British Journal ofHaemafology, 1975,29, 413.

Platelet Kinetics in Idiopathic Thrombocytopenic Purpura (ITP) before and at Different Times after Splenectomy INGMAR BRANEHOG

Unit of Medical Oncology, Department of Medicine l I , Sahlgren’s Hospital, University of Goteborg,’Goteborg, Sweden (Received 4 Febrtiary 1974; acceptedfor pablication

2

April 1974)

SUMMARY.Platelet kinetics were studied in I 8 patients with idiopathic thrombocytopenic purpura (ITP) before splenectomy, I month and 8 months after splencctomy. A gamma function was used for the calculation of platelet mean life span

(MLS). Before splenectomy platelet MLS was greatly reduccd and platelct production was 2.8 times normal. The peripheral platelct count and platelet rccovery were significantly related to platelet MLS. One month after splenectomy platelet MLS increased appreciably while platelet production decreased but continued to be significantly above normal. These changes together with the removal of the splenic platelet pool resulted in a peripheral platelet count significantly higher than normal and a total platelet mass not differing from normal. Eight moiiths after splenectomy platelet MLS increased slightly but was not significantly different from that found I month after splenectomy. Platelet production, however, decreased significantly and became normal. This resulted in a normal peripheral platelet count and a decreased total platelet mass which was significantly lower than in non-splenectomized control subjects. The results suggest that platelet production is regulated by a feed-back mechanism that is governed by the peripheral platelet count. The high platelet count encountered I month after splenectomy is due to a sluggishness of this regulatory mechanism. Several studies indicate that the peripheral blood platelet count has a regulatory effect on platelet production. It has been shown in animal experiments that thrombocytopenia, whether produced by exchange transfusion or administration of anti-platelet antiserum, is followed by increased platelet production (Craddock et al, 1955; Matter et al, 1960; Odell et al, 1962; Ebbe et al, 1968; Kraytman, 1971). On the other hand, thrombocytosis produced by hppertransfusion is followed by rebound thrombocytopenia which has been interpreted as secondary to suppression of platelet production (Cronkite et al, 1961 ; Odell et al, 1967; de Gabriele & Penington, 1967a; Evatt & Levin, 1969). The effect of a low peripheral platelet level on platelet production has becn studied in Correspondence: Dr Ingmar Branehog, Unit of Medical Oncology, Department of Medicine 11, Sahlgren’s Hospital, University of Goteborg, Gotcborg, Sweden.

413

414

Ingmar Branehog

idiopathic thrombocytopenic purpura (ITP). The results are consistent with findings in experimental animals and have shown that platelet production is stimulated by a low peripheral count (Harker, 1970; Branehog et al, 1974). It has been shown that the inverse relationship between platelet production and peripheral platelet count is best described by a sigmoid curve. Thus for ITP patients with platelet counts above 50 ooo/pl, platelet production was found to be within the upper nornial range but with further reduction of the platelet level, production progressively increased (Branehog et al, 1974). When ITP patients are splenectomized the peripheral platelet count often rises to the degree of thrombocytosis. This might be due to various factors, such as prolongation of platelet mean life span (MLS), continuous increased production or altered platelet distribution. The latter might be caused by removal of the exchangeable splenic platelet pool, which usually conceals about one third of the platelet mass. At a later stage after splenectomy a new steady state is usually established with a lower platelet count than during the initial period following splenectomy. Previous studies indicate that in ITP a fraction of labelled platelets is rapidly destroyed immediately after infusion (Branehog et al, 1973). It has been shown that this rapid initial destruction is related to platelet mean life span (MLS) (Branehog et al, 1974). Subsequently it was found that during corticosteroid therapy there was not only a prolongation of platelet MLS but also a reduction of the postinfusional destruction (Branehog & Weinfeld, 1974). A prolongation of platelet MLS after splenectomy might thus also affect the postinfusional platelet destruction. In view of the above considerations it was thought to be of interest to study platelet kinetics in ITP patients before splenectomy and in relation to the changes occurring at different times after splenectomy. In previous studies an exponential function was used for calculation of platelet MLS in ITP with short platelet survival (Branehog et al, 1974; Branehog & Weinfeld, 1974). In the present study a gamma function was adapted for computer calculation and employed for analysis of the platelet survival curves. This function was recommended on theoretical grounds by Murphy & Francis (1971) and has the advantage that it can be used both before splenectomy when MLS is very short and after splenectomy when MLS might be normal. MATERIAL Eighteen patients with ITP (nine men and nine women) aged from 17 to 58 years (mean 33 years) were investigated. The diagnosis of ITP was based on criteria previously reported (Branehog et al, 1974). In eight patients there was an insidious onset of symptoms and a duration of disease of at least 5 months before splenectomy. In nine the onset of symptoms was acute and the history shorter than 5 months. One patient had recurrent episodes of bruising and normal platelet survival during recovery (Table I). It has previously been pointed out (Branehog et af, 1974) that the subdivision of ITP into acute, recurrent and chronic forms (Karpatkin, 1971 ;Baldini, 1972) can hardly be based on the mode of onset alone since unnoticed disease might become manifest by sudden onset of symptoms. Thus some of the ‘acute’ cases might have been chronic. In the analysis of data all ITP patients have been treated as one group. Platelet survival studies were performed in all I 8 subjects I week before splenectomy.

F F F M M M M F M F F M F F F M M M

Mean SD SE Controls* Mean SD SE

17. J.J. 18. B.-A.B.

--

188000

37 34000 7000

37000 39000 9000

24000 31000 33000

20000

2600 56000 8800 3 800 84000

8~000

83000

26000

33000

4000

2100

142000

22000

3000

Platelet count per PI blood

H A A H H A A A A H A H H A H A A H

Autologous (A) Homologous ( H )

0.3

1.2

6.9

21

6 I

13000

3000

I44 30 .6

23 24 6

24.4

17.4 21.5

29 46

10.0 21

26

2.0

44.9 47.5 1.6 31.3 6.5

22.0

50.7

53 28 7

month months 2 months I month 2 months years 514months

60 40

60

60

60

60

7 years 1/4 month 3 months 6 years 5 months I month Recurrent 5 months 30 years I month

10years

I

2

60

Duration of disease

2.1

28

93 67

80 32

90 53 34 I9 57

58 85

29

105

Prednisolone (mglday)

14.0 94.3 1.7 2.7 21.9

x 10~')

XIO~O

per day)

no.

Total body platelet mass (no.

Platelet production rate

43000

60000 14000

I22000

190000 191000 69000 77000 45000 65000 94000

88000

119000 60000 5 3000 153000 196000

201000

227000 69000 132000 I 59000

* BranehGg et a1 (1974).

2

60 9

3

I1

30

23

45 26

30 18

0.96 0.07 0.03 1.83 0.39 0.81 0.72 0.53 0.61 0.69 0.16

0.02

0.03 0.42 0.65 2.41 0.84

21

27 24 44 49 30 26 28

0.02

44

0.02

0.48 1.63

I4

(%)

Recovery

Platelet turnover per d Per day

~

TABLE I. Platelet survival studies in 18 subjects with ITP before splenectomy

33

26

58

40 23 26 30

21

38

22

I7

38 30 27 I8 37 47 57 44

M.S. A.-M.I. 3. I.K. 4. S.P. 5 . R.F. 6. G.J. 7. H.B. 8. B.E. 9. A.K. 10.A.J. 11. U.B. 12. R.L. 13. I.N. 14. B.H. IS. B.L. 16. M.L.

2.

I.

Sex

Subject no.

-

3

3

-_

5'

f",

!T -.

2

P

'-j

-s.

Ingniar Branehog

416

In 16 of them,a second study was performed I month after splenectomy and in 12 of them a third study was performed 8 months (range 6-12) after splenectomy. Two subjects were studied before and 8 months after splenectomy. Seven of the 18 patients were on corticosteroid therapy for 2-3 weeks prior to the first study. The medication and dosage was not changed during the period of the study (Table I). After splenectomy corticosteroid therapy was rapidly withdrawn. Twenty-one hazmatologically normal men of comparable age were used as controls (Branehog et af, 1974). METHODS In all subjects but one, autologous ”Cr-labelled platelets were used when the peripheral platelet count was above 20 ooo platelets perpl. In the others homologous platelets from ABO and Rh-compatible healthy donors were used (Table I). None of the subjects studied with homologous platelets had previously received blood transfusions. The 51 Cr-labelling techniques, the procedure for blood sampling and differential centrifugation and the principle for calculation of platelet recovery have been described in detail previously (Kutti & Weinfeld, 1971 ;Branehog et d,1974)- Platelet-bound radioactivity (PBR) obtained from peripheral blood 15 rnin after infusion of labelled platelets was used for recovery calculations. For the determination of platelet mean life span (MLS) the following arbitrary mathematical function (Murphy & Francis, 1971) was used :

c c

I n-1

Y(t)= Y(0)n

i=o

i

j=o

e-at(at)j j!

-

The above function was fitted to experimental data by the least-squares’ method using a digital computer (IBM 360/65). A weight factor of I was applied to every experimental point. The activity of the 15 min sample was used as the first experimental value. Experimental data were thereafier used until about 20% of the 15 min activity was reached. Y(t) represents the platelet button radioactivity at time t after the infusion of labelled platelets. From the parameters Y(o),a and n, Yr(o)was calculated. Platelet MLS is then given by - Y(o)/Y’(o) (Mills, 1946; Dornhorst, 1951; Kutti & Weinfeld, 1971). As this fwiction has three parameters, Y(o),a and n, at least four experimental points are needed for a non-trivial least-squares’ fit. In the stationary state platelet production rate (P) is equal to platelet destruction rate (0). Platelet production rate is obtained from P = D = N/MLS, where N denotes the total number of circulating platelets including those in the splenic pool. Before splenectomy platelet production/day was calculated from the formula :

P=

platelet countlpl x BV x 1.51 MLS

and platelet turnoverlpllday from: platelet count/pI x 1.51 MLS BV denotes blood volume and was calculated from height and weight measurements

Platelet Kinetics in I T P

4.17

(Nadler et al, 1962) and 1.51 is the correction factor for splenic pooling (for dctails see Branchog et al, 1974). Accordingly, after spleiiectomy platelet production is given by: platelet countlpl x BV MLS and platelet turnover by: platelet count/pl MLS

Platelet counting was performed with a Coulter Countcr as previously described by Kutti & Weinfeld (1971). In patients with platelet counts below 30 ooo platelets perpl, counting was carried out by phase microscopy according to the method ofBrecher et a1 (1953). To minimize the counting error at least 500 platclets were counted in every case and in no patient were

less than four counting chambers and pipettes used. Standard statistical methods were used (Snedecor, 1959). Unless otherwise stated, mean+ standard error of the mean (SE) are reported. Mean values were tested with Student's t test or with the Fisher test (OdCn & Wedel, 1973) if a skew distribution of values was present. Results obtained in the same individuals before and at different times after splenectomy were compared by the paired Wilcoxon test. A difference was considered to be significant if P

Platelet kinetics in idiopathic thrombocytopenic purpura (ITP) before and at different times after splenectomy.

Platelet kinetics were studied in 18 patients with idiopathic thrombocytopenic purpura (ITP) before splenectomy, 1 month and 8 months after splenectom...
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