[Barcroft & Florey, 1929].

Transcription

1 132 J. Physiol. (I939) 95, I I2.4I-I8I:6I2.1I7.2 SIZE OF THE SPLEEN IN RELATION TO BLOOD SEDIMENTATION RATE BY J. G. STEPHENS From the Sir William Dunn School of Pathology, Oxford (Received 21 October 1938) THE persistent contraction of exteriorized spleens of dogs first observed as a concomitant of pregnancy by Barcroft & Stephens, has since been described in a variety of conditions. These may be summarized as: (1) During the latter part of pregnancy [Barcroft & Stephens, 1928]. (2) During lactation [Barcroft, 1932b]. (3) Aseptic necrosis of the skin [Barcroft, 1932a]. (4) After the operation by which a portion of intestine was exteriorized [Barcroft & Florey, 1929]. (5) Peritonitis [Barcroft & Florey, 1929]. (6) Aseptic laparotomy under anaesthesia and manipulation of viscera [Barcroft, 1932a]. Hitherto no explanation has been forthcoming to account for the splenic contraction in this apparently unrelated group of conditions. It was pointed out, however, that there is a common factor associated with each case, that is, an increased blood sedimentation rate [Stephens, 1938a]. The evidence that the sedimentation rate has been increased calls for consideration: (1) In a pregnant dog the rate was observed to be 14 mm./hr., the normal value being approximately 1 mm./hr. In nine pregnant cats the rate was from 28 to 8 mm./hr.; normally it is 3-4 mm./hr. In the human subject the high sedimentation rate and altered plasma protein composition is familiar. (2) During lactation the sedimentation rate of three dogs was found to be high, viz. 12, 15 and 5 mm. per first hour. The normal value is 05-1 mm. Increased sedimentation rate during lactation is known in human subjects.

2 SPLEEN SIZE-BLOOD SEDIMENTATION (3) In skin and tissue damage in the human case similar to that described by Barcroft, the sedimentation rate is increased [Reichel, 1936]. (4) and (5) The effect of aseptic operative procedure under anaesthesia in accelerating the sedimentation rate is well known and is discussed by Reichel [1936]. (6) Acute peritonitis produces an increased sedimentation rate in the human subject [Reichel, 1936]. 90a l Po 70 j Si of.n X zn60 Size of spleen coc 50 bd 133 a, spleen partially contractile; b, lump in groin suppurating spleen not contractile; c, suppuration ceased; d, excision of oat seed (ether); e, excision suture suppurating; f, spleen not contractile; g, spleen contractile-wound healed; h, spleen normally contractile. 15- * Sedimentation rate 40- ~~~~~b a, upper level undefinite; b-c, upper level 1-43 mm. undefinite; d, stratification commenced; e, no stratification in one hour. t ~~~~~~~Haematocrit a, haematocrit in mm. for 100 mm. column of citrated blood. Fig. 1. Sedimentation rate, spleen size, haematocrit relationships in presence of septic focus. Confirmation of this view that increase in the sedimentation rate is associated with a contraction of exteriorized spleens was forthcoming when the exteriorized spleen of a dog prepared by the method previously described [Barcroft & Stephens, 1927] exhibited changes which are shown in Fig. 1. The sedimentation rate determinations were already proceeding before the onset of the present changes, and were measured on 100 mm. columns in Wintrobe tubes of 3 mm. bore. The blood was diluted one-quarter its volume of 38 % sodium citrate. Haematocrit values were determined by centrifugation of the same specimens in the same tubes for a standard time at a standard velocity.

3 134 J. G. STEPHENS For 2 days the spleen became fixed in size at the normal resting size and during this stage contracted scarcely at all in response to exercise, adrenaline injections or amyl nitrite inhalations. This fixation was noticed by accident during an attempt to photograph the contraction due to these agents which the spleen had previously shown quite well. In external appearance the spleen was then a little more blue in colour than it had previously been, but otherwise looked normal. The appearance at this stage is shown in Fig. 2. There occurred next a stage of persistent self-contraction lasting 7 days and during this phase there was no response whatever to exercise or adrenaline injections. Concurrently with the self-contraction the sedimentation rate of femoral vein blood increased from 7-5 mm. per first hour to 12 mm. and later to 16 mm. It was noticed that a lump 3 x 2 cm., exuding pus, had appeared in the right groin. This was thought to be a gland abscess. Four days after the onset of the splenic shrinkage the inguinal lump ceased to exude pus. On the fifth day pus again appeared. Accordingly, ether was administered, the lump excised and the incision sutured. It proved to be, not a gland, but an inflammatory mass around a large oat seed about 1-5 cm. in length. Two days after its removal the spleen became enlarged and red in colour. The change was marked and apparent to the naked eye. The cessation of suppuration coincided approximately with a return of the sedimentation rate to almost its original value of 7-5 mm./hr. But after the anaesthesia, although the spleen enlarged the sedimentation rate increased to 22 mm. as shown. The complicating effects of the ether anaesthesia and of the fact that any sedimentation rate increase is known to follow late after the onset of disturbances which cause it must be considered here. (Sedimentation rate increase follows some days after the pyrexia indicating the onset of some lesion, for example.) On the tenth day from the commencement of the splenic shrinkage, the sedimentation rate suddenly increased to 38&5 mm./hr., with a diffuse upper level, the haematocrit value remaining at 25 mm. This was only 2 days after the spleen had enlarged, and it was now found to be shrunken again. Simultaneously the stitches of the operation incision in the groin were found to be suppurating. The spleen shrank still further during the next 2 days and was not contractile. Its size returned to the normal value that it had before the onset of the entire preceding cycle, only when the incision healed, and it then exhibited normal contractility. The subsequent steady diminution in size during a period of 31 months presents nothing unusual in the behaviour of exteriorized spleens. These

4 THE JOURNAL OF PHYSIOLOGY, VOL. 95, No. 1 PLATE I,:"..:'.; l1 Fig. 2. Exteriorizcd spleen before onset of contraction cycle. 19 actual size. To face p. 134

5 SPLEEN SIZE-BLOOD SEDIMENTATION 135 have always been observed gradually to become smaller over periods of months [Barcroft & Stephens, 1928]. Eleven months later the spleen at present described was approximately one-quarter of its bulk at the commencement of these observations. Protuberances which appeared on its surface during this period may have represented attempts at regeneration. Strangulation by epithelium and connective tissue is one of the causes of this gradual diminution in size. From the time of onset of the stitch suppuration the sedimentation rate changes became complicated by the onset of stratification and the release into the circulation of red cells of peculiar aggregation character, which have been identified as immature cells [Stephens, 1938b]. Five of seven other exteriorized spleen dogs examined showed this phenomenon of stratified blood sedimentation at some stage in their history [Stephens, 1939], but in these cases the onset was gradual. The findings here suggest that this occurrence was precipitated by the splenic shrinkage which preceded it. This would seem to indicate that the temporary shrinkage was equivalent to a temporary splenectomy. The fact that the stratification persisted after the spleen had enlarged again shows that the spleen never fully recovered normal function, but at this stage it was not different from other exteriorized spleens, as previously stated. The haematocrit values remained approximately constant until towards the end of the phase of splenic shrinkage when a small increase occurred. It is possible that this increase represents corpuscles disgorged from the spleen. But the significant point is that there was no decrease in the haematocrit value. The results must therefore be interpreted to mean that the changes in sedimentation rate are to be ascribed to alterations in the plasma composition rather than the corpuscular content of the blood. Persistent contraction of exteriorized spleens therefore apparently occurs as a concomitant of increased red cell aggregation tendency. There seems no reason why these effects should not occur with the normal spleen as far as its red cell content is concerned. In the human subject, however, the occurrence of high sedimentation rate may be associated with proliferation of the spleen macrophages and with disturbances in the leucocyte picture, reversing the splenic size changes. Artificial increase of the sedimentation rate by intravenous injection of 10 % gelatin solutions, c.c./kg. body weight, or by injection of the serum of pregnant animals was observed to cause a transient shrinkage of the spleens of cats whilst intravenous saline or glucose

6 136 J. G. STEPHENS injections caused a transient dilatation. But in these experiments several factors such as the blood volume, the red cell aggregation tendency and the red cell concentration were being varied simultaneously so that no conclusions are possible. It was noticed, however, that after gelatin injections when the sedimentation rate was mm./hr., faradic stimulation of the spleen caused infarcts in it with great facility. MECHANISM OF SPLENIC SHRINKAGE IN ASSOCIATION WITH INCREASED SEDIMENTATION RATE Concerning the fixation of the spleen at its resting size prior to shrinkage, no explanation is forthcoming from the data at hand. Nor can it be decided whether the persistent contraction results from or is the cause of the increased red cell aggregation tendency, or whether both changes are merely associated as simultaneous effects of an unknown common cause. The phenomena must be considered in relation to the observations on living spleens by Knisely [1936], who showed that there are continuous walled channels from arteriole through capillary and sinus to the collecting veins. Pulsating blood flow occurs in the sinus and capillary just as in the arteriole followed by a storage phase which occurs when the efferent end of the sinus closes. Red cells are then closely packed in the splenic sinuses whilst the plasma separates off, passes through the sinus wall to the spleen pulp, and later rejoins the red cells usually in the trabecular veins. Some red cells also penetrate the sinus wall and reach the pulp, returning the same way, but these are relatively few unless the spleen is injured. The increased red cell aggregation tendency could thus cause shrinkage of the spleen due to aggregates formed in vivo impeding the passage of blood through the splenic vessels. Fahraeus [1929] has shown that such aggregates necessitate the application of large pressures for their disintegration and to force them through small orifices. Shrinkage of the spleen could thus occur due to impeded circulation apart altogether from nervous factors. Indeed Barcroft has shown that the shrinkages associated with lactation [1932b], aseptic operation [1931], and skin necrosis [1932a] occur even when the nerves to the spleen are cut. This may be taken to indicate that an aggregation or hydrodynamic mechanism is responsible. On the other hand, the shrinkage associated with pregnancy was not seen when the nerves entering the hilus of the spleen were cut [Barcroft, 1932b]. This would seem to indicate that a nervous factor was also

7 SPLEEN SIZE-BLOOD SEDIMENTATION 137 involved in this case, but the result may also be related to the fixation of the spleen at its resting size as described above. Some uncertainty attaches to the degree of denervation produced by section of the hilar nerves [Barcroft, 1936] so that further discussion must await clarification of this point. Proliferation of the lymphoid tissue of the spleen or resumption of haematopoetic function could account for its fixation at the resting size and may also be concerned in the production of splenic shrinkage due to effects on the circulation. Persistent contraction of the spleen could produce increased sedimentation rate of the peripheral blood if the spleen normally acts to diminish the red cell aggregation tendency and sedimentation rate of the entire circulation. Such an action of the spleen has been observed in blood obtained from the splenic vein or by spleen puncture [Bergenhem & Fahraeus, 1936; Meligren, 1938; Stephens, 1938c], and if this effect extends to the general circulation its cessation during contraction of the spleen would account for the correlated changes observed. SUMMARY 1. The size of an exteriorized spleen has been observed to diminish as the blood sedimentation rate and red cell aggregation tendency increased. This association is correlated with the previously described similar persistent shrinkage in pregnancy, lactation, aseptic operative procedure, skin necrosis and peritonitis. If the increased red cell aggregation tendency is the cause of the splenic shrinkage, the effect may arise from augmented formation of aggregates impeding the flow through the splenic vessels. 2. When the spleen is stimulated to contraction in the presence of a high sedimentation rate of the general blood circulation, infarcts appear in it with great facility. I am indebted to Prof. H. W. Florey for his interest and encouragement in this work, and to Dr A. G. Sanders for assistance with the photography. I wish also to thank the Medical Research Council for a personal grant and the Trustees of the Nuffield Fund for a disbursement towards the laboratory expenses.

8 138 J. G. STEPHENS REFERENCES Barcroft, J. [1931]. Vet. J. 87, 466. Barcroft, J. [1932a]. J. Physiol. 76, 443. Barcroft, J. [1932b]. J. Physiol. 76, 436. Barcroft, J. [1936]. J. Physiol. 87, 189. Barcroft, J. & Florey, H. W. [1929]. J. Physiol. 68, 181. Barcroft, J. & Stephens, J. G. [1927]. J. Physiol. 64, 1. Barcroft, J. & Stephens, J. G. [1928]. J. Physiol. 68, 32. Bergenhem, B. & Fkhraeus, R. [1936]. Z. ges. exp. Med. 97, 555. F&hraeus, R. [1929]. Physiol. Rev. 9, 241. Knisely, M. H. [1936]. Anat. Rec. 65, 23. Mellgren, J. [1938]. J. Physiol. 94, 483. Reichel, H. [1936]. Blutk6rperchen8enkung. Wien: J. Springer. Stephens, J. G. [1938a]. J. Physiol. 92, 39 P. Stephens, J. G. [1938b]. Nature, Lond., 141, Stephens, J. G. [1938c]. J. Physiol. 94, 411. Stephens, J. G. [1939]. J. Physiol. 95, 92.