The cardiac troponins form part of the regulatory mechanism for muscle contraction. Specific cardiac isoforms of cardiac troponin T and cardiac troponin I exist and commercially available immunoassay systems have been developed for their measurement. A large number of clinical and analytical studies have been performed and the measurement of cardiac troponins is now considered the 'gold standard' biochemical test for diagnosis of myocardial damage. There have been advances in understanding the development and structure of troponins and their degradation following myocardial cell necrosis. This has contributed to the understanding of the problems with current assays. Greater clinical use has also highlighted areas of analytical and clinical confusion. The assays are reviewed based on manufacturers' information, current published material as well as the authors' in-house experience.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by intravascular hemolysis and venous thrombosis. Thrombosis is the most feared complication in PNH and is reported to occur in >40% of patients. Proposed mechanisms of thrombosis include depletion of the coagulation regulator nitric oxide (NO) by intravascular hemolysis and increased sensitivity of PNH platelets to activation. The occurrence of subclinical thrombosis in PNH patients has not been previously studied using modern imaging techniques. In order to evaluate for subclincal thrombosis we evaluated PNH patients with a comprehensive state-of-the-art MRI protocol (which included the use of both blood pool and conventional Gadolinium based contrast agents) for the detection of subclinical thromboses and its sequelae. The detailed protocol consisted of: lung perfusion and pulmonary MRA, cardiac MR - including quantitative studies of both ventricles, right heart flow dynamics and delayed enhancement for the detection of left ventricular damage, and abdominal MR for the assessment of hepatic and portal venous systems and kidneys. 10 PNH patients (median age 31.5 yrs) with large PNH clones but without previous clinical evidence of venous or arterial thrombosis underwent imaging. Five (50%) of the patients were on primary anticoagulant prophylaxis with warfarin. There was evidence of significant renal hemosiderosis, which was distributed throughout the cortices, in 8/10 patients. Two patients had small myocardial scars suggestive of previous unsuspected ischemic damage. Six patients had sub-segmental perfusion defects mainly distributed in the peripheries of the lung fields indicative of previous small pulmonary emboli. No such subclinical thromboses would be anticipated in an age-matched control population. 8 patients had mildly reduced right ventricular ejection fractions (mean 42.2±1.8%; normal range 48–63%). The plasma B-type natriuretic peptide (BNP) level was high in all 10 patients (median 29.4pmol/l; range 18.7–373.90; normal subjects 4.89±1.00pmol/l). BNP has been shown to increase in proportion to right ventricular dysfunction in pulmonary hypertenstion. No intraabdominal defects were identified with the current protocol. In summary, we identified abnormalities suggestive of previous subclinical thromboses in 6 of 10 hemolytic PNH patients by high-resolution MR imaging, including in patients on primary prophylaxis with warfarin. Effective prevention of thrombosis is an important aspect of the therapy in PNH.
The depletion of nitric oxide (NO) by cell-free plasma hemoglobin and arginase during intravascular hemolysis has been implicated in the dysregulation of vasomotor tone and the enhancement of procoagulant and prothrombotic activities. Pulmonary hypertension (PHT), an emerging common complication of hereditary hemolytic anemias, has been mechanistically and epidemiologically linked to intravascular hemolysis and NO depletion. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic and brisk hemolysis, as well as elevated cell-free plasma hemoglobin. We have previously reported that approximately 50% of PNH patients have PHT as measured by doppler echocardiograpy. Further, the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been generally demonstrated to be a sensitive and specific measure of right-sided cardiac stress due to PHT and has more recently been shown to be a strong predictor of pulmonary hypertension (PHT) and mortality in patients with hemolytic anemias (defined as NT-proBNP ≥ 160 pg/ml). Eculizumab, a terminal complement inhibitor, has been demonstrated to significantly and rapidly reduce hemolysis, thereby providing beneficial effects on regulation of smooth muscle tone and thrombosis in patients with PNH. To evaluate the efficacy of eculizumab in the regulation of cell-free plasma hemoglobin levels, nitric oxide depletion, and subsequent cardiovascular morbidities in patients with PNH. Levels of hemoglobinemia, arginase and nitric oxide depletion were assessed in 73 evaluable eculizumab- and placebo-treated PNH in the phase III randomized, placebo-controlled trial (TRIUMPH). In addition, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were assessed as a measure of PHT, and systolic and diastolic systemic arterial pressures were examined in eculizumab- and placebo-treated patients. At baseline, levels of lactate dehydrogenase (LDH), cell-free plasma hemoglobin, arginase 1 and arginase 1 enzyme activity were highly elevated compared to normal values. Levels of hemolysis and NO consumption were shown to be much greater in PNH (more than 6- and 10-fold, respectively) than in patients with other hemolytic diseases. There were substantial correlations between cell-free plasma hemoglobin levels and both LDH (R = 0.5094) and plasma consumption of nitric oxide (NO) (R = 0.9529). Strong correlations between arginase 1 and both cell-free plasma hemoglobin (R = 0.9367) and arginase 1 enzyme activity (R = 0.9081) were also demonstrated. Following eculizumab therapy, measures of hemolysis were significantly reduced from baseline, including LDH (2200 ± 158 to 327 ± 68 U/L) and cell-free plasma hemoglobin (98.8 ± 23.24 to 15.2 ± 5.05 mg/dL), while levels in placebo-treated patients remained unchanged; a concomitant reduction in NO consumption was also observed (see Figure). In addition, at baseline, 46.6% (34/73) of PNH patients in the TRIUMPH study had levels of NT-proBNP ≥ 160 pg/ml, indicating PHT in these patients. Eculizumab-treated patients showed a 50% reduction in the incidence of PHT over the course of the 26-week treatment period from 52.5% to 26.3%, while PHT did not change with placebo (39.4% to 43.8%; P<0.001). Additionally, eculizumab significantly improved dyspnea (EORTC-QLQ-C30) compared to placebo (Effect size 0.69; P=0.0002). Similarly, eculizumab treatment was associated with a concomitant decrease in systemic arterial blood pressure as compared to patients receiving placebo. To summarize, in patients with hemolytic anemia, the depletion of NO is associated with the development of cardiovascular morbidities, including PHT. The current data demonstrate that intravascular hemolysis in untreated patients with PNH is associated with high levels of plasma ferrous oxyhemoglobin, which stoichiometrically catabolizes NO, and high levels of plasma arginase 1, which catabolizes arginine – all leading to significant depletion of NO. We show a high prevalence of PHT in untreated patients with PNH as indicated by levels of NT-proBNP. Further, the data demonstrate that in a placebo-controlled study, the anti-hemolytic effect of chronic eculizumab treatment significantly increases nitric oxide bioavailability and reduces pulmonary hypertension. Figure. Effect of eculizumab on cell-free plasma hemoglobin and NO consumption Figure. Effect of eculizumab on cell-free plasma hemoglobin and NO consumption
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