FROM T H E OPHTHALMIC CLINIC, U N I V E R S I T Y OF HELSINGFORS. HEAD: P R O F E S S O R M A U N O V A N N A S

FUNDUS CHANGES IN CONSTITUTIONAL THROMBOPATHY (v. WILLEBRAND-JtllRGENS DISEASE)

By Henr ik Forsius.')

In 1916 u. Willebrand (18) discovered on the Aland ar- chipelago in Finland a family suffering from a hemorrhagic diathesis which could not be hemophilia as it affected both males and females. The disease was later on called Constitu- tional Thrombopathy or v. Willebrand-Jiirgens Disease. In 1932 v. Willebrand, Jiirgens and Dahlberg (16, 1 7 ) examined on Aland 18 persons belonging to two separate families. The type of inheritance was investigated by Federley.

Periodical hemorrhages mainly occurring from the mucous membranes are the characteristic features of constitutional thrombopathy. The patients suffer specially from severe nose bleeding. Cases of death following bleeding have occurred, e. g. after tooth extractions, cuts, enterohemorrhages, during men- struation and delivery. Joint bleedings are rare as distinguish- ed from hemophilia. Laboratory examinations show a pro- longed bleeding time in spite of normal platelet count, normal coagulation time, often a positive Rumpel-Leede sign etc.

Constitutional thrombopathy is next related to Morbus Maculosus Werlhofii and other purpura diseases. Morbus Werlhofii is seldom hereditary. In addition to this the pre- dilection spots differ from each other. Wound bleeding are rare in Morbus Werlhofii. The platelet count is low in the latter disease. The coagulation time is prolongefl in hemo- philia, on the other hand the bleeding time is normal. The type

' f Received April lst, 1951.

348

of interitance in hemophilia is sex-linked recessive. Only males are affected almost without any exceptions. Pseudohemophilia is a diagnosis often seen in the American literature. It is a common name for v. Willebrand-Jiirgens disease, Glanz- mann’s thrombastheny (6) and perhaps in addition to these for some still undifferentiated diseases. Thrombastheny and constitutional thrombopathy are differentiated by the clot retraction, it is good in the latter one but poor in the former one.

In 1949 and 1950 Jiirgens and Forsius undertook new in- vestigations of the families suffering from hemorrhagic dia- thesis on Aland. Two new families were discovered. The two previously examined ones had common distant ancestors. One of the newly discovered families had ancestors from the same islands as the first two family groups. Anyhow no relationship could be proved to exist between them.

Informations were obtained about 286 persons belonging to 4 separate family groups. 73 of them were affected by con- stitutional thrombopathy. 14 of them had died of bleeding. 26 of those still living on Aland had hemorrhages every now and then. All of them were examined in 1949. 6 of the most severe cases were re-examined in August 1950.

The most important results from the investigations can be seen in Table 1. In addition I would like to mention that enlargement of the spleen was found in one case. Owren’s Factor V ( l o ) was present. Another paper will give a report of the medical findings and laboratory examinations and of the type of inheritance.

One of us (Forsius) has examined systematically the eyes of the 26 patients.

All of them had a good visual aquity and were emmetropic or slightly hypermetropic. One of them had a divergent squint. The two oldest patients had an incipient peripheral cataract. Retinal hemorrhages were found in 4 cases.

1) Mrs. S., age 69 years. RR 190 mm Hg. Slight Gunn’s signs were seen ophthalmoscopically. An oval hemorrhage could be seen in the right eye a t the end of a small artery. A few pigmented spots were found a t the periphery. Because of the hypertension the etiology of the retinal hemorrhages is doubtful.

Tabl

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No

350

2) Mrs. J., age 34 years. Daughter of the previous patient. 5 of her sisters had died of bleeding. She herself was suffering from a n in- creasing tendency to bleeding. She had been nearly bleeding to death in her last delivery. Her life was saved by a blood transfusion. RR 125 mm Hg. Right eye: no abnormality. Left eye: An oval sharply defined hemorrhage about the length of the disc could be seen me- dially above the disc. It was situated in the nerve-fibre layer. In the re-examination ten days later only rests of the hemorrhage could be seen and a small haziness showed its place.

3) Mrs. G., age 60 years. R R 1351100 mm Hg. Ophthalmoscopically a diffuse hemorrhage with a somewhat hazy area around it could be seen in the right eye close to the disc in the neighbourhood of a crossing between an artery and a vein. (A hemorrhage in the stage of resorption).

4) E. G., a boy age 10 years. Right eye: no abnormality. Some pigmented areas and a small hemorrhage on the disc could be seen in the left fundus.

The hemorrhages were all situated relatively superficially in the retina and were rather small. They all were near the disc. The general tendency to bleeding in these patients was not greater than in the rest of the 26 examined ones. Neither was the fragility of the blood vessels increased. The first two cases showed a slightly positive Rumpel-Leede phenomenon, in the two latter cases it was negative. A farmer, age 50 years, had previously had a subconjunctival hemorrhage, a t the pre- sent time he showed no sign of hemorrhagic diathesis.

I have gone through the literature concerning hemorrhagic diathesis with a prolonged bleeding time and I have made a note of their reports on the ophthalmoscopical findings and hemorrhages occurring in the eye or close to it. It is surprising to notice how few ophthalmological examinations were men- tioned. Evidently no systematic investigations concerning fa- milies suffering from this type of hemOrrhagic diathesis a r e made. The laboratory examinations have very often been in- sufficient and it is impossible even to make a definite dia- gnosis. This applies specially to the older publications. I have found retinal hemorrhages in pseudohemophilia mentioned in 6 publications (Hutchinson 1885 ( 3 ) , Kromeke 1922 ( 8 ) , C i f - fin 1928 (51, Little & Ayres 1928 ( l l ) , Frank 1922, (121, Evans & Mac Laren 1945 (20) ). Little & Ayres (11 ) mentioned a large family suffering from hemorrhagic diathesis. Both

35 I

males an females were affected. 2 of them where blind as a result from retinal hemoirhages. 2 of them where examined in a hospital. One of them a 13-year-old boy got in his right eye an extensive retinal hemorrhage which caused almost total blindness. His spleen was easy to palpate. The coagulation time was 4-6 minutes, the bleeding time varied between 30 and 120 minutes. The retractibility of the blood clot was not in- vestigated. The patient died after splenectomy. Evans & Mac Laren (20) examined a Greek soldier 1945. Following intra- ocular hemorrhages. he had been blind for a year a t the age of 14. At the time of the examination he was suffering from severe nose bleeding. The platelet count was 135000, Duke 2 min. The bleeding time was up to 2 hours. 18 of the 44 family members born alive had died of bleeding. A brother and a sister of the patient had evidently had similar intraocular hemorrhages.

8 investigators have mentioned subconjunctival hemor- rhages, Bailey & Alpin (71, Glanzmann ( 6 ) , Kromeke (81, Hutchinson (3) , Frank (12), Hess (131, Fonio (22) and Car- penter. & Allen (9) .

Constitutional thrombopathy may be difficult to diagnose and apparently contradictory reports are common in the li- terature. The result has been that many authors readily clas- sify all the hereditary thrombopathies with prolonged bleeding time in the same group. Many authors (15, 21, 14) deny the difference between constitutional thrombopathy and Glanz- mann’s thrombastheny. Advanced methods of examination will surely throw new light on these diseases. Perhaps the .fundus examinations will be of use in the differential dia- gnoses. On the cases found in the literature probably only the families published by Little & Ayres and Evans & Mac Laren are cases of constitutional thrombopathy ; but not quite surely, because investigations are insufficient in both of them. In no publication are systematic ophthalmological examina- tions on the members of the affected families reported.

Hemorrhages on the lids and in the conjunctiva occur often in hemophilia. Hemorrhages from the iris occur less frequent. ( Werner-Adlercreutz) (4) Retinal hemorrhages are extremely rare. The diagnosis in these cases is uncertain because the

352

investigations are made long ago. Hemorrhages on the lids occur in essential thrombopenia, and comparatively often even in the retina. They are generally small and superficial and are located in the neighbourhood of the disc. Consequently they resemble the hemorrhages I have seen in cases of constitu- tional thrombopathy. Only one of my patients told about sug- gillations in the conjunctiva. Retinal hemorrhages are ex- tremely rare in scurvy.

Small retinal hemorrhages seem to be rather common in constitutional thrombopathy, as so many cases were found in only one examination. In one case I have been able to notice that the hemorrhages were resorbed quickly.

Summary. Constitutional thrombopathy is a hemorrhagic diathesis

with a prolonged bleeding time. (Pseudohemophilia). The disease is familial and affects both males and females. The author describes in this paper his ophthalmological findings during a hematological expedition he made together with Jiir- gens to Aland islands in Finland. The eyes of 26 patients be- longing to 4 separate families suffering from hemorrhagic diathesis were examined.

4 of them showed retinal hemorrhages. The. hemorrhages were situated in the nerve-fibre layer, they were small and were resorbed quickly. No reports on previous systematic fundus examinations in constitutional thrombopathy were found in literature. The differential diagnostic value of the retinal hemorrhages with regard to hemophilia etc. is dis- cussed.

LITERATURE 1) Hirschberg: Arch. f. Aughk. 8: 174: 1879. 2) Bramwell: Edington M. Journ. 32: 101: 1886. 3) H u ~ c h ~ ~ ~ o n , 2.: The Pedigree of Disease 101: 1885, New York, ref.

Rothman, P. F. and Nixon, N. K. J. A. M. A. 93: 15: 1929. 4) W e r n e r , S. and Adlercreutz: Finska lakares. handl. 883: 78: 1931. 5) Giff in , H . Z.: Am. J. M. Sci. 175: 44: 1928. 6) Glan-mann , E.: Jahrb. f. Kinderheilk. 83: 271: 1916. 88: 1: 113: 1918.

7) Bailey, F. R. and Alpin, K . B.: Am. J. Med. Sci. 190: 263: 1935. 8) Kromeke, F.: Deutsche Med. Wchnschr. 48: 1102: 1922. 9) Carpenter, G . and Al lev , J . G.: Am. J. MecI. Sci. 220: 655: 1942.

10) Owren, P . A.: Acta Med. Scand. 1947 supplem. 11) Litt le, W. D. and Ayres, W. W.: J. A. M. A. 1251: 91: 1928. 12) F r a n k , E.: Ergebnisse der gesamten Medizin I11 171: 1922. 13) Hess, A. F.: Arch. Internat. Med. 17: 203: 1916. 14) lmers lund , Olgu: Nord. Med. 42: 1191: 1949. 15) Mac Farlane: Quart. J. Med. 10: 1: 1941. 16) v. Willebrand, R. Jiirgens and U l f Dahlberg: Finska lakares.

17) D. Willebrand and Jiirgens, R.: Klin. Wchnschr. 414: 1933. 18) v. Wil lebrand: Finska lakares. handl. 87: 68: 1926. 19) Bailey, F. R. and Alpin, K . B.: Am. J. Med. Sci. 190: 263: 1935. 20) Evans and M a c Luren: Lancet. b. 24912: 175: 1945. 21) Estren, S., Medal, L. S. and Dameshek, W.: Blood 504: 1946. 22) E’onio: Korr. B1. f. Schweitz. Artzte 1915 Nr. 48, ref. Glanzxhann

handl. 193: 76: 1933.

1918.

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