Neutralizing autoantibody against factor XIII A subunit resulted in severe bleeding diathesis with a fatal outcome - characterization of the antibody.

UNLABELLED: Essentials Autoantibody against factor XIII (FXIII) is a rare but severe acquired hemorrhagic diathesis. In an elderly patient, anti-FXIII-A antibody led to severe bleedings with fatal outcome. The neutralizing autoantibody bound to FXIII with high affinity (Ka≈10(9) m(-1) ). The dominant effect of the autoantibody was the inhibition of activated FXIII. SUMMARY: Autoantibodies may develop against the catalytic A subunit of factor XIII (FXIII-A) or the carrier B subunit (FXIII-B). Autoimmune FXIII-A deficiency was diagnosed in an elderly (75 years) patient with severe bleeding symptoms. The patient had 3% FXIII activity, and unmeasurable FXIII-A2 B2 and FXIII-A antigens in the plasma, whereas, in the platelet lysate, activity and FXIII-A antigen values were normal. As revealed by western blotting, FXIII antigen was present in the plasma, but the autoantibody interfered with the immunoassays. A mixing study indicated the presence of inhibitor with a titer of 63.2 Bethesda units (BU). The patient's IgG bound to FXIII-A2 B2 and to FXIII-A2 with equally high affinity (Ka in the range of 10(9) m(-1) ). It exerted a multiple inhibitory effect on FXIII activation/activity (IC50: 50 µg mL(-1) ). Immunosupressive therapy gradually decreased the autoantibody titer to 8.0 BU, but FXIII activity remained very low, and, owing to recurrent bleeding, the patient died.

Potential therapeutic targeting of platelet-mediated cellular interactions in atherosclerosis and inflammation.

Cellular interactions among platelets, leukocytes and endothelial cells are considered as a major cause of inflammation and atherosclerosis in many diseases. Via exposed surface receptors and released soluble substances, activated platelets play a crucial role in the initiation of inflammatory processes, resulting in endothelial injury and leading to formation of atherosclerotic plaque with possible thrombotic complications. Classic anti-platelet treatments (e.g. cyclooxygenase inhibitor or ADP-receptor antagonist) have favorable effects in patients with vascular diseases, but they also have several limitations such as increased bleeding risk or non-responsiveness. Thus, the need and opportunities for developing novel therapeutic inhibitors for platelet-mediated events are obvious. Animal and (pre)clinical human studies have suggested that some recently produced specific antagonists of P-selectin from α-granules, as well as its main ligand/receptor P-selectin Glycoprotein Ligand-1, the two major platelet chemokines CXCL4 and CCL5, as well as CD40L, may be considered potential new candidates in the treatment of atherogenesis and inflammation. In this review, we summarize the pathophysiological roles of these effectors in platelet activation and acute or chronic inflammation, and discuss the latest findings on promising antagonistic agents in basic and clinical studies in the prevention of platelet-mediated cellular interactions.

Antiphospholipid antibodies in acute coronary syndrome.

Antiphospholipid (aPL) antibodies entailing anticardiolipin (aCL) and anti-beta2 glycoprotein I (anti-beta2GPI) antibodies may be involved in a number of vascular diseases including coronary artery diseases (CAD) or stroke. Here we assessed the presence of aPL antibodies in acute coronary syndrome (ACS). The frequency of anti-beta2GPI antibodies was significantly higher (14.4%) in ACS in comparison to control healthy subjects (2%). In addition, serum concentrations of anti-beta2GPI antibodies were also increased in ACS. Anti-beta2GPI antibodies of the IgA isotype might be the most relevant for the onset and outcome of ACS. Regarding subclasses of ACS, anti-beta2GPI IgA antibodies were elevated in unstable angina (UA) and myocardial infarction with ST elevation (STEMI), but not in myocardial infarction without ST elevation (NSTEMI). The involvement of anti-beta2GPI antibodies in ACS was more pronounced in men than women, and in younger rather than older patients. Finally, anti-beta2GPI antibodies in ACS were associated with previous stroke, but not with hypertension or previous myocardial infarction. Thus, anti-beta2GPI antibodies may be involved in the thrombotic events underlying ACS.

Comparison of the O'Brien filter test and the PFA-100 platelet analyzer in the laboratory diagnosis of von Willebrand's disease.

Von Willebrand's disease (vWD) is the most common congenital haemorrhagic diathesis, characterized by the quantitative or qualitative disorder of von Willebrand factor (vWF). A number of methods have been used for the diagnosis of the disease, and the bleeding time determination is widely accepted as a screening test in spite of its low sensitivity. Our aim was to evaluate and compare the performance of two high shear systems (the O'Brien filter test and the PFA-100 device) in the screening and diagnosis of vWD. Thirty patients (n=13 type 1 with mild symptoms, n = 9 type 1 with severe symptoms, n = 2 type 2A, n = 3 type 2B and n = 3 type 3 vWD) and twenty controls were investigated. In mild vWD the platelet retention in the second phase of the filter test with citrated blood showed the highest sensitivity (91.6%). The sensitivity of the PFA-100 method with collagen-epinephrine cartridges in this group was 76.9%, while the bleeding time was prolonged only in 15.4% of the cases. In severe type 1, in type 2A and type 3 all functional tests reflected the bleeding tendency of the patients. In type 2B disease the bleeding time was prolonged only when the patient was thrombocytopenic, but both high shear systems revealed the disease independently of the presence of thrombocytopenia. The overall sensitivity of the bleeding time determination was 50% compared to the 80-90% sensitivity of the O'Brien filter test and the PFA-100 system. The sensitivity values of the filter test and the PFA-100 device with collagen-epinephrine cartridges were in the same range, but the collagen-ADP cartridges showed a lower (65.5%) sensitivity, though the results were specific and had high positive predictive value. We conclude that both high shear systems are suitable for the screening of vWD, and that they are superior to the traditional bleeding time determination in case of mild disease or type 2B vWD.

[High-shear force-induced platelet aggregation in the screening and diagnosis of von Willebrand disease]. / A nagy nyíróerejü áramlási viszonyokat vizsgáló módszerek szerepe a von Willebrand-betegség szürésében és diagnosztikájában.

Von Willebrand's disease (vWD) is the most common congenital haemorrhagic diathesis, characterized by the quantitative or qualitative disorder of von Willebrand factor (vWF). A number of methods have been used for the diagnosis of the disease, and the bleeding time determination is widely accepted as a screening test in spite of its low sensitivity. Our aim was to evaluate and compare the performance of two high shear systems (the O'Brien filter test and the PFA-100 device) in the screening and diagnosis of vWD. Thirty patients (n = 13 type 1 with mild symptoms, n = 9 type 1 with severe symptoms, n = 2 type 2A, n = 3 type 2B and n = 3 type 3 vWD) and twenty controls were investigated. In mild vWD the platelet retention in the second phase of the filter test with citrated blood showed the highest sensitivity (91.6%). The sensitivity of the PFA-100 method with collagen-epinephrine cartridges in this group was 76.9%, while the bleeding time was prolonged only in 15.4% of the cases. In severe type 1, in type 2A and type 3 all functional tests reflected the bleeding tendency of the patients. In type 2B disease the bleeding time was prolonged only when the patient was thrombocytopenic, but both high shear systems revealed the disease independently of the presence of thrombocytopenia. The overall sensitivity of the bleeding time determination was 50% compared to the 80-90% sensitivity of the O'Brien filter test and the PFA-100 system. The sensitivity values of the filter test and the PFA-100 device with collagen-epinephrine cartridges were in the same range, but the collagen-ADP cartridges showed a lower (65.5%) sensitivity, though the results were specific and had high positive predictive value. We conclude that both high shear systems are suitable for the screening of vWD, and that they are superior to the traditional bleeding time determination in case of mild disease or type 2B vWD.

Leiomyoma of The Ciliary Body and Hemangiopericytoma of the Choroid.

Two unusual uveal tumors occurring in eyes enucleated for presumed malignant melanoma are discussed. One was a leiomyoma of the ciliary body, affecting a 22-year-old female, the other a hemangiopericytoma of the choroid in an 84-year-old male patient. The latter case is the fourth intraocular hemangiopericytoma reported in the literature to date. The histopathologic diagnosis was confirmed by immunohistochemistry and electron microscopy.

[Case reports on the problem of atypical roentgen pictures in lung tuberculosis]. / Kasuistische Beiträge zum Problem "nichttypischer" Röntgenbilder bei Lungentuberkulose.

With four cases the authors are demonstrating radiographic findings showing that pulmonary tuberculosis has changed its pattern in the recent period. The reasons are analyzed by reviewing literature. Also in " nontypical " roentgenograms tuberculosis must be remembered. Even in future the x-ray picture will remain an important part of finding and identifying this disease, but bacteriological examinations by smear and culture are the essential parts of diagnosis. In cases of x-ray pictures apparently noncharacteristic intensive examinations by bronchological methods or percutaneous needle biopsy may become necessary.

Postocclusion hyperemia in the isolated fibrillating blood-perfused dog heart.

Reactive hyperemia following occlusions of 15, 30, 60 and 120 sec duration was studied in the left coronary vascular bed of the isolated fibrillating dog heart perfused with arterial blood at constant pressure or constant volume. Except for repayment, linear correlations were found between occlusion time and the characteristics of reactive hyperemia. At a basal perfusion pressure of 50 mm Hg the postocclusion reaction was absent. The maximum hyperemic response was observed at 100 mm Hg, while on a further increase of perfusion pressure reactive hyperemia decreased. The postocclusion reaction was more marked but of briefer duration under constant pressure perfusion. The results can be explained by the joint effects of metabolic, myogenic, and physical factors on coronary vascular tone.

Regulation of myocardial oxygen consumption by perfusion pressure in isolated fibrillating canine heart.

In order to evaluate whether perfusion pressure or coronary flow affect myocardial oxygen metabolism, oxygen consumption of the isolated fibrillating blood-perfused canine heart was investigated at perfusion pressures of 100, 150, and 200 mm Hg. To obtain different coronary flow rates at a given coronary perfusion pressure, alpha-adrenergic blockade by phenoxybenzamine (10 mg/kg b.w.) was applied, resulting in an increase in coronary flow and a decrease in myocardial oxygen extration. Myocardial oxygen consumption was increased by elevation of perfusion pressure in both the control and phenoxybenzamine-pretreated group. At the same level of perfusion pressure there was no significant difference between the oxygen consumption of control and phenoxybenzamine-pretreated preparations. It can be concluded that in the isolated fibrillating canine heart oxygen consumption is primarily regulated by perfusion pressure, and is independent from coronary blood flow.

Effect of external compression on the postocclusion hyperaemic response of the coronary arteries in the isolated fibrillating dog heart.

The effect of external compression on the postocclusion hyperaemic responses (occlusion time 15, 30, 60 sec) has been studied on the fibrillating canine heart. The heart was placed in a closed organ box containing physiological saline solution, and the coronaries were perfused with blood from a donor dog using a constant volume perfusion technique at 150 mmHg perfusion pressure. The pressure in the organ box varied between 0--50 mmHg. As the compression pressure increased in the organ box, coronary blood flow, basal conductance as well as the parameters of the postocclusion hyperaemic reaction (peak conductance, reactivity, mean transit time of hyperaemia, postocclusive conductance area, and repaymen) decreased. The factors (tissue diffusion, tissue pressure, transmural pressure) at the capillary level can influence the regulation of the postocclusion vasodilatation and the results cannot be explained by metabolic and/or myogenic processes alone.

Effect of vasopressin on myocardial reactive hyperaemia in the isolated fibrillating dog heart.

The effect of 0.15 IU/min vasopressin (VA) administered intracoronarily on postocclusion reactions following 15 sec, 30 sec, 60 sec, and 120 sec occlusions of the left coronaries of the isolated fibrillating dog heart were studied at constant pressure or constant volume perfusion with arterial blood of another dog. Basal perfusion pressure was kept at the level of 150 mmHg. Preocclusion state and postocclusion reactions were characterized by changes in coronary conductance. Peak conductance, maximum conductance, reactivity, time to peak conductance, mean transit time and repayment were computed for characterizing reactive hyperaemia. In the control state the post-occlusive conductance--time curve was higher, but shorter in duration with constant pressure perfusion than with constant volume perfusion. Upon the administration of VA, basal conductance decreased considerably while with constant pressure perfusion the hyperaemic reactions underwent hardly any change. In contrast, using constant volume perfusion, the duration of reactive hyperaemia was shortened by VA. Consequently, the differences in mean transit time observed in the controls resulted from the unequal perfusion techniques disappeared on the application of VA. On both constant pressure and constant volume perfusion, maximum conductance decreased as a result of the decrease in basal conductance, therefore the reactivity of the coronary vessels increased markedly. It is concluded that myogenic vasorelaxation may contribute to reactive hyperaemic responses not only on brief, but also on prolonged occlusion. The basal vascular tone is of importance in the coronary adaptation to ischaemia.

Effect of norepinephrine on myocardial reactive hyperaemia in the isolated fibrillating dog heart.

The effect of intracoronary norepinephrine (NE) infusion in a dose of 2 microgram/min on postocclusion hyperaemic reactions following occlusions of 15 sec, 30 sec, 60 sec, and 120 sec was studied on isolated fibrillating, blood-perfused canine hearts. Basal perfusion pressure was kept at the level of 150 mm Hg; perfusion was done with constant pressure or constant volume. During administration of NE, basal flow and basal coronary conductance increased with both perfusion techniques. In the postocclusion period during administration of NE, peak conductance, maximum conductance, reactivity, mean transit time of reactive hyperaemia, postocclusive conductance area and repayment decreased. The differences found in postocclusion reactions in the control state originated from the different perfusion techniques disappeared when NE was infused. The phenomena may be explained by the stimulation of alpha and beta receptors as well as of myocardial metabolism by NE. The results support earlier views which ascribe a decisive role to vasoactive metabolites in the postocclusion reaction after prolonged occlusions. The decrease in reactive hyperaemia by NE may contribute to the development of angina pectoris.