RUSSELL L. HADEN, M.D. Plycythemia vera is characterized by an increase in the number f red bld cells. This disease is insidius in rigin, chrnic, and withut pathgnmnic symptms r physical findings. Early in the disease and in mild cases there may be n detectable abnrmality n physical examinatin. In well advanced cases the spleen usually is enlarged, the mucus membranes are injected, and the patient is cyantic r rather a raspberry-red clr. The enlargement f the spleen results frm the excess strage f red cells; the injectin and cyansis depend n the slwed circulatry rate resulting frm the high viscsity f the bld. On physical examinatin r labratry study, the ne cnstant finding in plycythemia vera is the high red cell cunt. In erythrcytsis the erythrcyte cunt is high als. Here, hwever, the ttal bld vlume is nt increased. In plycythemia vera the ttal bld vlume as well as the red cell cunt is cnstantly high. This increase ccurs in symptmatic plycythemia vera as well as in the idipathic type. The determinatin f the bld vlume thus becmes a valuable aid in differentiating erythrcytsis and plycythemia vera. The increase in bld vlume is due entirely t the increase in the red cells s the mst valuable indicatr f the increase is the red cell mass per kilgram f bdy weight 1. The mean mass f red cells in nrmal men is 30 cc. and in wmen 26.4 cc. per kilgram. While this figure is nt increased in erythrcytsis, althugh the red cell cunt may be high, it is always increased in plycythemia vera and may be increased even t five times its nrmal vlume. A classificatin f plycythemia with the mre imprtant causes fr the high red cell cunt is given in Table 1. In ur labratry the bld TABLE 1 CLASSIFICATION OF POLYCYTHEMIA I. Erythrcytsis (secndary r simple plycythemia) Increase in number f erythrcytes withut increase in red cell mass per kilgram II. Plycythemia vera r erythremia Increase in number f erythrcytes with increase in red cell mass per kilgram A. Symptmatic plycythemia vera due t 1. Lw barmetric pressure 2. Impaired xygenatin in lungs frm: a. Bypassing f lungs in cngenital heart disease b. Decreased aerating surface by lung disease 3. Impaired capacity f hemglbin t carry xygen as in methemglbinemia B. Idipathic plycythemia vera frm unknwn cause 166
vlume is determined by the methd f Rwntree, Brwn and Rth 2. The ttal red cell mass is calculated frm the hematcrit reading and the ttal bld vlume. Erythrcytsis is simply treated by an ccasinal venesectin r may need n treatment at all. In plycythemia vera, hwever, treatment is always required since the symptms f headache, dizziness, and weakness depend upn the high viscsity which can be lwered nly by decreasing the number f red cells. The vascular symptms can be helped nly by remving the excess f cells. Plycythemia vera has been treated bth frm the standpint f destrying the excess cells and frm preventing the frmatin f the excess. Acetylphenylhydrazine is the drug f chice in destrying the excess cells. It is less txic than phenylhydrazine and less txic than benzl which als has been used. Patients vary greatly in the sensitivity t the drug, bth frm the standpint f txic effect and hemlytic actin. Sme patients can take large amunts with little destructin f cells; thers will develp a skin rash, fever, nausea, vmiting, and liver disturbances frm small dses. With such a great variatin in effect, the use f the drug is very unsatisfactry in mst cases. If the drug is effective, the red cells may be destryed at a very rapid rate s the amunt f bld destructin cannt be cntrlled. The bne marrw usually respnds rapidly t such a hemlytic anemia with a high reticulcyte cunt, which indicates rapid red cell regeneratin. All the materials, especially irn, needed fr red cell frmatin are still present s the new cells are frmed rapidly. In an ccasinal patient the drug will have just the desired effect s the level f red cells is well cntrlled. Thus ne patient treated himself satisfactrily fr ver ten years with small dses, using the clr f his nse as the criterin fr dsage. With the hemlytic anemia prduced by acetylphenylhydrazine, the cells are larger than nrmal s the red cell mass which is primarily treated is larger than nrmal fr the number f cells instead f smaller as in an irn deficiency anemia. If acetylphenylhydrazine is t be tried, 0.1 gram is given daily fr ten days unless cntraindicatins arise. The hemlysis may cntinue after the drug is withdrawn s if daily cunts shw evidence f rapid cell destructin, the drug shuld be discntinued at nce. It is desirable t wrk ut a regular dsage after the initial curse. One dse f 0.1 gram weekly may be sufficient. Irradiatin f the spleen and lng bnes has been emplyed ften. In the patients we have treated and in cases bserved s treated elsewhere, there has been little beneficial effect frm such treatment. Irradiatin may have sme place as an adjunct in treatment. It is valuable when the spleen is very large frm cincidental myelid hyperplasia. The mst satisfactry methd f treatment is venesectin. If sufficient 167
RUSSELL L. HADEN bld is remved, an irn deficiency is prduced, thus preventing the frmatin f cells. With an irn deficiency, the cells decrease in vlume s the red cell mass is small fr the number f cells instead f large as with a hemlytic anemia due t acetylphenylhydrazine. All patients respnd t this methd f treatment and all txic reactins are avided. In treatment by venesectin, it is mst imprtant t remve a sufficient quantity f bld. The excess f red cells shuld be cmpletely remved if n cntraindicatins arise. In this way the regeneratin f cells will be very slw. It is very pr therapy t remve nly small prtins at a time. This may even stimulate bld frmatin rather than retard it. The ttal red cell mass is calculated first frm the ttal bld vlume and the hematcrit reading. Knwing the nrmal red cell mass fr the patient, it is easy t calculate the amunt f bld t be remved. An illustrative calculatin is as fllws: Male patient weight 70 Kg. The hematcrit reading shws 60 cc. f cells per 100 cc. f bld and the ttal bld vlume is 8,000 cc. Red cell mass = 8,000 X 60 = 4,800 cc. Nrmal fr patient = 70 X 30 = 2,100 cc. Excess cells 2,700 cc. As bld is withdrawn, the hematcrit reading will fall t the nrmal value f 45 cc. The mean will be abut 52 cc. The amunt f whle 2,700 bld t be remved is X 100 5,200 cc. As the bld is withdrawn, a balance sheet is kept t determine the exact result f the treatment (Table 2). If the red cell mass is exceedingly high, it may nt be pssible t reduce the red cell mass t nrmal during the first curse f treatment. This ne patient recently had a red cell mass f 9,096 cc. when the nrmal fr his weight was 2,100 cc. Nearly 7,000 cc. f bld was remved during a week and the red cell mass was still almst twice t high. This was reduced t nrmal by mre venesectins later. After the red cell mass is reduced t nrmal by venesectin, the regeneratin f bld is very slw, seemingly due t the irn deficiency. Patients vary in the rate f regeneratin but usually venesectins are required nly at intervals f six t twelve mnths. The mean cell vlume remains lw due t the irn deficiency (Table 3). All patients in ur series are nw being treated by venesectin. If the spleen is very large and the leukcyte cunt high, especially if myelcytes appear, irradiatin f the spleen and marrw is utilized als. An ccasinal patient is taking sme acetylphenylhydrazine where this treatment has been fund satisfactry and n txic effects have develped. The effect f the bleeding n the bld findings is shwn in Table 3. A detailed histry f ne patient bserved fr the past twelve years illustrates the many phases f idipathic plycythemia vera, the chrnic curse, and the respnse t treatment. 168
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RUSSELL L. HADEN CASE REPORT Case 1: This patient, a merchant thirty-seven years f age, was first seen in 1928, cmplaining f pain in the right ft which had been present fr three mnths. The tes became red and painful but were nt swllen. He had tried varius measures such as arch supprts withut relief. The general examinatin was negative and n definite cause fr the symptms was fund. At that time the red cell cunt was recrded as 4,780,000 and the hemglbin as 85 per cent. The leukcyte cunt, hwever, was 16,300. N explanatin fr the leukcytsis was given. It is evident that this was due t plycythemia in view f the later develpments. The patient was nt seen again until 1934, when he returned cmplaining f pain and swelling f the middle te f bth feet. Three weeks befre admissin blisters had appeared n the right middle te. The ft became swllen and red. The te was incised but n pus was btained. He was nw having similar symptms n the same te f the left ft. The tes were painful. He had large varicse veins. In an rthpedic examinatin it was nted that bth feet were livid and that a fungus infectin was present. The clinical diagnsis was vascular disease f bth feet and epidermphytsis. The spleen was nt palpable. A bld cunt nw, hwever, shwed 6,290,000 red cells and 117 per cent hemglbin. The leukcytsis bserved six years previusly was still present (white bld cunt 12,600). A bld vlume study tw weeks later shwed 56 cc. f red cells per kilgram f bdy weight, (Nrmal, 30 cc.). The red cell cunt was nw 7,100,000. The administratin f acetylphenylhydrazine was begun and a ttal f 2 gm. f the drug in 0.1 gm. dses was taken. The patient returned ne week later cmplaining f retrsternal discmfrt, burning in the epigastrium, and fd distress. The icterus index was 10 units, the leukcyte cunt 16,800, and the red cell cunt was abut the same. Three weeks later the cngestin f the cnjunctiva previusly nted and the pain in the feet had decreased. The red cell cunt had fallen t 4,730,000 and the hemglbin t 81 per cent. The leukcyte cunt was 18,600. The reticulcyte cunt was 3.5 per cent, indicating a rapid regeneratin f cells. Tw weeks later the bld cunt was much the same and the red cell mass was 28 cc. Tw mnths later the red cell cunt and cell mass were again high s acetylphenylhydrazine was again given. This time the medicatin was nt well tlerated and the patient develped fever, chills, and vmiting. The medicine was discntinued. The patient was nt bserved again until ten mnths later when the red cell cunt was 6,950,000, the hemglbin was 111 per cent, and the white cunt was 19,100. The ttal red cell mass was 50 cc. The use f acetylphenylhydrazine was advised but was nt taken because f the previus experience with unpleasant reactins. Fifteen mnths later the patient began t feel dull, listless, and dizzy. He had had a marked redness f ne eye fr the preceding week. The red cell cunt was nw 7,010,000, the hemglbin 111 per cent, and the ttal red cell mass 55 cc. per Kg. The patient was next seen tw mnths later at his hme with his lcal physician. He stated that fllwing a single dse (0.1 gm.) f acetylphenylhydrazine, fever, jaundice, and malaise develped. The leukcyte cunt was 18,000. There was tenderness ver the gall bladder; the cnjunctivae were icteric. An acute chlecystitis was suspected and peratin was advised. On examinatin there was marked cngestin f the cnjunctivae and the lips were livid. The viscsity was 9.2 units. The findings suggested that the symptms were secndary t the 170
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RUSSELL L. HADEN high viscsity. The red cell cunt was 6,750,000. Fllwing venesectin and the use f physilgic sdium chlride slutin intravenusly all the symptms cleared up quickly. It was evident that this patient shuld be given n mre acetylphenylhydrazine s bleeding was cntinued. Several venesectins were dne during the next six mnths. During the past tw years venesectin has been dne mre frequently. One year ag fur venesectins were dne t bring the bld t a nrmal level as fllws : Ttal red cell mass befre treatment Cells remved first venesectin Cells remved secnd venesectin Cells remved third venesectin Cells remved furth venesectin 348 cc. 280 cc. 270 cc. 260 cc. 3,838 cc. Ttal red cell mass after treatment Ttal remved 1,158 cc. 2,733 cc. Difference 1,105 cc. During the next eleven mnths, nly 1,200 cc. f bld were remved. A bld study at this time shwed a ttal red cell mass f nly 52 cc. The cnjunctivae were again injected. The spleen still was nt palpable. The patient was having few symptms. The red cell cunt was 7,920,000 and the white cell cunt was 17,650. The patient was again bled as fllws: Ttal cell vlume befre bleeding 4,062 cc. Cells remved- first venesectin 482 cc. Cells remved secnd venesectin 482 cc. Cells remved third venesectin 450 cc. Cells remved furth venesectin 384 cc. Ttal cell vlume after bleeding Ttal remved 1,798 cc. 2,204 cc. Difference 1,858 cc. The actual number f cc. f cells remved (1,798 cc.) checks clsely with the calculated amunt (1,858 cc.). The red cell mass was nw nrmal. Bleeding prbably will nt be necessary again fr several mnths. The red cell mass in relatin t treatment is shwn in figure 1. Cmment: This patient is free f symptms since the last treatment. He is very interesting and illustrates the chrnic curse f the disease and gd cntrl in bleeding. The leukcytsis and vascular disease were the first manifestatins f any abnrmality. The nature f the disease was nt recgnized early in its curse. He was very sensitive t acetylphenylhydrazine as shwn by the severe txic symptms with small dses and the exaggerated hemlytic respnse t the drug. The spleen 172
has never heen palpable. The disease, when prperly treated, has nt interfered with nrmal activity. The vascular symptms have nt prgressed. l/ld/39 2/2/39 5/H/U 7/JI/39 H/6/J9 FIGURE 1: (Case 1): The red cell mass per Kg. f patient reprted. Nte the large mass befre treatment. This fell t a pint belw nrmal with the administratin f acetylphenylhydrazine but quickly rse again. The increase after venesectin is very slw. REFERENCES 1. Haden, R. L.: The red cell mass in plycythemia in relatin t diagnsis and treatment, Am. J. M. Sc., 196:493-502, (Octber) 1938. 2. Rwntree, I.. G., Brwn, S. E., and Rth, S. M.: The Value f the Bld and Plasma in Health and Disease, W. B. Saunders C.. Philadelphia. 1929. 173