blood-dyscrasia (i933)blood dyscrasia," andit can be divided into twostages: i....

v

BLOOD-DYSCRASIA

IN THE TREATMENT OF VENEREAL DISEASES *By E. T. BURKE, D.S.O., M.B., Ch.B.(Glasg.)

DEFINITIONSMoore (I933) classifies the post-arsphenamine blood-

dyscrasias into four groups: (a) Thrombocytopenia-Purpura h?emorrhagica belongs to this class. In all otherpurpixras the platelets are normal; (b) Granulocytopenia(Agranulocytic angina)-where there is a great decreasein the number of polymorphonuclear neutrophils andeosinophils; (c) Thrombo-granulocytopenia-a combina-tion of the two foregoing classes-presenting clinicallyas an acute purpura h?emorrhagica with a blood-pictureshowing a diminution of both platelets and granulocytes ;and (d) Aplastic ana-emia where there is great leucopeniawith a relative lymphocytosis and a great diminution ofplatelets. There is also an absence of nucleated erythro-cytes and very slight poikilocytosis and anisocytosis.My opinion is that Moore's classification is needlessly

complicated and that it is impossible accurately to-makesuch a differentiation either clinically or haematologicallybetween -the conditions he enumerates. I suggest thatMoore's four classes are but different stages and degreesof the same essential condition and that they merge,the one into the other, in such a way that a sharp dis-tinction between them cannot be made. The essentialcondition might conveniently be termed " Arsphenamineblood dyscrasia," and it can be divided into two stages:i. Thrombocytopenia-where the only change from thenormal in the blood-picture is a decrease in the numberof platelets. In pure thrombocytopenia there is a pre-purpuric phase where the decrease of platelets has notprogressed far enough to give rise to vascular leakage.One has the impression also, that even with a marked drop

* Based on the Address delivered before-the Medical Society for the Study ofVenereal Diseases, on June 22nd, I940.

1 2I25

on February 23, 2020 by guest. P

rotected by copyright.http://sti.bm

j.com/

Br J V

ener Dis: first published as 10.1136/sti.17.1-2.125 on 1 January 1941. D

ownloaded from

http://sti.bmj.com/

BRITISH JOURNAL OF VENEREAL DISEASES

in platelets haemorrhages do not occur until some damagehas been sustained by the capillary endothelium. In thisstage there is no leucopenia and no diminution of neutro-phils and eosinophils. For purposes of classification" mild thrombocytopenia" means a platelet-count offrom 300,000 to IOO1,0; "moderate thrombocytopenia,"a count of from IOO,000 to 40,000; and " severe throm-bocytopenia " a count below the critical level of 40,000.

2. Granulocytopenia.-This is a development of throm-bocytopenia and indicates that the bone-marrow damageis now extending. There are probably two factorsinvolved here: (i) an aplastic process in which there isa more or less complete failure of the marrow to formmegaloblasts, Doan's cells or megakaryocytes; and(2) an abundance of these precursor cells may be pro-duced but they may fail to mature-a maturation defect.The latter is probably the predominant factor and thisseems to be borne out by the fact that such cases respondto the administration of pentose nucleotide much moresatisfactorily than do cases of pure aplastic anaemia.This stage embraces the three groups of Moore-granu-locytopenia, thrombo-granulocytopenia and aplasticanaemia. There is a decrease of platelets -xcept wherethe etiological agent is sulphonamide-leucopenia,diminution of neutrophils and eosinophils with a relativelymphocytosis. Normoblasts are absent and there isusually only slight poikilocytosis and anisocytosis. Theblood-picture is frequently that of typical aplasticaneemia but the bone marrow appearances are more sug-gestive of " agranulocytosis "-a slight leucoblastic hyper-plasia, especially in the upper third of the femur.

Dickson (1935) points out that granulocytopenia isoften referred to as" agranulocytosis "-a term proposedby Schultz in I922 but that term is not a good onesince " agranulocyte " was the name originally chosenfor those neutrophils devoid of granules which are foundin leukaemia. Friedmann used the term " agranulo-cytic angina" because of the severe throat-lesions whichare usually present ; but, as Dickson observes, thatname is not to be recommended because cases occur inwhich throat-lesions are absent and also because theterm conveys the idea that the infection of the mouthcauses the granulocytopenia, whereas the reverse is thecase. To grade this condition into " mild," " moderate '

I26



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

or " severe," there requires to be taken into considerationnot only the haematological picture but also the clinicalcondition.The chief clinical manifestations of thrombocytopenia

and granulocytopenia are the occurrence of subcutaneoushaemorrhage-purpura-and h?emorrhage from mucousmembranes.

POST-ARSPHENAMINE BLOOD-DYSCRASIAETIOLOGY

There are three elements inVolved in the natural pre-vention of haemorrhage: (i) integrity of the vessel-walls,(2) normality of the blood-coagulation complex, and(3) a sufficient number of blood-platelets.

Syphilis itself, the agents used in its treatment, andsome of the drugs administered for gonorrhoea, are allcapable of causing serious interference with one or moreof these elements. Purpura may follow the administra-tion of amidopyrin, antipyrin, antitoxins, arsenicals,benzoic acid, calx sulphurata, chloral, chloroform, cop-aiba, cubebs, ergot, hyoscyamus, iodoform, lead acetate,phosphoric acid, potassium chlorate, sandalwood oil,quinine, salicylates, stramonium, sulphonamides, andsulphonal. It has also been recorded as occurring aftervaccination for smallpox.

VESsEL-WALLSS-Syphilis is essentially a disease of theperi-vascular lymph-channels; and, while its end-resultis to cause an obliterative endarteritis and periarteritis,there occurs during the acute stage of the disease-thesecondary phase-cutaneous and mucous-membranemanifestations which are in great part due to an increasedpermeability of the vessel-walls. Sch6nlein's purpuraresembles secondary syphilis in many respects. It beginswith a sore throat, there are arthritic pains and macularcutaneous lesions appear. It would seem, then, thatsyphilis and pburpura arthritica possess some commonfactor which allows vascular leakage.

Peacock (I924) in describing two cases of purpurahaemorrhagica came to the conclusion that the conditionwas due to destruction of the capillary endotheliumallowing the blood to leak through. In both cases theclotting time was normal and this was taken to indicatethat there was neither a fall in the number of platelets

I27



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


nor any interference with the blood-coagulation complex.Borbely (I930) drew attention to the fact that arsphena-mine increased capillary fragility. Home and Scarborough(1940) showed that in post-arsphenamine erythema anddermatitis there is an associated low capillary resistance.Emanuel (I933) reported a fatal' case of universal pur-

pura with haemorrhage from mucous-membranes, and hewas of the opinion that this was due to injury to thecapillary epithelium. Tidy (I926) and Mackay (I93I)regard increased permeability and damage to the capil-lary endothelium as the most important cause of purpura.BLOOD-COAGULATION COMPLEX.-Both syphilis and the

arsphenamines are capable of inflicting damage uponhepatic cells. If this is sufficiently intense, it mayseriously interfere with the production of prothrombin.Oliver and Douglas (I923) found that " 6o6 " did not actas an anti-thrombin in causing incoagulability, althoughwhen it came into contact with that part of the blood-coagulation complex containing fibrinogen, a markedanticoagulating effect was produced. The drug appa-rently acts directly upon the fibrinogen.

Coagulation is caused by the action of thrombin uponthe soluble fibrinogen with the production of the in-soluble fibrin. Thrombin is not, of 'course, present assuch in the circulating blood, but in the form of -theinactive prothrombin. Activation is brought about byfree calcium ions and thrombokinase-the latter beingliberated by the disintegration of blood-platelets. The.mechanism of coagulation according to the theory ofMorawitz isProthrombin + Calcium ions + Thrombokinase =Thrombin.

Thrombin + Fibrinogen = Fibrin.Although hoemorrhage may be due in part to lack of

fibrinogen because of liver damage or a destruction of itby arsphenamine, the good results obtained by treatmentwith calcium suggest that a potent causal factor is adeficiency of calcium in the blood.

Flandin and Tzanck (I92I) were apparently the firstto call attention to the anticoagulating effect of thearsphenamines upon the blood, both in vitro and in vivo.They found that if blood is collected in a glass tube thesides of which have been moistened with a weak solution

128



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

of " 9I4," coagulation is delayed for from 30 minutes to 24hours or longer. If further samples of blood are taken atintervals, incoagulability continues for a period varyingfrom several hours to several days. This phenomenongradually passes off. They are of the opinion that theanti-coagulating effect is due to the arsphenamine andthat it has nothing to do with the syphilis. It occurs innon-syphilitics. -According to Flandin and Tzanck thearsphenamine does not seem to act upon the cellularelements of the blood but upon thrombin or its pre-cursors.Trost (I922) found that " 9I4 " is, among organic

arsenical compounds, that which is most prone to impedecoagulation of the blood in vitro.Anwyl-Davies and Mellanby (I923) reported that an

addition of i part of arsphenamine to I,OOO parts of bloodprevented coagulation in vitro. A similar concentrationgiven intravenously to rabbits temporarily (less than anhour) prevents coagulation. After an hour normal coagul-ability returns. In their experience, therapeutic dosesused in human therapy have practically no effect uponcoagulation except to a slight degree after prolongedadministration. During their in vitro experiments theyfound that blood-coagulation is prevented by addingo-i per cent. of arsphenamine to the blood, and that theanticoagulant action is exerted in the last phase ofcoagulation, i.e., during the interaction between thrombinand fibrinogen. They consider that arsphenamine unitesdirectly with fibrinogen and that the resulting complex isless readily coagulated by thrombin. They found thatall the arsphenamine-preparations do not equally affectthe coagulability of the blood, thus: neo-arsphenamineand sulpharsphenamine are. distinctly effective in pre-venting coagulation, but Stabilarsan-which is one mole--cule of arsphenamine base linked to two molecules ofglucose-has no such anticoagulant action. Anwyl-Davies and Mellanby consider it probable that theportion of the arsphenamine-base which combines withthe glucose is that which, in the absence of glucose, com-bines with fibrinogen. In this connection they callattention to the finding that inorganic arsenicals do notaffect coagulation in any degree. They consider that thecombination of arsphenamine with fibrinogen must bedue to the particular molecule structure which enables

I29



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


combination with glucose to take place as readily as withfibrinogen.The in vivo experiments of Anwyl-Davies and Mellanby

were carried out on rabbits. The amount of neo-arsphenamine injected into the animal was equivalentto an injection of I0 grams into the human subject.Before injection, the blood-coagulation time for therabbit was 2 minutes. Blood withdrawn I0 minutes afterinjection showed no coagulation in 24 hours, while bloodwithdrawn I hour after injection, coagulated in thenormal time of 2 minutes. Contrary to the resultsobtained by Flandin and Tzanck, Anwyl-Davies andMellanby report that there was no tendency for arsphen-amine to accumulate in the blood and produce cumu-lative effects. They also found that Stabilarsan did notaffect the coagulability of the blood in vivo and that theglucose it contains is not detached from the arsphenamine-base before absorption from the blood. In their clinicalexperiments they found that intravenous injections oftherapeutic doses had practically no effect upon thecoagulability of human blood. The coagulation-figuresfor Stabilarsan-which compound does not affect coagul-ability-did not differ appreciably from those of neo-and sulpharsphenamine, both of which entirely preventcoagulation in vitro.

Emile-Weil and Isch-Wall (I923) found that theaddition of two drops of human serum to an aqueoussolution of sulpharsphenamine caused colloidal pre-cipitation to take place, which precipitate becomes dis-solved when more serum is added. If the serum is takenfrom a purpuric patient, flocculation takes place; butthe precipitation is not dissolved on the further additionof serum. These workers believe that post-arsphenaminepurpura is of that nature of " colloidoclastic shock " andthat it occurs in patients suffering from hepatic insuffi-ciency. Such persons have few or no haematoblasts in theblood and they possess an especially fragile capillarysystem.

Copher (I924) could find no appreciable change in thecoagulability of the blood upon the addition of arsphen-amine.

It seems that the balance of evidence, experimental andclinical, goes to show that the arsphenamines are capableof so altering the non-cellular elements of blood-coagula-

I30



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

tion complex that the tendency to haemorrhage is in-creased. It would also appear that into this there entersthe matter of individual idiosyncrasy.BLOOD-PLATELETS.-In I906, Wright (I906) put for-

ward the theory that the blood-platelets are derived fromthe megakaryocytes and this has been accepted by themajority of haematologists. More recently, however,Hittmair (I938) and also Tocantins (I938) in reviewingthis subject have pointed out that the evidence in sup-port of Wright's theory is not completely convincing. Aleading article in the British Medical Journal for 26thNovember, I938, page IO90, states that more plausibletheories are (i) that fragmentation of the pseudopodsproduces platelets in the same way as the mammaryepithelium degenerates into colostrum granules, or (2) thatthe megakaryocytes exert a physico-chemical influenceon the neighbouring fluid in the same way as the fibro-cytes lay down collagen fibres in the intercellular spaces.Megakaryocytes are present not only in the bone-marrow,but also in the spleen and in the lungs (Howell, I937). Itis therefore quite probable that a great deal of plateletproduction takes place in the lungs. There has beenmuch interest taken recently in a group of leukoemia-likeconditions-leuco-erythroblastic anoemia, chronic non-leuksemic myelosis, megakaryocytic myelosis with oto-sclerosis and erythro-leukxemia-in all of which there arepresent excessive numbers of megakaryocytes in the bone-marrow and also in the spleen, liver and lymphatic glands.The blood-platelets, however, are not increased; there is atendency to haemorrhages; there is no accumulation ofmegakaryocytes in the lungs; and the condition pro-gresses to fibrosis of the bone-marrow, encroachment onthe marrow-cavity by cancellous tissue, and increaseddensity of the cortex of the bones. The giant cells areidentical with those normally present in the bone-marrow to which are attributed the formation ofplatelets.However they may originate, the blood-platelets are

to be regarded as being a particulate secretion rather thanas a cellular element of the blood. In consideringthrombocytopenia, there has been considerable disputeas to whether the decrease in the number of platelets isto be attributed to diminished production or to increaseddestruction. In what is known as " idiopathic " throm-

I3I



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BRITISH J OURNAL OF VENEREAL DISEASES

bocytopenia, the symptoms disappear in a very strikingfashion after splenectomy. The explanation for thismay be one of two things: (i) that the spleen inhibits thematuration of the platelets in the bone-marrow, or (2) thatit removes the fully-developed platelets from the cir-culating blood.Troland and Lee (1938) found that a substance

contained in the spleens of patients suffering fromthrombocytopenic purpura had, when introducedinto the circulating blood of normal rabbits, the effectof reducing the platelet-count by 90 per cent. Forthis substance, the name " Thrombocytopen " is sug-gested.

In connection with this matter of blood-platelets, it isexpedient here to refer to the theory of Howell withregard to coagulation of the blood. It is epitomised byWhitby and Britton (I937) as follows

"Howell states that calcium ions by themselves can change prothrombininto thrombin without any action on the part of disintegrated platelets ortissue juices. In circulating blood the change is prevented by an anti-prothrombin known as heparin. This substance may be prepared fromthe liver by a complicated method, and if added to blood in vitro willprevent clotting for several days. Many authorities, however, do notbelieve that heparin is present in normal circulating blood. During theprocess ofclotting heparin is neutralised by the thrombokinase (or cephaline)from the destroyed platelets." Howell's view of the mechanism of coagula-tion may be summarised thus:

"Prothrombin + calcium ions = thrombin.Prothrombin + calcium ions + heparin = no thrombin.Prothrombin + calcium ions + heparin + cephaline = thrombin.

(neutralise)Thrombin +fibrinogen =fibrin."

Whatever theory be adopted, blood-platelets mustbe present before the phenomenon of blood-coagulationcan occur. They are also intima-tely concerned withthe occurrence of clot-retraction. A study of this phe-nomenon may furnish important diagnostic. informationwith reference to post-arsphenamine blood-dyscrasia.When the platelets are well below the normal number,coagulation may still take place but the clot is soft,friable, and does not retract. Platelets may be greatlyin excess of normal, but if there is a lack of fibrinogen,clot-retraction will be poor. Dearth of platelets alsocauses a prolongation of bleeding-time.

I32



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

Purpuric eruptions, indicative as a rule of thrombo-cytopenia, were recorded as occurring in both treatedand untreated syphilis before the advent of arsphenamine.Prenatal syphilis occasionally gives rise to purpura neo-natorum. I have seen an instance of purpura annularistelangiectodes (Majocchi's disease) in a man suffering fromuntreated tabes dorsalis. Petechial lesions may occurafter the administration of iodides; and mercurialpurpura has also been described. The same condition hasalso been recorded as supervening upon the administra-tion of bismuth. It would appear that syphilis, mercuryand the iodides, in causing purpura act chiefly upon thecapillary endothelium, increasing the permeability ofthese vessels. To a much less degree they may exertsome damaging effect upon the non-cellular elements ofthe blood-coagulation complex-and here, the plateletsare considered to be non-cellular even though it beaccepted that they are derived from megakaryocytes.The influence of the arsphenamines upon -the bone-marrow will be discussed presently, but in the meantimeit may be expedient to refer to certain other etiologicalfactors.

Castex (I924) came to the conclusion that post-arsphenamine purpura was sometimes due to the toxicaction- of the arsenical agent upon the spinal cord.Eliet (I933) described two cases in which serious reactionsfollowed the use of arsphenamine; and he consideredthat the arsenic, because of its elective action on thesympathetic nervous system, was the cause. In reportinga case of nitritoid crisis followed by severe haematemesisand haemoptysis after small doses of neo-arsphenamine,Kosioulas (I933) was of the opinion that this agentcaused a vagus-sympathetic disturbance. Sezary andDuruy (1933) report the case of a woman of haemorrhagicdiathesis (very excessive menstrual flow) who received" 9I4 " and developed purpura with haemorrhage. Treat-ment was stopped and 8 months later she' was givenO-I5 gram of " 9I4 " which produced a nitritoid crisis and4 hours later another attack of purpura with haemorrhage.At this time there was found imperfect clot-formationand clot-retraction. These authors consider that thispurpura was due to a disturbance of the sympatheticnervous system. They quote the case as an example ofso-called "anaphylactic" purpura. It differs from

I33



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BRITISH JOURNAL OF VEREREAL DISEASES

dyscrasic purpura in that it is unaccompanied by seriousblood-changes.

It would seem that sometimes platelet-reduction isbrought about by arsphenamine in the peripheral circula-tion without there occurring any specific toxic action onthe megakaryocytes of the bone-marrow. Rich (I933)described a case of this kind in which, after the adminis-tration of neo-arsphenamine, the patient developedgeneralised purpura with the blood-platelets markedlydiminished in number. He considers that in this casethe destruction of platelets must have taken place peri-pherally because their prompt reappearance in the blood-stream 4 days later rules out the possibility of anydamage having been inflicted upon the bone-marrow.

Nevertheless, the balance of evidence goes to show thatwhile the lesser degrees of blood-dyscrasia-mild andmoderate thrombocytopenia-may be brought about byincreased permeability of the capillaries, by interferencewith thrombin and fibrinogen and by peripheral destruc-tion of platelets, there is probably present in the majorityof cases some damage to the bone-marrow. When thisprogresses sufficiently far, the cellular elements of theblood become involved and the result is that variousdegrees of granulocytopenia are produced.When the number of platelets in the peripheral blood

falls below the critical level of 40,000 per c.cm., purpuraalmost invariably follows. When it occurs with theplatelets well above that level (as in Cases 5, 6 and iiof the present series) some other factor must be operative.The ages of these patients were 52, 49 and 5I yearsrespectively; and this suggests that after the age of,say, 45 years, syphilis plus increasing senescence maytend to give rise to vascular permeability. There may,of course, have been some interference with the blood-coagulation complex also.The etiological factors would seem to fall into two

groups:(I) Where there is a combination of increased vascular

permeability plus a deficiency of prothrombin plus adecreased amount of fibrinogen brought about, severallyand collectively, by syphilis or arsphenamine or both;and

(2) Where damage has been done to the bone-marrowby arsphenamine.

I34



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

In each of the cases in this series where a blood-examination was carried out, there was found to be areduction in the number of platelets. It may, therefore,be permissible to assume that the chief factor in causingpost-arsphenamine blood-dyscrasia is damage to thebone-marrow.The literature on post-arsphenamine blood-dyscrasia

up to the year I932 was reviewed by Loveman (I932)and by McCarthy and Wilson (1932). Their papers havebeen epitomised by Moore (I933), who, as already men-tioned, divides the blood-dyscrasias into four classes.Moore analyses the 70 cases this manner:

TABLE I

Dyscrasia No. of Cases No. of Deaths Death-rate %

Thrombocytopenia . . I2 _Granulocytopenia . . I5 5 33*3Thrombo-granulocytopenia 7 I I4.2Aplastic anamia . . 36 29 8o05

Total . . . . 70 35 50-0

According to the authors mentioned, thrombocytopeniasupervenes immediately or from a few hours to a weekafter an injection of arsphenamine. Granulocytopenia hasa more gradual onset, and symptoms may not appearuntil several weeks after the discontinuance of the drug.Sloughing of the oral and pharyngeal tissues may occurwith an accompanying brawny cedema of the neck(agranulocytic angina). About 30 per cent. of cases ofgranulocytopenia are associated with jaundice or derma-titis. Aplastic ancemia appears between one and thirtydays after the last injection of arsphenamine. Theclinical picture is made up of fever, purpura, bleedingfrom mucous surfaces, necrotic pharyngeal angina, oftenin association with jaundice, dermatitis and extremeprostration.If the cases analysed by Moore are re-grouped

according to the classification I suggest, we have thefollowing:

I35



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


TABLE II

Dyscrasia No. of Cases No. of Deaths Death-rate %

Thrombocytopenia . . I2 _Granulocytopenia . . 58 35 6o.3

Total . . . 70 35 50*O

This Table shows how necessary it is to diagnose andto treat post-arsphenamine blood dyscrasia in the stageof thrombocytopenia, otherwise it may progress toagranulocytosis which has the high death-rate of 6o03per cent.

WHITECHAPEL SERIESIn the literature of syphilis there seems to be general

agreement that injuries to the hoematopoeitic system areuncommon. It has, however, been pointed out byStokes (I934) that this belief would probably requiremodification if periodical blood examinations were doneupon patients showing malaise, pallor, pruritus andpurpura during arsphenamine therapy.

Table III shows the incidence of post-arsphenamineblood dyscrasia at the L.C.C. (Whitechapel) Clinic duringthe four-year period from I934 to I938.

TABLE IIINo. of Cases of

Patients Blood Dyscrasia

Males . 2,I67 7 0o323Females I,o83 6 0.554

Total . 3,250 I3 0-4

The incidence at Whitechapel is much higher than isusual; but even there, this complication is not a commonone. It is, however, important because of the fact that itcauses a long and anxious period of invalidity which fre-quently has a fatal termination. The difference betweenthe incidences for the two sexes is not a significant one.

I36



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

Until ist January, I937, the routine course of treat-ment for syphilis at Whitechapel Clinic extended forI3 weeks. It consisted of two unit-courses of 5 weekseach, separated by an interval of 3 weeks during whichpotassium iodide was given. In each of the unit-courses,there was given on the first day of each 7-day period anintravenous injection of neoarsphenamine and a deepsubcutaneous injection of bismuth oxychloride; on thefourth day of each week sulpharsphenamine was givenalong with bismuth oxychloride. At the end of the I3weeks, there was a rest period of 8 weeks during the last 3of which the patient received potassium iodide. Furthercourses were carried out according to the clinical andserological indications.

Before describing and commenting upon the cases inthis series, it is desirable to have some formula whichwill, in a practical manner, express what may be termed" intensity of therapy." The difficulty in this matter isthat in this series under review, the duration of therapyand the amount of drug given, vary within very widelimits. So it is that in order to make comparisons, it is.necessary to resolve the two factors-total amount ofdrug and time taken to administer that amount-into an" Intensity Index." This has been done by taking thetotal amount in grams, multiplying it by the arbitraryfigure of ioo and dividing the result by the number ofweeks from the first injection to the last.

CASE No. i (A.25I6), MALE, 53, SERO-POSITIVE PRIMARY:Had 3 unit-courses of Neo., Sulph. and Bi. with KI. in intervals.

After 2nd course had pain in upper chest. During 3rd course hadarthritic pain in right shoulder and was " feeling seedy." 4th coursebegun. Had received o030 gram Sulph. and o go gram Bi. when, 4 daysafter last injection, purpuric spots appeared on legs, forearms, face,lower lip and inside left cheek. Next day purpuric spots on tongue.Month later spots practically gone, but on receiving a scratch therewas subcutaneous extravasation of blood. No record of blood picture.Diagnosis: Thrombocytopenia (mild).The total amount of Sulph. plus Neo. given in 32 weeks was

I2-45 grams, giving an Intensity Index of 38-9. No blood examinationwas done but the case may, on clinical grounds and from a considerationof the other cases in the series, be regarded as one of mild thrombo-cytopenia.

CASE No. 2 (B.6582), MALE, 42, SERO-NEGATIVE PRIMARY:Had 2 unit-courses of Neo., Sulph. and Bi. During subsequent

interval while on K1., developed erythematous rash on forearms which

'37



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


was interpreted as an occupational dermatitis. General arthritic pains.3rd unit-course given. KI. in following interval. 4th course begun.After 0o30 gram Sulph., Ehrlich test was positive. Continuation withBi. alone. 2I days after last arsphenamine injection, purpuric rashon feet, ankles and legs. Pains in long bones at shoulders, elbows,knees and ankles. Sodium thiosulphate given. Bone pains becameworse. Bled freely from site of buttock-injections on i6th day afterpurpura appeared. Much bruising. Admitted to hospital on i8th dayof eruption. Blood-picture while in hospital:

On Admission 4th Day 8th Day 12th Day

Erythrocytes . . . 2,000,000 I,6o0,00o 2,200,000 I,300,000Haemoglobin . . . 36% 28% 35% 27%Colour index . . . o g og o-8 ILeucocytes . . . 2,200 2,200 88o 920Platelets . . . I00,000 Very Very Very

scanty scanty scantyPolynuclear neutrophils . 35% 29% 9% 5%

do. eosinophils . 2% o5o Nil NilSmall lymphocytes . . 59% 47 5% 56% 66%Large do. . . J I75% 34% 28%do. hyaline cells . . 3% 55% I% I°%

There was some anisocytosis and poikilocytosis. Soon after admis-sion, temperature rose to I05° F. where it remained. Gums bleeding.Petechix palate and fauces. None on conjunctive. Purpuric spotsall over body. On 7th day, blood transfusion of 650 c.c. On 14th daylarge necrotic sloughs on uvula and fauces. Hxematoma buttock.Gums and tongue oozing blood. Extensive subconjunctival haemor-rhages. Semi-comatose. Respiratory distress. Double incontinence.Blood transfusion of 6oo c.c. Died 2 hours afterwards. The autopsyfindings were broncho-pneumonia, severe anaemia with purpura andlittle iegeneration of bone-marrow. There was reddish-brown marrowin the neck of the femur and in subcortical areas in upper third ofshaft of femur. There were two small flecks in middle third of shaft.Beneath the corticalis of the whole of the shaft of the humerus therewere a few distinct similar reddish-brown areas-these being largerin the upper fourth. Throughout the vertebra, sternum and ribs, redmarrow was present. Free iron was present in the liver and spleenbut not in the kidneys. The spleen was only slightly enlarged, the cutsurface was firm and blackish-purple in colour showing distinctMalpighian bodies.

Diagnosis: Granulocytopenia (severe).

This patient had Sulph. plus Neo. in the amount of 9g20 grams in 36weeks, giving an Intensity Index of 25-5. The dermatitis was possiblya mild arsenical one and not occupational as it was thought to be atthe time.

I38



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

CASE No. 3 (B.I2090), MALE, 58, ENDOSYPHILIS:Neo. omitted from Ist course; Sulph. and Bi. given. Ehrlich

positive. In 2nd course, Sulph. and Bi. only; Ehrlich positive.Defaulted for 9 months. On return stated had had pleurisy. In next6 months had Bi. only. Arthritic pains and prickling of feet. 3 monthsrest. Next course was Sulph. alone. Felt " seedy" for 3-4 hoursafter each dose. Defaulted for 2 months. On return had Sulph. fornearly 4 months. After this, 4 weeks rest and then Bi. for 2 months.Defaulted for 4 months; on return, lumbar puncture. 5 monthsdefault. On return, Stab. for 4 weeks. 58 days after last injectiondeveloped purpuric spots on legs, feet, ankles, thighs and forearms.Arthritic pains, giddiness. Admitted to hospital where blood-picturewas:

On Admission

Erythrocytes . . . . 5,300,000Haemoglobin. . . . . 82%Colour index . . . . 77Leucocytes . . . . . 9,200Platelets . . . . . 50,000Polynuclear neutrophils . . 75%

do. eosinophils. . . I%Small lymphocytes . . . i8%Large do. . . . 2%do. hyaline cells . . . 4%

Diagnosis: Thrombotytopenia (moderate).This man recovered after injections of sodium thiosulphate although

it is doubtful if that agent can be credited with the result. He receivedI3'05 grams of Sulph. and Stab. in i88 weeks, which gives an IntensityIndex of 6-4.

CASE No. 4 (B.I9542), MALE, 41, NEUROSYPHILIS:Had Ist unit-course of Neo., Sulph. and Bi. followed by 3 weeks of

Bi. and KI. 2nd, 3rd, 4th and 5th unit-courses of Sulph. and Neo. Bi.was given in intervals. One day after last arsphenamine injection,purpuric spots on lower abdomen, back and thighs. Sodium thio-sulphate given. In ii days purpura gone. Bi. recommenced. Noblood-report available.Diagnosis: Thrombocytopenia (mild).

This patient had I7'7 grams of Neo. and Sulph. in 48 weeks, whichis equivalent to an Intensity Index of 36-8. He recovered in ii daysafter sodium thiosulphate.

CASE No. 5 (B.22384), MALE, 52, ENDOSYPHILIS:Ist 3 months, Bi. only; then KI. for 4 weeks. Next 2 months had

Sulph. and Bit concurrently. Four weeks rest, then 4 weeks KI. Neo.V.D. XI39



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


for 4 weeks. Two days after last dose, purpuric rash on legs, arms andtongue. Admitted to hospital where blood-picture was:

On Admission

Erythrocytes . . . . 5,200,000Hemoglobin. . . . . 98%Colour index. . . . . 0-94Leucocytes . . . . . 7,200Platelets . . . . . I20,000Polynuclear neutrophils . . 67%

do. eosinophils. . . ISmall lymphocytes . . . 25%Large do. . . . 7%do. hyaline cells

Diagnosis: Thrombocytopenia (moderate).In hospital this case was given calcium lactate, glucose, adrenalin,

and autogenous blood injection. His 3-5 grams of Neo. and Sulph.give an Intensity Index of Io09.

CASE No. 6 (B.268I6), MALE, 49, SERO-NEGATIVE PRIMARY:

Ist course Neo., Sulph. and Bi. for 4 weeks. Defaulted for 4 months.On return stated that 3 months after last dose spots appeared on legsfrom knees down. Jaundice ii days after spots.. When returned toClinic, purpuric spots on feet and legs below knee and on forearms.Admitted to hospital where blood-picture was:

On Admission

Erythrocytes . . . . 4,730,000Haemoglobin. . . . . 93%Colour index . . . . o g8Leucocytes . . . . . 4,900Platelets . . . . . I30,000Polynuclear neutrophils . . 43%

do. eosinophils. . . I%Small lymphocytes . . . 47%Large do. * * . 8.5%do. hyaline cells

Diagnosis: Granulocytopenia (mild)..This man received I.20 grams of Neo. and Sulph. in I2 weeks, the

Intensity Index being io0o. The purpura appeared 77 days after theI40



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

last arsenical injection. His blood-picture is that of a slight leucopenia,moderate thrombocytopenia with some relative lymphocytosis. Inhospital he had It injections of sodium thiosulphate, adrenalin,glucose, liver extract orally and he was put on a fat-free diet. Herecovered in 8 weeks.

CASE No. 7 (B.I5738), MALE, I4, PRENATAL SYPHILIS:

IO weeks Sulph. alone. KI. for 4 weeks. io weeks Sulph. alone.Rest for 8 weeks. KI. for 3 weeks. Sulph. alone for I2 weeks suc-ceeded by KI. for 2 weeks (lodism). Sulph. alone for 4 weeks and then4 weeks of Bi. Rest for 6 weeks. Stovarsol tablets for next 2 years.Stab. for i2 weeks. In week following last injection purpuric spots onlegs. Blood-picture:

On Admission

Erythrocytes . . . . 4,900,000Haemoglobin. . . . . 94%Colour index. . . . . IOLeucocytes . . . . 5,000Platelets . . . . . 254,800Polynuclear neutrophils . . 50.5%

do. eosinophils. . . 2.5%Small lymphocytes . . . 335%Large do. . . . 6.o%do. hyaline cells . . . 7.0%

Mast cells . . . . . 0.5%

Diagnosis: Thrombocytopenia (mild).He received in I64 weeks Io3 grams of Sulph. and Stab. plus

66 grains of Stov. Omitting the Stovarsol, the Intensity Indexis 6-2, and if Stovarsol is included it might be rated as io.This might possibly be an instance of pre-thrombocytopenia, theclinical condition being mainly due to some upset of the non-cellular elements of the blood-coagulation complex-thrombin, etc.He recovered after 4 weeks' treatment by orally given calciumlactatei

CASE No. 8 (A.6559), FEMALE, 2I, PRENATAL SYPHILIS:

Ist course of Sulph. and Bi. Four weeks KI. During 2ndcourse of Sulph. and Bi. Ehrlich test became positive. Twomonths KI. Giddiness and slight nausea. Third course of Sulph.and Bi. One day after last dose, petechiae on each buttock atsites of injections. A few spots over back and chest. Gums spongyand bleeding. Bruising on right shin. Admitted to hospital. Blood-pictures thus:

IC 2I4I



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


On Admission 3rd Day 13th Day

Erythrocytes . . . 4,900,000 4,400,000 5,200,000Hamoglobin . . . 8o% 80% 94%Colour index . . . oo8i 0 90 0 90Leucocytes . . . IO,400 8,8oo I2,600Platelets. . . . Very scanty ? Very scantyPolynuclear neutrophils . 6o% 64.5% 55%

do. eosinophils . 2% I.0% f/Small lymphocytes . . 340/ 2I-0% 25%Large do. . . J 3 50 15%do. hyaline cells . . 4% 8.5% 4%

Diagnosis: Thrombocytopenia (severe).The 6*9 grams of Sulph. which this woman received in 32 weeks gives

an Intensity Index of 2I-8. Before going to hospital she was treatedwith calcium lactate and sodium thiosulphate. There are no notes asto treatment in hospital. She attended the clinic 3 months later,quite recovered.

CASE No. 9 (A.6657), FEMALE, 26, ENDOSYPHILIS:

Began with 4 weeks KI. During Ist unit-course of Neo., Sulph. andBi. the Ehrlich test became positive. Then there were 4 weeks of KI.Another course followed, the same as the Ist; then another 4 weeks ofKI., and a 3rd unit-course of Neo., Sulph. and Bi. This was succeededby 4 weeks of Bi. when, again, the Ehrlich test was positive. KI.followed and then a month of Bi. KI. again for 4 weeks and then aunit-course of Neo., Sulph. and Bi. KI. was then repeated. Therewas then another unit-course of Neo., Sulph. and Bi.; and this wassucceeded by 4 weeks of KI. A Neo., Sulph. and Bi. unit-course wasagain repeated and so was a further 4 weeks of KI. A last unit-courseof Neo., Sulph. and Bi. was given; and 6 days after the last injectionthere was bruising all over the body with purpuric spots on neck,upper chest, forearms and over shins. There were no mouth lesions.Admitted to hospital. No reports available.Diagnosis: Thrombocytopenia (mild).

This woman received 205 grams of Sulph. and Neo. in 72 weeks,the Intensity Index being 28-4.

CASE No. IO (A.68ii), FEMALE, 24, SERO-NEGATrVE PRIMARY:

Ist unit-course, Neo., Sulph. and Bi., followed by 4 weeks KI. In2nd course, same as ist, Ehrlich test became positive. " Hard lumpson legs " lasting a few days. KI. for 2 months, then 3 months of Neo.,Sulph. and Bi. during which Ehrlich test again positive. KI. for next4 weeks; then 3 months of Sulph. and Bi. Rest for 3 months. Finally,4 weeks of Neo., Sulph. and Bi. Day after last dose, petechie on bothlegs and in right antecubital fossa. Bleeding from gums. Admittedto hospital. No blood report available.

I42



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

Diagnosis: Thrombocytopenia (severe).This woman had I4'55 grams of Sulph. and Neo. in 68 weeks, which

gives an Intensity Index of 42-5. She was in hospital for 4 weeks.

CASE No. ii (B.2443), FEMALE, 3I, ENDOSYPHILIS:First course, 4 weeks Sulph. and Bi. In next 4 weeks, Bi. only.

Next 6 weeks, Sulph. alone. 3 days after last dose, profuse purpura onlegs. Much bruising. Bleeding from gums. Admitted to hospital.Blood transfusions on 8th, ioth and 32nd days. Blood-picture:

8th Day 2ist Day

Erythrocytes . . . . . I,940,000 2,700,000Hamoglobin . . . . . 28% 43%Colour index . . . . . .7 o-8Leucocytes . . . . . 8,ooo 4,200Platelets . . . . . . 5,000 ?Polynuclear neutrophils . . . 70% 76%

do. eosinophils . . . I%°%Small lymphocytes . . . . 25%e7%Large do. . . . . 2% 2%do. hyaline cells . . . . 2% 4%

Marked anisocytosis, poikilocytosis and punctate basophila.Diagnosis: Thrombocytopenia (severe) with a secondary anaemia dueto haemorrhage.

This patient received Sulph. only - 5-I grams in I2 weeks, whichgives an Intensity Index of 42-5. She was in hospital for 2 months.

CASE No. I2 (B.4025), FEMALE, 5I, LATE SECONDARY SYPHILIS:Neo. for IO weeks, followed by 7 weeks Bi. In I3th week there was

considerable cedema and redness of right labium majus. Sulph. for IOweeks, then Bi. for 5 weeks. This was followed by 7 weeks of Sulph.A few days after last injection purpuric spots appeared on arms andlegs with scattered areas of bruising. Patient was not hospitalized.Blood-picture:

ist Day

Erythrocytes . . . . 5,1O0,000Haemoglobin. . . . . 70%Colour index. . . . . o-68Leucocytes . . . . . 5,6ooPlatelets . . . . . I93,000Polynuclear neutrophils . . 58-5%

do. eosinophils. . . 4o0%Small lymphocytes . . . 26o0%Large do. . . . 5o0%do. hyaline cells . . . 6.5%

I43



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


Diagnosis: Thrombocytopenia (mild).The i8-6 grams of Sulph. and Stab. received by this woman gives an

Intensity Index of 46-6-the highest in the series. As an out-patientshe was treated with Ametox and Hepol. Although she had the greatestintensity of treatment in the series, she was the mildest case of blood-dyscrasia.

CASE No. I3 (B.5709), FEMALE, 35, PRENATAL SYPHILIS:From Ist October to i8th October, I934, had Sulph. (o09 gram), Neo.

(0.45 gram) and Bi. Fainted after last injection of Sulph. From22nd October to 5th November had Bi., then 3 weeks KI. Bi. from29th November, I934, to 3rd January, I935. Rest with KI. till igthMarch. From then till 23rd April had Bi. KI. for 3 weeks. From.2Ist May to 2Ist June had Bi. Mercurial pills from gth July, 1935,to 2nd April, I936. On 7th May, I936, began weekly doses of Sulph.and Bi. which continued to 28th September, I936. During this periodcomplained of " pains all over body " and not feeling well afterinjections. On 29th September, had swelling and oedema of face. Nonausea, vomiting or dermatitis. Hospital on 30th September witharsphenamine dermatitis. Improved on sodium thiosulphate. Tookown discharge from hospital on 30th October. From 4th December,I936, to 20th March, I937, had Mist. Hydrarg. Iodid. From ioth Aprilto 20th August had Bi. injections. Rest till I5th October, I937, whenbegan Stab. injections weekly till I3th January, I938. Complained ofred patches on skin which " come and go." Bi. from 22nd January to8th February. On I5th February had 0o45 gram Stab. and 2 daysafterwards purpuric patches on lower limbs. Ametox given and by24th February the patches had practically gone.Admitted hospital 26th February on account of (?) uterine fibroid.

Final diagnosis: Microcytic anaemia (?). Early menopausal changes.Severe vaginal haemorrhage. Uterus anteverted. Given Campolon.Blood-picture:

3.3.38

Erythrocytes . . . . 2,790,000Haemoglobin. . . . . 47%Colour index. . . . . o84Leucocytes . . . . . 2,500Platelets . . . . . Not donePolynuclear neutrophils . . 33%

do. eosinophils.Small lymphocytes . . . 67%Large do. .do. hyaline cells . .

Anisocytosis and slight poikilocytosis. Reticulocytes = I%.On ioth March discharged improved. On I3th March returned to

Clinic with bleeding from gums and purpuric patches on feet. Hospital.Slight oozing from gums. Bruising on both feet and right hand. Herblood-pictures after her second admission to hospital were as shown:

I44



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA0a'

H 0

00

H

0 00 '01<en tl-%en 'ICz

00

'00 0

1T.o0 6 H 00

00~~~0 o o

.o 00 0C 0 0

0 ~ ~ ~0 0H

0%090 0 0 ~

*~ 0 "C~ 0T &'

0 0~6 00 0co H

0

00

~~o"26 H ~~~ 00

0~~~~~~~0 ~0 ~~0

.0 0 H 0

0~~~~~0H

0 0~~~~0 t? 0 i) 0 i

t~~)~H 00

000 H tf 0 0000~ t

0

0~~~~

0 00.AR (70 00

0

H

*-j . .4

0 0

0 C.) S"--

'45



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


Here we have a severe granulocytopenia with some of the featuresof aplastic anaemia. The blood-films showed anisocytosis and slightpoikilocytosis.

This case contrasts strongly with the previous one. She received9-45 grams of Sulph., Neo. and Stab. in I56 weeks, which gives anIntensity Index of 6-the lowest in the series.On 29th March there developed purpuric lesions on inside of right

cheek and on right tonsil. The autopsy showed a few petechialhaemorrhages in the skin. Small abscess right jaw. Interstitialkeratitis. Trace fibrinous pleurisy both bases. Numerous petechie inperi- and endocardium. Slight fatty mottling of myocardium. Lungscongested; cedema and collapse at left base. Upper cervical glandswere dark-red. Petechiae in mucosa of stomach. Melanosis of colon.Liver and spleen oedematous and slightly rusty. Anmmia of pancreas.Kidneys showed pelvic hamorrhage, anemia and cedema with a fewsubcapsular petechiwe. Brain anaemic with small subarachnoid hemor-rhages over left Sylvian fissure. Petechiae in cerebellum. Fattymarrow in sternum and vertebra. Clot filling uterus and projectinginto vagina. Haemorrhage round gums. Fat bright yellow. Musclesrather red.

The series of cases consists of 7 men and 6 women.Among the men, the average age was 49-the youngestbeing I4 and the oldest, 58. Among the women, theaverage age was 30-the youngest being 2I and theoldest 5I. Five patients-38 per cent.-were in the acuteor early stage of syphilis, while 7-or 62 per cent.-werein the chronic or late stage. One factor was common toall-sulpharsphenamine. No case of blood-dyscrasiahave I discovered where this agent has been withheld.The prodromal signs in order of frequency were: posi-

tive Ehrlich test, arthralgia, malaise, giddiness, dermatitis,jaundice and bone-pains.The average number of days between the last injecfion

and the occurrence of purpura was 14-the shortestperiod being i day, and the longest 77 days.

There were io cases of thrombocytopenia-5 mild, 2moderate and 3 severe. There were 3 cases of granulo-cytopenia-i mild and 2 severe. The 2 severe cases werefatal. There was no relationship between the amountof drug given, the intensity of arsenical treatment andthe occurrence of blood-dyscrasia. The 2 fatal cases hadrespectively received 9'2 grams in 36 weeks with anIndex of 26, and 9-45 grams in I56 weeks with an Indexof 6*o. The case with the highest Intensity Index of47-Case No. I2-suffered the mildest blood dyscrasia.The average Intensity Index in the series was 33.

I46



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

* ~oIb Z

N.

o IN6100

'0.0 * c& vo o*. o, vo01

. 0 0 0 0 0 0 0 0 |oo0<' ob 6 4 i0O

0~~~~~~~~~~~~~~~~~~~*tOSlAOIS

e - o I o _

OaN o 1009 0? OI&' ' 0 N 0 N 0

*4dInS oo0c $ 0o I on co 0I N N° 00 N00 in1 ,- ;4 %°0No I I

@<~~N1A0) 111a! ii'- li' T-l -I)|paJaAoNa + ++ + ++ + + + + _

PlOwAD I1111 -- I 111^;1 ~~~alelapow -

PUNAS I11 I 111111

alulaPow 1+I 1+I I IIIII|III

HF.Do I Pi'±l!w 1+1 1+ 1+1 1+1stuo;dtuAS pue uo!loaf . N N N N | N 00 F | N|0_

-ul isol uaavtXaq sA)0 Jo *° NO ¢ 11|

| + |++suots+TT I + Il +I+Il +| ++4|.° SUOTS0)'"1U +.I+I+I + + + + ++ 00

IuQ sUoTsal' lun.kL ±1+ +

| s su o!sa)lITe + + | | |

z~~~~~10I0flSUr.I+I_|| suoFso q1nojq +I I I I I I +I|I|+1+I| |+ TCI~ ~~So~~if+iSUI@YnX+1+ + +IIII 1+1+1111+

|| stuoisSuu tX3atlmea l

sured0)ug TT++1 II + + + + N°

suosaSU lnao)q

Iueo;iii +1 1+IF!ema+, 1

Ifi asN!p0.O fl0 I. 1+1I I,IqojIq + I I III ++I~~~~~~~~~~~~~~r.I

_| ssaul~~~~~PP!O | +. .+ T'! +11

qe 1s.lS r I .l= I..d s |_I_I-I_-IiiI'i-I+ _ii- JI,

+i+iIi+i+i+il It +i+ IIII I INI'I +IT I+I + 1 N

I| + 0 |II

0 N * 00 00

*°NNI!i|0No |fo|0 00 000 en C0 00 Na,N

N00¢N N 0

m 0I i0 0 Nm | |

ONSlOiSl NInIWO(Oi010t0100 0010%OINNK-ONsauas~~~~~~~~~N"VN~a

I4711

(A

ce

0

BLOOD-DYSCRASIA

Hm

[os 0AOS+q0eS+1cdr-qdm0000 qeXS snld qdlnS

oaN snld qdlnSauole qdlnS

soloqdAS jo aNaiaNj

xas

-

=1

:1

111- +

aTsr;aa



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


Combining the cases analysed by Moore with the presentseries, we have the following

TABLE VDyscrasia No. of Cases No. of Deatbs Deatb-rate %

Thrombocytopenia . . 20Granulocytopenia . . 6i 36 59

Total . . . . 8i 36 44

Any condition occurring during or after arsphenaminetherapy which has a death-rate of 59 per cent. is obviouslyone which must give the syphilologist furiously to think.

DIscuSSIONAt the Salford Municipal Clinic, where I was Director

for a period of eight years, 2,838 syphilis cases werehandled; but no case of arsphenamine blood dyscrasiawas encountered. There, neo-arsphenamine, sulph-arsphenamine, arsphenamine-diglucoside, bismuth andiodides were all in use, the only difference from the pre-I937 Whitechapel routine being that the arsenical andthe bismuth were not given concurrently. That factalone, however, does not seem sufficient to account forthe absence of post-arsphenamine blood-dyscrasia in theSalford Clinic. On investigating the matter further, twoadditional differences were found: (i) At Whitechapel,suipharsphenamine was given as a routine to every syphilispatient; whereas at Salford it was only used when intra-venous medication was impossible-a very low proportionof cases; and (2) the brand of sulpharsphenamine usedwas different in the two Clinics. Experience at Salfordshowed that in general, sulpharsphenamine was prone tocause dermatitis; and that some brands were, in thatrespect, worse than others. That brand which was foundat Salford to be the least dermatropic, was not the one inroutine use at Whitechapel.

Belding (I924) in 1924 directed attention to the highincidence of dermatitis following the use of sulphar-sphenamine-i6 per cent. of cases. Other workers founda lower incidence but still higher than with neo-arsphen-amine. Schamberg and Wright (I932) mention purpura

148



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

as being the most dreaded complication of sulpharsphen-amine therapy; and they consider that this drug has aparticularly powerful anticoagulating effect upon the blood.

It is necessary to consider some of the chemical factorsinvolved in the problem of post-arsphenamine blood-dyscrasia.Arsphenamine-base has the formula:-

AS AS

/ \

2 \H2N\ /

OH

/ \

I\ /NH2OH

Formula A

Neo-arsphenamine is a formaldehyde-sulphoxylate-sodium (rongalit) derivative of arsphenamine-base andhas the formula:

/ \

2 \H2NO\

OH-Formula B

/ \

\ /NH.CH20 SONa

OH

In this formula it will be seen that only one aminogroup (NH2) -iis closed, the other remaining open.Apparently the French neo-arsphenamine preparationshave both the amino groups closed, for, according toFourneau (I925) they are represented by the formula:

AS- As

/ \

NaOS.O.CH2HN\

OHFormula C

I49

/ \

\ /INH.CH20 SONa

OH



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


This matter of open and closed amino groups has, it issuggested, a considerable bearing upon the sulpharsphen-amines.

In I9I2, under the German patent No. 249,726, therewas registered an organic arsenical compound in whichan amino group of arsphenamine-base was substituted bymethylene-sulphonic acid. This would give the for-mula

As As

/ \

H2N\

OH

/ \

0

( NH.CH20.SONa

OHFormula D

Levy-Bing, Lehnhof-Wyld and Gerbay (I919) in I919introduced " Sulfarsenol," and this was apparentlyidentical with the German preparation just mentioned,for Harrison (1939) gives the above as the formula for it.As will be noted, only one of the amino groups is closed.In the most recent literature, however, issued by themanufacturers of Sulfarsenol (Laboratoires de BiochemieMedicale, Paris; British agents: Modem PharmacalsLtd.) the drug is described as being " the sodium salt ofthe acid sulphurous ether of methylol-amino-arseno-phenol " and the formula is given as:

AS AS

0

NaOS.O.CH2HN\OH

/ \

0/~~~~~~~~1\I 7NH.CH20.SONaOH

Formula E

In the above, both the amino groups are closed. For-mula E is that given in the British Pharmacopoeia forSulpharsphenamine.The difference between Formula D and Formula E is

comparable to that between Formula B and Formula C.I50



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

Formula E is also that given by Voegtlin, Johnson andDyer (I922) for the American sulpharsphenamine. Thereis a great deal of confusion and uncertainty with regardto the true formula of sulpharsphenamine and it wouldseem that Formula E has been adopted by the BritishPharmacopoeia as being a conventional one without anyclaim to strict accuracy, and that many manufacturershave adopted it in the same manner.

"uSlphostab, according to the makers (Boots PureDrug Co. Ltd.) "may be regarded as disodium-dihydroxy-arsenobenzene-dimethylene-bisulphite." They state,however, that work by Dyke and King indicates that thisstructure requires modification, but that for purposes ofcomparison, Sulphostab may be regarded as being repre-sented by Formula E-both amino groups closed.

" Metarsenobillon " is a sulpharsphenamine manufac-tured by Pharmaceutical Specialities (May and Baker)Ltd. They state that the exact composition of theirproduct is unknown, but that there is evidence of it beinga mixture of two, or perhaps three, closely related sub-stances. They think it probable that Metarsenobillon isa mixture of the substance represented by Formula Ewith the following:

As As

0

Na.OS.O.CH2HN\ /

OHFormula F

7/\0

\ NICH2. SONa\CH2O.SONa

OH

Dyke and King considered that the formula for sulph-arsphenamine was:

As/ \

0 NH2

H.SO.O.CH200\ /

OHFormula G

I5I

As0

/ \ OI11NH.CH20.SO.H.

\CO .CH20 .SO. H.H 011OHO



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


but in I935 they, as the result of further work, were of theopinion that commercial sulpharsphenamine conformingto B.P. I932 corresponds approximately to a sodium saltof 3: 3'-diamino-4: 4'-dihydroxy-arsenobenzene-NNN'-trimethylene-sulphurous acid with the formula-

A _Sts

/ \

0

H.SO.O.CH2HN\ /OH

Formula H

/ \

| ) CH20.SO.H\ CH2O.SO.H

OH 01

Another sulpharsphenamine is made by BurroughsWeilcome and Co. and is named " Kharsulpkan." Theformula for this is:

As As

NH2I\O\OH

Formula I

/ \

I\ /NH.SO3NaOH

The sulpharsphenamine put upon the market in thiscountry by Allen and Hanburys Ltd. and manufacturedby the Diarsenol Co. Ltd. of Canada, is stated to berepresented by Formula E. The makers state, however,that there is some difference of opinion as to its correctnessand they therefore prefer to designate the product interms of its manufacturing process, i.e., " a compoundformed by the successive condensation of arsphenamine,formaldehyde and sodium bisulphite."There are, no doubt, various processes of manufacture

of the different brands of sulpharsphenamine, and thismay be the reason why some are more liable than areothers to give rise to dermatitis and blood-dyscrasia. InAmerica, where the incidence of such untoward effectswas so high that in many quarters the use of sulpharsphen-amine was given up, it would appear that the brandswere of the type in which both amino groups were closed.

I52



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

The general impression is also gained that when a neo-arsphenamine of this type is used, more cases of dermatitisoccur. This matter would seem to be worth while investi-gating statistically. All the I3 cases in the present seriesreceived a brand of sulpharsphenamine correspondingto Formula E.From a general survey of the literature and a particular

study of the I3 cases in the present series, the conclusionsarrived at with respect to post-arsphenamine blood-dyscrasia are:

I. Although inorganic arsenic can give rise to blood-dyscrasia, this condition is more apt to occur subsequentto the administration of organic arsenicals, particularlythose belonging to the diphenyl-nucleus group.

2. All sulpharsphenamines are much more prone to giverise to dermatitis and blood-dyscrasia than are arsphena-mine, neo-arsphenamine or arsphenamine-diglucoside.

3. Some brands of sulpharsphenamine appear to bemore potent than others in causing these untoward effects.It is desirable that these particular brands should beidentified so that their use may be discontinued untilsuch time 'as the manufacturers have eliminated theirundesirable qualities.

4. The variation in the toxic effects caused by differentbrands appears to be related to molecular structure andthis, in turn, to process of manufacture. It is eminentlydesirable that a greater degree of standardisation bebrought into this group of remedial agents.

5. A preliminary step towards standardisation is apooling of the British experience in respect of the incidenceof dermatitis and blood-dyscrasia following the use ofdifferent brands. For this purpose a committee ofinquiry might be set up.

6. The appearance of purpuric patches in a patientreceiving any arsenical therapy for syphilis-but par-ticularly a sulpharsphenamine preparation-is an indica-tion for the withdrawal of the drug and for the per-formance of frequent blood examinations with specialreference to platelets and granulocytes.

7. Prodromal signs calling for platelet counts are:positive Ehrlich test, arthritic pains, bone pains, malaise,giddiness, jaundice and dermatitis.

8. Pains at the ends of the long bones would seem toindicate severe bone-marrow damage.

I53



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


9. The, progress of events in these blood dyscrasiaswould appear to be: (a) pre-thrombocytopenia, where onlynon-cellular elements of the blood coagulation complexare affected; (b) thrombocytopenia, as evidenced by theblood-picture but without' clinical signs such1 as mucousor subcutaneous haemorrhages; (c) purpuyra; (d) bleedingfrom mucous surfaces ; (e) bruising; (f ) granulocytopenia;(g) leucopenia; (h) relative lympiocytosis; (i) decrease oferythrocytes; (j) fall in haIsnoglobin; (k) pharyngealsloughing ; (1) death.

IO. It is prudent to have a blood examination carriedout before beginning arsphenamine therapy. Duringtreatment, this should be repeated upon the appearanceof any of the prodromal signs enumerated above.

ii. The occurrence of thrombocytopenia calls for dailyblood examinations after the discontinuance of arsphen-amine.

I2. The occurrence of granulocytopenia calls for hos-pitalisation of the patient and the administration ofnucleotide.

I3. Post-arsphenamine blood-dyscrasia is unrelated todosage but it tends to appear late in the' course of treat-ment.

I4. Its principal cause seems to be the action of thebenzene radical upon the bone-marrow.

I5. It would appear that the platelets in the peri-pheral circulation invariably suffer some damage fromarsphenamine therapy. This may explain the mild casesof thrombocytopenia-the symptoms having too acutean onset to be likely to arise from bone-marrow damage.

i6. When the marrow is attacked, the leucopoieticelements are the first to suffer-the earliest being themegakaryocytes which are the cells from which theplatelets are derived.

I7. As the attack progresses, the erythropoietic ele-ments become involved, leading to a decrease in thenumber of red corpuscles with, in severe cases, someanisocytosis and poikilocytosis.

i8. In severe blood-dyscrasia, the picture tends to beone of an overwhelming infection. Moore and Keidel(192I) have pointed out that these patients are verysusceptible to other infections because the capability ofthe body for producing anti-substances, is largely residentin the bone-marrow.

I54



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

I9. An index as to the progress of the case is to befound in the blood-picture. A progressive decrease of allthe cellular elements with a relative lymphocytosis showsa very grave condition. When there are seen youngpolynuclears and reticulocytes, the prognosis is muchmore favourable.

It may have been noted with regard to some of the I3cases described in this paper, that in many instancesthere is no record of the blood-picture or that it is incom-plete. The explanation is to be found in the fact thatthese were hospitalised where effective contact betweenthem and the clinic could not be maintained. All patientsadmitted to hospital on account of any untoward effectarising from anti-syphilitic therapy, should remain underthe care of the Clinic-in other words, bed-accommoda-tion should be provided at all large V.D. Clinics.

POST-SULPHONAMIDE BLOOD-DYSCRASIAFor a considerable time there have been used at White-

chapel Clinic various sulphonamide preparations in thetreatment of gonorrhoea. So far, no clinical instance ofblood-dyscrasia has been encountered. A large numberof hoematological examinations have, however, beencarried out upon patients receiving these agents; andfrom these, the general impression is gained that wherethere occur such symptoms as malaise, nausea, vomiting,jaundice and cutaneous eruptions, there are frequentlyfound increased capillary fragility, prolongation of coagu-lation-time and bleeding time, and unsatisfactory clot-retraction. Only very rarely, however, if ever, is thereany diminution in the number of blood-platelets.What may-somewhat loosely-be termed the

"mother-substance " of the sulphonamides is "Sul-phanilamide." This is represented by the followingformula:

NH2 Amino group/\ (Class I Substituents)

/ \

\ /SO2NH2 Amide group.

(Class II Substituents)V.D. I55 L



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


Buttle (I939) states that sulphanilamide consists of abenzene ring, to opposite ends of which are attached anamino group and a sulphonamide group as is indicatedabove. From the chemical point of view, the derivativesof sulphanilamide can be divided into: (i) those inwhich the substituents are introduced into the aminogroup, and (2) those in which the substituents are intro-duced into the amide group.

" Prontosil " belongs to Class I and has the formula:

N N

/ \ /\~NH2

\ / \ /SO2NH2 NH2

" Uleron" belongs to Class II and has the formula:

NH2

/ \

/ \/

S02 NH /SO2N(CH3)2\/

" M. & B. 693" also belongs to Class II and has theformula:

NH2

/ \ /

\ /\S02- NH\

NI56



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

" Albucid" is another member of Class II and has theformula:

NH2

/ \

\ /SO2NHOCCH3

All the aforementioned agents have been employed atWhitechapel Clinic.Campbell (I938), in discussing the effect of the sul-

phonamides on the blood-picture, comes to the conclusionthat the bulk of the evidence suggests that blood-dyscrasias are due to individual idiosyncrasy. He alsoconsiders moderate doses have the effect of mildly stimu-lating the bone-marrow.

Marshall and Walzl (I937) consider that the cyanosiswhich sometimes follows sulphonamide therapy is prob-ably due to the formation of a pigment in the body fromthe condensation products of the drug. Sulphaemo-globinaemia is thought to be due to the union of intestinalsulphuretted hydrogen with the haemoglobin. It is to beprevented by the avoidance of saline purgatives con-taining sulphur and by giving a low-residue diet excludingeggs, according to Archer and Discombe (I937) and toPaton and Eaton (I937). From their experiments onanimals receiving sulphonamides, Webb and Kniazuk(I939) came to the conclusion that foreign pigments arisebecause of a disorderly production of compounds relatedto haemoglobin, this being caused by indirect stimulationof the haematopoietic mechanism. Harris and Michel(I939) demonstrated the presence of methaemoglobin inthe blood of 277 out of 467 patients receiving sulphon-amide-roughly 50 per cent. They found that theaverage methaemoglobin-content was directly propor-tional to the concentration of the drug in the blood.These findings agree with those previously published byWendle (1938) and by Campbell and Morgan (1939).Harris and Michel (939) record, however, that the methae-moglobinaemia tends to diminish as the duration oftherapy extends. They observed that it quickly vanishes

I57 L 2



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


when sulphonamide is discontinued; and because of this,they consider that the pigment must be produced byoxidation of the haemoglobin by a derivative of sulphon-amide, and that it is reduced to haemoglobin by thetissues. Its accumulation in the blood, therefore, dependsupon the strength of these two factors. It was shown byHarris (I939) that a methaermoglobin-producing sub-stance is formed in the tissues. He incubated a solutionof sulphonamide with rat-liver and found that it acquiredthe property of changing heemoglobin to methoemoglobin.With regard to these matters, it is-interesting to note theviews of McDonagh (I940) :

t. . . All invaders act alike and in a physical manner upon the host'smain resistance, which resides in what I call the 'protein particles ' inthe plasma. These protein particles are made to undergo first dehydrationand then hydration. In the first, chemico-physical-change-activity, orenergy, is liberated and is responsible for fever. In the second, chemico-physical-change-activity is conserved, and the particles use it for theirown metabolism, instead of conveying it to the cells of the tissues andorgans. The manifestation of disease resulting, and the area of the bodywhere it appears, are regulated by the extent to which the cells are robbedof their power of activity. In this way, the hydrated protein particlesbecome Public Enemy No. i.

" Chemotherapeutic products are but invaders, and the action of themis twofold: to restore the dehydrated protein particles to normal, andto disperse the hydrated protein particles. The first action is effectedthrough so-called positively charged atoms groups, what I refer to asradiating activity to the protein particles; and the second action isthrough so-called negatively charged atoms or groups, attracting activityfrom the protein particles. Invaders act for the most part by attractingactivity from the host's first line of defence. Robbing the protein particlesof activity is reflected upon the red blood corpuscles, and the latter conservetheir energy when the former undergo hydration. This step interfereswith the red blood corpuscles acting as radiators of activity to the proteinparticles-the action I infer the latter to have. Certain of the oxygenatoms in the red blood corpuscles are intimately concerned in the exhibitionof the radiation of activity, and they are prevented from acting in this waywhen the red blood corpuscles undergo hydration. The result of interferingwith the part oxygen plays in the cycle of attracting, storing, and radiatingactivity, is to convert oxyhemoglobin into methamoglobin. Should theprocess extend to the depth of the red blood corpuscles, where sulphurplays the chief role oxygen plays on the surface, sulph-emoglobin isformed. Met- and sulph- hemoglobin are, therefore, merely indicatorsof the extent to which the red blood corpuscles have been called upon tostore their energy instead of attracting and radiating it. Energy is storedWhen the constituents become more firymly ' linked ' together. I use theterm 'linked' because most of the links in Nature areforged out of oxygen."

The Lancet in an annotation (I940) points out thatthere has been considerable difference of opinion as to

I58



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

the eti6logy and prevention of sulphaemoglobinemia.Eggs have been prohibited and a low-residue diet pre-scribed. The egg-theory, however, appears to be basedupon a misconception. While it is true that the bacterialdecomposition of eggs outside the alimentary tract givesrise to sulphuretted hydrogen, yet in normal digestionthe sulphur-containing amino acids are absorbed withvery little sulphide-formation. It has never been shownthat an egg-containing diet promotes the formation ofsulphaemoglobin when the intestine is normal. Theannotation points out that this also applies to other foodscontaining sulphur, many of which-e.g., cheese-containmore than do eggs. Another prohibition which is sound-though not for the usually accepted reason-is that ofEpsom and Glauber salts. These cause sulphoemo-globinaemia, not because the sulphates are reduced tosulphides, but simply because they are purgatives. Pur-gatives of any kind hurry the fluid contents of the smallintestine into the colon; and it is the bacterial decom-position which takes place in these liquid freces while inthe colon which produces the sulphides. Certain drugs-of which phenacetin is one-predispose to the formationof methaemoglobin; and if even small quantities ofsulphides are present, they give rise to sulphaemoglobin.Such drugs, therefore, must not be given along with thesulphonamides. Aspirin, however, is harmless. Whenadministering sulphonamides, purgatives and phenacetinare to be avoided; but the patient should be permittedas normal a mixed diet as his general condition will allow.Hewer (I940) drew attention to the fact that wounded

persons with heavily infected wounds have, as a rule,received massive doses of some sulphonamide prepara-tion. Many reach the operating theatre markedlycyanosed. This condition is due to methemoglobineemiaand it cannot be relieved by inhalations of oxygen. Tocombat this cyanosis, an intravenous injection of 2-o c.c.of a I per cent. solution of methylene-blue has been foundeffective, the cyanosis usually disappearing within I-hours after the injection. He also (I938) previously men-tioned the possibility of an anaesthetic risk from the useof pentothal in patients who have been taking a sul-phonamide agent.

In an interesting paper on " Porphyrinuria followingSulphanilamide," Rimington and Hemmings (I938) con-

I59



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


clude that a certain degree of blood-cell destruction iscaused by this agent, but that the disturbance in pig-ment metabolism is not to be explained by this fact alone.They suspect a more deep-seated effect upon the haemo-poietic system, possibly analogous in some ways to lead-poisoning.A large number of cases have been reported in which

.various *cutaneous eruptions have supervened uponsulphonamide therapy. These appear to be invariablyassociated with blood-dyscrasia. Schlesinger and Mitchell(I938) consider that the steps in a sulphonamide eruptionare: a prodromal fever, sometimes preceded by a tran-sient leucopenia, followed by a morbilliform rash oftenwith splenomegaly. The rash appears in from 5 to I7days after beginning the drug and it lasts from 36 to96 hours. Subsequent secondary leucopenia has beennoted. Later administration of sulphonamide has beenfollowed within a few hours by a scarlatiniform rash withfever and leucocytosis. Persistence with the drug hasresulted in increased capillary fragility and sometimesarthritis. They observed that the passage of time, andincrease of the dose for a short period, decreased orabolished these untoward effects.Hallam (I939) reported a case of severe cutaneous and

general reaction following M. & B. 693 and exposure toultra-violet light. In this instance, the dose of the drugwas a small one and the onset of symptoms occurredvery shortly after a single exposure to the ultra-violetlight. Hallam considers that the patient's skin wasphotosensitised by the sulphonamide and that exposureto the ultra-violet light precipitated the intense generaland cutaneous reaction. Eidinow (I939) comments uponHallam's report. His experiments show that the sul-phonamides are sensitive to light as they are rapidlydecomposed when solutions of them are exposed to ultra-violet rays. He has given to 22 patients receiving sul-phonamide, general ultra-violet irradiation without anyuntoward effect. He suggests that in Hallam's case theerythema reaction produced by the ultra-violet rays mayhave aggravated the toxic symptoms following theadministration of sulphonamide. Such reaction is, hestates, quite independent of exposure to light; and heconsiders that rashes described as light-sensitisation bysulphonamides are not proven. In neither Hallam's nor

i6o



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

Eidinow's communication is there any reference to theblood-picture.

Various other blood-conditions have been attributedto the sulphonamides, but the most important are thosefalling into the category of granulocytopenia. Gompertz(I937) reported a case occurring after i8 days of treat-ment with Prontosil. White cells numbered 300. Therewere no polymorphs, only lymphocytes. Erythrocytesand platelets were normal. In the Medical Annual forI937, Davidson mentions the proneness of amidopyrineto cause granulocytopenia ; and this point is well broughtout by Plum (I937) in his excellent monograph. Prontosilflavum was responsible for a fatal case of granulocyto-penia reported by Borst (I937) and here also the plateletcount was normal. Cases have been reported by manyother workers. An excellent paper on sulphonamidegranulocytopenia is that by Jennings and Southwell-Sanders (I937). Levitt (1940) drew attention to thedanger of granulocytopenia resulting from administeringthe sulphonamides in association with or following X-raytherapy, especially where large areas have been irradiated.A rapidly fatal case of granulocytopenia following smalldosage-4X5 grams of sulphapyridine and 4-5 grams ofsulphanilamide-administered during four days wasrecorded by Spain (1940). In this particular patient therewas., apparently, no idiosyncrasy towards the sulphon-amides. Where such an idiosyncrasy exists, the sensitis-ing dose may be very small indeed; and, as McGrath(4940) points out, once a patient is sensitised, a smallfurther dose (5 grains) might precipitate a fulminatingattack of granulocytopenia. McGrath mentions thedanger of allowing any drugs belonging to this series to besold without control.

" A few tablets taken for a sore throat on casual medical advice, orwithout advice at all, might alternately result in the sensitisation of anumber of persons. . . . There was some indication that metabolism andexcretion might be hindered in some persons, with the result that theconcentration in the blood became unduly high."

It would appear that the sulphonamides do not causethrombocytopenia. All the recorded cases seem to comeinto the category of granulocytopenia, but in most ofthem no actual platelet-count was carried out. In thefatal case reported by Nicol and Freedman (I939), thenumber of platelets as judged from the ordinary stainedfilm was normal. In respect of this apparent maintenance

I6I



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


of the normal platelet-count in cases of post-sulphonamidegranulocytopenia, the suggestion naturally presents itselfthat the mechanism whereby that condition is broughtabout differs from that producing post-arsphenamineblood-dyscrasia. The difference would appear to be thatwhile both sulphonamide and arsphenamine cause upsetof the non-cellular elements of the blood-coagulationcomplex, increased capillary fragility and granulocyto-penia, the former exercises no deleterious effect upon theplatelets. While I do not hazard an opinion as to thereason why this should be, it is, I think, a point whichmust have some bearing not only upon treatment butalso upon the diagnosis of an impending post-sulphon-amide granulocytopenia. I am unable, likewise, to offeran explanation as to why post-arsphenamine blood-dyscrasia is apparently invariably accompanied bythrombocytopenia.

PREVENTION AND TREATMENT OF BLOOD-DYSCRASIAPost-arsphenamine. When the arsphenamines are being

given, prevention depends upon frequent haematologicalexaminations with'special reference to the platelet-count.A count of from 200,000 to ioo,ooo is a warning and callsfor the withdrawal-at least temporarily-of these agents,and for their replacement by bismuthials.When the platelets fall below the " critical level " of

40,000 the patient should be hospitalised, for he isheading for granulocytopenia. Liver extract, ordinaryblood-transfusion and sodium thiosulphate do not seemto be of very much use except where anaemia is marked.Pentose nucleotide is of great value in most instances.This agent is issued in phials as an 8 per cent. solution;and io c.c. of this is given daily by the intramuscularroute until definite improvement is registered. Duringthe first four days of this treatment, the pentose nucleotideis also given intravenously in IOO c.c. doses, by dilutingio c.c. of the solution with distilled water to a strengthof o-8 per cent. An index as to the progress of the caseunder this treatment is to be gleaned from the blood-picture. Where there is a progressive decrease of all thecellular elements accompanied by a relative lympho-cytosis, the outlook is bad. When young polynuclearsand reticulocytes appear, the prognosis is much morehopeful.

I62



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

Several cases of granulocytopenia have been treatedwith extract of yellow bone-marrow. In one patient whofailed to respond to pentose nucleotide, the marrowextract caused the granulocyte count to rise from 3,500to 7,500, the associated angina disappearing in 72 hours.Gorrie (I940).

Transfusions of blood from leukaemic patients havegiven good results in some cases. Pearson (I939) recordsan instance, however, in which this was unsuccessfulalthough the donor's blood contained I20,000 white cellsper c.mm.Adenine sulphate-a degradation product of pentose

nucleotide-has been used successfully in granulocyto-penia; and so also has ascorbic acid.

Irradiation-over the splenic area and splenectomy havebrought about cure in some instances

Vitamin P gave a good result in a case of thrombo-cytopenia reported by Gorrie (I940).

Conclusions(i) Sulpharsphenamine and sulphonamide are dan-

gerous drugs and require most careful handling.(2) The least toxic brand of sulpharsphenamine should

be identified.(3) Sulpharsphenamine should never be given if the

intravenous route is available for the injection of neo-arsphenamine.

(4) The sulphonamides, although of exceedingly highvalue in the treatment of gonorrhoea, have brought tothe handling of that disease a very real element of danger,and it is essential to impress that fact upon those who aretreating cases without having at hand the facilities forfrequent haematological examinations.

(5) Special care is needed in patients suffering fromsyphilis and gonorrhoea when both arsphenamine andsulphonamide are employed.

REFERENCESANNOTATION (I940) Lancet, 1, 97I.ANWYL-DAVIES, T., and MELLANBY, J. (I923) Lancet 2, 555.ARCHER, H. E., and DISCOMBE, G. (I937) Lancet, 2, 432.BELDING, D. L. (I924) Arch. Derm. Syph. N.Y., 9, 470.BORBJLY, F. (I930) Munch. med. Wschr., 77, 886.BORST, J. G. G. (I937) Lancet, 1, I519.

I63



j.com/

Br J V


ownloaded from

http://sti.bmj.com/


BUTTLE, G. A. H. (I939) Brit. Med. J., 2, 269.CAMPBELL, C. M. (I938) Lancet, 1, 247.CAMPBELL, D., and MORGAN, T. N. (1939) Lancet, 2, I23.CASTEX, M. R. (I924) Bull. Acad. Mid. Paris, 91, 259.COPHER, G. H. (I924) J. Missouri State Med. Ass., 21, io6.DICKSON, S. (I935) Medical Annual, p. 47.EIDINOW, W. (I939) Brit. Med. J., 1, 692.ELIET, G. (I933) Rev. fran,. Derm. Venereal., 9, I74.EMANUEL, S. (I933) Derm. Z., 66, 24.EMILE-WEIL, P., and ISCH-WALL (I923) Presse Mid., 31, 657.FLANDIN, C., and TZANCK, A. (I92I) C.R. Soc. Biol. Paris, 84, II7;

(I922) Lancet, 2, II77.FOURNEAU, E. (I925) " Organic Medicaments." J. & A. Churchill,

p. 98.GOMPERTZ, J. L. (I937) Ned. Tydschr. geneesk., 81, 5932.GORRIE, D. R. (1940) Lancet, 1, IOO5.HALLAM, R. (I939) Brit. med. J., 1, 559.HARRIS, J. S. (I939) J. clin. Invest., 18, 52I.HARRIS, J. S., and MICHEL, H. C. (I939) ibid., 18, 507.HARRISON, L. W. (I939) Brit. J. Vener. Dis., 13, I.HEWER, C. L. (1938) Brit. med. J., 1, io68; (1940) ibid., 1, 993.HITTMAIR, A. (I938) Folia Haemat. Leipzig., 59, 50.HORNE, G., and SCARBOROUGH, H. (1940) Lancet, 2, 66.HOWELL, W. H., and DONAHUE, D. D. (I937) J. Exp. Med., 65, I77.JENNINGS, G. H., and SOUTHWELL-SANDER, G. (1937) Lancet, 2, 898.KOSIOULAS, A. (933) Bull. Soc. franc. Derm. Syph., 40, 77I.LEVITT, W. M. (I940) Brit. med. J., 1, 414.LEVY-BING, A., LEHNOF-WYLD, J., and GERBAY, P. (I919) Ann. de Mal.

Ven., 14, 520.LOVEMAN, A. B. (I932) Ann. Int. Med., 5, 1238.MCCARTHY, F. P., and WILSON, R. (1932) J. Amer. Med. Ass., 99, I557.MCDONAGH, J. E. R. (1940) Brit. med. J., 1, 549.MCGRATH, J. (I940) ibid., 1, 947.MACKAY, W. (93I) Quart. J. Med., 24, 285.MARSHALL, E. K., and WALZL, E. M. (937) Bull. Johns Hopk. Hosp.,

61, I40.MOORE, J. E. (933) " Modern Treatment of Syphilis." London, p. 93.MOORE, J. E., and KEIDEL, A. (I92I) Arch. Derm. Syph. N.Y., 4, i69.NICOL, H., and FREEDMAN, B. (1939) Lancet,- 2, 647.OLIVER, J., and DOUGLAS, E. (I923) Arch. Derm. Syph. N.Y., 7, 573.PATON, P. J. P., and EATON, J. C. (937) Lancet, 1, II59.PEACOCK, A. H. (I924) Urol. Cutan. Rev., 27, 5I4.PEARSON, H. E. S. (939) Brit. med. J., 1, I03I.PLUM, P. (937) " Clinical and Experimental Investigations in

Agranulocytosis." London.RICH, M. L. (933) J. Amer. Med. Ass., 101, I223.RIMINGTON, C.. and HEMMINGS, A. W. (I938) Lancet, 1, 770.SCHAMBERG, J. F., and WRIGHT, C. C. (I932) "Treatment of Syphilis."

New York, pp. 304-320.SCHLESINGER, E. R., and MITCHELL, W. L. M. (1938) Amer. J. Dis.

Child., 56, I256.SEZARY, A., and DURUY, A. (I933) Bull. Soc. franc. Derm. Syph., 40, I3I.SPAIN, A. W. (1940) Brit. med. J., 1, 930.

r64



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

BLOOD-DYSCRASIA

STOKES, J. H. (I934) " Modern Clinical Syphilology." Philadelphia,P. 478.

TIDY, H. L. (I926) Lancet, 2, 365.TOCANTINS, L. M. (I938) "Medicine." Baltimore, 17, I55.TROLAND, C. E., and LEE, F. C. (I938) Bull. Johns Hopk. Hosp., 62, 85.TROST, W. (I922) Arch. f. Derm. Syph. Wien., 139, I25.VOECGTLIN, C., JOHNSON, J. M., and DYER, H. A. (I922) Publ. Hlth. Rep.

Wash., 37, 2783.WEBB, T. J., and KNIAZUK, M. (I939) J. Biol. Chem., 128, 5II.WENDLE, W. B. (I938) J. Lab. clin. Med., 24, 96.WHITBY, L. E. H., and BRITTON, C. J. C. (I937) "Disorders of the

Blood." London, p. I05.WRIGHT, J. H. (I906) Boston Med. Surg. J., 154, 643.

I65



j.com/

Br J V


ownloaded from

http://sti.bmj.com/

blood-dyscrasia (i933)blood dyscrasia," andit can be divided into twostages: i....

Documents