance in every subject there was a fall in P. The mean for with the above findings the thrombocytosis seen in P at the second study (19 + 2 x 1010) was signi- GCA should be regarded as reactive to the inflam- ficantly lower (P <0-001) and did not differ from mation present in this disease. the control mean (21 + 2 x 1010). Before the institution of therapy P was about 1 * 7 times higher than in the controls. After corticosteroid Discussion treatment, when the GCA patients were studied in an asymptomatic phase, P was shown to have In this study the raised values for the peripheral become normal. This depression of P was reflected platelet counts in untreated patients with GCA were by the overall lowering in the peripheral platelet explained by increased platelet production. Pred- concentration. It therefore seems that the reduction to in the platelet count which occurs in response http://ard.bmj.com/ corticosteroid therapy reflects clinical improvement, 100O as do other laboratory tests such as the ESR and levels of fibrinogen and haptoglobin. for LL As shown in Fig. 1, the values platelet recovery, > 80 an indirect measure of the size of the exchangeable 0 splenic platelet pool (ESPP), were significantly U -1J. LU 1 raised in the second experiment. This is an interesting , 60 observation, but it is not easily explained. It is on October 4, 2021 by guest. Protected copyright. LU. -J tempting to speculate that corticosteroid therapy LU affects the magnitude of the ESPP. On the other X... 40 hand the possibility cannot be excluded that the disorder itself, despite corticosteroid therapy, z LUJ compromises the splenic microcirculation, so that U 20 the ESPP is reduced. ce LU cL This study was supported by grants from Riksforbundet mot Reumatism and Gothenburg Medical Society. The authors 15 30 60 wish to thank Miss Marianne Dahlberg for skilful technical assistance. MINUTES References Fig. 1 Initial platelet recovery in 8 patients with Aster, R. H., and Jandi, J. H. (1964). Platelet sequestration GCA in whom duplicate platelet survival studies were in man. I. Methods. Journal of Clinical Investigation, 43, performed. In the first study (O -O) the patients 843-855. received no therapy. In the second study ( 0) Brecher, G., Schneiderman, M., and Cronkite, E. P. (1953) the patients were on prednisolone therapy. The symbols The reproducibility and constancy of the platelet count. denote mean values - SE. American Journal of Clinical Pathology, 23, 15-26. Ann Rheum Dis: first published as 10.1136/ard.38.3.244 on 1 June 1979. Downloaded from

Thrombokinetics in giant cell arteritis, with special reference to corticosteroid therapy 247 Dornhorst, A. C. (1951). The interpretation of red cell subjects using two different incubation media. British survival curves. Blood, 6, 1284-1292. Journal ofHaematology, 31, 57-64. Hamrin, B. (1972). Polymyalgia arteritica. Acta Medica Malmvall, B.-E., and Bengtsson, B.-A. (1978). Giant cell Scandinavica, Suppl. 553, 103-105. arteritis, clinical features and involvement of different Harker, L. A., and Finch, C. A. (1969). Thrombokinetics in organs. Scandinavian Journal ofRheumatology (in press). man. Journal of Clinical Investigation, 48, 963-974. Mills, J. N. (1946). The life span of the erythrocyte. Journal of Physiology, 105, 16-17P. Kutti, J., and Weinfeld, A. (1971). Platelet survival in man. Nadler, S. B., Hidalgo, J. U., and Block, T. (1962). Prediction Scandinavian Journal of Haematology, 8, 336-346. of blood volume in normal human adults. Surgery, 51, Kutti, J., Ridell, B., Weinfeld, A., and Westin, J. (1973). 224-232. The relation of thrombokinetics to bone marrow mega- Olhagen, B. (1963). Polymyalgia rheumatica a form of senile karyocytes and to the size of the spleen in polycythaemia arteritis? Acta Rheumatologica Scandinavica, 9, 157-164. vera. Scandinavian Journal of Haematology, 10, 88-95. Weinfeld, A., Branehog, I., and Kutti, J. (1975). Platelets in Kutti, J., and Safai-Kutti, S. (1975). In vitro labelling of the myeloproliferative syndrome. Clinics in Haematology, platelets: an experimental study on healthy asplenic 4, 373-392. http://ard.bmj.com/ on October 4, 2021 by guest. Protected copyright.