cancer procoagulant and haemostatic anbormalities in melanoma
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blistering. His WCC rose to 11 - 1 x 109/1 with 31% eosinophils(3-64X 109/1). 2 days later his eosinophilia was 44% of 7-7x 109 II(absolute count 3.24 X 109 II). The rash did not respond to
prochlorperazine or trimeprazine so the spironolactone was
stopped. 24 hours later, his eosinophil count had fallen to 10% of6 - 1 x 109/1 (0-7x10’/I) and there was a progressive fall over thenext 5 days. During the course of the eosinophilia, tests forconnective tissue diseases and parasitic infections were negative.His only other drug therapy was multivitamin tablets. The patientwas discharged. Before a challenge test could be done he wasreadmitted with pneumonia. During the second admission, 3 weekslater, his eosinophil count was normal, being 3% of 10 x 109 /1 whitecells.A 56-year-old man with alcoholic liver disease was admitted with a
gram-negative septicaemia and acute renal failure, which requiredtreatment with parenteral antibiotics, dopamine, and
haemodialysis. Before admission he had been prescribedspironolactone 100 mg twice daily although his compliance wasprobably poor. Eosinophilia was not noted on a routine blood filmon admission. All drug therapy was stopped on admission. He madea good recovery from his acute illness but remained icteric withmarked ascites and peripheral oedema. Spironolactone 100 mg perday (Norton Pharmaceuticals) was started 14 days after admission,and 12 hours later he complained of severe pruritus and was noted tohave an erythematous macular rash on his legs and lower abdomen.Spironolactone was stopped and haematological indices 12 hourslater were WCC 8-4x10/1, 14% eosinophils (calculated count1-18x10/1). 2 days later, his WCC was 6-2x10/1 and hiseosinophil count had dropped to 4% (calculated count 0’ 25 x 109/1).Spironolactone was reintroduced at a dose of 50 mg the followingday. 12 h later he complained of pruritus and 24 h later anerythematous macular rash had reappeared. He continued onspironolactone for a further 3 days, during which time his
symptoms worsened and his eosinophil count rose to 20% of8 - 7 x 10/1 (calculated count 1 74x 10*’/1). Withdrawal of the drugresulted in slow resolution of the eosinophilia, pruritus, and therash. Dermatological opinion and skin biopsy confirmed the natureof the rash. This man had other significant haematologicalabnormalities, including a persisting normochromic anaemia of 9’ 4g/dl, high MCV at 110 fl, and a low platelet count at 90x109/1.Although the Coombs test was negative, his serum contained a coldantibody of I specificity.Both these patients reacted to spironolactone with severe
eosinophilia and a rash, which suggests a type I allergic reaction.Both occurred in patients with alcoholic cirrhosis and ascites butwere noted independently on separate medical units. The otherconstituents of the tablets are widely used with many drugformulations and it seems unlikely that they were in any way relatedto the reaction. Spironolactone has been in general clinical use for20 years so it is interesting that two similar adverse reactions shouldpresent almost simultaneously and that this effect has not
previously been described.
Departments of Medicineand Clinical Pharmacology,
Royal Infirmary,Edinburgh EH3 9YW
C. G. WATHENT. MACDONALDLESLEY A. WISESHEILAGH M. BOYD
1. Stricker BHC, Oei TT. Agranulocytosis caused by spironolactone. Br Med J 1984;289: 731.
CANCER PROCOAGULANT AND HAEMOSTATICANBORMALITIES IN MELANOMA
SIR,-The origin and management of low-grade asymptomaticintravascular coagulation in cancer patients remain a puzzle (Feb 8editorial). A low-grade intravascular coagulation found inmelanoma patients was more pronounced when metastaticmelanoma was apparent than in patients with localised disease,suggesting a role for haemostatic mechanisms in tumour
progression. We have tested tissue extracts and freshly isolatedtumour cells from nineteen melanoma patients for procoagulant
activity (PCA) by a one-stage clotting assays All samples containedconsiderable amounts of PCA which was characterised as anactivator of coagulation factor X by virtue of the independence ofthe activity from factor VII and by the fact that it was not abolishedby antibodies to tissue thromboplastin, the other procoagulantfound in human cells.Further biochemical and immunological analysis led us to
identify the PCA of melanoma cells as a cysteine proteinase whichreacted in an Outcherlony diffusion gel with a monoclonal antibodyraised against the activator of factor X expressed in rabbit V2carcinoma (cancer procoagulant).3 No normal human tissue hasever been reported to produce this activity, exceptamnion-chorion.When tumour extracts from six primary lesions were compared
with those from thirteen metastatic melanomas we found a four-foldincrease in PCA of metastatic melanoma (4 - 5 t I - 7 vs 18 - 0±5 - 4Russell viper venom units/mg protein; p<0 001). When we tested,in three patients, specimens of both primary and metastaticmelanoma we found that the metastatic lesions contained more
activity than the primary melanoma, with ratios of 2 - 0, 7 - 1, and7’ 8. Extracts from three benign melanocytic naevi were devoid ofthis activity when tested with both the biological and the
immunological assay.These data suggest that melanoma cells, but not naeval
melanocytes, produce a peculiar procoagulant; this activity is
present in primary melanomas and is greater in metastatic lesions.This PCA could be responsible, at least in part, for the low-gradeintravascular coagulation observed in melanoma patients,particularly in those with metastatic lesions.
Division of Experimental Oncology D,Istituto Nazionale Tumori, Milan
CARLO GAMBACORTI PASSERINIGIUSEPPE FOSSATI
Iststuto di Ricerche Farmacologiche"Mario Negri",
Milan 20157, Italy
NICOLA SEMERARO*MARIA BENEDETTA DONATI
Department of Medicine,University of Denver,Denver, Colorado, USA STUART G. GORDON
*Present address: Istituto di Patologia Generale, University of Ban.
1. Mannucci PM, Vaglini M, Maniezzo M, Magni E, Man D, Cascinelli N. Hemostaticalterations are unrelated to the stage of tumor in untreated malignant melanoma andbreast carcinoma. Eur J Cancer Clin Oncol 1985; 21: 681-85.
2. Donati MB, Gambacorti Passerini C, et al. Cancer procoagulant (factor X activator) intumor cells from patients with malignant melanoma. Thromb Haemost 1985; 54:259.
3. Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant: acysteine proteinase from malignant tissue. Biochemistry 1985; 24: 5558-67.
4. Gordon SG, Hasiba U, Poole MA, Cross BA, Falanga A. Cysteine proteinaseprocoagulant from amnion-chorion. Blood 1985; 66: 1261-65.
MATERNAL MORTALITY FROM MENDELSON’SSYNDROME
SiR,-I liked Dr MacLennan’s essay (March 15, p 587). Freshideas on this topic, which continues to haunt obstetric anaesthetists,are always welcome. ’However, there are several points whichshould be considered in conjunction with her hypothesis.Although the acid-aspiration syndrome is commonly held to be
peculiarly associated with obstetric anaesthesia, there is no firmevidence that the case-fatality rate among those who aspirate acidicstomach contents is higher among patients who are pregnant thanamong the remainder. Indeed, the opposite may be the case, andthe incidence of aspiration-and of death associated with it-may behighest among males and young children. The evidence fromOlsson and colleagues’ review is not, in my opinion, conclusive,but it is highly suggestive. Unfortunately we have no evidence fromthe UK on the frequency of the event among non-pregnant patientsor of the mortality rate relating to it. A comprehensive surveyseveral years ago revealed that of 10 pregnant women who hadregurgitation/aspiration, and had not received prophylaxis beforedelivery, 2 died.MacLennan states that "cardiac output increases by 40%" and
that "further rises occur during labour and immediately post