Variability in response to clopidogrel: where is the threshold for 'low response'?: reply

We appreciate to read Dr Komócsís comments toour article entitled ‘Low response to clopidogrel is associatedwith cardiovascular outcome after coronary stent implantation’. He critically remarked the mortality rate in our study. Indeed,we found an all-cause mortality of 5.2% within 3 months (cardiovascularmortality: 3.9%). However, it is worthy to note that we investigatedan unselected patient collective with moderate- to     

Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy

Background  

Hypophosphatasia (HP) is characterized by a genetic defect in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and predominantly an autosomal recessive trait. HP patients suffer from reduced bone mineralization. Biochemically, elevated concentrations of substrates of TNSALP, including pyridoxal-5'-phosphate and inorganic pyrophosphate occur in serum, tissues and urine. The latter has been associated with chronic inflammation and hyperprostaglandinism.     

Akuter thrombembolischer ST-Hebungs-Infarkt bei einem Patienten mit essenzieller Thrombozytose

A 48-year-old man presented with acute chest pain and a greatly increased platelet count. Emergency coronary angiographc revealed thrombotic occlusion of the right coronary artery. Coronary angioplasty and stenting were successfully combined with intracoronary abciximab administration. Due to inadequate postinterventional platelet inhibition an intensified dual antiplatelet therapy with acetylsalicylic acid (ASS) and clopidogrel was applied to prevent stent thrombosis. Due to the thrombo-embolic complication and a platelet count over 1 million/µl a cytoreductive treatment with hydroxyurea was initiated.     

Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation

BACKGROUND: Monocyte activation induces different procoagulant and proadhesiveinflammatory responses and thus may play a role in thromboticcomplications after coronary interventions. Monocyte-plateletinteraction may trigger these effects inducing monocyte activation. AIMS: To characterize the effect of antiplatelet vs anticoagulationtherapy on monocyte-platelet interaction and monocyte functionafter intracoronary stenting. METHODS AND RESULTS: Immediately before, and during the first 12 days after successfulcoronary stenting, monocyteplatelet conjugates and monocytefunction were assessed by flow cytometric detection of GPIIb/IIIa(CD41) on monocytes and by monocyte surface exposure of Mac-1(CD11b/ CD18) and L-selectin (CD62L). Twenty patients receivingcombined antiplatelet therapy (ticlopidine, aspirin) were comparedto 20 patients with standard anticoagulation (phenprocoumon,overlapping heparin, aspirin). Before stenting, monocyte-plateletconjugates and Mac-1 surface expression in both groups weresignificantly increased, while L-selectin was significantlydiminished. Anticoagulation did not change these variables significantlyduring the subsequent 12 days. In contrast, antiplatelet therapyreduced platelet-monocyte conjugates by 46±9·3%(mean±SEM, P=0·0019) within 4 days, which wasassociated with a decrease in Mac-1 expression (28±6·7%,P=0·0013) and an increase in L-selectin (56±15·0%,P=0·0061). CONCLUSION: After intracoronary stenting, combined antiplatelet therapy,but not anticoagulation, causes reduction of monocyte-plateletinteraction, which is associated with monocyte deactivation.This may contribute to a decreased risk for thrombotic events.     

Absolute concentrations of high-energy phosphate metabolites in normal,hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy

OBJECTIVE: The purpose of the present study was to measure absolute concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in normal, hypertrophied, and failing human heart. BACKGROUND: Conflicting evidence exists on the extent of changes of high-energy phosphate metabolites in hypertrophied and failing human heart. Previous reports using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) have quantified metabolites in relative terms only. However, this analysis cannot detect simultaneous reductions. METHODS: Four groups of subjects (n = 10 each), were studied: volunteers and patients with hypertensive heart disease (HHD), aortic stenosis, and dilated cardiomyopathy (DCM). Left ventricular (LV) function and mass were measured by cine magnetic resonance imaging. Absolute and relative concentrations of PCr and ATP were determined by (31)P-MRS with spatial localization with optimum point spread function. RESULTS: Left ventricular ejection fraction remained normal in HHD and aortic stenosis, but was severely reduced to 18% in DCM; LV mass was increased by 55%, 79%, and 68% respectively. In volunteers, PCr and ATP concentrations were 8.82 +/- 1.30 mmol/kg wet weight and 5.69 +/- 1.02 mmol/kg wet weight, and the PCr/ATP ratio was 1.59 +/- 0.33. High-energy phosphate levels were unaltered in HHD. In aortic stenosis, PCr was decreased by 28%, whereas ATP remained constant. In DCM, PCr was reduced by 51%, ATP by 35%, and reduction of the PCr/ATP ratio by 25% was of borderline significance (p = 0.06). Significant correlations were observed among energetic and functional variables, with the closest relations for PCr. CONCLUSIONS: In human heart failure due to DCM, both PCr and ATP are significantly reduced. Ratios of PCr to ATP underestimate changes of high-energy phosphate levels.     

Changes in membrane glycoproteins of circulating platelets after coronary stent implantation.

OBJECTIVES: To evaluate platelet function in patients with coronary stents. DESIGN: A non-randomised control trial in 30 patients who had immediate implantation of Palmaz-Schatz coronary stents because of a suboptimal angioplasty result. All patients received a standardised anticoagulation regimen including intravenous heparin (activated partial thromboplastin time (APTT) 80 to 120 s), oral vitamin K antagonist (target international normalised ratio (INR) of 3.5), and 100 mg aspirin twice daily. Platelet surface expression of glycoprotein IIb-IIIa, activated fibrinogen receptor, and P-selectin as well as binding of von Willebrand factor and fibrinogen were determined by flow cytometry in peripheral venous blood samples collected before the intervention and then daily for 4 days after it. The results were compared with those in 30 patients undergoing elective coronary balloon angioplasty. SETTING: University hospital. RESULTS: After coronary stenting surface expression of the activated fibrinogen receptor significantly increased, peaking at day 2 (P < 0.001). Similar results were found for von Willebrand factor binding and P-selectin surface expression, with a maximum at day 2 to 4 after stenting (von Willebrand factor, P < 0.001; P-selectin, P < 0.001). The changes in platelet membrane glycoproteins coincided with a significant drop in peripheral platelet count after stent placement (P < 0.01). No significant change in fibrinogen receptor activity, von Willebrand factor binding, P-selectin surface expression, or platelet count was seen in the control group. CONCLUSIONS: The present study shows that current anticoagulation treatment is inefficient in suppressing platelet activation in patients with coronary stents and, therefore, might not be the best treatment for reducing the incidence of subacute stent thrombosis.     

Severity of multiple organ failure (MOF) but not of sepsis correlates with irreversible platelet degranulation

Summary Multiple hemostatic changes occur in sepsis and multiple organ failure (MOF). To evaluate the role of platelets in patients with sepsis and MOF, we examined changes in surface glycoproteins on circulating platelets of 14 patients with suspected sepsis and MOF. The severity of sepsis and MOF was assessed by the Elebute and APACHE II scoring systems, respectively. Using flow cytometric techniques and platelet specific monoclonal antibodies, platelet surface expression of fibrinogen receptor on GPIIb-IIIa, of von Willebrand Factor receptor GPIb, and of granule glycoproteins (thrombospondin (TSP), GMP-140, GP53) was measured. Plasma membrane expression of GPIIb-IIIa and GPIb on circulating platelets was not affected by sepsis or MOF. Septic patients, however, showed a significantly elevated fibrinogen receptor activity (LIBS1 expression) (p<0.05) that correlated with severity of disease (r=0.597, p=0.043). No significant change in surface expression of granule glycoproteins (TSP, GMP-140, GP53) was noted in septic patients. In contrast, degranulation of granule glycoproteins was significantly elevated in MOF (p<0.05) which correlated well with severity of MOF (GMP-140, r=0.611, p=0.013; TSP, r=0.643, p=0.026). We speculate that platelets in sepsis circulate in a hyperaggregable but still reversible state that results in increased risk of microthrombotic events. In the course of the disease, irreversible platelet degranulation of adhesion molecules occurs that may play an important role in the development of MOF.

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Schweregrad des Multiorganversagens (MOV) jedoch nicht der Sepsis korreliert mit irreversibler Degranulation zirkulierender Thrombozyten

Zusammenfassung Ziel der vorliegenden Pilotstudie war es, die Thrombozytenfunktion von 14 Intensivpatienten mit unterschiedlicher Ausprägung von Sepsis und Multiorganversagen (MOV) zu untersuchen. Schweregrad der Sepsis und des MOV wurde anhand intensivmedizinischer Scoresysteme (APACHE II, Elebute) beurteilt. Die Thrombozytenfunktion wurde durch durchflußzytometrische Bestimmung von membranständigen Glykoproteinen (GPIIb-IIIa, GPIb, Thrombospondin (TSP), GMP-140, GP53) untersucht. Weder Sepsis noch MOV beeinflußten die Oberflächen-expression von GPIIb-IIIa oder GPIb. Die Aktivierung des Fibrinogenrezeptors war jedoch bei Sepsis deutlich erhöht (p<0.05) und korrelierte signifikant mit dem Schweregrad der Erkrankung (r=0,597, p=0,043). Eine signifikant gesteigerte Degranulation der Thrombozyten bei Sepsis konnte jedoch nicht beobachtet werden. Im Gegensatz dazu war die thrombozytäre Freisetzung von Granula-Glykoproteinen (TSP, GMP-140, GP53) bei MOV deutlich erhöht (p<0,05) und korrelierte mit dem Schweregrad der Erkrankung (GMP-140, r=0,611, p=0,013; TSP, r=0,643, p=0,026). Die Ergebnisse dieser Arbeit zeigen, daß Blutplättchen in Patienten mit Sepsis in einem aktivierten jedoch noch reversiblen Aggregationszustand zirkulieren (Aktivierung des Fibrinogenrezeptors), einhergehend mit einem erhöhten Risiko von Mikrothrombosen. Im Laufe der Erkrankung kann es zur gesteigerten Freisetzung und Oberflächenexpression von thrombozytären Glykoproteinen kommen, die eine entscheidende pathophysiologische Rolle in der Entwicklung von Mikrozirkulationsstörungen und MOV spielen könnten.

     

The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease.

AIMS: The aim of this clinical cross-sectional study was to investigate the cardiac interrelation of morphological and functional abnormalities in patients with Fabry disease. METHODS AND RESULTS: Fifty-one patients (5-78 years) were compared with 25 controls (8-77 years). In all subjects, end-diastolic thickness of the left ventricle was measured by echocardiography and ultrasonic peak systolic strain rate (SR) was extracted to assess regional myocardial function. Magnetic resonance imaging was performed to assess late-enhancement for the detection of myocardial fibrosis in Fabry patients (n=39). In patients, women <20 years of age had no hypertrophy, no late-enhancement, and normal radial and longitudinal function (SR longitudinal=-1.7+/-0.5 s(-1); P=n.s. compared with controls). Ten women, >20 years of age, had no hypertrophy, no late-enhancement, normal radial and longitudinal function in the septal wall, but reduced longitudinal function in the lateral wall (SR=-1.4+/-0.5 s(-1)). All male patients without hypertrophy and no late-enhancement had normal radial function but reduced longitudinal function in both the septal and lateral walls (SR=-1.3+/-0.3 s(-1)). Patients with hypertrophy but without late-enhancement (n=13) had reduced radial and longitudinal function. Twelve patients displaying hypertrophy and late-enhancement had severely reduced radial and longitudinal function (SR=-1.1+/-0.5 s(-1)). Two of them with the worst impairment of regional function (SR=-0.8+/-0.6 s(-1)) died in the follow-up period. CONCLUSION: These results illustrate the variation of morphological changes and its functional consequences in Fabry cardiomyopathy.     

Retroviral infection and selection of culture-derived platelets allows study of the effect of transgenes on platelet physiology ex vivo and on thrombus formation in vivo

Background- We recently reported the development of culture-derived (CD) platelets with the aim to express any protein of interest in these platelets. We now report a specific protocol of retroviral infection into the progenitor cells and subsequent selection, which allows to generate large amounts of highly homogenous transgene-expressing CD platelets and to study transgene function rapidly and reliably at large-scale ex vivo and in vivo settings. METHODS AND RESULTS: After retroviral infection and selection, the activation-dependent expression profile of surface markers, aggregation, and granule release were investigated. The function of transgene-expressing CD platelets, the precursor cells of which had been retrovirally infected, compared well to noninfected CD platelets or freshly isolated platelets. Hence, the retroviral infection protocol did not alter platelet physiology. In contrast, adenoviral infection of precursors to CD platelets resulted in marked functional alterations that obviated their use in analytic experiments. Additionally, sufficient amounts of selected CD platelets were generated to warrant intravenous injections into living mice. This approach permitted study of their adhesive profile at endothelial lesions and their effect on thrombus formation in vivo by intravital videofluorescence microscopy. CONCLUSIONS: The novel selection method allowed us to produce recombinant transgene-expressing platelets in sufficient amounts to study genetically modified platelets in vitro and in vivo.