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Multiple embolism in a patient with protein C deficiency should raise the possibility of an intracardiac thrombus.
An Asian man aged 43 developed ischaemia in the lower limbs. Protein C deficiency had been diagnosed at age 20, and his history included repeated deep venous thromboses, pulmonary emboli and a thrombotic cerebrovascular accident. He was on anticoagulant therapy with the aim of achieving an international normalized ratio (INR) of 2.0-3.0. On admission the INR was 2.4. Antithrombin III activity was 95% (normal range 80-120%), protein C activity < 22 μg/dL (70-130), protein S bioassay activity 151% (60-140) and activated protein C resistance (APC) ratio 3.45 (2.35-4.00). The normal APC ratio implies that anticoagulation was sufficient to inhibit the functional and antigenic activity of other vitamin-K-dependent procoagulant factors (factors II, VII, IX and X) in an otherwise normal individual. Lupus anticoagulant was absent and there was no homocysteinuria; plasma homocysteine was 88 μmol/L (normal range 50-200). On DNA analysis, factor V Leiden was not detected. The above results confirmed the diagnosis of heterozygous protein C deficiency. Three of his maternal uncles had protein C deficiency, with recurrent deep vein thromboses.
A femoral angiogram having revealed stenosis of the left popliteal and posterior tibial arteries, a left femorodistal bypass was performed. Vascularity to the left leg did not improve and a left below-knee amputation became necessary. Later during the same month the patient developed an ischaemic right foot and dry gangrene of two toes on the right side. This prompted further investigations to rule out an embolic source.
Recent myocardial infarction was ruled out by electrocardiography and cardiac enzyme measurements. Transthoracic echocardiography showed an intraventricular echogenic mass, with a calcified stalk attaching it to the anterior wall of the left ventricle at the apex. Left ventricular function was normal and no intracardiac septal defects were seen. The aortic and mitral valves were normal, as were left atrial dimensions and contours. A coronary angiogram showed no obstructions. On spin-echo magnetic resonance imaging (MRI) in the coronal plane, a rounded mass was seen attached to the inferolateral wall of the left ventricle (Figure 1). Its shape and signal characteristics, and the absence of enhancement after gadolinium DTPA administration, were consistent with a mural thrombus. Under standard cardiopulmonary bypass, a 2.5 cm ventriculotomy was performed between the left anterior descending coronary artery and its first diagonal branch. The ventricular muscle was normal in appearance. In the left ventricular cavity, amongst the trabeculi at the apex, was a 1.5 × 2.0 cm mass that was held against the septum by fibrous trabeculi. The endocardial surface adjacent to the thrombus had a slightly roughened appearance. The ventricular side of the thrombus was smooth and bosselated. The mass was not attached to the papillary muscles, and was excised with its trabecular attachments. On histological examination it consisted of organized thrombus. The patient was re-anticoagulated with warfarin before discharge.
Protein C binds to the endothelial cell surface protein thrombomodulin and is converted to APC by thrombin. The APC molecule then interacts with protein S to inactivate two critical coagulation cofactors, factors Va and VIIIa1. Deficiency of protein C is usually transmitted in an autosomal dominant manner. In the heterozygous state the typical manifestations are recurrent venous thrombosis and associated pulmonary embolism2. The homozygous state, which is rare, shows itself as fulminant neonatal intravascular coagulation3. APC may also stimulate fibrinolysis and accelerate the lysis of formed blood clots4. Absence of protein C activity despite normal amounts of the protein is due to the presence of a dysfunctional protein C molecule5.
Cardiac intraventricular thrombus is most commonly associated with an area of myocardial infarction. Left ventricular thrombi can also develop in congestive heart failure and cardiomyopathies. It is unusual for cardiac intraventricular thrombus to form in the high shear environment of the left ventricle when the heart is structurally and functionally normal. We find no previous report of this happening in protein C deficiency.