Disseminated intravascular coagulation after aortic aneurysm repair, intraoperative salvage autotransfusion, and aprotinin

patients 2 and 5 heparin treatment.

remained stable after the cessation of

one could speculate that the anticoagulant anti-aggregating properties of intact vessel wall are high enough to prevent the occurrence of thrombosis and thrombocytopenia, whereas at the surface of the implanted graft these properties are overcome and thrombosis is induced. Our data therefore indicate that a normal platelet count does not exclude the presence of heparin-associated autoantibodies typical of HAT. We conclude that in all patients developing thrombotic complications during heparin treatment, heparin administration should be immediately stopped and the patient tested for HAT, even when the platelet counts are within the normal range.

and

Viola Hach-WunderleKarlfried Kainer, Brigitte Krug, Gert Muller-Berghaus, Bernd Pötzsch fur

Tadaaki

physiologische

Chong BH. Heparin-associated thrombocytopenia. Aust N Z J Med

2

1992; 22: 145-52. Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A,

4

71: 247-51. 5

Rapid induction of hepatocyte growth factor by heparin SIR-Hepatocyte growth factor (HGF) was first identified as potent stimulator of hepatocyte growth, and later, its pleiotropic functions in several cell types were demonstrated.’ We have studied circulating HGF by an enzyme-linked immunosorbent assay in cancer patients and found HGF concentrations in sera to be frequently raised in breast cancer patients with liver metastases. While doing this study we found a patient with an especially high concentration of HGF. This patient had received a heparin injection by chance just before blood sampling. We studied the induction of HGF after heparin injections in 3 patients with recurrent breast cancer with liver metastases and in 3 healthy volunteers. In the patients, 5000 units of heparin were administered with one injection via a catheter in the hepatic artery, and in volunteers the same amount of heparin was injected intravenously. A striking and rapid increase in HGF was found in both groups (table). The fourfold difference in increase of HGF between intrahepatic arterial and intravenous injections suggested a dose-dependent effect of heparin; about onea

fifth of the total blood volume circulates to the liver. Peak concentrations of HGF were thought to be high enough to exert its functions in cells with HGF receptors. The concentration of HGF in tumour tissues has value as a prognostic indicator in primary breast cancer. In addition, HGF has activity as an angiogenic factor.3 Therefore, it is

IA=intra-artenal injection, IV=intravenous injection (ng/mL); ND=not detected; detection limit was 0.4 ng/mL. Mean (SD) values are shown. *Low molecular

470

Masakazu Toi, Takeshi

Tominaga

Tajima H, Matsumoto K, Nakamura T. Regulation of cell growth and motility by hepatocyte growth factor and receptor expression in various cell species. Exp Cell Res 1992; 202: 423-31. 2 Yamashita J, Ogawa M, Yamashita S, et al. Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res 1994; 54: 3

Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994;

heparin, daltepann sodium, was injected via hepatic artery. Changes with time in induction of HGF in sera by

Taniguchi,

Department of Surgery, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113, Japan

1

1

Table:

the

tumour

In these cases,

William-Harvey-Klinik and Kerckhoff-Klinlk, Max-Planck-Institut und klinische Forschung, D-61231 Bad Nauheim, Germany

circulating HGF induced by heparin might cell growth and tumour angiogenesis in promote patients with malignancy. In vitro, more than 85% of bound HGF was released from the cell surface by washing with heparin.4 Because heparin is known to have important roles in the activation of many growth factors including HGF, which has heparin binding functions,arapid increase in serum HGF after heparin treatment suggests that HGF bound to liver cells including Kupffer cells and endothelial cells might be released. possible that

heparin

1630-33. Bussolino F, Renzo MF Di, Ziche M, et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 1992; 119: 629-41. Naka D, Ishii T, Shimomura T, et al. Heparin modulates the receptorbinding and mitogenic activity of hepatocyte growth factor on hepatocytes. Exp Cell Res 1993; 209: 317-24. Sporn MB, Roberts AB. Peptide growth factors and their receptors. Handbook of Exp Pharmacol 95, Berlin: Springer-Verlag.

Disseminated intravascular coagulation after aortic aneurysm repair, intraoperative salvage autotransfusion, and aprotinin SIR-Intraoperative salvage autotransfusion and high-dose aprotinin have each been reported to reduce homologous blood transfusion in patients undergoing aortic aneurysm repair and each modality appears to be safe is isolation.1-3 We describe a case of disseminated intravascular coagulation (DIC) with a fatal outcome after an elective aortic aneurysm repair during which intraoperative autotransfusion and aprotinin were used. A 60-year-old male Jehovah’s Witness was admitted for elective repair of an abdominal aortic aneurysm. He had type II hyperlipidaemia with widespread vascular disease. Coronary angiography one year previously had shown a severe stenosis in the left anterior descending coronary artery and an occluded right coronary artery. Preoperative haemoglobin was 140 g/L, platelet count 197xlO"/L, coagulation screen normal, urea 7-3 mmol/L, sodium 132 mmol/L, potassium 4-2 mmol/L, creatinine 126 µmol/L, normal chest radiograph, and a left ventricular ejection fraction of 47% by isotope scanning. An electrocardiogram showed inferolateral ischaemia. Aprotinin 500000 IU was given intravenously at induction and a further 1500000 units were given during the operation. Heparin 5000 IU was given intravenously before aortic cross-clamping. Autotransfusion was carried out using a Solcotrans system after heparin had been given. The operative blood loss was 2100 mL of which 1400 mL was autotransfusion. by Immediately salvaged all four limbs were extensively mottled. The postoperatively diarrhoea and patient subsequently developed 5 after of hours the end haemoglobinuria. Investigations revealed count 75x 109/L, prothrombin operation platelet ratio 1-25, activated partial thromboplastin ratio 1-4, fibrinogen 1.8 g/L, and D-dimers 1-2 (normal range <0’25). Urine output decreased overnight despite a central venous pressure of 5-10 cm H2O. The next day the patient suddenly

developed tachypnoea

with evidence of followed and, despite he died. At necropsy there were

and

tachycardia

anterolateral ischaemia. Cardiac attempts

at

resuscitation,

arrest

of myocardial infarction around an old posterior infarct. The left ventricle was dilated and pulmonary oedema was present. The right kidney was infarcted; histology showed foci of cortical infarction with multiple fibrin microthrombi in small arteries, arterioles, and glomerular tufts. Microthrombi were also found in the liver and heart. Intraoperative autotransfusion and aprotinin used alone are apparently safe, but there are no published data on their combined use. Activation of the clotting system occurs in the Solcotrans reservoir, presumably via the contact pathway, with associated fibrinolysis and generation of D-dimers.3 The plasma concentration of aprotinin in this patient is unlikely to have inhibited D-dimer formation. However, systemic antifibrinolytic therapy may accentuate the clinical features of severe DIC and, although reinfusion of reservoir blood usually causes no systemic adverse effects, in this patient aprotinin could have contributed to deposition of fibrin microthrombi from the reinfused blood in the microvasculature and subsequent failure to clear such microthrombi by fibrinolysis. Although additional causes, such as mild perioperative hypotension and a pre-existing subclinical prothrombic state from clotting activation in the aneurysm sac, may have contributed to the clinical picture, fatal DIC following elective aneurysm repair is rare/ We suggest that caution should be exercised when considering the use of Solcotrans and aprotinin for blood saving at surgery.

new areas

detect the presence of A2 in the AB blood, it is not surprising that virtually all such donations are detected. The only subgroup of AB donors who might be misgrouped as B in the initial duplicated testing scheme would be those of weak A antigens such as A3. Our system of labelling packs is tightly controlled, with a computerised bar code-based verification procedure and concatenation, which reduces very considerably any chance of packs being inadvertently mislabelled. Hence, although not denying that packs of blood labelled group B could actually contain group AzB blood-or possibly blood with weaker A subtypes-we are confident that such an occurrence is infrequent. We suggest, therefore, that when hospital blood banks conduct compatibility proceduresincluding those for patients of group B-approved and wellestablished methods should be used as an alternative to the way Cummins and Downham use the DiaMed system. Indeed Cummins and Downham may not have used the DiaMed system in full accordance with the manufacturers’ instructions. The anti-A titre in group B individuals is usually lower than that in group 0 individuals; and the reactivity of anti-A from group B individuals is further reduced against group AzB cells. The severity of any reaction, if blood of group A2B to be transfused into a group B individual, is likely to be mild. Although such a situation should be strenuously avoided, the suggestion that all donations-or even all donations labelled group B-be regrouped in the hospital blood bank before issue, is unjustified. F E Boulton, M

Nightingale

Wessex Blood Transfusion Service, Coxford Road,

Southampton SO16 5AF,

UK

Alan A Milne, Gordon B Drummond, David A Paterson, William G Murphy, C Vaughan Ruckley Vascular Surgery Office, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh

EH3 9YW, UK

Pregnancy and breast cancer 1 Thompson JF, Roath OS, Francis JL, Webster JHH, Chant ADB. Aprotinin in peripheral vascular surgery. Lancet 1990; 335: 911. 2 Duchateau J, Nevelsteen A, Suy R, et al. Autotransfusion during aorto-iliac surgery. Eur J Vasc Surg 1990; 4: 349-54. 3 Clifford PC, Kruger AR, Smith A, Chant ADB, Webster JHH. Salvage autotransfusion in aortic surgery: initial studies using a disposable reservoir. Br J Surg 1987; 74: 755-57. 4 Gibney EJ, Bouchier-Hayes D. Coagulopathy and abdominal aortic aneurysm. Eur J Vasc Surg 1990; 4: 557-62.

Failure of DiaMed-ID system to detect ABO

compatibility SiR-Cummins and Downham (June 25, p 1649) describe failures of the DiaMed system to detect the A antigen on A2B cells, which leads them to recommend that users should verify the ABO group of all donor red cell units before transfusion. Users should be aware of the cost implications of such verification, and should also note the realistic chances of clinically adverse reactions in the event of the serum of a group B patient failing to react with donor cells in the compatibility procedure. In our centre, all donations from new donors are grouped twice by auto-analyser, and those reacting as group B (on average 5 a day) are further tested for the presence of weak A antigen with the use of different batches of reagents of enhanced sensitivity. We have identified weak A antigen in less than 1 per 1000 of such donations. Since we would expect 7 donors in every 1000 to be of group A,B, we are confident that our initial testing procedure detects all such donors; and indeed, because the auto-analyser is set to

SiR-Guinee and colleagues’ report (June 25, p 1587) of the deleterious effect of concurrent pregnancy on young women with breast cancer seems to finally confirm beyond doubt that the immunosuppressive effect of pregnancy can be deleterious to cancer patients and is one of the principal tenets of the immunosurveillance hypothesis for cancer. There is increasing evidence that immunosuppression does not increase risk of mutagenic transformation but does increase speed of progression of cancer growth.’ This evidence is supported by Guinee’s findings of only 71 pregnancies per 1000 women per year of observation in their population rather than 110 expected. 87% of pregnant women had tumours larger than 2 cm compared with 48% of those who developed tumours more than 49 months after a pregnancy or had never been pregnant. There is some evidence from study of tumours arising in immunosuppressed individuals that they demonstrate more differentiated characteristics such as less loss of HLA class I or II antigens than tumours arising spontaneously in individuals with normal immune function.2 If this situation occurred in pregnancy-associated breast cancer, such tumours might be more responsive to immunotherapy3 and benefit less from chemotherapy than spontaneous tumours. Although none of the patients in Guinee and colleagues’ report received immunotherapy, there is increasing evidence that castration, by inducing lymphocytosis (unpublished observations) and regeneration of the thymus (ref 4 and Sperandio P et al, unpublished) may boost immune response and so would be preferable to chemotherapy for the tumours arising during pregnancy. The fact that 217 of Guinee and colleagues’ patients received chemotherapy and only 59 hormone therapy suggests that one factor in the poor 471