Joanna Gąsowska, Krzysztof Brzeziński, Andrzej Nestorowicz
Hageman's anomaly as a risk factor during extracorporeal circulation
Chair and Department of Anaesthesiology and Intensive Therapy,
Head: prof. A. Nestorowicz Medical Academy, Lublin, Poland
We present a case of a 48-yr-old woman with Hageman's anomaly (congenital factor XII deficiency), undergoing open-heart valvular surgery. In order to be able to perform the ACT test we transfused 10 mg/kg of fresh frozen plasma, raising the factor XII concentration from 0 to 18%). At the end of surgery, after protamine, the left coronary artery became occluded, requiring surgical intervention. An emergency bypass was performed after antoher FFP infusion which raised the factor XII concentration to 50%. Recovery and the postoperative period went uneventfully and patient recovered completely.
Hageman's anomaly (deficiency of factor XII) is a genetic, autosomal, recessive disorder, belonging to the group of haemorrhagic diatheses. Most frequently it does not give clinical signs nor symptoms, and is usually diagnosed during routine laboratory haemostasis tests performed before surgery . Factor XII plays a significant role in many processes, such as coagulation, fibrynolysis, kininogenesis, and in the complement and renine-angiotensine-aldosterone systems [1, 2]. According to some authors, no increased intraoperative bleeding is observed in patients with Hageman's anomaly, so there is no need to the routine use of substitute treatment in the perioperative period [1, 2, 3, 4]. It cannot be neglected, however, that the lack of factor XII, handicaps plasminogenesis, which may be the cause of postoperative thromboembolic complications.
A specific problem in patients with factor XII deficiency arise during the "open-heart" surgical procedures. In this type of surgery interference in the haemostasis system may be necessary, and routine tests of the degree of blood heparinisation are useless.
Different opinions on the intra- and postoperative management of patients with Hageman's anomaly undergoing open-heart surgery, and scarce reports in the literature, concerning this problem, were the reason for presentation of our own observations.
A 48-year old female was scheduled for elective correction of a valvular defect. Preoperative diagnosis was: mitral stenosis and regurgitation, chronic circulatory insufficiency (NYHA III), coronary disease, recurrent paroxysmal atrial fibrillation. At admission, the general condition of the patient was satisfactory. Congestive heart failure symptoms were stabilised by pharmacologic treatment including digoxin, verapamil, quinidine and aspargine. ECG tracing revealed a regular heart rate of 60/min, normogramme, intermediate heart position and signs of left ventricular ischaemia.
The results of haemodynamic measurements were as follows: right atrium - 5 mmHg (0.7 kPa); right ventricle - 63/1 mmHg (8.4/0.1 kPa); pulmonary artery - 63/31 mmHg (mean 48 mmHg) (8.4/4.1 kPa, mean: 6.4); pulmonary artery wedge pressure - 27 mmHg (3.6 kPa); cardiac index - 3.2 l/min/m2; mitral gradient - 29.2 mmHg (3.9 kPa); systemic vascular resistance - 928 dyne/s/cm-5, pulmonary vascular resistance - 160 dyne/s/cm-5. The respiratory function was normal, as confirmed by the results of spirometry and blood gas analysis.
Coagulation profile demonstrated: platelet count - 332 g/l; prothrombin time (PT) - 17 s; activated partial thromboplastin time (APTT) - 140 s; thrombin time (TT) - 12 s; fibrinogen concentration - 2.4 g/l. The levels of coagulation factors presented: factor VII>100%; factor IX>100%; factor XI>100%; factor XII<1%.
No circulating anticoagulants were detected. On the basis of laboratory coagulation test results a diagnosis of Hageman's anomaly was made. The patient was qualified for mitral valve replacement in extracorporeal circulation.
As premedication the patient received morphine and scopolamine i.m. Induction was performed with diazepam and fentanyl in a continuous i.v. infusion. Muscle relaxation for intubation and during the procedure was achieved with pancuronium. Anaesthesia was maintained with fractionated doses of fentanyl. Controlled ventilation with a 3/5 oxygen/air mixture under blood gas control was maintained. A membranous oxygenator was used for extracorporeal circulation. To minimize myocardial lesions resulting from hypoxemia during the procedure, the coronary arteries were perfused with cold St.Thomas Hospital II cardioplegic solution, and the heart was embedded in ice. Extracorporeal circulation was carried out in moderate hypothermia and haemodilution. Monitoring during anaesthesia and surgery consisted of: bioelectrical heart activity, heart rate, invasive blood pressure, internal temperature (oesophageal and rectal), pulmonary artery pressure (Swan-Ganz catheter) and cardiac output (thermodilution method). After induction of anaesthesia the activated coagulation time - ACT.) and APPT (obtained values: 514 s and 145 s, respectively) were measured. As these results made impossible the control of heparinisation, planned for the procedure, frozen plasma was administered at a dose of 10 ml/kg. After the infusion ACT shortened to 161s and APTT - to 90 s. Concentration of factor XII rose to 18% of normal. Before connecting the patient to the heart-lung machine, heparin 3 mg/kg. was administered, which prolonged the ACT to 1060 s. After 3 hours of extracorporeal circulation shortening of ACT to 430 s required administration of additional heparin dose of 1 mg/kg, resulting in ACT rise to 1145 s.
After successful mitral valve implantation and restoring of normal cardiovascular performance the patient was weaned from the heart-lung machine. Heparin was reversed with protamine sulphate in a dose equalling the initial heparin dose (1:1). Fifteen minutes later the left-side heart failure symptoms with a limited compromise of myocardial contractility were observed. After identification of a critically narrowed part of the left coronary artery, a coronary by-pass graft was performed, again in extracorporeal circulation. Before the second neutralisation of heparin, used during the by-pass, the patient received frozen plasma (15 ml/kg). The coagulation parameters, measured after this infusion were: ACT - 135 s; PT - 21 s.; TT - 15 s; APPT - 68 s; fibrinogen concentration - 1.8 g/l; factor XII - 50%). The heart resumed its function spontaneously, after restoring of coronary perfusion. During the reperfusion period the patient had to receive inotropic drugs (continuous dopamin infusion at the rate of 8 mg/kg/min).
During the first postoperative day the patient did not require plasma infusions. The coagulation measurements were: PT - 23 s; TT - 12 s; APPT - 74 s; fibrinogen concentration - 2.3 g/l; factor XII - 40%. From the second postoperative day, anticoagulant treatment with syncumar was begun under prothrombin index control. Its values oscillated between 25 and 45% normal. During this time APTT gradually returned to the preoperative value and factor XII concentration to 0% normal.
Papers reporting on Hageman's anomaly in patients undergoing surgery in extracorporeal circulation include only 5 case reports [5, 6, 7, 8, 9], none of which has been published in Polish medical literature. The presented case confirms the occult character of this anomaly, as the patient has never had symptoms of haemorrhagic diathesis. Only the coagulation tests, triggered by the abnormally high APPT value, led to the diagnosis of Hageman's disease.
It is commonly known, that the contact of factor XII with a foreign surface triggers the intrinsic pathway of prothrombin activation. During recent years, the relationship between extrinsic and intrinsic mechanisms of coagulation activation has been proved. It was suggested that the activation of factor XI (the second stage of the intrinsic pathway cascade) may occur without Hageman's factor [2, 10]. One can state, that in view of possible alternative pathways of prothrombin activation, the coagulation process in Hageman's anomaly is not disturbed in vitro and the anomaly is clinically silent.
The condition sine qua non for open-heart surgery is maintaining of blood fluidity, which implies the use of heparin and, in consequence, the reversal of its action by protamine . Both, the dosage and neutralisation of heparin require appropriate coagulation tests assay. A very sensitive test, independent of contact factors and enabling the detection of low heparin concentrations in plasma, is the thrombin time (TT). Unfortunately, it rapidly becomes undeterminable, even when the heparin concentration in plasma too low for maintenance systemic anticoagulation required for the safe coourse of extracorporeal circulation .
The most useful and reliable coagulation test in the operation theatre is the activated coagulation time (ACT), described in 1966 by Hattersley. Its principle is the measurement of full blood coagulation time after maximal activation of factor XII with diatomite . In heparinised patients its prolongation is dose-dependent [13, 14]. In patients with factor XII deficiency, however, it is not reliable in monitoring heparin activity, as the prolongation of coagulation time in vitro does not depend on the action of the drug, but on the lack of contact factor [1, 2].
Restoring the normal function of the haemostasis system requires the presence of only small amounts of factor XII [1,2]. That is why, in the case described, we decided to supplement preoperatively the Hageman's factor deficiency by frozen plasma transfusion. This caused a rise in factor XII concentration (to 18% normal) and shortening of APTT, which in turn enabled monitoring of blood heparinisation by the ACT test. The similar algorithm was described in patients undergoing coronary by-pass surgery by Wood and Wallock at al. [7, 8].
An important problem in patients with Hageman's anomaly is the suppression of fibrinolytic system, which may contribute to myocardial infarction and venous thrombosis . This is confirmed by the history of a patient with factor XII deficit, who died from pulmonary artery embolism .
The disturbance in dynamic balance between coagulation and fibrinolytic systems is particularly dangerous during protamine administration. When heparin action cease, thromboplastic substances liberated during perfusion and activated thrombin  favour the abrupt acceleration of coagulation process. Insufficient response of the fibrinolytic system may significantly compromise the permeability of the vascular system.
Total thrombotic occlusion of coronary artery by-pass graft, 20 minutes after protamine administration, was described by Moorman et al. . Immediate urokinase infusion to coronary vessels and heparin treatment sawed the patients' life. For 13 days before surgery she received heparin for exacerbating symptoms of angina pectoris, so the APPT prolongation seemed normal. The diagnosis of Hageman's anomaly was made in this patient during retrospective analysis.
In the described case, the preoperative correction of factor XII concentration enabled the proper monitoring of heparinization. It did not protect the patient, however, from the occlusion of a branch of coronary artery. It cannot be excluded that the embolising material consisted not only of an atheromatic plate, but also of a thrombus, formed on it. Immediate surgical treatment, together with repeated supplementation of the factor XII deficiency enabled the safe termination of surgery. The patient, in good general condition, was discharged home 3 weeks after the operation.
1. Although the congenital lack of factor XII is a rare disease, usually silent clinically, one have to have in mind that improper treatment during an open-heart surgery in these patients may lead to severe complications.
2. Substitute treatment before surgery enables adequate control of heparin dosing during extracorporeal perfusion and limits the number and severity of thromboembolic complications after heparin neutralisation with protamine.
Originally published in Anestezjologia Intensywna Terapia 31; (3), 191-193, 1999.
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