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Abstract Zakynthinos EG, Vassilakopoulos T, Kontogianni DD, Roussos C, Zakynthinos SG (Department of Critical Care and Pulmonary Services, University of Athens Medical School, ‘Evangelismos’ Hospital, Athens, Greece). A role for transoesophageal echocardiography in the early diagnosis of catastrophic antiphospholipid syndrome (Case Report). J Intern Med 2000; 248: 521–526.
We describe a previously healthy 28-year-old woman who presented with the clinical picture of large vessel occlusions (stroke with left hemiparesis, myocardial infarction) and developed multi-organ failure (i.e. kidneys, heart, brain, liver, blood, skin) over a very short period of time. Peripheral blood smear was consistent with thrombotic thrombocytopenic purpura. Transesophageal echocardiogram was supportive of the diagnosis of catastrophic antiphospholipid syndrome (CAPS), revealing Libman–Sacks endocarditis. Blood cultures were negative, anticardiolipin antibodies were highly increased and lupus anticoagulant was positive. Cerebral and coronary angiograms were negative, suggesting possible microthrombotic occlusive disease in the setting of CAPS.
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- Case report
A previously healthy 28-year-old woman, who had never smoked, was admitted to the Neurology Department because of stroke with left hemiparesis, in good mental status. A cranial computed tomographic (CT) scan demonstrated parietal lobe infarction. Cerebral angiogram performed 2 days later was normal. Despite initial improvement, eight days later the patient’s mental status deteriorated. She became confused and was admitted to the intensive care unit (ICU). Her consciousness was alternating between lethargy and coma. Her blood pressure was 110/70 mmHg and her heart rate 130 beats min–1. Chest radiograph and blood gases were normal. Physical examination revealed extensive petechiae. Laboratory findings on admission to ICU are presented in Table 1. A peripheral blood smear showed striking red blood cell (RBC) fragmentation (schistocytes and helmet cells) consistent with microangiopathic haemolytic anaemia, along with nucleated RBCs and polychromatophilic RBCs, indicating increased bone marrow production. Platelets were markedly diminished. Coombs test was negative. Lipid status [cholesterin, LDL, HDL, Lp(a)] was within normal limits. Urinalysis showed proteiuria (++). The electrocardiogram (ECG) demonstrated 2–3 mm ST segment elevation in the precordial leads V2–V4, whilst nonspecific ST changes were registered on III and aVF (Fig. 1f). CPK was elevated. Troponin T-test was positive.
Table 1. Laboratory findings
|Admission||3rd day||Discharge 10th day||Reference values|
|Hb (g dL–1)|| 6.1|| 8.1|| 9.3|| 12–16|
|Hct (%)|| 19|| 25|| 29|| 36–46|
|WBC (cells mm–3)|| 24 × 103|| 13.4 × 103|| 9.1 × 103|| 5–10 × 103|
|Poly/lympho|| 90/8|| 80/14|| 71/20|| |
|Reticulocytes (%)|| 7.2|| 6.1|| 3.7|| 0.5–1.5|
|Platelets|| 8 × 103||105 × 103||260 × 103||150–400 × 103|
|INR|| 1.7|| 1.5|| 3.5|| <1.2|
|aPTT (s)|| 36|| 61|| 33|| 21–35|
|Fibrinogen (mg dL–1)|| 250||340||440||200–400|
|FDPs (µg mL–1)|| 7|| 3|| 3|| 0–5|
|Bilirubin (mg dL–1)|| 12.3|| 1.9|| 0.9|| 0.3–1.2|
|direct bilirubin|| 3.5|| 0.7|| 0.3|| 0.1–0.3|
|SGOT (UI L–1)|| 182|| 76|| 35|| 10–38|
|SGPT (UI L–1)|| 105||135|| 29|| 10–40|
|Urea (mg dL–1)|| 200||170|| 55|| 10–50|
|Creatinine (mg dL–1)|| 3.01|| 2.4|| 1.3|| 0.6–1.4|
|LDH (UI L–1)||1350||485||240||120–300|
|CPK (UI L–1)|| 540||230||115|| 60–220|
|CPK-MB (%)|| 12.8|| 3|| 2|| <5|
Figure 1. Main echocardiographic and electrocardiographic findings on admission to ICU. Schematic diagrams below the echocardiographic illustrations indicate the important structures. (a, b, c) Transthoracic echocardiogram. (a) Apical akinesia (arrows) at end-systole. Dotted line on accompanying sketch indicates the expected (normal) wall movement. (b) Transmitral Doppler flow indicating diastolic dysfunction of the left ventricle. Wave E (corresponding to early diastolic filling) < wave A (corresponding to atrial contribution to diastolic filling), which is abnormal for the patient’s age. Dotted diagram represents a normal MV inflow. (c) M-Mode echocardiogram at the base of the heart indicating mild pericardial effusion (arrow). (d, e) Transesophageal echocardiogram. Marantic wartlike vegetations firmly attached to the posterior (d) and the anterior (e) leaflets. In (e) the vegetation of the posterior leaflet is faintly shown due to the section. Vegetations are depicted by arrows. (f) Main ECG findings. ST in V2–V4, nonspecific ST changes in inferior leads. LV: left ventricle; LA: left atrium; PE: pericardial effusion; MV, mittral valve; VEG, vegetation.
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Transthoracic echocardiogram (TTE) showed normal cardiac dimensions. Localized left ventricular apical dyskinesia was evident (Fig. 1a). All the other segments of the left and right ventricles performed normal systolic function. Left ventricular ejection fraction was 55%. A mild pericardial effusion was present at the posterior surface of the heart (Fig. 1c). Mitral valve (MV) leaflets were mildly thickened, yet without MV prolapse, which raised the suspicion of vegetations without documenting them. Pulsed Doppler echocardiography of MV inflow showed a peak early filling velocity (wave E) of 95 cm s–1, an atrial filling (wave A) of 102 cm s–1 and an atrial contribution to filling [velocity time integral (VTI) of wave A/VTI of wave A] of 52% (at heart rate of 110 beats min–1), indicating diastolic dysfunction of the left ventricle (Fig. 1b). Colour Doppler echocardiography revealed only trivial mitral regurgitation. Transesophageal echocardiography (TEE) demonstrated a ‘clublike’ mass measuring 4 × 3 mm2, firmly attached at the mid-atrial surface of the posterior leaflet of the MV, not exhibiting any independent movement, whilst another mass of smaller size was evident on the anterior leaflet (Figs 1d and e).
Because of altered mental status, microangiopathic anaemia, thrombocytopenia and renal failure, thrombocytopenic purpura (TTP) was diagnosed and plasma exchange was initiated. In addition, since the echocardiographic findings with the concomitant clinical picture were highly indicative of antiphospholipid syndrome, anticoagulation with heparin was started before the results of tests for autoantibodies were known. The next day the patient developed seizures and was intubated and mechanically ventilated. A repeat cranial CT showed subacute (evolving) infarction in the same area (Fig. 2). Pulse therapy with methylprednisolone was started. After three days rapid neurological and laboratory improvements were noted (Table 1). In addition, peripheral RBC morphology had improved. ST elevation on ECG returned to normal by day 5. Q-waves were absent. Left-sided cardiac catheterization, on day 7, showed a localized apical aneurysm. Coronary angiography was normal.
Anticardiolipin antibodies were highly positive. IgG was 118 GPL units (normal value 0–15) and IgM was 113 MPL units (normal value 0–15). Lupus anticoagulant and antinuclear antibodies (ANA) were positive. Anti-dsDNA antibodies were not elevated and C3 and C4 levels were normal. All (six) blood cultures were negative.
The patient underwent daily plasma exchange for 7 days. Anticoagulation therapy, initially with heparin and later with coumadin targeting an INR of 3–4, as well as pulse steroid therapy for 3 days (methylprednisolone 1 g day–1) followed by 1 mg kg–1 day–1 prednisone p.o. were prescribed. One dose of i.v. cyclophosphamide (1 g m2) was used after the first week in the ICU. The patient remained in the ICU for 10 days and was discharged from the Hospital after 30 days. She finally recovered with no apparent neurological sequalae. Renal failure was also resolved. During 3 months of follow-up, under prednisone 0.4 mg kg–1 day–1 and coumadin adjusted for INR of 3–3.5, there was no evidence of recurrent thromboembolism. Laboratory findings were normal except that aCL titres were mildly elevated and LAC was still positive.
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This patient was a young woman presenting with left hemiparesis and cerebral infarction on CT. This made us suspicious of the existence of APA, as these have been associated with increased tendency for thromboembolism especially if met in females of such age . In addition, the protrusions demonstrated on MV leaflets by TEE (Figs 1d and e), having the appearance of Libman–Sacks vegetations (sessile, wartlike echodensities, usually found at the base or at the middle atrial portion of the leaflets ), was very supportive of the diagnosis of APS, before the laboratory proof of the existence of APA was available. Finally, aCL antibodies (IgG and IgM), as well as LAC, were highly positive. The patient’s deteriorating mental status in association with the peripheral smear and other laboratory findings were consistent with TTP. The differential diagnosis between TTP and CAPS is difficult as laboratory and clinical findings are similar [4, 6, 7]. The combination of APS and multiple organ failure over a very short period of time, in association with laboratory findings of TTP present in this patient, is diagnostic of CAPS [6, 7].
However, the patient presented differences from the usual picture of this rare syndrome.
1 In CAPS there is overwhelming evidence of microthrombic occlusive disease of small vessels, in contrast to APS where large vessels (venuses or arteries) are mainly involved. As a result, segmental organ infarctions are rare . The clinical presentation of our patient suggested large vessel involvement, but even invasive work-up failed to confirm it. More specifically, a cerebral infarction was evident on CT resulting in left hemiparesis. Nevertheless, the angiogram was negative. Spontaneous thrombolysis could be a possible explanation, but the deterioration of mental status that resulted in her admission to the ICU, whilst the repeat CT only showed an evolving, subacute infarct, suggests that ‘thrombotic microangiopathy’ was possibly responsible for the CNS involvement from the very beginning. Non-Q myocardial infarction (MI) might have also been the result of microthrombic occlusive disease, as coronary angiogram was also normal. Typical MI is not usual in CAPS patients, but multiple microthrombi within intramyocardial arteries were evident at autopsy in many of them, resulting mainly in diffuse myocardial hypokinesia .
2 Renal failure, which is the commonest clinical manifestation of CAPS, was present, but was not associated with hypertension, as usually happens in CAPS .
3 Thrombocytopenia was very severe and was accompanied by purpura, which is unusual in CAPS, as contrasted to TTP .
4 A triggering factor could not be identified .
The association between APA and cardiac manifestations is well recognized in APS and CAPS. Nearly 30% of patients have evidence of cardiac valve pathology [1, 6–11], usually consisting of mild valvular regurgitations and leaflet thickenning. Libman–Sacks endocarditis is the hallmark of cardiac involvement . However, it is not often identified whilst the patient is alive. In only 6% of reported cases with CAPS, marantic (nonbacterial) vegetations were discovered. A possible explanation is that TTE, which is usually used, is unable to recognize marantic vegetations, which are generally small (1–4 mm in diameter)  as in our case. This is the reason why TEE (which is clearly superior to TTE for evaluation of suspected intracardiac masses ) was very supportive to the diagnosis of APS. By identifying small vegetations on the atrial surface of the mitral valve with characteristic picture in association with the clinical findings, Libman–Sacks endocarditis was diagnosed and heparin was immediately started despite severe thrombocytopenia. We believe that TEE should be performed in every patient with suspected APA, since the finding of small vegetations with ‘clublike’ appearance (located away from the leaflet tips and not performing chaotic, flopping motion, as the vegetations of infective endocarditis usually do), in the appropriate setting (young age, female sex, native valves, stroke) can be reasonably diagnostic.
The cardiac manifestations of our patient have not been reported in CAPS, since we had the coincidence of acute MI, valvular marantic vegetations and pericarditis which is very rare in the same patient. In fact, to our knowledge, pericarditis has not been described in association with primary APS or CAPS, as yet [6, 11]. The mild pericardial effusion observed could be attributed to MI. However, this is not likely because other cases of MI present in patients with CAPS were not accompanied by pericardial effusion . In addition, it was observed very early in the course of MI. Thus, it stands to reason that pericarditis is another possible cardiac manifestation of CAPS. Diastolic dysfunction of the left ventricle has been described in APS , although it could be attributed solely to MI.
Treatment of CAPS is not currently standardized. In our patient treatment consisted of plasmapheresis, anticoagulation and steroids. Fortunately, plasmapheresis is indicated in both TTP and CAPS and must be started as soon as possible, since it is associated with an improved outcome, probably resulting from a prompt reduction of APA titre . This triad of treatment has been associated with the highest survival rate (70%). We also used one pulse of cyclophosphamide to prevent any APA rebound following plasmapheresis (because of the primarily very high levels of aCL and the severity of the condition), although benefit from the additional use of cyclophosphamide has not been convincingly documented . However, this drug has probably been used in the most severe cases of CAPS, so its usefulness is difficult to estimate. The duration of treatment required remains unknown. Long-term and perhaps lifelong anticoagulation may be indicated, as in refractory APS [6, 7, 10], in association with steroids in an attempt to suppress production of APA, as a relapse of the syndrome might be lethal. aCL levels could be used to lead therapy during follow-up. Although correlation between APA levels and prognosis has not been established in CAPS, Harris et al.  found a strong correlation between aCL-IgG isotype levels and subsequent arterial or venous thrombosis in patients with autoimmune disorders. Further studies are, of course, needed to establish the best therapy for CAPS.