Myocardial infarction associated with homozygous resistance to activated protein C

ischaemic necrosis of bone and the fat embolism syndrome, as sometimes occurs in systemic lupus erythematosus.’ Some have suggested that a leucocytosis of 21 % is a risk factor for stroke in patients with Hb SS diseased The leucocytosis in our patients was at least partly due to corticosteroids. Leucocytes are large, poorly deformable, and adherent to endothelium, thereby reducing blood flow in the microcirculation resulting in ischaemia. Paradoxically, corticosteroid therapy has been used for severe fat embolism.5 The ill effects of corticosteroids may be diminished by simultaneous hydration and anticoagulation. Coma, in the absence of cerebral haemorrhage or infarction, is uncommon during sickle cell crisis;2 if it develops fat embolism syndrome should be sought and exchange transfusions considered. Jun C

Huang, Roy Gay, Sami L Khella

Presbyterian Medical Center of Philadelphia, Philadelphia, PA 19104,

1

for ocular irrigation could prevent the serious and untoward effects of the diving reflex.

warm water

A Assi, J Hickman Casey, A McGuinness Departments of Ophthalmology and Accident and Emergency, Royal Free Hospital, London NW3 2QG, UK

Furedy JJ. The human dive reflex: an experimental, topographical and physiological analysis. Physiol Behav 1986; 36:

1

Hurwitz BE,

2

Whayne TF Jr, Killip T. Simulated diving in man: comparison of facial stimuli and response in arrhythmia. J Appl Physiol 1967; 22: 800-07. Whitman V, Friedman Z, Berman W, Maisels MJ. Supraventricular tachycardia in newborn infants: an approach to therapy. J Pediatr

287-94.

3

1977; 91: 304. 4

5 USA

(>30°C)

Arnold

RW, Dyer JA, Gould AB Jr, Hohberger GG, Low PA. Sensitivity to vasovagal maneuvers in normal children and adults. Mayo Clin Proc 1991; 66: 797-804. Hunt NG, Whitaker DK, Willmott NJ. Water temperature and the "diving reflex". Lancet 1975; i: 572.

Shapiro MP, Hayes JA. Fat embolism in sickle

cell disease, report of a with brief review of the literature. Arch Intern Med 1984; 144: 181-82. Charache S, Lubin B, Reid CD. Management and therapy of sickle cell disease. National Institutes of Health, 1992; 92-2117: 25-28. Diggs LW. Sickle cell crisis. Am J Clin Pathol 1965; 44: 1-19. Balkaran B, Char G, Morris JS, Thomas PW, Serjeant BC, Sergeant GR. Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 1992; 120: 360-66. Fischer JE, Turner RH, Herndon JH, Riseborough EJ. Massive steroid therapy in severe fat embolism. Surg Gynecol Obstet 1971; 132: 667-72. case

2 3 4

5

Diving reflex induced by ocular irrigation SIR-The diving reflex is defined as bradycardia without hypotension in response to cold water stimulus to the face. 1,2 The cardioinhibitory component of this reflex has been exploited clinically to control supraventricular tachycardias.3 However, clinicians should be aware of the potential serious complications of facial water irrigation. We report a case of diving reflex produced by ocular irrigation in the treatment of a chemical injury. A 6-month-old girl was brought to hospital with bilateral total corneal epithelial loss from accidental alkali burns. She was clinically stable with no signs of distress. Cold 0-9% saline irrigation of the eyes was started, using an intravenous drip set, but the baby became alarmingly pale and her pulse rate dropped to 84/min. Irrigation was stopped and the patient was transferred to the resuscitation room where her colour improved and her pulse increased to 100/min. However, when ocular irrigation was restarted (the conjunctival pH was still alkaline) she relapsed into marked pallor and severe bradycardia (66/min). The irrigation was again promptly discontinued. 15 min later her pulse had increased to 120/min and her pallor had subsided. We do not think that the oculocardiac reflex was involved because there was no stretching of the ocular muscles, nor pressure on the globe from the weak irrigating jet of water. The diving reflex seems to be more prominent in infants and children than in adults, the drop in heart rate correlating with age.’ The bradycardia seems to be related to the water temperature but Hunt and associates obtained maximal results at temperature of 18°C.’ The water temperature in our case was at 19°C. Copious water irrigation is an essential emergency procedure in the treatment of chemical burns to the eye. This treatment can induce a strong diving response and lead to serious arrhythmias and bradycardia. Infants and elderly patients with cardiovascular disease are at an increased risk of complications. Continuous electrocardiographic monitoring, resuscitation facilities to hand, and the use of

952

Myocardial infarction associated with homozygous resistance to activated protein C SiR-Resistance to the anticoagulant response to activated C (APC) is a major cause of venous thrombosis.I,2 APC is a key component in a physiologically important anticoagulant system that cleaves and inactivates factors Va and VIlla.1 Genetic defects of this system, such as deficiencies of protein C or protein S, are associated with venous thromboembolic disease, but only a few cases with deficiency of protein S (a co-factor of APC) associated with myocardial infarction have been reported.3 APC-resistance is due to a single mutation in factor V gene; arginine at position 506 in the APC-cleavage site is replaced by glutamine, creating APC-resistant factor Va.45 The high prevalence of APC resistance in the population (3-7%) makes it by far the most common genetic defect associated with thrombophilic disorders.’ We report two cases of myocardial infarction in young women homozygous for this mutation. Patient A was a previously healthy 34-year-old smoker with no history of angina pectoris. Her sudden chest pain kinase and creatine (ECG), electrocardiographic (CK/CKB), and scintigraphy patterns were consistent with acute infarction. Tissue anteroseptal myocardial plasminogen activator (tPA) was given. An exercise test before discharge indicated ischaemia and coronary arteriography revealed normal coronary arteries by a transient vasospasm accompanied by angina and ST depression developed during the examination. She has had no further symptoms of angina or heart failure during 3 years of follow-up. Patient B was a 33-year-old non-smoker who had suffered from influenza accompanied by pleural effusions 9 months earlier. For 6 months preceding her myocardial infarction she had had chest pain occasionally in stressful situations. Myocardial infarction was confirmed by ECG changes and a raised CK/CKB. She was successfully treated with streptokinase, and a follow-up exercise test was normal. Coronary arteriography was not done. Neither patient used oral contraceptives. Patient A and B both had normal plasma values for protein C, protein S, antithrombin III, fibrinogen, von Willebrand factor antigen, factor VII coagulation activity, cholesterol, and triglycerides. However, severe APC resistance was detected in both (APC ratio 1-2 [reference limit >2’0-’]). DNA analysis’ showed both patients to be homozygous for the factor V gene mutation related to APC

protein

resistance.

Figure: Pedigree

of

patient A (arrow)

Filled left and nght half of symbols denote APC resistance and thrombosis, respectively. Asterisks indicate history of myocardial infarction. Several forbears who had died had also had myocardial infarction (age 56-76). Individual 111:8, besides having had myocardial infarction, had had a stroke. The plus and minus signs indicate presence and absence of factor V gene mutation. nd=not determined. Results of APC resistance test are given. Perfect cosegregation of low APC ratio and factor V gene mutation was seen, homozygosity being reflected by very low APC ratios.

infarction and venous thrombosis were found families. Two relatives of patient A both heterozygous for the factor V gene mutation, had had a myocardial infarction (figure). Factor V is present in plasma besides being released from platelet a-granules during primary haemostatis. APC resistance, with failure to cleave and inhibit factor Va, may lead to uncontrolled coagulation and thrombus formation. Thus homozygous APC resistance probably contributed to the myocardial infarction in the cases described. The normal arteriogram in patient A raises the question of a possible role of APC resistance in endothelial dysfunction. Our observations call for epidemiological and case-control studies to find out whether the factor V gene mutation is a risk factor for myocardial infarction.

Myocardial

in both

Bengt Zöller, Peter J Svensson, Erik Berntorp, Leif Erhardt, Björn Dahlbäck

that HIV-1 transmission takes place mainly via HIV-1 seropositive female sex workers to their male clients. However, owing to the consideration that sperm, lymphocytes, and HIV-1 in semen survive well when in an alkaline environment that is not customary in the vaginae we might suspect that some of these men might well have been HIV-1-infected through semen ejaculated by a preceding client. Although this suspicion might be difficult to confirm by serological concordance, discordance, and PCR technology, young men frequenting brothels might prudently wear condoms to protect themselves from the semen of others, as well as to protect members of the

opposite

sex.

Jack W Shields 1950 Las Tunas Road, Santa Barbara, CA 93103, USA

Johan Holm,

1

Shields JW.

2

27: 21-40. Hill JA, Anderson DJ. Human vaginal leukocytes and the effects of vaginal fluid on lymphocyte and macrophage defense functions. Am J Obstet Gynecol 1992; 166: 720-26.

Departments of Cardiology, Clinical Chemistry, and Coagulation Disorders, University of Lund, Malmo General Hospital, S-214 01 Malmo, Sweden

1 Dahlbäck B. Physiological anticoagulation. Resistance to activated protein C and venous thromboembolism. J Clin Invest (in press). 2 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by a poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-08. 3 Nordøy A. Haemostatic factors in coronary heart disease. J Intern Med 1993; 233: 377-83. 4 Bertina RM, Koeleman BPC, Koster T, et al. Mutation in the coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67. 5 Zoller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-38.

HIV transfection in brothels SIR-In monogamous sexual

relationships, a high incidence of male-to-female, compared with female-to-male transmission of HIV-1 can be explained rationally on anatomical and physiological bases.’ In lands such as Thailand, in which young military recruits often pursue sexual relationships in brothels, the male incidence of HIV-1 seropositivity has become much greater than expected (Hanenberg and colleagues, July 23, p 243). Many assume

Lymph, lymphomania, lymphotrophy, and HIV lymphocytopathy: an historical perspective. Lymphology 1994;

HIV-1

subtype

E in

Yunnan, China

SiR-80% of the 1243 HIV infections reported in China in 1993 were from Yunnan, a southwestern province of 38 million people that shares 4000 km border with Myanmar (Burma), Laos, and Vietnam.’ In 1989, an epidemic of HIV infection was detected among injecting drug users (IDUs) in remote mountainous areas bordering Myanmar.’ Several HIV-1 isolates from people in these areas have been genetically characterised and classified within subtype B.2 This subtype accounts for virtually all HIV-1 infections in North America and Europe, most infections among IDUs in nearby Thailand2-4 and Malaysia, and some infections among IDUs in Myanmar.’ In Thailand, the explosive epidemic of heterosexually transmitted HIV-1 is due largely to subtype E (Thailand genotype A). 2-5 Development of highly specific serologic enzyme immunoassays (RIAs) using gp 120 V3 loop peptides from subtype E and B strains found in Thailand (Thailand genotypes A and B, respectively) has greatly aided 953