Acts ledica, Scandinavics. Yol. CXXIX, hsc. VI, 1948.

Department of Medicine, Kolding Sygehus, Denmark.

Throrribocythemia Hemorrhsgica. BY

OLE MORTENSEN.*

(Sobmitted for publication June 16, 1947.)

Introduction.

Compared with the other formed elements of the blood the thrombocytes are those which have received the least attention and they have not very often been mentioned in literature. Dis- eases with a reduced number of thrombocytes have more often been discussed, while cases with an increased number have been dealt with in very few publications. These conditions will there- fore be examined through a case of excessive thrombocyte in- crease, and a special attempt will be made t o clarify whether or not a thrombocyte increase occurs as an independant disease.

Thrombocytes in General. The thrombocyte is the smallest formed element of the blood

and was first seen by Donne in the year 1844. In size it is about 2-4 my and often disc- or lens-shaped. The volume is 10-12 mys. Giant specimens of 30-40 my are found in pathological conditions and these are often oblong and whip-like in shape. In the centre of the usually pale coloured protoplasm is found often coarse granules. These nucleus-like formations are probably caused by precipitation phenomena, as the granules in the live thrombocyte are fine and evenly distributed in the protoplasm. The greatest number of thrombocytes are found in the arterial blood and the smallest number in the cutaneous blood. They do not leave the blood stream and are therefore not found in lymph

* Aarhns Kommunehospital, Aarhne (Denmark).

548 OLE MORTENSEN.

nor in serous cavities. The total number is said to be 150--500,000 (800,000) per cmm depending on the counting method. There are a little less thrombocytes in women than in men, and in the bone marrow is found a less number than in the blood. A mere glance at the blood films gives quite a good estimation of the number. In a healthy person this changes from day to day, from morning to night, increasing in cold weather and in exer- tions and decreasing at the menses and in the middle of the menstrual cycle.

The origin of the thrombocytes seems to be certain. As first demonstrated by Wright they arise by budding from the proto- plasm of the megacaryocytes. Some authors believe that also the nucleus takes part in the formation, as nucleus substance has been found in the thrombocytes. There does not seem to be any certain relationship between the number of thrombocytes in the blood and the number of megacaryocytes in the bone marrow. The number of megacaryocytes is stated with great variation be- cause of their uneven distribution in the smears. Some authors are satisfied to note if the number has been pathologically al- tered. The survival time of the thrombocytes varies from a few hours to 3-4 days. About 100,000 per day are formed per cmm. The destruction takes place in the reticulo-endothelial tissue, especially in the epleen. The function of the thrombocytes is t o assist coagulation, although their presence is not necessary for this process. The thrombocytes seem to play a more important part in the formation and function of the clot. Thus clots formed by blood without platelets are of a loose consistence, they neither retract well nor do t,hey adhere well to the vessel wall.

Conditions with an Increase in the Number of Thrombocytes.

-4 thrombocyte increase is found in a number of various con- ditions, such as infections, e. 9. tuberculosis, in conditions after operations and fractures, after parturition, in Hodgkin’s disease and in pernicious anemia in remission.

An increase in the number of thrombocytes is also recorded after splenectomy when the number rises probably due both to a decreased destruction of the thrombocytes and to increased production by the bone marrow because of the absence of some inhibitory splenic factor.

THROMBOCYTHEMIA HEMORRHABICA. 549

Of special interest is the increase of thrombocytes in poly- cytemia Vera which has been observed ny numerous authors. The increase in this condition is often very considerable, 2-3 millions. A rise in the number of platelets is also often found in myeloid leukemia.

Finally, thrombocytemia is described as an independent dis- ease, an essential thrombocytemia.

I n literature reference is made to the following cases of this disease.

Beview of Literature. Guglielmo described in 1920 a pathological condition called

Hpiastrinemia)). There was a t the same time an increase in the number of thrombocytes, red and white cells, ))a complete mye- losiso.

Epstein & Kretz and Epstein & Goedel follow a case which first shows signs of polycytemia. Later are found 2.2 mill. plate- lets and prolonged bleeding time, leucocytosis with a few im- mature white cells and up to 23 per cent eosinophils. A post mor- tern examination shows a spleen weighing 7 grammes, cirrhotic kidney, pronounced arterio-sclerosis and many megacaryocytes in the bone marrow. They believe that the missing inhibitory splenic factor is essential for the described syndrom, hemorrhagic thrombocytemia.

Brugsch's patient had after splenectomy 2.5 mill. thrombo- cytes, a typical myeloid blood count with eosinophilia and leukemic infiltrations in the organs. There was no bleeding tendency. They considered it unsettled if thrombocytemia can appear isolated or only associated with leukemia.

Drake's patient had subcutaneous hemorrhages, epistaxis and hematemesis. 2.5 mill. platelets, neutrophile leucocytosis with a few immature white cells and many normoblasts were found. He believes that these cases of pronounced thrombocytemia without immature white cells will prove to be leukemia after sufficiently long observation time.

Uotila finds in his case 5 mill. platelets, pronounced neutrophile leucooytosis, eosinophilia and a few immature white cells. In the bone marrow the number of megacaryocytes is increased. The patient was found to have these symptom, dyspnea, sore tongue and a tendency to bleed. No enlargement of the spleen but arterio-

550 OLE MORTENSEN.

sclerosis and a previous thrombophlebitis. He believes this to be a case of similar kind as that of Epstein and Goedel.

Rowland & Vaizey find in their first patient 1.9 mill. throm- bocytes, a moderate neutrophile leucocytosis with pronounced eosinophilia but no immature cells. Bleeding time is normal but there has been melena and hematemesis for several years. The tongue is red and smooth and there is sore throat, brittle nails and a peculiar skin disease. Their second patient has a total of 1.8 mill. thrombocytes. There is a neutrophile leucocytosis but no eosinophilia. The spleen is enlarged. They call the syndrome primary thrombocytemia and suggest that the cases described are manifestations of a condition of the platelets analogous to that of the white cells in leucemia and of the red cells in poly- cytemia.

Akazaki & Hamaguchi find in a patient with a large spleen 2.7 mill. thrombocytes. There is a tendency to bleed and a mod- erate leucocytosis with a few immature white cells. W. R. is positive. In the bone marrow is found a huge increase in the number of megacaryocytes. A post mortem examination shows a spleen weighing 800 grammes and tuberculosis pulmonum.

Reid's patient has had hematemesis, thrombosis and arterio- sclerosis for several years. The spleen is palpable and there is neutrophile leucocytosis with a few myelocytes. A total of 3.8 mill. thrombocytes of various shapes and sizes. In the bone marrow an increased number of thrombocytes and megacaryo- cytes. The bleeding time is slightly prolonged. Capillary resistance test, coagulation time and prothrombin time are normal. His definition of the disease is: a permanent increase of the thrombo- cytes in the circulating blood, tendency to bleed and thrombosis combined with arterio-sclerosis, prolonged bleeding time, slight leucocytosis, aniso- and poikilocytosis, perhaps anemia. Is not inheritable.

Lachnit's patient has been suffering from hematemesis for many years. The number of thrombocytes was then normal. Un- der the diagnosis of thrombosis of the splenic vein an enlarged spleen was removed without signs of leukemia or cirrhosis. After the splenectomy the thrombocyte number rose to over 1 mill. and there were numerous giant cells in the bone marrow. There were moderate leucocytosis and eosinophilia. Coagulation time and bleeding time were normal.

Petrescu, Olaru & Vereanu describe a case of Bthrombocytemia

THROMBOCYTBEMIA HEMORRHAQICA. 551

or myeloid megacaryocytic leukemia, in a 67 year old patient. At first 11.5 mill. red cells and 12,000 white cells were found. Later the number of red cells fell to 3.2 mill. and 34,000 leucocytes and 1.4 mill. thrombocytes were found. I n the bone marrow a dubious increase in the number of megacaryocytes.

Owren’s patient had been suffering from indigestion for several years. Was treated in hospital in 1937 for ulcus duodeni. At the same time the spleen was found to be enlarged and five years later also an enlarged liver. At this time 1.4 mill. thrombocytes were found, mostly of normal morphology. In the bone marrow 3.8 mill. thrombocytes. Slight leucocytosis in the blood. Bleeding time and coagulation time are normal. Serum iron 60 gamma per cent. The disease is probably related to polycytemia and leukemia and is an unusual manifestation of hyperfunction of the bone marrow.

Leitner mentions three patients with an increase in the number of thrombocytes. A 45 year old man with bronchial cancer and secondary bone growths has 768,000 thrombocytes. A 26 year old man with Boeck-Schaumanns diesase had 876,000 and a 43 year old woman probably with suprarenal hyperfunction had 680,000 thrombocytes. He believes that essential thrombocytemia must be distinguished from 1) megacaryocytic leucosis 2) poly- cytemia and 3) infectious thrombocytemia.

Soderstrom finds in a 63 year old man, admitted with severe nose bleeding, a total of 2.2 mill. thrombocytes, neutrophile leuco- cytosis and 2 per cent myelocytes in the blood. Radiography showed an enlarged spleen.

In the case of Epstein, Kretz & Goedel the small spleen, and the now missing inhibitory splenic factor might probably have aggravated the condition. Brugsch’s patient first had thrombo- cytemia after the splenectomy but a t the same time there were typical signs of a myeloid leukemia. Also in this case the now missing inhibitory factor of the spleen might have aggravated the symptoms. Laohnit’s patient did not get the thrombocyte increase until after the splenectomy. The three patients of Leitner who have only a moderate thrombocyte increase do not seem to be of the same kind as the other cases referred to, as the thrombo- cyte increase seems to be secondary in proportion to the main illness of the patients.

In connexion to the above mentioned cases will be reported the following, which seems to match those by Reid, Drake, Uotila, Rowhind & Vaizey, Akazaki & Hamaguchi, Guglielmo, Omen,

552 OLE MORTENSEN.

Petrescu, Olaru & Vereanu and Soderstrom described cases'. The case of Epstein, Kretz & Goedel seems to be of B similar kind.

Report of Case. A 64 year old builder. Has probably had diphtheria but hardly ever scarlet fever nur

rheumatic fever. Has always been inclined to bleed even from quite small wounds. Has often had severe attacks of nose bleeding, for in- stance, when he was in the army, 20 yeara old. He wag than treated in hospital for ))chronic gastritis)). 47 years old he vomited blood with- out previous gastric symptoms. In periods from the age of 56 has had oppressing pains across the abdomen, getting worse in spring and autumn. Occasional vomiting of acid stomach content. Since the year of 57 pains in the left leg when walking, the pains growing less when a t rest and increasing in cold weather. At one time a feeling of coldness in the left hand. Frequent expectorations of blood-stained mucus.

1st. admission: 2*/4-30/5 1941. Diagnosis: Polycytemia Vera, ulcus duodeni. Clinical examination: Appears rather congested. No distinct pulsa-

tion felt in left radial artery. Some cyanosis of left hand and foot and pains in 1st and 5th toe of right foot. No enlargement of abdominal organs felt. Continual bleeding of the gums. Test meal normal. Radio- graphy of heart, lower arm and lower leg and pelvis showed nothing abnormal and there were no signs of arterio-sclerosis. Radiography of the stomach showed a duodenal ulcer. B. P. 120/80 mm.

Electrocardiogram: left axis deviation. Blood count see table 1. Venesection was performed and the duodenal ulcer was treated

with diet and X-ray treatment of the stomach. 750 r in all was given on three different areas. No dyspepsia when hscharged.

In 1943 hemorrhage for several days after tooth-extraction. 2nd admission. 1/19-84/18 1945. Diagnosis: Chronic myeloid leukemia? Three months previous had black stools for 3 -4 days, after which

the hemoglobin percentage fell from 100 to 42. While the hemoglobin percentage was low there are pains in the left leg. Was treated with liver injections. A few days before the admission the stools were again black. Is tired and indisposed. On admission pale of appearance, no enlargement of the lymph nodes felt apart from bean sized glands in the groins. Liver and spleen not palpable. On admission epistaxis and pains in left leg. Blood in stools. B. P. 170/80 mm.

Sternal marrow composition see table 2. In histologic sections were found excessive hyperplastic marrow flakes, the distribution of which matches the smears. There is a remarkable lively proliferation of megacaryocytes. No focal changes. The result of the marrow investi- gations indicates chronic myeloid leukemia (signed Harald Cormen).

X-ray treatment is therefore given, 4 x 10 r universally, in all. Blood cous2t see table 1.

~ ~~

After thin pa er has been finished, H. Lebel has published L similar case. (Nordisk Medicin f3, 303, 1947.)

TEROMBOCYTHZEMIA IIEMORHHAQICA.

Table 1.

553 - Date

110 7.11 120 8.32

115 7.16

42 2.15 44 2.12 32 35 52 2.69 88 5.53 78 4.90 63 3.79 72 4.41 97 4.85 45 2.56 58 3.05 70 5.32 90 5.39

100 5.05 93 4.93

~ 9.79

125 7.35

- c g 8 !z w

20,920 27,080 24,200

53,600 24,840 23,920 33,120 40,400 43,200 47,800 46,400 33,500 33,800 29,500 25,880 24,200

~ 0.22

Abundant 3.34 3.66 3.66 3.90 6.00 6.00 3.80 3.76 1.53

- - 2 2 z 3 E -

79 97 94

82 89 86 91

91 86

89 93 90 90

aa

-

=

-

17 3

1 4

6 1 4 3 3

1 4 5 4 5 1 9

a 1 2

~

The thrombocytes were counted according to Oluf Thomsen's method.

' h b b 2.

S t e r n a l M a r r o w

Neutrophil segm. nucleus ......................... * rod-shaped nucleus .................... s metamyelocytes ....................... D myelocytes ........................... )) promyelocytes ........................

Eosinophil mature ............................... H not mature ...........................

Lymphocytes .................................... Normoblasts .................................... Erythroblasts polychrom .........................

@ basophil ........................... Megacaryocytes .................................. Reticulum cells .................................. Plasma cells ....................................

7

"1P 45

21 % 9 %

22 % 18 % 10 % 1 % 3 % 3 % 6 % 2 % 2 %

2.5 % increased

0.5 yo

- 46

41 % 5 %

21 % 9 % 5 % 1 % 2 % 3 % 3 % 1 %

2 % 7 %

numerous

Out patient treatment 1946. h e lately had bleeding from the gums. For the first time is found

8 great excess of thrombocytes in the blood films.

554 OLE MORTENSEN.

Since the taking of last blood specimen there has been bleeding for nearly 24 hours from the lobule of the ear.

Sternal marrow: Differential count see table 2. Numerous large masses of thrombocytes. In histologic sections numerous megacaryo- cytes (signed Harald Gormsen).

Long lasting bleeding after tooth-extraction. There is permanently some bleeding of the gums but the patient is feeling fit and is working. Is sunburnt and looks well.

3rd admission. z6/7-14/is 1946. Diagnosis: Thrombocytemia hemorrhagica. Admitted on account of melena and hematemesis. Examination of patient: Appearance in accordance to age. Nutri-

tional condition normal. Pale, but no cyanosis, jaundice nor dyspnea. No glandular enlargement, except for a few bean sized glands in the groins. No abnormal pigmentations nor hyperkeratosis. No subcutane- ous hemorrhages. No hypertrophia of the tonsils. The tongue is smooth but not red. Steth. pulm. nothing abnormal. Steth. cor. frequency is high but otherwise nothing abnormal found. Spleen and liver not pal- pable and there is no abnormal dilation of the superficial abdominal veins. Reflexes of the extremities poor. Pulsation in right radial artery stronger than in left. B. P. 100/30 mm. Radiography: Spleen and liver show a moderate enlargement. Oesophagus: no varices seen. Lower leg show arterio-sclerosis.

During the hospital stay several vomiting attacks and abdominal discomfort. X-ray treatment 4 x 10 r universally given.

Out patient treatment. 28/8 1946. No bleeding of gums nor abdominal pains. Has started working again.

27/1 1947. Apart from a single rather violent attack of bleeding from the gums

the previous month state of health has been perfectly normal. Has managed to work more lately.

The X-ray treatment seems to have been of good effect. Results of blood counts see table 1. During the hole period of investigation the thrombocytes have been normal in appearance, apart from a few which are quite large. Weight during the time of observation 56-58 kilograms. Height 174 om. Temperature normal during all investiga- tions. W. R. negative after repeated tests. Urine: no albumin, sugar nor leuoocytes.

Other laboratory investigations July-September 1946. Blood grouping: 0. Capillary resistance test: -+- petechiae. Prothrombin time normal. Plasma protein: Fibrinogen 0.53 yo.

Albumin 3.8 Yo. Globulin 1.6 yo.

Osmotic resistance: incipient hemolysis 0 .50 % NaCl.

Serum iron: 0.111 mg%. Serum phosphorus: 3.5 mg%.

complete )) O.ao % o

'IHROMBOCYTHEMIA IIEMORRHAGICA. 555

Serum calcium: 10.5 mg%. Takata-ATa: t. Blood urea: 41-56 mg%. Plasma colour (Meulengracht) normal. Urine amylase normal. Uric acid 12.1 mg%. Antistreptolysin titre normal. Acid phosphatase 1 . 7 units.

Epicrisis. A 64 years old man has for the last 40-50 years been inclined

to bleed from even quite small lesions. Has had numerous attacks of severe nose bleeding and several times bematemesis and melena followed by a marked fall in the hemoglobin percentage. During the last few years there have been signs of gastro-duodenitis. Has during later years suffered from claudicatio intermittens, with arterio-sclerosis proved by X-ray investigation.

When 59-60 years old he had polycytemia Vera with 7-9 mill. erythrocytes. Hemoglobin percentage 120. After an attack of melena about three years later there were 2.75 mill. erythro- cytes and the hemoglobin 42 per cent.

In December 1945 the bone marrow investigations indicated a chronic myeloid leukemia wherefore X-ray treatment was given. A total blood count after X-ray treatment shows a large num- ber of thrombocytes, about 3.5 mill. rising to 6 mill. The bone marrow showed a t the same time an increase in the number of megacaryocytes. There are 20--50,000 leucocytes and the dif- ferential count shows all the time a pronounced neutrophile leuco- cytosis. I n periods up to 12 per cent eosinophils. No immature cells found. Bleeding time prolonged as the number of thrombo- cytes increases. Coagulation time is 61/z-12 minutes. Prothrom- bin time normal. No swelling of lymph nodes nor is there clinic- ally proof of an enlargement of either liver or spleen. The con- dition seems to be improved after X-ray treatment.

Is Thrombocytemia a Malignant Hyperplash of the Bone Marrow?

The question now arises if thrombocytemia is an independant disease or just a secondary phenomena found with other diseases. It has already been mentioned that an increase in the number of thrombocytes might be found in various diseases, e. g.

556 OLE MORTENSEN.

Hodgkin’s disease, tuberculosis and after operations. It is of spe- cial interest to notice that there is an increase in leukemia and polycytemia. These two diseases seem closely related, each one is an expression of a malignant hyperplasia of the bone marrow. The relationship is proved by the fact that the two diseases are rarely found in a pure form, when the one is predominant there will often at the same time be found symptoms of the other. Thus in polycytemia is often found leucocytosis and a few im- mature white cells. A typical case of polycytemia might end as a typical case of leukemia and vice versa. I n most described cases of thrombocytemia there is a t the same time signs of polycytemia and leukemia.

There are numerous examples of the various combinations of the three diseases.

Thus Brugsch, Forkner and Minot & Buckman describe leukemia with an increase in the number of thrombocytes. Leu- kemia and polycytemia at the same time is described by Klumpp & Hertig. The development from leukemia to polycytemia has been observed by Meulengracht & Petri, Ghiron and Winter.

Cases of polycytemia with an increase in the number of throm- bocytes are reported by Rosenthal, Dameshek, Fowler, Tiirk, Gutzeit and Petrescu, Olaru & Vereanu.

The development from polycytemia to leukemia has been ob- served by Minot & Buckman and Naegeli. An increase in the number of erythrocytes is seen in the early stages of leukemia (Klumpp & Hertig and Bode & Weber.).

Guglielmo, Forkner and Minot & Buckman report cases of complete myelosis, hyperplastic pan-myelopathia, when all three elements of the bone marrow are increased in number.

A number of cmes where the hyperplasia only affects the me- gacaryocytes have also been described (v. Boros and Dubinskaja). The myeloid megacaryocytic hepato-splenomegalia (&nile-Weil, Chevallier & SBe and Downey & Nordland) should also be men- tioned.

The above described case shows the development from poly- oytemia to a leukemia-like condition which later developes into B thrombocytemia.

Conclusion. The above described close relationship between leukemia, poly-

oytemia Vera and thrombocytemia (and megacaryocyte leukemia)

TBROYBOCYTEEMIA HEYORRHAGICA~ 557

seems to make it probable that these diseases are exactly the same disease with the same unknown etiology. They are different ex- pressions for the same illness.

All the described cases of thrombocyte increase might there- fore be placed under the following groups: 1) Thrombocytemia hemorrhagica - malignant hyperplasia, 2) conditions after splenectomy and 3) secondary, following symptoms in other diseases.

The Symptoms. The symptoms in the described syndrome: bmsential thrombo-

cytemia)), $thrombocytemia hemorrhagica, are thus: A permanently marked increase in the number of thrombocytes in the blood, hemorrhages, an increase in the number of megacaryocytes in the bone marrow, neutrophile leucocytosis in the blood in some cases with eosinophilia, enlargement of the spleen and a few immature white and red cells in the blood. In a number of the cases there is a tendency to the formation of thrombosis and in about half of the cases there is gastro-duodenitis with hematemesis. In all the cases the thrombocytemia is pronounced, over 1 mill.

The tendency to bleed (with prolonged bleeding time, normal coagulation time and normal prothrombin time), which is an out- standing feature in the case here reported and in a number of cases described as thrombocytemia, occurs in other diseases of thrombocyte increase, thus in polycytemia, after splenectomy, in leukemia and also in myeloid megacaryocytic splenomegalia. Dameshek believes that the hemorrhage in polycytemia is due to the strongly dilated vessels, while Minot & Buckman are of the opinion that in leukemia the cause is the altered physical con- dition of the blood because of the many cells. The thrombocytes which in these diseases have been formed in abnormal numbers by an abnormal process may probably not possess the same prop- erties as normal thrombocytes. A further explanation can how- ever not be given at this moment. In the case reported in this paper there has for several years been severe hemorrhages, epi- staxis and hematemesis and the patient has always hemorrhaged for a long time from even quite small wounds - before the blood disease has shown any real symptoms.

Leucocytosis appears in all the caaes described. In the case now published are found up t o 60,000 leucocytes with 80-90 per

8 8 4 7 2 8 7 7 . Acla med. acandinau. Vol. C X X I X .

558 OLE MORTENSEN.

cent neutrophils. This seems to match the case sneutrophile leuke- miao described by Tuohy.

The gastric symptoms might probably be due to the formation -of thrombosis in the stomach vessels caused by the increase in number of thrombocytes, The danger of formation of thrombosis is greater when at the same time there is artaio-sclerosis.

Prognosis. Regarding the prognosis only a few conclusions can be drawn

from literature. Minot & Buckman indicate that a high number of thrombocytes in myeloid leukemia predicts a speedy progress of the disease and that a large increase in number is a threatening and rather serious symptom. If the number of thrombocytes is not decreased by X-ray treatment together with the white blood cells, in leukemia, then the patient will get shorter remissions.

Treatment. If thrombocytemia is regarded as a condition analogous with

leukemia and polycytemia it would be a natural thing to attempt x-ray treatmept also in this case. The numbers of thrombocytes and megacaryocytes have been decreased accordingly, by this treatment (Olef, Minot C Buckman). A similar effect is seen in the case reported in this paper.

Epstein & &eta have without effect treated with spleen ex- tractions assuming that the thrombocytemia is due to the ab- sence of the inhibitory splenic factor.

Summary. The author reports a case of thrombocytemia in a 64 year old

man. He has earlier had symptoms of polycytemia Vera which has later been followed by a leukemia-like condition. At the same time as there is a tendency to bleed 6 mill. thrombocytes in the blood per cmm are found. Coagulation time and prothrombin time are normal. There is a marked neutrophile leucocytosis, in periods with eosinophilia. There are signs of gastroduodenitis as in a number of the cases earlier described. Similar cases from the literature are discussed. The syndrome is regarded a8 a malignant hyperfunction of the bone marrow of the same type as myeloid leukemia and polycytemia Vera.

TEROMBOCPTElEMIA BEMORRHAGICA. 559

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