Levels Of Degradation Products Research Articles

298: Admission Fibrin Degradation Product Level Predicts the Need for Massive Transfusion and Mortality in Adult Blunt Trauma Patients

When a large volume of coagulum generates in body cavity after blunt trauma, secondary fibrinolysis occurs and the serum level of fibrin degradation product (FDP) elevates immediately. Acute trauma coagulopathy associated with massive transfusion (MT) and mortality is characterized by anticoagulation and hyperfibrinolysis. On the hypothesis the admission FDP level correlates with the volume of coagulum and hyperfibrinolysis, we evaluated whether the admission FDP level is predictive of the need for MT and mortality in adult blunt trauma patients.

Stability of gabapentin 300-mg capsules repackaged in unit dose containers

The stability of a gabapentin 300-mg capsule product in the original bulk containers and repackaged in unit dose blister strips was studied. Both products were stored for one year under long-term storage conditions (25 degrees C and 60% relative humidity [RH]) and for three months under accelerated storage conditions (40 degrees C and 75% RH) and tested for weight change, potency, and dissolution using validated analytical method. The capsules in the original containers showed no change in weight during the study period. However, the repackaged drug product stored under long-term storage conditions and under accelerated storage conditions showed significant weight increases (p < 0.001) during the study period. No significant differences in potency between the original and repackaged drug products were detected. Potency exceeded 97% for the products stored under the long-term storage conditions and exceeded 95% for the products stored under the accelerated storage conditions. At 13 weeks, samples from the original container and the blister strips stored under the accelerated storage conditions showed quantitative levels of the lactam degradation product; however, these levels were within acceptable limits. No other difference was observed between the original and the repackaged drug products, and both products remained stable throughout the study period. Gabapentin 300-mg capsules in the original containers and repackaged in blister strips were stable up to one year under long-term storage conditions and up to three months under accelerated storage conditions.

Degradation of Lindane by Zero-Valent Iron Nanoparticles

Thus far, zero-valent iron has been studied mostly for the degradation of structurally simple one- and two-carbon halogenated organic contaminants such as chlorinated methanes, ethanes, and ethenes. In this research, laboratory synthesized particles of nanoscale iron were explored to degrade lindane, also known as γ-hexachlorocyclohexane, a formerly widely utilized pesticide and well-documented persistent organic pollutant. In general, lindane disappeared from aqueous solution within 24h in the presence of nanoiron concentrations ranging from 0.015to0.39g∕L. By comparison, approximately 40% of the initial lindane dose remained in solution after 24h in the presence of 0.53g∕L of larger microscale iron particles. However, the surface area normalized first-order rate constants were all within the same order of magnitude regardless of dose or iron type. A key reaction intermediate, γ-3,4,5,6-tetrachlorocyclohexene from dihaloelimination of lindane was identified and quantified. Trace levels of additional degradation products including benzene and biphenyl were detected but only in the high concentration experiments conducted in 50% ethanol. While up to 80% of the chlorine from the lindane molecules ended as chloride in water, only 38% of the expected chloride concentration was observed for the microscale iron experiment. This work together with previous published studies on the degradation of polychlorinated biphenyl, chlorinated benzenes, and phenols suggest that zero-valent iron nanoparticles can be effective in the treatment of more structurally complex and environmentally persistent organic pollutants such as lindane.

Calpain activation contributes to endotoxin-induced diaphragmatic dysfunction.

Calpain activation occurs in skeletal muscle in response to infection, but it is unknown if calpain inhibition improves muscle functional capacity. We hypothesized that infection induces diaphragm calpain activation, that calpain activation results in cleavage of important diaphragm cytoskeletal proteins, and that inhibition of calpain attenuates infection-induced diaphragm dysfunction. Mice (n = 4-6/group) were given: (1) saline (intraperitoneal); (2) endotoxin (12 mg/kg intraperitoneal); (3) calpain inhibitor peptide III (12 mg/kg intraperitoneal); and (4) endotoxin (12 mg/kg) plus calpain inhibitor peptide III (12 mg/kg). At 24 hours, diaphragms were removed and the following determined: (1) calpain activity by fluorogenic assay; (2) calpain I and II protein levels; (3) talin protein levels; and (4) the force-frequency relationship. Endotoxin significantly increased diaphragm calpain activity (P < 0.001), active calpain I protein (P < 0.001), active calpain II protein (P < 0.01), levels of a calpain-specific cleavage talin degradation product (P < 0.003), and reduced diaphragm force (P < 0.001). Calpain inhibitor III administration prevented endotoxin-induced increases in calpain activity, reduced talin degradation, and attenuated reductions in diaphragm force. Diaphragm-specific force at 150 Hz stimulation was significantly higher in control, endotoxin plus calpain inhibitor III, and calpain inhibitor III alone groups (23 +/- 1, 20 +/- 1 and 23 +/- 1 N/cm(2), respectively) than in the endotoxin alone group (15 +/- 1 N/cm(2)) (P < 0.01). This model of sepsis results in significant diaphragm calpain activation and calpain-dependent diaphragm cytoskeletal protein cleavage. Moreover, calpain inhibition attenuates endotoxin-induced diaphragm weakness, suggesting that such inhibitors may be a potential treatment to improve respiratory muscle function in infected patients.

Hemostatic Abnormalities in Patients with Closed Head Injuries and Their Role in Predicting Early Mortality

Abnormalities of blood coagulation are frequently found in patients following traumatic brain injury. Exposure to thromboplastin, which is abundant in brain, plays an important role in initiating coagulopathy. Eighty patients of moderate-to-severe head injury were screened for platelet count, prothombin time (PT), activated partial thromboplastin time (a-PPTK), fibrinogen degradation product levels (FDP), D-dimer levels, and disseminated intravascular coagulation scores (DIC), calculated within the first 24 hours of injury. Increased consumptive coagulopathy at admission, as reflected by high DIC scores, predicted mortality in both moderate and severe head injury patients with a high degree of accuracy (p < 0.001). Similarly, increased PT, FDP, and D-dimer values correlated with higher mortality in both groups, but platelet counts and a-PPTK values correlated with mortality only in the severe head injury group. From this study we conclude that hemostatic abnormalities are independent predictors of early mortality in moderate-to-severe head injury patients.

Chemical characterization of a degradable polymeric bone adhesive containing hydrolysable fillers and interpretation of anomalous mechanical properties

An experimental, light-curable, degradable polyester-based bone adhesive reinforced with phosphate glass particles ((P 2O 5) 0.45(CaO) x (Na 2O) 0.55− x , x = 0.3 or 0.4 mol) or calcium phosphate (monocalcium phosphate/β-tricalcium phosphate (MCPM/β-TCP)) has been characterized. Early water sorption (8 wt.% at 1 week) by the unfilled set adhesive catalysed subsequent bulk degradation (4 wt.% at 2 weeks) and substantial decline in both elastic and storage moduli. Addition of phosphate glass fillers substantially enhanced this water sorption, catalysed greater bulk mass loss (40–50 and 52–55 wt.%, respectively) but enabled generation of a microporous scaffold within 2 weeks. The high levels of acidic polymer degradation products (38–50 wt.% of original polymer) were advantageously buffered by the filler, which initially released primarily sodium trimetaphosphate ( P 3 O 9 3 - ). Calcium phosphate addition raised polymer water sorption to a lesser extent (16 wt.%) and promoted intermediate early bulk mass loss (12 wt.%) but simultaneous anomalous increase in modulus. This was attributed to MCPM reacting with absorbed water and β-TCP to form more homogeneously dispersed brushite (CaHPO 4) throughout the polymer. Between 2 and 10 weeks, linear erosion of both polymer (0.5 wt.% week −1) and composites (0.7–1.2 wt.% week −1) occurred, with all fillers providing long-term buffer action through calcium and orthophosphate ( PO 4 3 - ) release. In conclusion, both fillers can raise degradation of bone adhesives whilst simultaneously providing the buffering action and ions required for new bone formation. Through control of water sorption catalysed filler reactions, porous structures for cell support or substantially stiffer materials may be generated.

The use of antifibrinolytic drugs to prevent early recurrent aneurysmal subarachnoid haemorrhage.

The purpose of the present study was to investigate the incidence of early recurrent haemorrhage and the survival rate in a series of 34 patients with aneurysmal subarachnoid haemorrhage treated with an antifibrinolytic drug (AMCA) for three weeks. The fibrinolytic activity in blood and CSF from these patients was determined before and at regular intervals during the treatment. The invariably high levels of fibrin degradation products in CSF noted before treatment showed that fibrinolysis was already increased, a finding also made in our previous investigations. Although the present clinical material was relatively small, the data obtained suggest that inhibition of fibrinolysis reduces the incidence of early recurrences during the preoperative period of patients eligible for surgical treatment and those conservatively treated. There were six recurrences in the series, but two of them occurred after the third week of treatment. In both cases the recurrence was ascribed to the fibrinolysis that had started again as soon as AMCA in the CSF was no longer demonstrable. In one patient the recurrence was not associated with increased FDP in CSF, and in the remaining three, the recurrence was presumably due to insufficient inhibition of local fibrinolysis in addition to hypertension. The fact that rebleeding occurred after the third week of treatment suggests the necessity of prolonging the prophylactic antifibrinolytic therapy to six weeks with gradual reduction of the dose of AMCA. During such reduction, however, it is imperative to examine the CSF repeatedly to check that complete inhibition of the local fibrinolysis is maintained. Such prophylactic treatment is useful in the management of cases in which operation must be postponed owing to the patient's poor general condition and in cases allocated to conservative treatment.

Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

IntroductionDisturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.MethodsIn this randomized controlled in vivo laboratory study rats were challenged intratracheally with S. pneumoniae, inducing pneumonia, and randomized to treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin or danaparoid, by means of nebulization.ResultsS. pneumoniae infection increased pulmonary levels of thrombin-antithrombin complexes and fibrin degradation products. All nebulized anticoagulants significantly limited pulmonary coagulopathy. None of the agents except danaparoid resulted in changes in systemic coagulopathy. Treatment with plasma-derived AT reduced outgrowth of S. pneumoniae and histopathologic damage in lungs. In vitro experiments confirmed outgrowth was reduced in bronchoalveolar lavage fluid (BALF) from rats treated with plasma-derived AT compared with placebo. Neutralizing of cationic components in BALF diminished the inhibitory effects on bacterial outgrowth of BALF, suggesting a role for cationic antimicrobial proteins.ConclusionsNebulization of anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia in rats while only danaparoid affects systemic coagulation. Nebulized plasma-derived AT reduces bacterial outgrowth and exerts significant lung-protective effects.

The Prothrombin Factor II G20210A Mutation with Pulmonary Thromboembolism and a Normal Level of Fibrin Degradation Products

The Prothrombin Factor II G20210A Mutation with Pulmonary Thromboembolism and a Normal Level of Fibrin Degradation ProductsDiagnosis of pulmonary thromboembolism (PTE) usually includes clinical pretest probability assessment, testing for specific degradation products of cross-linked fibrin (D-dimer) and imaging studies. Patients with radiological findings attributable to pulmonary infarction and normal D-dimer level, may present a diagnostic and therapeutic challenge. A 37-year-old Caucasian female had episodes of hemoptysis, and bilateral pulmonary nodular infiltrates on chest radiograph and computerized tomography. The plasma D-dimer level was normal, perfusion lung scan was not conclusive and histological examination of an open lung biopsy revealed recent thrombotic pulmonary infarction. She deteriorated and more perfusion defects were detected on perfusion lung scan. Genetic analysis revealed her to be a carrier of the prothrombin factor II (FII) G20210A mutation.

Renal vein lymphoma embolism in non-Hodgkin lymphoma

This report is, to the best of our knowledge, the first description of a case of non-Hodgkin lymphoma (NHL) which was accompanied by a renal vein lymphoma embolism. A 49-year-old female was admitted to our hospital complaining of a right axillary tumor 10 cm in diameter. Biopsy disclosed that the tumor was diffusely infiltrated by abnormal immunoblastic lymphocytes, which were positive for LCA, L26, CD10 and CD79a, but negative for UCHL-1, CD3, CD5, and Ki-1. Serum levels of lactate dehydrogenase 823 IU/L (normal range 110–220) and soluble interleukin-2 receptor 6,600 U/mL (220–530) were elevated. Coagulation tests, such as prothrombin time, activated partial thromboplastin time or plasma level of fibrin degradation products, showed normal results. Systemic examination identified splenomegaly and lymph node (LN) swelling at the hepatic hilum. Bone marrow study findings were normal. According to the WHO classification and Ann Arbor criteria, the patient was diagnosed with NHL, diffuse large B cell-type (DLBCL), stage IIIAXs. Two months after the initiation of combination chemotherapy, enhanced computed tomography (CT) identified an embolus in her left renal vein as a low density lesion (Fig. 1a). We diagnosed the embolus as a thrombus, and initiated anticoagulation therapy. For 8 months, the disease was refractory to multiple courses of combination chemotherapies, including a regimen of rituximab plus CHOP therapy, after which the patient died of systemic disease dissemination. Autopsy was performed in accordance with the guidelines of Matsushita Memorial Hospital and with the informed consent of the patient’s family. Macroscopically, multiple nodular lesions were identified in the right infra-axillary lesion, para-aortic lesion, stomach, uterus, right ovary, skin, pleura and mesenterium. Microscopic examination showed that nodules were uniformly infiltrated by lymphoma cells which were positive for LCA, L26, CD10, CD79a and Bcl-2. Approximately 30% of the lymphoma cells were also positive for MIB-1. Of particular interest was that the large embolus in the left renal vein was found to be a whitish tumor partially covered by a thrombus (Fig. 1b). The tumor was microscopically confirmed as lymphoma involvement (Fig. 1c–e). Microscopic examination also showed lymphoma cell infiltration in the left renal cortex and fat tissue around the left renal vein (Fig. 1f). Lymphoma embolus was not identified in other veins. Venous tumor embolism is occasionally complicated with solid cancers, such as hepatocellular carcinoma invading the portal vein or renal cell carcinoma invading renal veins, and these cancers tend to occur in the more advanced, later clinical phase. They have an unfavorable effect on treatment outcome due to further tumor cell dissemination, organ damage by inadequate blood flow, or venous rupture. DLBCL has a well-established variant entity termed intravascular lymphoma, which is characterized by exclusive or predominant intravascular tumor growth in the lumen of small to intermediate-sized blood vessels. However, tumor embolism in large veins is extremely rare, and, according to our search results, only five NHL cases have been reported with venous tumor embolism, three in the portal vein [1–3], one in the superior vena cava [4], and one in the internal saphenous vein [5], but no reports have been published on M. Yamamoto T. Kobayashi N. Uoshima Department of Hematology, Matsushita Memorial Hospital, 5-55, Sotojima-cho, Moriguchi 570-8540, Japan

Strongly increased levels of fibrinogen elastase degradation products in patients with ischemic stroke

Ischemic stroke is associated with leucocyte activation. Activated leucocytes release elastase, an enzyme that can degrade fibrinogen. Fibrinogen elastase degradation products (FgEDP) may serve as a specific marker of elastase proteolytic activity. In a case-control study of 111 ischemic stroke patients and 119 controls, significantly higher FgEDP levels were observed in cases than in controls, both in the acute phase and in the convalescent phase. Results were only slightly affected by adjustment for cardiovascular risk factors, C-reactive protein and fibrinogen. Our findings suggest that FgEDP might be involved in the pathogenesis of stroke.

Erosive arthritis in a patient with pycnodysostosis: An experiment of nature

The excellent poster painter Henri de Toulouse-Lautrec is the most famous patient with cathepsin K-deficient pycnodysostosis. Cathepsin K is believed to play a major role in osteoclast-driven bone resorption. In this study we explored the role of cathepsin K in bone resorption in a patient with a cathepsin K mutation causing pycnodysostosis in whom psoriatic arthritis also developed. We hypothesized that the patient would develop only inflammatory synovitis but would not develop bone erosions or other osteolytic changes. Monocytes from the patient with pycnodysostosis and normal control monocytes were isolated and stimulated to fuse and form multinuclear osteoclast-like cells, which were identified by evaluating messenger RNA expression of osteoclast markers. The ability to resorb bone was assessed by determining the extent of pit formation and levels of collagen degradation products generated by cathepsin K (C-terminal crosslinking telopeptide of type I collagen [CTX]) and matrix metalloproteinases (pyridinoline crosslinked C-terminal telopeptide of type I collagen). These experiments were also done in normal control cells after incubation with the cathepsin K inhibitor E64 during bone resorption. In contrast to our a priori hypothesis, the patient developed a mutilating disease with extensive bony erosions associated with lysis of some of the distal phalanges of her hands and feet. After stimulation of monocytes from this patient, the cells formed multinuclear tartrate-resistant acid phosphatase-positive and calcitonin receptor-positive multikaryons, which, however, totally lacked cathepsin K. These multinuclear cells were able to resorb bone but, in contrast to normal control osteoclasts, did not produce CTX. The resorption pattern was abnormal in that, unlike normal control osteoclasts, both osteoclasts from the patient and E64-inhibited osteoclasts did not leave extensive osteoclast trails, but were relatively sessile. In this "experiment of nature" we observed that cathepsin K is not necessary for bone degradation. These findings may be pertinent to our understanding of the functions of cathepsin K inhibitors, which are currently being developed as drugs to treat metabolic bone diseases.

Thrombotic thrombocytopenic purpura associated with myelodysplastic syndrome

Thrombotic thrombocytopenic purpura (TTP), a lifethreatening disseminated thrombotic microangiopathy (TMA) syndrome, is characterized by bicytopenias with thrombocytopenia and hemolytic anemia (HA) with schistocytes, neurological disturbances, acute renal failure, and pyrexia. It has an incidence of 2–7 per million person per year with a peak incidence between the ages of 30 and 40 [1, 2]. Myelodysplastic syndrome (MDS) is also characterized by multilineage cytopenias due to ineffective hematopoiesis, and predominantly affects the elderly with a peak incidence between the ages of 60 and 75. Compared with other disorders, such as aplastic anemia, phenomena secondary to leukemias, autoimmune disorders, such as systemic lupus erythematosus or Evans syndrome, viral infection, or adverse drug effects, both MDS and TTP are less common as causatives for multilineage cytopenias in young patients. This report describes a rare case of MDS associated with TTP in a young female presented with multilineage cytopenias. A 21-year-old female was referred to our hospital with complaints of purpura, petechiae, headache, numbness and pancytopenia. She was not pregnant, showed no sign of recent infection and had no recent history of drug exposure. Peripheral blood count findings were pancytopenia with white blood cells at 2.4 9 10/L (3.4–7.3 9 10) (neutrophils 47%, lymphocytes 44%, abnormal cells 0%), red blood cells at 2.21 9 10/L (3.62–4.99 9 10), hemoglobin at 7.3 g/dL (11.7–15.1) and platelet count of 20.0 9 10/L (160–327 9 10). Blood examination also demonstrated the presence of HA, shown by elevated serum levels of total bilirubin 2.2 mg/dL (0.2–1.0), and lactate dehydrogenase 453 IU/L (114–243), serum haptoglobin reduced to below detectable levels and the presence of schistocytes. Serum vitamin B12 and folic acid were normal, 384 ng/L (180–914) and 3.9 lg/L ([3.1), respectively. Coombs test, Ham test, and the cell surface expression of glycosyl phosphatidilinositol-anchored proteins were all negative. Other examinations showed no evidence of autoimmune disorders. Bone marrow (BM) examination revealed hypercellular marrow with 300 9 10/L BM nucleated cell counts, and multilineage dysplasia, such as pseudo-Pelger neutrophils or micromegakaryocytes, but with no abnormal increase of myeloblasts at 1.6% of all BM nucleated cells (Fig. 1). Chromosome aberration was not identified by either Gbanding or spectral karyotyping analysis. According to the WHO classification criteria, the patient was diagnosed as MDS, comprising refractory cytopenia with multilineage dysplasia (RCMD) [3]. One month later, she suddenly showed various neuropsychological symptoms, such as disorientation, aphypnia, and anxiety neurosis. Serum urea nitrogen and creatinine levels were normal, 21.1 mg/dL (8.0–23.0) and 0.7 mg/dL (0.4–1.2), respectively. Coagulation tests, such as prothrombin time, activated partial thromboplastin time, or plasma levels of fibrinogen or fibrin degradation product, were normal (data not shown), while a decrease in ADAMTS13 activity (\0.5%) and an increase in the autoantibody for ADAMTS13 (14 Bethesda unit/ml), which functions as an inhibitor of ADAMTS13, were detected in her serum. We diagnosed her as having N. Sasaki J. Kuroda (&) M. Taniwaki Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan e-mail: junkuro@koto.kpu-m.ac.jp

Plume persistence caused by back diffusion from thin clay layers in a sand aquifer following TCE source-zone hydraulic isolation

This paper concludes that back diffusion from one or a few thin clayey beds in a sand aquifer can cause contaminant persistence above MCLs in a sand aquifer long after the source zone initially causing the plume is isolated or removed. This conclusion is based on an intensive case study of a TCE contaminated site in Florida, with the processes evaluated using numerical modeling. At this site, the TCE DNAPL zone formed decades ago, and was hydraulically isolated by means of an innovative system performing groundwater extraction, treatment and re-injection. Treated water is re-injected in a row of injection wells situated a short distance downgradient of the extraction wells, creating a clean-water displacement front to efficiently flush the downgradient plume. This scheme avoids the creation of stagnation zones typical of most groundwater pump-and-treat systems, thereby minimizing the time for aquifer flushing and therefore downgradient cleanup. The system began operation in August 2002 and although the performance monitoring shows substantial declines in concentrations, detectable levels of TCE and degradation products persist downgradient of the re-injection wells, long after the TCE should have disappeared based on calculations assuming a nearly homogenous sand aquifer. Three hypotheses were assessed for this plume persistence: 1) incomplete source-zone capture, 2) DNAPL occurrence downgradient of the re-injection wells, and 3) back diffusion from one or more thin clay beds in the aquifer. After careful consideration, the first two hypotheses were eliminated, leaving back diffusion as the only plausible hypothesis, supported by detailed measurements of VOC concentrations within and near the clay beds and also by numerical model simulations that closely represent the field site hydrogeologic conditions. The model was also used to simulate a more generalized, hypothetical situation where more thin clayey beds occur in a sand aquifer with an underlying aquitard. While there is no doubt that DNAPL source mass reduction can eventually improve downgradient groundwater quality, the magnitude and time scale over which the improvement occurs is the major uncertainty given current characterization approaches. This study shows that even one thin clay bed, less than 0.2 m thick, can cause plume persistence due to back diffusion for several years or even decades after the flux from the source is completely isolated. Thin clay beds, which have a large storage capacity for dissolved and sorbed contaminant mass, are common in many types of sandy aquifers. However, without careful inspection of continuous cores and sampling, such thin clay beds, and their potential for causing long-term back-diffusion effects, can easily go unnoticed during site characterization.

Detection/exclusion of deep vein thrombosis (DVT) in post-operative patients using plasma D-Dimer assay

Background Measurement of plasma D-Dimer (fibrinogen degradation product) levels is an easy & effective modality of ruling out deep vein thrombosis in post-operative patients. The present study intended to evaluate the diagnostic reliability of D-dimer assay in detecting deep vein thrombosis in post-operative general surgical patients by following the assay with a Doppler sonography in the same setting.

Usefulness of Fibrinogen/Fibrin Degradation Product to Predict Poor One-Year Outcome of Medically Treated Patients With Acute Type B Aortic Dissection

Previous studies have indicated that medical therapy provides excellent outcomes for patients with uncomplicated Stanford type B acute aortic dissection. However, affected aortas are often compromised by aneurysmal dilatation and rupture, resulting in poor outcomes. The purpose of this study was to determine predictors of aortic events in patients with Stanford type B acute aortic dissection receiving conservative medical therapy. The study group consisted of 78 consecutive patients with Stanford type B acute aortic dissection who were admitted to the hospital within 48 hours of onset. These patients were treated medically and followed up for 1 year. Aortic events were defined as rupture, recurrent dissection, aortic expansion with diameter>or=60 mm, rapid aortic expansion at a rate of >or=10 mm/yr, and the development of visceral or limb ischemia. Predictors of these events were determined using multivariate analyses. During 1-year follow-up, aortic events were observed in 13 (17%) patients, including aortic rupture in 3 (4%), aortic diameter>or=60 mm in 4 (5%), rapid expansion of the aorta in 3 (4%), and the development of visceral or limb ischemia in 3 (4%). On multivariate analysis, fibrinogen-fibrin degradation product level>or=20 microg/ml (odds ratio 7.802, 95% confidence interval 1.405 to 43.335) on admission was the only independent predictor of aortic events at 1 year. In conclusion, careful monitoring is required for patients with medically treated Stanford type B acute aortic dissection associated with fibrinogen-fibrin degradation product level>or=20 microg/ml on admission.

DISSEMINATED INTRAVASCULAR COAGULATION CADE

Disseminated intravascular coagulation (DIC) is a syndrome of deposition of platelet-fibrin thrombi in the microcirculation, with consumption of platelets and clotting factors and possible clinical features of bleeding or thrombosis or both. It may be produced by activation of coagulation, platelet aggregation or endothelial damage. It is not a primary disease, but a common and important complication of many serious illnesses, especially sepsis, carcinoma and obstetrical accidents. Shock and acidosis are frequent precipitating factors, and vitamin K deficiency is a common complicating factor. DIC usually produces no clinical features, but it may give rise to bleeding, ischemic organ damage or shock. Although its clinical contribution is often difficult to separate from that due to the underlying disease, DIC remains the commonest cause of a generalized bleeding tendency in acutely sick patients. Laboratory confirmation consists of the demonstration of thrombocytopenia, coagulation impairment, hypofibrinogenamia, raised levels of fibrin degradation products, and positive results of para-coagulation tests. The most important therapeutic measure is control of the underlying disease, but replacement therapy and heparin may be required, especially if bleeding is significant and the process is not acute and self-limited.

Correlation between dialysis solution type and cardiovascular morbidity rate in patients undergoing continuous ambulatory peritoneal dialysis

Peritoneal dialysis (PD) patients have an increased risk for cardiovascular diseases. The aim of the study was to evaluate the cardiovascular changes in patients undergoing chronic PD and the eventual existing differences depending on biocompatibility of dialysis solutions. After 3 +/- 2 years of starting PD, 21 PD patients on the treatment with bioincompatible dialysis solutions (conventional glucose- based solutions: PDP-1), average age 47.43 +/- 12.87 years, and 21 PD patients on the treatment with biocompatible dialysis solutions (neutral solutions with lower level of glucose degradation products, lower concentration of Ca2+ and neutral pH: PDP-2), average age 68.62 +/- 13.98 years, participated in the longitudinal study. The average number of episodes of peritonitis was similar in both groups: 1 episode per 36 months of the treatment. The control group included 21 patients with preterminal phase of chronic renal failure (Glomerular Filtration Rate: 22.19 +/- 10.73 ml/min), average age 65.29 +/- 13.74 years. All the patients underwent transthoracal echocardiography (in order to detect: eject fraction (EF), left ventricular hypertrophy (LVH), and valvular calcification (VC) and B-mode ultrasonography of common carotid artery (CCA): IMT, lumen narrowing, and plaque detection. The values of EF were: in PDP-1 group 62.05 +/- 5.65%, in PDP-2 group 53.43 +/- 7.47%, and in the control group 56.71 +/- 8.12% (Bonferroni test, p = 0.001). The recorded LVH was: in PDP-1 group in 47.6% of the patients; in PDP-2 group in 61.9% of the patients; and in control the group in 52.4% (chi2 test; p = 0.639). The detected VC was: in PDP-1 in 52.4% of the patients, in PDP-2 group in 42.9% of the patients, and in the control group in 23.8% of the patients (chi2 test; p = 0.776). The IMT was: in PDP-1 group 1.26 +/- 0.54 mm, in PDP-2 group 1.23 +/- 0.32, and in the control group 1.25 +/- 0.27 mm (Bonferroni test; p = 0.981). An average lumen narrowing was: in PDP-1 group 13.78 +/- 18.26%, in PDP-2 group 18.57 +/- 22.98%, and in the control group 25.00 +/- 28.02% (Kruskal Wallis test; p = 0.413). Calcified plaques of CCA were detected in PDP-1 group in 61.9% of the patients, in PDP-2 group in 85.7%, of the patients and p = 0.159). Generally, PD had a significant influence on cardiovascular morbidity in the treated patients, especially on the left ventricular function and peripheral atherosclerosis. The age of the patients had more influence on acceleration of atherosclerosis than the length of dialysis or biocompatibility of dialysis solutions.

The value of proteomics for the diagnosis of a platelet-related bleeding disorder

Familial bleeding problems are frequently difficult to diagnose because currently used clinical tests cannot identify intracellular molecular defects of platelets. Using platelet proteomics, a comprehensive analytical tool, we diagnosed a family with severe bleeding problems of unknown origin with Quebec Platelet Disorder. Prior to proteomic analysis, we determined platelet counts, presence of glycoprotein (GP) Ib and GPIIb/IIIa, platelet aggregation, dense granule content and release, plasma levels of fibrinogen, Factor XIII and fibrin degradation products in four family members. Abnormalities were detected in platelet aggregation studies, which revealed variably reduced responses to ADP, collagen and epinephrine with concomitantly decreased ATP/serotonin secretion. In addition, D-dimer levels were significantly elevated 72 hours after in vitro thrombin stimulation of platelet-rich plasma. Together with the autosomal dominant inheritance and the delayed onset of bleeding in two of the four patients these results did not support any known platelet disorder. Therefore, the proteome of platelet lysates separated by one-dimensional SDS-PAGE was analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet proteomics showed reduced amounts of α-granule proteins multimerin, fibrinogen and thrombospondin-1 in patient compared to control samples suggestive of Quebec Platelet Disorder. The diagnosis of Quebec Platelet Disorder was confirmed by urokinase-specific Western blots. Urokinase causes the degradation of α-granule proteins in this disorder. Diagnosis of rare bleeding disorders has important implications for prophylactic and acute treatment of bleeding patients. This is the first report using proteomics to identify a familial platelet defect.

Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats*

Alveolar fibrin deposition is a hallmark of pneumonia. It has been proposed that natural inhibitors of coagulation, including activated protein C, antithrombin, and tissue factor pathway inhibitor, exert lung-protective effects via anticoagulant and possibly anti-inflammatory pathways. We investigated the role of these natural anticoagulants in Streptococcus pneumoniae pneumonia. A controlled in vivo laboratory study. Research laboratory of a university hospital. Total of 98 male Sprague-Dawley rats. Rats were challenged intratracheally with S. pneumoniae (serotype 3, 10(6) colony forming units), inducing pneumonia. Rats were randomized to intravenous treatment with normal saline, activated protein C, antithrombin, tissue factor pathway inhibitor, heparin, or tissue-type plasminogen activator. Rats infected with S. pneumoniae had increased thrombin-antithrombin complexes in bronchoalveolar lavage fluid, with decreased levels of antithrombin activity and fibrin degradation products. Administration of activated protein C, antithrombin, and tissue factor pathway inhibitor significantly limited these procoagulant changes. Furthermore, antithrombin treatment resulted in less bacterial outgrowth of S. pneumoniae and less histopathologic damage in lungs. Anticoagulant treatment attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. Antithrombin seems to exert significant lung-protective effects in pneumococcal pneumonia in rats.