FIBRINOPEPTIDE A AND SUDDEN CORONARY DEATH

607

Preliminary Communication FIBRINOPEPTIDE A AND SUDDEN CORONARY DEATH D. J. HOWARTH T. W. MEADE YVONNE STIRLING Medical Research Council Epidemiology and Medical Care Northwick Park Hospital, Harrow, Middlesex

Unit,

thrombotic tendency" though they do not, of course, prove it. An additional part of the evidence for a thrombotic component in sudden coronary death would be the demonstration of indicators of’ thrombogenesis in the minutes or hours before the event, but the difficulty or impossibility of obtaining this evidence is obvious. We have therefore looked for biochemical evidence of thrombogenesis in blood taken very soon after sudden death, both coronary and non-coronary. We measured the plasma level of fibrinopeptide A (FPA), the initial cleavage product of the thrombin proteolysis of fibrinogen.2

T. P. WELCH Accident and Emergency Department Northwick Park Hospital The

M. R. CROMPTON

Department of Forensic Medicine,

St

George’s Hospital Medical

School, London A (FPA) concentrations measured in blood taken by direct cardiac puncture from 31 patients who had died suddenly of ischaemic heart disease (IHD) and from 8 patients who had died suddenly of other causes. Mean FPA concentration in the IHD group was five times higher than that in the nonIHD group. This difference was almost entirely due to the high FPA level in the IHD subjects with a history of the disease. The FPA difference between the IHD and non-IHD groups is unlikely to have been due to differences in methods of resuscitation. A possible interpretation of the findings is that thrombin production causes or aggravates the course of events leading to sudden IHD death, particularly in subjects with a past history of IHD.

Summary

METHODS

Fibrinopeptide

were

INTRODUCTION

THE suggestion that "sudden coronary death" is a thrombotic event remains controversial. Early prospective results from the Northwick Park Heart Study (NPHS) have indicated that high concentrations of certain clotting factors are associated with an increased risk of death from cardiovascular disease, including sudden coronary death.’I These findings are compatible with the hypothesis that there is a definable "hypercoagulable state" or "increased

study

carried

was

out

between 1979 and 1983 and

was

approved by the Harrow District ethical committee and by Her

Majesty’s Coroner for the Northern District of Greater London. Subjects.-Those studied had either died in the accident and emergency department of North wick Park Hospital, or had died at a known point during their transfer to the department by ambulance. In all cases, death

was

sudden and unexpected at the time,

though 2

patients had malignant disease (see fig 1), and most of those dying of ischaemic heart disease (IHD) had probably had previous episodes. When death had been certified, up to 50 ml blood was taken by direct cardiac puncture and transferred at once to tubes containing 3 - 13% trisodium citrate. (Most of the blood in samples obtained by direct cardiac puncture is likely to come from the ventricles, the right more often than the left3Details of attempts at resuscitation were recorded. In nearly all cases, medications (eg, bicarbonate) are given intravenously. Direct intracardiac adrenaline is only occasionally used. A coroner’s necropsy was performed in all but one case. M.R.C. performed 76% of the necropsies. He had no knowledge of the FPA level. In all but 7 of the necropsy cases (all in the IHD group, see below) standard details concerning the presence of occlusive thrombi and of evidence of past or recent myocardial infarction were available. Analyses have been confined to findings where the interval between death and blood sampling was certainly or probably less than 20 min. There were 31 such cases (22 male, 9 female) in which the cause of death was considered to be a manifestation of IHD and the mean interval between death and sampling was 7 - 0 min. There were 8 (5 male, 3 female) in which other causes were responsible (non-IHD), including 1 case of sudden infant death syndrome (SIDS); and the mean interval between death and sampling was 8, 6’ min. Mean ages of the IHD and non-IHD cases were 65 and 58

years,

respectively.

R. STUART-HARRIS AND OTHERS: REFERENCES 1 Smith 2

IE, Fitzharris BM, McKinna JA, et al Aminoglutethimide in the treatment of metastatic breast carcinoma Lancet 1978; ii: 646-49. Santen RJ, Worgul TJ, Lipton A, et al. Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med 1982; 96:

94-101. 3 Cash R, Brough AJ, Cohen MNP, Satoh PS Aminoglutethimide as an inhibitor of adrenal steroidogenesis J Clin Endocrinol Metab 1967, 27: 1239-48. 4. Dexter RN, Fishman LM, Ney RL, Liddle GW. Inhibition of adrenal corticosteroid synthesis by aminoglutethimide: studies of the mechanism of action. J Clin Endocrinol Metab 1967, 27: 473-80. 5. Kahnt FW, Neher R On the adrenal biosynthesis of steroids in vitro. III. Selective inhibition of adrenocortical function. Helv Chem Acta 1966, 49: 725-32. 6 Harris AL, Powles TJ, Smith IE. Aminoglutethimide in the treatment of advanced postmenopausal breast cancer. Cancer Res 1982; 42 (suppl): 3405s-08s. 7. Smith IE, Harris AL, Morgan M, Gazet J-C, McKinna JA. Tamoxifen versus aminoglutethimide versus combined tamoxifen and aminoglutethimide in the treatment of advanced breast carcinoma. Cancer Res 1982; 42 (suppl): 3430s-33s. 8 Chakraborty J, Hopkins R, Parke DV. Inhibition studies on the aromatization of androst-4-ene 3,17-drone by human placental microsomal preparations. Biochem J

(Elipten-Ciba)

1972; 130: 19.

9. Thompson EA, Siiteri cytochrome P-450 in

PK. The involvement of human placental microsomal J Biol Chem 1974, 294: 5373-78. 10 Santen RJ, Santner S, Davis B, Veldhuis J, Samojlik E, Ruby E. Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma J Clin Endocrinol Metab 1978; 47: 1257-65. 11 Graves PE, Salhanick HA Stereoselective inhibition of aromatase by enantiomers of aminoglutethimide. Endocrinology 1979; 105: 52-57. 12 MacDonald PC, Rombaut RP, Siiteri PK. Plasma precursors of estrogen; I extent of conversion of plasma androstenedione to estrone in normal males and nonpregnant, aromatization.

normal,

castrate

and adrenalectomized females.

J Clin Endocrinol

Metab

1967; 27:

1103-11. 13. Grodin JM, Siiteri PK, Macdonald PC Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 1973; 36: 207-14. 14. Murray FT, Santner S, Sanojlik EA, Santen RJ. Serum aminoglutethimide levels: studies of serum halflife, clearance and patient compliance. J Clin Pharmacol 1979; 19: 704-11. 15. Harris AL, Dowsett M, Jeffcoate SL, McKinna JA, Morgan M, Smith IE. Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer. J Clin Endocrinol Metab 1982; 55: 718-22 16 Harris AL, Dowsett M, Jeffcoate SL, Smith IE. Aminoglutethimide dose and hormone suppression in advanced breast cancer. Eur J Cancer Clin Oncol 1983, 19: 493-98 17. Hayward JL, Carbone PP, Heuson JC, Kumaoka S, Segaloff A, Rubens RD. Assessment of response to therapy in advanced breast cancer. a project of the programme on clinical oncology of the International Union Against Cancer, Geneva, Switzerland. Cancer 1977; 39: 1289-94. 18. Segaloff A, Weeth JB, Meyer KK, Rougue EL, Cunningham MEG. Hormonal therapy in cancer of the breast XIX Effect of oral administration of testolactone on clinical course and hormonal excretion. Cancer 1962, 15: 633-35 19. Co-operative Breast Group. Results of studies of the co-operative breast group 1961-63. Cancer Chemother Rep 1964; 41: 1-24. 20. Goldenberg IS. Clinical trial of testolactone (NSC 23759), medroxyprogesterone acetate (NSC 26386) and oxylone acetate (NSC 47438) in advanced female mammary cancer. Cancer 1969; 23: 109-12. 21. Volk A, Deupree RH, Goldenberg IS, Wilde RC, Carabasi RA, Escher GC A dose response evaluation of testolactone in advanced breast cancer. Cancer 1974, 33: 9-13. 22. Brodie AMH. Overview of

recent

1982; 42 (suppl): 33125-45

development of aromatase inhibitor.

Cancer Res

608

tests-Fibrinolytic activity was measured at onceand is expressed as 100/lysis time in hours (table). In fig 2, the lysis time itself is shown. FPA was measured by radioimmunoassay (Mallinckrodt) of samples stored in liquid nitrogen, fibrinogen being removed by absorption with bentonite. This study was begun some time before the FPA method used was generally available. The blood had been taken into citrate and not into heparin, trasylol, and Blood

edetic acid (EDTA), which suppress further thrombin

MEAN VALUES (NUMBER OF CASES) ACCORDING TO USE OF RESUSCITATIVE MEASURES IN CONJUNCTION WITH EXTERNAL CARDIAC MASSAGE IN IHD GROUP

production.

However, extensive comparisons in separate studies have been in this respect. Thus, in a comparison of split samples from 184 individuals, the mean FPA level was 27-22 ng/ml when citrate was used and 16.99 ng/ml with heparin, trasylol, and EDTA. The correlation between the two sets of results was 0-91. The total volume of each of the samples on which this comparison was based was about 60 ml. The potential for thrombin production during venepuncture probably increases with the size of the volume and this is likely to be the reason for the higher absolute FPA level in our study than in studies where, for example, only 5 ml blood was taken.

reassuring

Statistical analysis-Because of the skewed distribution of FPA, results in fig 1 are shown on a logarithmic scale. Log-transformed values have been used in calculating means, which have been

compared by unpaired t tests. Other subjects-The main comparison is between

the IHD and non-IHD sudden death cases. FPA results are also shown for samples taken by antecubital venepuncture from 22 participants in NPHS, 17 patients admitted to the coronary care unit at Northwick Park Hospital for myocardial infarction (MI) occurring within the preceding 72 h, and 12 patients with disseminated intravascular coagulation (DIC). Lysis times in antecubital venepuncture samples are shown for 962 NPHS participants in fig 2. RESULTS

From the coroner’s officer’s report, it seemed likely that 20 of the 31 IHD cases had had a clinical history of the condition. Fresh thrombi were found in 6 of the 23 IHD cases for whom standard details were available. There was pathological evidence of past infarction in 15 of these 23 cases and of recent infarction in 8. The only comparable finding in the non-IHD group was of past infarction in the case where death was ascribed to hypertensive heart disease. The mean FPA value for the IHD sudden death group (1009-8 ng/ml) was nearly 5 times higher than that for the non-IHD sudden death group (218-8 ng/ml) (p = 0 - 028) (fig 1). The high value in the IHD sudden death group was almost entirely due to those with a history of IHD. In the 20 with a history (mean age 65 years), the mean FPA value was 1822- 8 ng/ml while in the 11 without (mean age also 65 years) it was 345 -0 ng/ml (p<0 - 005).

Fig I-FPA

levels and

means

in different groups;

logarithmic scale.

Treated carcinoma of uterus in intestinal obstruction case; no tumour at necropsy. Unsuspected carcinoma of bronchus in pulmonary embolism case.

Full details of resuscitation

*p<005;

not

known in

some cases.

j-p<001.

Fig 2 shows the lysis time (in hours) of the IHD and nonIHD sudden death groups compared with the distribution of the times for the 962 NPHS participants seen over the same period of time. (Recording of lysis time is discontinued at 24 hours and this accounts for the large number of NPHS participants with results shown at this time point.) In the IHD group (one missing result) 25 out of 30 readings (83%) were of 2 h or less, compared with 10(1%) in the NPHS participants. Use of any of the four resuscitatiye measures was accompanied by external cardiac massage. There was no consistent suggestion that resuscitation had affected FPA concentrations in the IHD group (table). Each of the four methods was associated with a high level of fibrinolytic activity and when calcium and bicarbonate were used, the difference in activity was significant. Resuscitation was attempted in 5 of the 8 non-IHD cases. The numbers in this group for any particular type of resuscitation are too small for useful analysis. The mean FPA values for the NPHS participants, MI patients, and DIC patients were 10’4, 23’3, and 364,55

ng/ml, respectively. DISCUSSION

The effects of tissue damage during cardiac puncture, the volume of the blood samples taken, and the anticoagulant used may all have contributed to the high FPA levels in the sudden death cases. However, these factors operated to the same extent in IHD and non-IHD cases. Interpretation of the result depends on relative, not absolute, values. It seems unlikely that the FPA difference between the IHD and non-IHD groups was due to differences in resuscitation. Differences in FPA according to the use of various resuscitative measures (table) are not consistent and provide no reason for supposing that the difference in FPA between the IHD and non-IHD groups (fig 1) was due, for example, to an effect of the use of defibrillation in the IHD group but not in the non-IHD group. It is conceivable that agonal differences in the mode of death could be responsible for the FPA difference. Thus, IHD death might evoke a greater adrenergic response than non-IHD sudden death and a greater FPA level. However, administration of adrenaline (table) did not increase FPA levels. This apparent lack of effect was probably not due to failure of the adrenaline to circulate, since calcium and bicarbonate (and quite possibly adrenaline) almost certainly did influence fibrinolytic activity.

609

result of a greater extent and severity of arteriosclerosis in those with such a history.7 Whatever the reason for its generation, however, a high thrombin level could well aggravate, if not initiate, the proccess of sudden IHD death either through the deposition of fibrin or, as is increasingly

recognised, through stimulating platelet aggregation,

or

-

both. We are grateful to Dr D. M. Paul, Her Majesty’s Coroner for the Northern District of Greater London, and to his officers for their help.

Correspondence should be addressed to T.

W. M.

REFERENCES

1. Meade TW, North WRS, Chakrabarti R et al. Haemostatic function and cardiovascular death: early results ofa prospective study. Lancet 1980; 1: 1050-54. 2. Nossel HL. Radioimmunoassay of fibrinopeptides in relation to intravascular coagulation and thrombosis. In: Bleich HL, Boro ES, eds. Seminars in medicine. N Eng J Med 1976; 295: 428-32. 3. Sabin HI, Coghill SB, Khunti K, Mc Neill GP. Accuracy of intracardiac injections determined by a post-mortem study. Lancet 1983; i: 1054-55. 4. Meade TW, Chakrabarti R, Haines AP et al. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979; i: 153-56. 5. Schwartz CJ, Gerrity RG. Anatomical pathology of sudden death. Circulation 1975: 57, 52; suppl III 18-III 26. 6. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310: 1137-40. 7. Woolf N, Sacks MI, Davies MJ. Aortic plaque morphology in relation to coronary artery disease. Am J Path 1969: 57: 187-98.

Lysis time (h) Fig 2-Lysis times in subjects in whom death was sudden (cardiac puncture) and in participants in Northwick Park Heart Study (venepuncture). One of the main arguments against the view that thrombosis is involved in sudden cardiac death is the alleged absence of occlusive thrombi. In fact, however, occlusive thrombi are found in about 30% of sudden deaths, the proportion reported tending to rise (to about 80%) the longer the interval between the onset of the terminal episode and death itself.5 Fig 2 clearly demonstrates the intense fibrinolytic activity associated with sudden death (a wellknown phenomenon). In these circumstances, thrombi causing more or less instantaneous death due to an arrhythmia could be partly or completely lysed and thus not present long enough to lead to all the changes of classic MI or to be easily found at necropsy, even though they were originally present. In addition, a careful necropsy study leaves little doubt that thrombosis is involved in the chain of events leading to sudden death from IHD.6 Conclusions based on comparisons of the FPA results between the sudden death groups and the NPHS, MI, and DIC groups can only be tentative. The direct cardiac puncture technique in the former group may have given rise to more tissue damage and activation of coagulation than antecubital venepuncture. With this proviso, it seems possible that the intensity of thrombin production in IHD sudden death may be of the same order as that found in DIC. The absence of any pronounced increase in FPA in the MI patients is almost certainly due to the short half-life of FPA (about three minutes2), the shortest interval between the onset of symptoms and blood sampling in the 17 patients 12 h. The size of the FPA difference between the sudden death groups raises the possibility that sudden IHD death is often preceded by a high level of thrombin production. The stimulus need not necessarily originate in the coronary arteries-it could, for example, arise from an arteriosclerotic plaque in the aorta. The very much higher FPA level in those

being

with a history of IHD than in those without depends on the accuracy of the coroner’s officer’s report, but could be the

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DAVID G. HARNDEN

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