1535

Europe. We predict that the rate of infection among these migrants would be similar to that of the Israeli cohort. In this study, we used several methods to detect HTLV-II infection. Our rate of anti-p40tax seropositivity in carriers was somewhat lower than that found by others among healthy HTLV-I carriers,u4-16 Serum samples from 4 subjects were positive only for anti-p40tax antibodies. Independent evidence of infection was obtained by PCR in only 1 of the 4. Thus, detection of anti-p40tax antibodies did not appreciably add to the estimate of the rate of infection. Our findings on the use of PCR suggested that in a high-risk population, such as the old people’s home we studied or in families of HTLV-I carriers, PCR would increase the number of infected individuals above that detected by serological means. The usefulness of PCR as a screening assay in appropriate settings requires further study. We thank Prof Ernesto Lubin for logistical support. The study was supported by (to J. D. R.) the Leukemia Research Foundation, the Rashi Foundation, NIH grants CA01314 and CA52410-01, and a personal contribution from Edward and Dolly Ives; (to D. M.) the Chief Scientist’s Bureau, Ministry of Health, Israel, and the Israel Cancer Research Fund, and (to Y. D. and J. D. R.) a grant from the US Army Medical Research and Development Command. J. D. R. was a visiting Fulbright scholar to the Sackler School of Medicine.

3. Biggar RJ, Melbye M, Sarin PS, et al. ELISA HTLV retrovirus antibody reactivity associated with malaria and immune complexes in healthy Africans. Lancet 1985; ii: 520-23. 4. Blattner WA, Saxmger CA, Clark J, et al. Human T-cell leukaemia/ lymphoma virus-associated lymphoreticular neoplasia in Jamaica. Lancet 1983; ii: 61-64. 5. Bunn PA Jr, Schechter GP, Jaffe E, et al. Clinical course of retrovirusassociated adult T-cell lymphoma in the United States. N Engl J Med 1983; 309: 257-64. 6. Robert-Guroff M, Weiss SH, Giron JA, et al. Prevalence of antibodies to HTLV-I, -II, and -III in intravenous drug abusers from an AIDS endemic region. JAMA 1986; 255: 3133-37. 7. Ehrlich GD, Glaser JB, LaVigne K, et al. Prevalence of human T-cell leukemia/lymphoma virus (HTLV) type II infection among high-risk individuals: type specific identification of HTLVs by polymerase chain reaction. Blood 1989; 74: 1658-64. 8. Ben-Ishai Z, Haas M, Triglia D, et al. Human T-cell lymphotrophic virus type-I antibodies in Falashas and other ethnic groups in Israel. Nature 1985; 315: 665-66. 9. Karpas A, Maayon S, Raz R. Lack of antibodies to adult T-cell leukaemia virus and to AIDS virus in Israeli Falashas. Nature 1986; 319: 794. 10. Leor J, Langcuitz P, Tran H, et al. HTLV-I associated T-cell leukemia/lymphoma in Israel. Isr J Med Sci 1988; 24: 397-400. 11. Sidi Y, Meytes D, Shochat B, et al. Adult T-cell lymphoma in Israeli patients of Iranian origin. Cancer 1990; 65: 590-93. 12. Lee H, Swanson P, Shorty VS, Zack JA, Rosenblatt JD, Chen ISY. High rate of HTLV-II infection in seropositive IV drug absuers from New Orleans. Science 1989; 244: 471-75. 13. Encyclopaedia Judaica 1972; 11: 1399-400. 14. Ehrlich GD, Glaser JB, Abbott MA, et al. Detection of anti-HTLV-I

Tax antibodies in HTLV-I enzyme linked immunosorbent assay-

REFERENCES Y, Komoda H, Chosa T, et al. Antibodies to adult T-cell leukemia-virus-associated antigen (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide seroepidemiologic study. Int J Cancer 1982; 29: 631-35. 2. Hinuma Y. Seroepidemiology of adult T-cell leukemia virus (HTLV-I/ ATLV): origin of virus carriers in Japan. AIDS Res 1986; 2: 517-22. 1. Hinuma

negative individuals. Blood 1989; 74: 1066-72. 15. Yokata T, Cho MJ, Tachibana N, et al. The prevalence of antibody to p42 of HTLV-I among ATLL patients in comparisons with healthy carriers in Japan. Int J Cancer 1989; 43: 970-74. 16. Kamihara S, Toriya K, Amagasaki T, et al. Antibodies against p40tax gene product of human T-lymphotrophic virus type I under various conditions of HTLV-I infection. Jpn J Cancer Res 1989; 80: 1066-71.

Quinine-induced disseminated intravascular

coagulation

Recurrent disseminated intravascular coagulation occurred in 3 women after ingestion of quinine tablets for cramp. All had circulating quininedependent antibodies to platelets and in 2 there was initial evidence of antibody consumption, with low titres that rose steeply over the next few days and remained high for many months.

Introduction

Recognised haematological problems associated with ingestion of quinine include thrombocytopenia, erythrocyte haemolysis, and neutropenia. Quinine was first implicated as a cause of purpura in the late 19th century, and there have been several reports of associated thrombocytopenia.13 However, we are aware of only two published cases of disseminated intravascular coagulation induced by quinine,45 and report three further cases. Patients and methods Case histories A 74-year-old woman was admitted 5 times over 3 years with various symptoms, which included acute shortness of breath,

wheeze, generalised abdominal pain, fever, lower back and chest pain, melaena, haematemesis or haemoptysis, and bruising and petechiae. Most episodes occurred shortly after going to bed. Investigations on each occasion (table) showed evidence of disseminated intravascular coagulation (DIC). On the first 2 admissions she was treated with antibiotics, although blood cultures were always negative. On the third admission she was treated for asthma, and on the last 2 occasions no specific treatment was given. On each occasion, fever and other symptoms resolved within 24 h with a subsequent resolution of coagulation abnormalities. At least 2 similar, but milder, episodes also occurred for which she did not attend hospital. On 3 occasions recent quinine ingestion was clearly remembered by the patient or documented in the admission notes. A check

on

the number of tablets left in the bottle after her initial

prescription indicated that 10 tablets had been taken over 7 years. Retrospective quinine-dependent platelet antibody analysis on samples stored from the last 3 admissions and from intervening periods showed low or undetectable antibody concentrations during the first 2 days of each acute episode, which then rose sharply

ADDRESSES: Department of Haematology (R. L. Spearing, FRACP, C. M. Hickton, FNZIMLT) and Department of Nephrology (P Sizeland, MRCP, A Hannah, MB, R. B Bailey, FRCP), Christchurch Hospital, Private Bag, New Zealand. Correspondence to Dr R. L. Spearing, Department of Haematology, Christchurch Hospital, Private Bag, Christchurch, New Zealand.

1536

Fig 1-Drug-dependent platelet antibody analysis by 5’Cr

platelet lysis for patient 1. For admissions 3-5 and outpatient samples and remained

high for up to 18 months after the last exposure to quinine (fig 1). Quinine-dependent red-cell antibodies were not detected and the direct Coombs’ test was negative. She has since been warned of the dangers of quinine ingestion. An 18-year-old woman developed mild leg cramps and took 200 mg quinine sulphate plus a combination analgesic tablet that contained paracetamol, aspirin, and codeine phosphate. 30 min later she had more severe cramps in all limbs associated with headache, sweating, and rigors, followed over the next 12 h by severe abdominal pain, nausea, vomiting, and diarrhoea. Her only regular medication was a combined oral contraceptive pill and occasional inhaled salbutamol. On admission, examination was normal apart from a generally tender abdomen, with no palpable organs or masses. Investigations showed evidence of DIC (table), with intravascular haemolysis and red-cell fragmentation. Several hours later the coagulation parameters had returned to normal apart from a low platelet count and high D-dimers. Her urine was dark red, with protein and blood on dipstick analysis and 30 x 106/1 white cells, 50 x 10"/I red cells, and a few granular casts on microscopy. Plasma creatinine was initially 240 nmol/1, and peaked at 380 nmol/1 the day after admission. Antinuclear antibody was positive at a titre of 1 in 40 with a speckled pattern; no other autoantibodies were detected. Other investigations, including tests for red cell antibodies, blood cultures, and abdominal ultrasonography, were normal. Haemolytic uraemic syndrome was diagnosed, and 45 units of fresh frozen plasma was given over the next 6 days. The platelet count, which had fallen to 14 x 109/1, began to rise by day 4. The patient made a complete recovery and all laboratory investigations were normal by day 17. 2 months later the patient had a similar but more severe presentation after ingestion of 200 mg quinine sulphate for leg cramps. When admitted she was pale and distressed with generalised abdominal tenderness, and had been anuric for 12 h. There was evidence of severe DIC (table) associated with HAEMOSTATIC RESULTS AT TIME OF EACH ADMISSION

Fig 2-D rug -dependent platelet antibody analysis by 5’Cr platelet lysis for patient 2. For admission 2 and a subsequent outpatient sample. intravascular haemolysis and red-cell fragmentation. She was treated initially with 10 units of cryoprecipitate but on the next day, as the blood film showed worse red-cell fragmentation consistent with haemolytic uraemic syndrome, fresh frozen plasma was started. On day 3 her platelet count fell to 5 x 109/1 and she had adult respiratory distress syndrome which required ventilation for 2 days. On day 4 plasma exchange with fresh frozen plasma replacement was started (8700 ml over 5 days). Renal failure was managed initially with peritoneal dialysis and subsequently haemodialysis until day 13; renal function had recovered completely by day 46. On this occasion a possible association with quinine was considered; quinine-dependent platelet antibody studies (fig 2) showed no detectable antibody until day 3, after which there was a rapid rise in titre which remained unchanged for 6 months. Quinine-dependent red-cell antibodies were not detected, and a direct Coombs’ test was negative on both admissions. She has been warned of the potential dangers of ingesting quinine. A third woman had systemic lupus erythematosus diagnosed at 17 years of age; a subsequent renal biopsy showed diffuse proliferative glomerulonephritis, but despite intensive treatment with prednisone, azathioprine, and plasma exchange renal function deteriorated and she started home haemodialysis at 28. 5 years later she was admitted with nausea, vomiting, and generalised myalgia. Shortly before admission, towards the end of a dialysis treatment, she had taken 300 mg quinine sulphate for cramp; other medications included vitamin B complex and aluminium hydroxide. She had a normal blood pressure and temperature, but had a tachycardia (110 beats/min) and tender calves, thighs, and lumbar area. Investigations showed evidence of intravascular haemolysis, thrombocytopenia, and probable rhabdomyolysis (aspartate transaminase [AST] 1452 U/l with other liver function tests normal). She was treated supportively and discharged after 5 days. 9 months later cramp again occurred towards the end of a dialysis for which she had taken quinine sulphate. 4 h later she was admitted to hospital with a rapid onset of clinical findings similar to her previous admission. Investigation showed evidence of haemolysis, DIC (table), and rhabdomyolysis (creatinine kinase 18 800 U/l, AST 3146 U/1, other liver function tests normal); plasma glucose was below 1 ’0 mmol/l; and bone-marrow aspiration showed erythroid hyperplasia and increased megakaryocytes. She was treated supportively with intravenous dextrose and a platelet infusion; when discharged 18 days later, she was advised not to take quinine sulphate again. 1 month later, at the age of 34, she again had cramp towards the end of dialysis and took a tablet of quinine sulphate. She was admitted 4 h later; investigations showed pancytopenia with evidence of DIC (table), intravascular haemolysis, probable rhabdomyolysis (AST 1452 U/1), hypoglycaemia, and acidaemia (pH 6-78). Blood cultures, as before, were negative. Despite supportive therapy she had a cardiac arrest and died the following day. Subsequent investigations showed quinine antibodies with 89% immune lysis by the -5’Cr platelet lysis assay, and red-cell quinine-dependent antibodies.

Laboratory investigations PR = prothrombin

APTT=activated

partial

thromboplastin time, Fib = fibrinogen, D-d = D-dimer, FDP = fibrinogen degradation products, N D = not done

ratio,

Prothrombin ratio, activated partial thromboplastin time, assay, and platelet count, and plasma aspartate

fibrinogen

1537

aminotransferase, creatine kinase, creatinine, and glucose concentrations were measured by standard techniques. D-dimer assay

performed

was

with the ’Dimertest latex’ kit

(Agen

Biomedical, Brisbane, Australia) and fibrin degradation product assays with the ’Thrombo Wellcotest’ (Wellcome, Dartford, UK). The 51Cr platelet lysis assay followed the description of Cimo et al;6

red-cell antibodies described.’

to

quinine

were

measured

as

previously

Discussion

patients had DIC after ingestion of 200-300 mg quinine sulphate for cramps, and all had high concentrations of quinine-dependent anti-platelet antibodies. The effects were severe in 2 patients, with thrombotic microangiopathic haemolytic anaemia, renal failure, and acute respiratory distress in patient 2, and rhabdomyolysis, severe hypoglycaemia, quinine-associated red-cell haemolysis, and death in patient 3. The other patient had less severe systemic symptoms and coagulopathy, which spontaneously returned to normal within a few days. Despite the widespread use of quinine for leg cramps, we know of only two published accounts ofD IC associated with quinine ingestion.4’sHowever, this association may have been underestimated because other reports of quinineassociated thrombocytopenia do not always exclude D I C;2,3 on review of local case records of patients with idiopathic thrombocytopenic purpura and quinine-induced thrombocytopenia, tests for DIC are often not requestedas shown by the initial episode of thrombocytopenia in patient 3. Furthermore, figs 1 and 2 show that after quinine exposure there appears to be antibody consumption during the acute illness with a rapid rise in antibody concentration over the next few days, and persistently high antibody titres for many months. These initial false-negative results during the acute illness delayed diagnosis in patient 1; an association with quinine was suspected by her fifth admission but assays on admission were negative. This low antibody titre during the acute episode may explain the lack of positivity of quinine antibodies in a previously reported case in which the clot retraction inhibition method was used for antibody detection;4 we used the SlCr platelet lysis technique, which is a more sensitive method to detect drug-dependent All 3

patients showed antibody binding to GPIIIa but the concentration of this antibody was considerably less than that of the corresponding antibody to GPIb/IX in the same patient’s serum. GPIIIa is present on the surface of endothelial cells,13 and a possible explanation of the mechanism of quinine-dependent activation of coagulation and subsequent DIC in our patients is via antibody interaction with endothelial cell GPIIIa, with subsequent release of procoagulant material from these cells. The rhabdomyolysis which occurred in patient 3 remains unexplained, but the GPIIIa receptor is also found on smooth muscle. 13 A low serum glucose, which also occurred in patient 3, is a rare complication of quinine. 14 Clinical and laboratory evidence has shown that quinine may stimulate (3-cell secretion of insulinl5 and that hypoglycaemia is more likely to occur in patients who are severely ill, fasting, or who have renal failure.16 Further investigations on samples from our patients may help to identify whether the antibody specificities involved vary from those of thrombocytopenic non-DIC patients, and whether there is evidence of binding to endothelial and muscle cells. However, our findings indicate an association of quinine ingestion with DIC and other systemic features such as rhabdomyolysis-an important and potentially fatal syndrome that may have been underestimated. We thank Dr K. L. Lynn, Dr R. A. Robson, Dr D. C. Heaton, Dr D. N. J. Hart, and Dr M. E. J. Beard for their clinical assistance and advice, and Mrs S. Banks who prepared the typescript.

REFERENCES 1. Vipan WH. Quinine as a cause of purpura. Lancet 1865; ii: 37. 2. Belkin GA. Cocktail purpura, an unusual case of quinine sensitivity. Ann Intern Med 1967; 66: 583-86. 3. Powell SE, O’Brien SJ, Barnes R, Warren RF, Wickiewicz TL.

Quinine-induced thrombocytopenia. J Bone Joint Surg [Am] 1988; 70: 1097-99. 4. Elliott HL, Trash DB. Intravascular coagulation induced by quinine. Scot Med J 1979; 24: 244-45. 5. Barr E, Douglas JF, Hill CM. Recurrent acute hypersensitivity to quinine. Br Med J 1990; 301: 323. 6. Cimo PL, Pisciotta AV, Desai RG, Pino JL, Aster RH. Detection of drug-dependent antibodies by the 51Cr platelet lysis test. Am J Hematol

1977; 2: 65-72.

antibodies.8

Although believe quinine-induced DIC may be more common than previously recognised, we do not suggest that all cases of quinine-induced thrombocytopenia are associated with DIC: D-dimer assays on stored samples from 4 other patients with antibody-positive quininedependent thrombocytopenia showed no evidence of increased D-dimer concentrations to suggest a consumptive we

coagulopathy. How might quinine exert such an idiosyncratic effect in some patients? Connellan et al9 suggested that quinine induces widespread conformational changes in platelet membrane antigens which expose neoantigens and may induce quinine-associated antibodies. Such antibodies, in the presence of quinine, may bind a range of platelet glycoproteins by the Fab, rather than the Fc, domain.1o Early studies of quinine-dependent platelet antibodies on platelets from patients with Bernard-Soulier or Glanzmann’s disease showed heterogeneic populations of antibodies with different specificities within individuals, now shown to be GPIb, GPIIb, GPIIIa, and GPIX." Chong et a112 have used monoclonal antibodies to show that the predominant drug-dependent antibody in quinineinduced

thrombocytopenia reacts with the membraneregion of GPIb/IX complex; some of their

associated

7. Widmann FK, ed. Technical manual, 9th edn. Arlington, Va.: Association of American Blood Banks, 1985: 461-62. 8. Aster RH, Enright SE. A platelet and granulocyte membrane defect in paroxysmal nocturnal hemoglobinuria: usefulness for detection of platelet antibodies. J Clin Invest 1969; 48: 1199-210. 9. Connellan JM, Deacon S, Thurlow PJ, Dauer R. Changes in platelet function and reactivity induced by quinine in relation to quinine (drug) induced immune thrombocytopenia. Thromb Haemost 1989; 62: 46

(abstr 105). DJ, Mullen PC, Aster RH. Fab-mediated binding of drugdependent antibodies to platelets in quinidine- and quinine-induced

10. Christie

thrombocytopenia. J Clin Invest 1985; 75: 310-14. 11. Pfueller SL, Bilston RA, Logan D, Gibson JM, Firkin BG. Heterogeneity of drug-dependent platelet antigens and their antibodies in quinine- and quinidine-induced thrombocytopenia: involvement of glycoproteins Ib, IIb, IIIa and IX. Blood 1988; 72: 1155-62. 12. Chong BH, Horne S, Berndt MC, Chesterman CN. Studies of the interaction of the quinine/quinidine-dependent antibodies with platelet glycoproteins Ib-IX and IIB/IIIA. Thromb Haemost 1989; 62: 46 (abstr 13.

106). Knapp W, Dorken B, Gilks W, et al, eds. Leucocyte typing IV—white cell differentiation antigens. Oxford: Oxford University Press, 1989:

965-66. 14. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycaemia and hyperinsulinaemia in faldparum malaria. N Engl J Med 1983; 309: 61-66. 15. Hughes TA. Effects of quinine on the sugar of the blood. Ind J Med Res

1925; 13: 321-36. 16. Editorial. Uraemic hypoglycaemia. Lancet

1986; i: 660-61.