bluuebunny/crossref_metadata_2025 huggingface dataset:
Heparin-Associated Thrombocytopenia: The Antibody Is Not Heparin Specific
Authors: Greinacher A , Michels I , Mueller-Eckhardt C
Published: July 2018

In this study the hypothesis was assessed whether heparin-associated thrombocytopenia (HAT) may be caused by an antibody dependent on polysulfated oligosaccharide epitopes, present not only on heparin but also on different polysulfated substances such as dextran sulfate and pentosan polysulfate. We found that the major factor for eliciting platelet activation with sera of HAT type II patients is neither the structure nor the AT III binding capacity of an oligosaccharide, but rather its grade of sulfation. This was shown by in vitro crossreactivity studies with 40 sera of HAT type II patients using unfractionated heparins, LMW heparins (Fragmin, Fraxiparin), enoxaparin, LMW heparinoid (Org 10172 and its subfractions), de-N-sulfated heparin, dermatan sulfate, dextran sulfate, pentosan polysulfate and dextran. Platelet activation was measured by the heparin induced platelet activation (HIPA) assay and the serotonin release assay (SRA). The platelet activating factor was isolated with the IgG fraction, but did not bind to heparin and dextran sulfate fixed to a solid phase. By isoimmune fixation electrophoresis a monoclonal gammopathy was ruled out in the three sera assessed. The in vivo effect of different LMW heparins and the heparinoid Org 10172 was observed in 10 patients with HAT type II. In a prospective study, a compatible heparin-like anticoagulant was selected for 10 HAT patients for whom further parenteral anticoagulation was required. The only substance that showed no crossreactivity in vitro was the LMW heparinoid Org 10172, which differs from heparin and LMW heparins by its low-grade sulfation. Upon treatment with the heparinoid, all 10 patients had a good clinical outcome, even if they had previously developed thromboembolic complications under LMW heparin administration. As Org 10172 contains a small amount of a LMW heparin-like substance (3%) this heparinoid should not be used in HAT patients without prior in vitro testing. We conclude that heparin-associated thrombocytopenia is not caused by a heparin-specific antibody and that a major factor contributing to the pathomechanism is the high grade of sulfation present in a variety of polysulfated oligosaccharides.
Three Distinct Candidate Point Mutations of the von Willebrand Factor Gene in Four Patients with Type IIA von Willebrand Disease
Authors: Sugiura Isamu , Matsushita Tadashi , Tanimoto Mitsune , Takahashi Isao , Yamazaki Tomio , Yamamoto Koji , Takamatsu Junki , Kamiya Tadashi , Saito Hidehiko
Published: July 2018

Type IIA von Willebrand disease (vWD) is the most common type II vWD and is characterized by the selective loss of large and intermediate sized multimers. One explanation for this disorder has been postulated to be a qualitative defect in von Willebrand factor (vWF) which results in increased susceptibility to proteolysis at the bond between residues Tyr842 and Met843. Four missense mutations that may cause type IIA vWD have recently been identified near the cleavage site. We analyzed the molecular basis for type IIA vWD in six patients. A 512 bp DNA sequence spanning the proteolytic cleavage site was targeted for PCR amplification and sequencing. We exploited a difference in restriction sites between the vWF gene and the pseudogene and have designed allele-specific oligomer used with PCR to distinguish these two genes. Three candidate missense mutations; Ser743 (TCG) → Leu (TTG), Leu799 (CTG) → Pro (CCG), and Arg834 (CGG) → Trp (TGG) were identified in 4 out of 6 patients. The amino acid substitution at Arg834 has been reported previously, but the other substitutions at Ser743 and Leu799 are novel candidate mutations locating 99 and 43 amino acids to the N-terminal side of the cleavage site, respectively. Our results indicate that amino acid substitutions located relatively distant from the cleavage site may also be involved in type IIA vWD.
Characterization of Three Mutations Causing von Willebrand Disease Type IIA in Five Unrelated Families
Authors: Inbal Aida , Seligsohn Uri , Kornbrot Nurit , Brenner Benjamin , Harrison Paul , Randi Anna , Rabinowitz Ian , Sadler J Evan
Published: July 2018

Von Willebrand disease (vWD) type IIA is characterized by decreased ristocetin-induced platelet aggregation, and by the absence from plasma of high molecular weight multimers of von Willebrand factor (vWF). Most mutations causing vWD type IIA are clustered within the A2 domain of the mature vWF subunit that is encoded by exon 28. Using the polymerase chain reaction (PCR), the entire exon 28 from patients with vWD type IIA and normal controls was amplified and sequenced. Three missense mutations were detected that result in the amino acid substitutions Arg(834)→Trp, Gly(742)→Glu, and Ser(743)→Leu. The first mutation occurred independently in three unrelated families; each of the latter mutations was found in one family. By restriction endonuclease analysis and allele-specific oligonucleotide (ASO) hybridization the mutations were confirmed in affected family members and excluded in unaffected members and 50 normal controls. The apparently high frequency of identical independent mutations among patients with vWD type IIA suggests that a precise diagnosis may be possible in a majority of patients using relatively simple recombinant DNA screening assays.
Low Molecular Weight Heparin and Prevention of Postoperative Thrombosis in Abdominal Surgery
Authors: Koppenhagen K , Adolf J , Matthes M , Tröster E , Roder J D , Haas S , Fritsche H M , Wolf H
Published: July 2018

In a prospective, double-blind, randomized multicenter trial the efficacy and safety of low molecular weight heparin and unfractionated heparin were compared for the prevention of postoperative deep vein thrombosis in patients undergoing abdominal surgery. Six hundred and seventy-three patients were randomly allocated to the two prophylaxis groups; 20 of these, however, did not undergo surgery and did not receive any prophylaxis. Of the remaining 653 patients 323 received one subcutaneous injection of 3,000 anti-Xa units of low molecular weight heparin and 330 received subcutaneously 5,000 U heparin three times a day. Treatment was initiated 2 h preoperatively and continued for 7 to 10 days. The occurrence of DVT was determined by the 125I-labelled fibrinogen uptake test and phlebography. Venous thrombosis was diagnosed in 24 of 323 patients (7.4%) treated with low molecular weight heparin and in 26 of 330 patients (7.9%) treated with low-dose heparin. DVT of proximal veins was detected in four patients of the low molecular weight heparin group and in three patients of the low-dose heparin group. During the observation period three pulmonary emboli - one fatal and two non-fatal - occurred in patients receiving prophylaxis with low-dose heparin. No pulmonary embolism was found in patients treated with low molecular weight heparin. Both prophylactic schemes were well tolerated. Intra-and postoperative blood loss, incidence of wound hematoma, frequency and volume of intra- and postoperative blood transfusion were similar in both groups with a slight advantage for the low molecular weight heparin group. The results of this trial show that the investigated low molecular weight heparin is at least as effective and safe as low-dose heparin in preventing deep vein thrombosis in patients undergoing elective abdominal surgery.
β2-Glycoprotein I Deficiency and the Risk of Thrombosis
Authors: Bancsi László F J M M , van der Linden Irma K , Bertina Rogier M
Published: July 2018

β2-glycoprotein I (β2-GP I) is a plasma protein with a high affinity for negatively charged surfaces. In vitro this protein shows a variety of anticoagulant properties (inhibition of contact activation and platelet dependent prothrombinase activity). Therefore we studied the possibility that a hereditary β2-GP I deficiency is a risk factor for (familial) thrombophilia.

Plasma β2-GP I levels were measured in healthy volunteers and four different groups of patients with (familial) thrombophilia. In these 5 groups the prevalence of β2-GP I deficiency (i. e. β2-GP I antigen <77%) was found to be very similar (6.8-12.5%) and statistically not significantly different. This observation suggests that β2-GP I deficiency in itself is not a risk factor for thrombosis.

One thrombophilic patient was found to be homozygous deficient of β2-GP I. The transmission of the defect in his family followed autosomal inheritance. One of his brothers was also homozygous deficient and at the age of 35 years still free of thromboembolic complications.

The possibility that β2-GP I deficiency could be an additional risk factor for the development of thrombophilia in families with protein C deficiency was evaluated in a panel of 70 unrelated patients with clinically dominant protein C deficiency. The prevalence of β2-GP I deficiency in this group of patients (12.8%) was very similar to that in other groups of normals and patients. Moreover, there was no difference in the frequency of β2-GP I deficiency in symptomatic and asymptomatic protein C deficient patients.
A Soluble Recombinant Factor VIII Fragment Containing the A2 Domain Binds to Some Human Anti-Factor VIII Antibodies that Are not Detected by Immunoblotting
Authors: Scandella Dorothea , Timmons Lisa , Mattingly Mora , Trabold Norma , Hoyer Leon W
Published: July 2018

Human factor VIII (f VIII) inhibitors are pathologic antibodies that inactivate fVIII. A cDNA clone was modified to encode f VIII amino acid residues 373-740 for expression in a baculovirus vector in insect cells. The encoded protein fragment H2 was produced as a soluble, secreted protein, and it was used to test inhibitor plasmas for the presence of antibodies that were not detected by immunoblotting. Seven of 13 inhibitors that bound, only to the fVIII light chain by immunoblotting also bound to fragment H2 in an immunoprecipitation assay. Thus multi-chain inhibitor reactivity of inhibitors is more frequent than previously reported. One of these inhibitors was shown to share the epitope for other inhibitors that bind to H2 within amino acid residues 373-541 in immunoblotting assays. The sensitive immunoprecipitation assay described allows determination of relative H2 binding capacity of the total IgG and epitope localization of inhibitors that cannot be similarly characterized by immunoblotting.
Prolonged Bleeding Time of Chediak-Higashi Cats Corrected by Platelet Transfusion
Authors: Cowles B E , Meyers K M , Wardrop K J , Menard M , Sylvester D
Published: July 2018

Cats with the Chediak-Higashi syndrome (CHS) have a platelet storage pool deficiency (SPD). Ten CHS cats were transfused with a concentrate of 51Cr-labeled platelets prepared from normal donor cats. Gne hour after transfusion, the donor platelet count in CHS recipient cats was 40,000-60,000/μl. Bleeding time before transfusion was 9.1 ± 3.0 min. When donor platelet count in CHS cats was 50,000/μl, bleeding time was 1.7 ± 0.2 min. Bleeding time of normal cats was 1.4 ± 0.3 min. Bleeding time increased to 3.3 ± 0.2 min and to 5.3 ± 0.2 min when the platelet count was 30,000/μl, and 15,000/μl, respectively. The close inverse relationship between bleeding time and number of donor platelets in CHS cats (r = —0.92), suggests that prolonged bleeding time is due to a platelet abnormality, that platelet transfusion can effectively correct prolonged bleeding time in an animal model of platelet SPD and that CHS cats may be an appropriate animal model to evaluate hemostatic capabilities of transfused platelets.
Platelet Interaction with Collagen Fibrils in Flowing Blood
Authors: Baumgartner Hans R.
Published: July 2018

The subendothelial surface of rabbit aorta and α chymotrypsin-digested subendothelium were exposed to anticoagulated human blood in an annular flow chamber. The wall shear rate was similar to that observed in large arteries (830 sec–1) and exposure times varied from 2½ to 40 min.

The platelet reactive substrate of α chymotrypsin-digested subendothelium consists of a three-dimensional meshwork of collagen fibrils which form islands of variable size and height in a matrix of virtually unreactive elastin. Collagen-induced aggregation in the aggregometer was similar with or without prior α chymotrypsin-digestion of a highly dispersed preparation of fibrillar collagen. The rate of platelet adhesion was decreased on the fibrillar collagen of α chymotrypsin-digested subendothelium as compared to intact subendothelium. On the other hand the rate of aggregation was increased once platelets adhered to the fibrillar collagen. Mural thrombi (aggregates) disappeared on subendothelium whereas they grew progressively on the fibrillar collagen. Thus the fibrillar collagen of α chymotrypsin-digested subendothelium appears to be a more thrombogenic surface. It is suggested that physical (loose three-dimensional meshwork versus a comparatively solid surface) and/or chemical (number of platelet reactive sites per unit surface area) differences between the two surfaces may explain the platelet-surface-interaction patterns which are characteristic for each surface.
Intermittent Plasminogen-Streptokinase Treatment of Deep Vein Thrombosis
Authors: Scully M. F , Lane D. A , Sagar S , Thomas D. P , Kakkar V. V
Published: July 2018

The fibrinolytic response of 12 patients receiving single daily infusions of 600,000 units of streptokinase (SK) and 90 mg of plasminogen for the treatment of DVT has been studied. The mean plasminogen concentration was maintained throughout the treatment period (4–6 days) at between 20–40 % the initial value, while mean circulating plasmin concentration rose to only about twice initial plasma levels. The degradation of fibrinogen as indicated by a fall in clottable fibrinogen and rise in serum FDP varied appreciably from patient to patient. In 9 patients fibrinogen did not fall below 1 mg/ml and serum FDP rose to greater than 1 mg/ml. Limited fibrinogenolysis occurred in 2 patients, while in another patient who bled there was immediate and extensive depletion to below 0.5 mg/ml. The beneficial clinical results obtained with this regimen (Kakkar et al. 1975), which produces only limited systemic plasminaemia, suggest that thrombolysis may be facilitated by higher levels of plasminogen than those maintained during conventional SK treatment.
Oxygen-Induced Consumptive Coagulopathy and its Enhancement by Lead Acetate
Authors: Kiesow L. A , Shapiro S , Lindsley B. F , Bless J. W
Published: July 2018

The exposure of rats to 100% oxygen at 1 atmosphere leads to a prolongation of prothrombin times and activated partial thromboplastin times. This development is associated with a consumption of factor XII, VIII, and VII activities and with the appearance of fibrin monomers and fibrinogen degradation products. Lead acetate enhances all oxygen-induced changes of the coagulation systems drastically. The O2 survival time of chicks which are naturally deficient in factor XII is greatly increased over that of rats and is not affected by lead acetate. Oxygen survival times of rats suffering from chronic respiratory disease (CRD) are also significantly increased when compared with normal rats. It appears that consumptive coagulopathy and disseminated intravascular coagulation are early events in oxygen exposure, and that their development is accelerated by lead ions.
Evaluation of a New Anti-Fibrinogen-Coated Latex Particle Agglutination Test in the Measurement of Serum Fibrin Degradation Products
Authors: Marder Victor J. , Cruz Genuina O. , Schumer Bruce R.
Published: July 2018

A new latex particle agglutination test (FIBROTEX®) has been compared with the Thrombo-Wellcotest® and the tanned red cell hemagglutination inhibition immunoassay (TRCHII) for sensitivity to purified fibrinogen and plasmic degradation products and for reactivity with 31 normal sera and 170 sera from patients with thrombotic disorders. The latex particles in the FIBROTEX® are coated with antibodies against fibrinogen and fragment E (anti-FE), in contrast with the anti-fragment D and anti-fragment E antibodies which coat the latex particles of the Thrombo-Wellcotest® (anti-DE). The relative sensitivities of the TRCHII and the anti-FE and anti-DE latex tests were, respectively, 0.5, 2.5 and 7.5 μg/ml for fibrinogen; 0.5, 0.5 and 4.0 μg/ml for fragment X; and 1.25, > 30 and 8.0 μg/ml for fragment D. Compared with anti-DE, the anti-FE particles demonstrated fewer false-positive results with sera and urines of normals and higher titers, fewer false negatives and better overall correlation with the TRCHII results (r = 0.89 vs. 0.75) on pathologic sera. The FIBROTEX® is simple and rapid (5 minutes) and provides a more sensitive and accurate determination of serum fibrin degradation products than the Thrombo-Wellcotest®.
Prevention of Platelet Adhesion and Aggregation by a Glutardialdehyde-Stabilized Heparin Surface
Authors: Olsson P , Lagergren H , Larsson R , Rådegran K
Published: July 2018

A stable heparinized surface was prepared by sequential treatment of polyethylene with water solutions of hexadecylamine hydrochloride, heparin and glutardialdehyde. In order to explain the “non-thrombogenic” properties of this surface, it was evaluated with regard to prevention of platelet adhesion and aggregation.

Human heparinized blood (2 and 10 IU/ml) with 51Cr-labelled autologous platelets was rotated for 60 minutes in untreated and heparin-treated circular tubings. The surface area/blood volume ratio was varied and an air-blood interface was present. In untreated tubings, platelet adhesion and aggregation increased in proportion to the size of the surface area/blood volume ratio, irrespective of the heparin concentrations of the blood. In the heparin-treated tubings, there was no measurable platelet adhesion to the surface and no platelet aggregation in the blood. The difference between the heparinized and the untreated surfaces with regard to platelet adhesion was discernible even after 10 minutes storage of stagnant blood.

It is concluded that platelet adhesion and aggregation induced by exposure of blood to a foreign surface in an in vitro experimental model can be prevented by a stable heparin coating of the surface.
Kinetic Parameters of Platelet Aggregation as an Expression of Platelet Responsiveness
Authors: Rossi Ennio C , Louis Gerlinde
Published: July 2018

The kinetics of platelet aggregation induced by collagen and by ADP were studied. The maximum aggregation (ΔLTmax) and the ADP and collagen concentrations required to produce half-maximum aggregation (Kd) were determined using platelets obtained from normal individuals, individuals who ingested aspirin and individuals whose platelet-rich plasma (PRP) demonstrated spontaneous aggregation. The Kd and ΔLTmaxfor ADP-induced platelet aggregation were variable and markedly affected by the citrate concentration. Conversely, kinetic parameters of collagen-induced aggregation were more reproducible and less affected by citrate. The Kd for collagen in platelet aggregation was increased following aspirin ingestion and decreased in samples of PRP that demonstrated spontaneous aggregation. These results suggest that kinetic parameters of platelet aggregation may be useful to express the responsiveness of platelets.
Ethanol-Induced Microaggregate Formation in Pig and Rabbit Blood
Authors: Elmér Olle , Göransson Göran , Saku Motonori , Bengmark Stig
Published: July 2018

Increased microaggregate formation was found after mixing ethanol with blood from pig and rabbit in vitro, measured with Swank’s Screen Filtration pressure method. Final ethanol concentrations were in the range found in ethanol-intoxication in man. No rise in SFP was noticed when plasma with 10,000 platelets/μl was used. It is therefore doubtful that altered plasma proteins caused the rise in SFP. It is suggested that if a direct effect of ethanol upon platelet aggregation exists in vivo, it may be of importance in acute ethanol intoxication and in chronic alcoholism.
Effects of Thrombin, Chymotrypsin and Aggregated Gamma-Globulins on the Proteins of the Human Platelet Membrane
Authors: Podolsak B
Published: July 2018

Analysis of platelet membrane proteins and glycoproteins by SDS Polyacrylamide gel electrophoresis was carried out before and after treatment with thrombin. Extended incubation with thrombin (in the presence of EDTA or adenosine, which inhibit aggregation) produced extensive changes in the bands observed. With incubation times of a few minutes however, the changes were restricted to a glycopeptide, GP IV (approx. 90,000 Daltons) and one or two polypeptides of low molecular weight, in particular polypeptide 16 (approx. 23,000 Daltons). At 0–3° C only polypeptide 16 was still hydrolyzed.

Chymotrypsin, which does not activate platelets, attacked glycopeptides I, II, III but no changes were apparent in GP IV and polypeptide 16. When chymotrypsin-treated platelets were further incubated with thrombin, only GP IV and one to two low molecular weight polypeptides, especially polypeptide 16, were affected. As polypeptide 16 appears to be an integral membrane component it is possible that it, either by itself or in combination with GP IV, represents the primary thrombin substrate involved in platelet activation.

Aggregated IgG, which also activates platelets, does not modify the membrane glycoproteins but does change the low molecular weight region in particular band 16.
Spectrophotometric Determination of Factor Xa Generation in Factor IX Concentrates
Authors: Pepper D. S , Banhegyi D , Howie Ann
Published: July 2018

Previous work from this department, concerned with testing the potential thrombogenicity of therapeutic factor IX concentrates, demonstrated that following recalcification of factor IX concentrates thrombin was generated within 3-30 minutes of incubation (Sas et al. 1975). The test developed (known as the TGt 50 test) is a two-stage assay and was thus found to be time consuming, tedious and tended to become inaccurate with long incubation periods and a large number of samples. A semiautomatic version of the test is reported in which the synthetic peptide Bz-ILE-GLU-GLY-ARG-pNA (S-2222) is added to recalcified, diluted factor IX concentrate in the micro-cuvette of a multiple sample recording spectrophotometer. Information can be obtained on (a) the amount of Xa (if any) present prior to recalcification (b) the initial amount of Xa formed and (c) the time taken to activate all factor X to Xa. Direct graphical interpretation shows a number of qualitative differences between commercial preparations, but by either of the criteria (b) or (c) above, it is possible to place the different products into “activated” and “non activated” groups such that both the Xa generation times and TGt 50 tests identify the same two groups of products. This agreement also indicates that the TGt 50 test is independent of the intrinsic factor V levels in the various concentrates.
Factor V Leiden: An Additional Risk Factor for Thrombosis in Protein S Deficient Families?
Authors: Koeleman B P C , Rumpt D van , Hamulyák K , Reitsma P H , Bertina R M
Published: July 2018

We recently reported a high prevalence of the FV Leiden mutation (R506Q, responsible for Activated Protein C resistance) among symptomatic protein C deficient probands (19%), and the involvement of the FV Leiden mutation in the expression of thrombophilia in six protein C deficient families. Here, we report the results of a similar study in protein S deficient probands and families. Among 16 symptomatic protein S deficient probands the prevalence of the FV Leiden mutation was high (38%). This high prevalence is significantly different from that in the normal population, and is probably caused by the selection of probands for familial thrombosis and protein S deficiency. In 4 families, the segregation of the FV Leiden mutation and the protein S deficiency could be studied. In sibships where both abnormalities were segregating, the percentage of symptomatic individuals with both abnormalities was 80%. Three of the seven subjects with only the FV Leiden mutation, and two out of the three subjects with only protein S deficiency had developed thrombosis. These results indicate that in the families presented here the combination of the FV Leiden mutation and the protein S deficiency is associated with a high risk for thrombosis. A reliable estimate of the penetrance of the single defects is not possible, because the number of individuals with a single defect is too low.
A Higher than Expected Incidence of Factor VIII Inhibitors in Multitransfused Haemophilia A Patients Treated with an Intermediate Purity Pasteurized Factor VIII Concentrate
Authors: Peerlinck Kathelijne , Arnout Jef , Gilles Jean Guy , Saint-Remy Jean-Marie , Vermylen Jos
Published: July 2018

In May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation.

Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII.

This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.
Diurnal Rhythm in Anticoagulant Effect of Heparin during a Low Dose Constant Rate Infusion
Authors: Krulder J W M , de Boer A , van den Besselaar A M H P , Cohen A F , Schoemaker H C , Briët E , Meinders A E
Published: July 2018

The objective of the study was to investigate possible diurnal rhythms in coagulation tests during a continuous intravenous infusion of unfractionated heparin. Six volunteers participated in the study, which was divided in a treatment (500 U heparin/h for 30 h) and a control experiment. Under basal conditions, no rhythm was found in coagulation tests. During heparin treatment, APTT, thrombin clotting time and anti-Xa activity showed a greater anticoagulant effect at night, with a striking decrease in the morning.

In a search for the explanation of this phenomenon we looked for diurnal variations in the urinary excretion of heparin, in the plasma concentrations of antithrombin III and platelet factor 4, and in the effect of heparin added to the plasma samples in vitro. None of these studies provided the explanation.
Clearance of Recombinant Tissue Factor Pathway Inhibitor (TFPI) in Rabbits
Authors: Palmier Mark O , Hall Lori J , Reisch Celeste M , Baldwin Margaret K , Wilson Alan G E , Wun Tze-Chein
Published: July 2018

The pharmacokinetics of recombinant tissue factor pathway inhibitor (TFPI) after an intravenous bolus injection was studied in rabbits. Clearance of TFPI was followed by measurement of the radioactivity of the 125I-labelled compound in the whole plasma or the trichloroacetic acid precipitate and by quantitation of the functional TFPI activity of the unlabelled compound using a tissue factor-induced coagulation assay. When iodinated TFPI was used, the ratios of the trichloroacetic acid precipitable counts vs. that of the whole plasma was about 1 in the first 10 min after TFPI injection, but this ratio gradually decreased to less than 0.5 after 2 h. This result suggested that the iodinated TFPI in the plasma was partially degraded after prolonged circulation in the animal. When unlabelled TFPI was used, the clearance of TFPI activity from the plasma exhibited bi-exponential elimination kinetics with a rapid alpha phase half-life $$(t
1/2α) of 2.3 min, and a terminal beta phase half-life $$(t
1/2β) of 79 min. The plasma clearance was 4.2 ml kg–1 min–1. The tissue distribution of intravenously administered 125I-TFPI in the rabbit was studied using whole-body autoradiography. At 3 min after dosing, significant levels of TFPI were apparent in the liver, kidney, and other highly blood perfused tissues. Signficant levels of 125I-TFPI-derived radioactivity were also apparent in the liver and kidney at 30 min after intravenous administration. The localization within the liver demonstrated a mottled appearance, suggesting regions of higher uptake within the liver. In the kidney, the outer cortex consistently revealed the highest activity.
Coagulation Factor IXa Binding to Activated Platelets and Platelet-Derived Microparticles: A Flow Cytometric Study
Authors: Hoffman Maureane , Monroe Dougald M , Roberts Harold R
Published: July 2018

Factor IX plays a central role in blood coagulation, since it can be activated by either XIa (intrinsic pathway) or tissue factor-VIIa (extrinsic pathway). Activated factor IX (IXa), in a surface-bound complex with factor Villa, then activates factor X. Platelets provide the catalytic surface upon which this Xase complex is assembled in vivo. We have used flow cytometry to examine binding of factor IXa to thrombin-activated platelets in the absence of added Villa. Platelet-bound IXa and platelet protein GPIb were detected by indirect immunofluorescence staining followed by two-color flow cytometric analysis. Microparticles were identified by their light scattering characteristics. Two binding sites for factor IXa were detected. The high affinity binding site saturated at about 10 nM, with a K
d of 1.6 nM. A second binding curve, with a K
d of about 100 nM, was observed at higher concentrations of IXa. The high affinity factor IXa binding sites comprise about 7% of the total factor IXa binding. Binding to both sites was dependent on the presence of calcium. Thus, we conclude that factor IXa, in addition to its high affinity binding, has a calcium-dependent low affinity association with activated platelets and microparticles. Sims et al. have shown that binding sites for a different coagulation factor, factor Va, are concentrated on microparticles relative to platelet membrane proteins, such as GPIb. GPIb is distributed on platelets and microparticle in proportion to plasma membrane surface. At 100 nM factor IXa, 1–3% of the total bound factor IXa was associated with microparticles, as was a similar proportion of the total GPIb. However, at 10 nM IXa, factor IXa binding to microparticles was concentrated about 2-fold relative to GPIb staining. Thus, the high affinity factor IXa binding site is concentrated on microparticles to a small degree, while the low affinity binding site is not.
Desmopressin Has No Beneficial Effect on Excessive Postoperative Bleeding or Blood Product Requirements Associated with Cardiopulmonary Bypass
Authors: Prost D de , Barbier-Boehm G , Hazebroucq J , Ibrahim H , Bielsky M C , Hvass U , Lacombe C , Français J L , Desmonts J M
Published: July 2018

Cardiopulmonary bypass during open-heart surgery is sometimes associated with excessive perioperative bleeding. Following a non-randomized study suggesting that desmopressin acetate (desmopressin) reduced blood product requirements in these patients, we conducted a double-blind, placebo-controlled randomized trial of desmopressin (0.3 µg/kg, i. v.) in 92 patients with overt bleeding and a prolonged bleeding time.

Mean blood loss during the first 24 h post-treatment was similar in the desmopressin and placebo groups (582 vs 465 ml, respectively; p = 0.15). Red-cell (p = 0.76), fresh frozen plasma (r = 0.66) and platelet unit (p = 0.74) requirements were also similar.

The haemostatic effect of desmopressin has been attributed to the release of von Willebrand factor (vWF) and a reduced bleeding time. In our study, vWF and factor VIII :C levels increased while the bleeding time decreased significantly at 90 min and 24 h in both groups and, although vWF and factor VIII: C levels were slightly higher in desmopressin-treated patients at 90 min, the difference was not significant. Thrombin-antithrombin III complex, fibrinogen degradation product and tissue plasminogen activator levels, reflecting activation of the coagulation and fibrinolytic systems, respectively, decreased uniformely in both groups.

We conclude that desmopressin is not useful in reducing blood loss or blood product requirements in patients with excessive immediate postoperative bleeding.
Fibrin Gel Network Characteristics and Coronary Heart Disease: Relations to Plasma Fibrinogen Concentration, Acute Phase Protein, Serum Lipoproteins and Coronary Atherosclerosis
Authors: Fatah Kamaran , Hamsten Anders , Blombäck Birger , Blombäck Margareta
Published: July 2018

The native fibrin gel structure formed in vitro from plasma samples was examined by liquid permeation of the hydrated fibrin gel networks in 18 men who had suffered a myocardial infarction before the age of 45 years and in 20 control subjects. Patients with an elevated plasma fibrinogen concentration had a considerably lower fibrin gel porosity (permeability coefficient, K
s) compared with patients with a normal plasma fibrinogen level and with controls. The calculated fiber mass-length ratio of the fibrin gel networks was decreased in both patient groups. Gel porosity differed markedly between individuals at a given plasma fibrinogen concentration. Fairly strong inverse correlations were found between plasma orosomucoid level on the one hand and K
s (r = –0.617, p <0.01) or fiber mass-length ratio (r = –0.499, p <0.05) on the other. The low density lipoprotein (LDL) cholesterol concentration also correlated inversely with K
s (r = –0.471, p <0.05) and fiber mass-length ratio (r = –.522, p <0.05). Significant inverse relations, which were independent of plasma fibrinogen and lipoprotein concentrations, were detected between K
s (r = –.519, p <0.05) and calculated fiber mass-length ratio (r = –.723, p <0.001) and number and severity of coronary artery stenoses determined by angiography. A proneness to formation of tight, rigid and space-filling fibrin network structures with small pores thus appears to be associated with premature coronary artery disease.
The Consumption of Antithrombin III During Coagulation, Its Consequences for the Calculation of Prothrombinase Activity and the Standardisation of Heparin Activity
Authors: Béguin S , Kessels H , Dol F , Hemker H C
Published: July 2018

The decay rate of thrombin in plasma is shown to be linearly proportional to the concentration of antithrombin III (AT III), not only in the absence but also in the presence of heparin. This is a consequence of partitioning of heparin between AT III and other plasma proteins.

In previous articles we calculated the prothrombin converting activity assuming a fixed concentration of AT III. Since AT III is consumed during the clotting process, prothrombinase activity is more accurately approximated using an algorithm that counts with the decrease of the AT III concentration. It is shown this leads to higher prothrombinase activities. The (absence of) inhibition of prothrombin conversion by prothrombinase in the presence of heparins found with the previous method is also found using the new algorithm.

From the results presented it is evident that characteristic parameters of heparin action have to be normalised to the AT III concentration. On this basis we define a Standard Independent Unit of the antithrombin activity of heparin.
Depression of Tissue-Type Plasminogen Activator and Enhancement of Urokinase-Type Plasminogen Activator as an Expression of Local Inflammation
Authors: Brommer Emile J P , Dooijewaard Gerard , Dijkmans Ben A C , Breedveld Ferdinand C
Published: July 2018

Inflammatory processes are accompanied by extravascular deposition and breakdown of fibrin. We measured fibrinolytic parameters in synovial fluid (SF) and in plasma of 36 patients with rheumatoid arthritis (RA). As a control, SF of 13 patients with blunt knee trauma, and plasma of 17 healthy volunteers were studied. In RA patients, extravascular t-PA mediated plasminogen activation was depressed: mean SF tissue-type plasminogen activator (t-PA:Ag) concentration (2.1 ± 1.6 ng/ml) was four-fold lower, and plasminogen activator inhibitor (PAI) activity (284 ± 212%) four-fold higher than the plasma values of the same patients or of healthy donors. In contrast, u-PA related plasminogen activation was strongly enhanced: urokinase-type plasminogen activator (u-PA) antigen (23.1 ±12.4 ng/ml) was more than four-fold higher, single-chain u-PA (scu-PA) (5.3 ± 1.9 ng/ml) three-fold higher than in plasma of the same patients or of healthy donors, and active two-chain u-PA (tcu-PA) was detected in 14 of the 36 SF samples of RA patients. All of these changes in extravascular fibrinolytic parameters correspond with those induced by inflammatory mediators in cell cultures. In joint effusions of patients with a blunt knee trauma, the effects were intermediate: u-PA related parameters showed moderate changes in the same direction as in arthritis; t-PA antigen was also decreased. The only exception was that PAI was not increased. We conclude that the findings in traumatic effusions reflect transient effects as a reaction to trauma. In joint inflammation, the depressed t-PA mediated plasminogen activation, although more than compensated by the enhanced u-PA mediated plasminogen activation, results in protraction of fibrin removal. Besides, the enhanced u-PA activation might lead to proteolytic damage of the cartilage.
Intravenous Acetylsalicylic Acid – Dose-Related Effects on Platelet Function and Fibrinolysis in Healthy Males
Authors: Husted S E , Kristensen S D , Vissinger H , Mørn B , Schmidt E B , Nielsen H K
Published: July 2018

Low-dose acetylsalicylic acid (ASA) has been shown to be beneficial in patients with acute myocardial infarction and unstable angina pectoris. Oral administration of ASA is difficult in the acute phase of these syndromes. In this study we evaluated the effect of 25 mg, 50 mg or 100 mg of ASA given as an intravenous bolus injection on platelet function and fibrinolysis in healthy males and related this to plasma concentrations of ASA. No adverse effects were found. A complete inhibition of serum thromboxane B2 synthesis was demonstrated 5 min after injection of 100 mg ASA intravenously. ASA disappeared from the circulation within 60 min after bolus injection and at this time thromboxane B2 synthesis was inhibited dose-dependently by 71%, 90% and 100% for doses of 25 mg, 50 mg and 100 mg, respectively. Inhibition of thromboxane B2 synthesis after 100 mg of intravenous ASA was still 96.5% at 24 h and 93.4% at 48 h after the injection. The bleeding time measured at 30 min after ASA administration was significantly prolonged on the average by 70 s, 144 s and 211 s after 25 mg, 50 mg and 100 mg of ASA, respectively. Minor, but significant changes were found in tissue plasminogen activator antigen and in plasminogen activator inhibitor within the first hour after injection of low dose ASA, but similar changes were found after injection of saline. No change in tissue plasminogen activator activity was found. We conclude, that intravenous administration of low dose ASA is safe and easy, and that almost immediate, complete blockage of serum thromboxane B2 synthesis can be obtained after a single intravenous bolus injection of 100 mg.
An Update on Unloading Knee Braces in the Treatment of Unicompartmental Knee Osteoarthritis from the Last 10 Years: A Literature Review
Authors: Mistry Dylan , Chandratreya Amit , Lee Paul
Published: July 2018

Background The incidence of osteoarthritis is increasing and it is one of the most common causes of chronic conditions. Total knee replacement is the mainstay of treatment for end-stage knee osteoarthritis; however, with long waiting lists and high levels of dissatisfaction, a treatment like knee braces could potentially delay surgery. Unicompartmental knee osteoarthritis is associated with misalignment of the knee, and unloader bracing has been recommended by various guidelines to correct this misalignment. The aim of this report was to provide an update of evidence from the past 10 years on knee braces.

Methods MEDLINE/EMBASE search was performed from the past 10 years.

Results We reviewed the evidence from 14 published articles. Almost all articles supported knee brace use and showed it to decrease pain, improve function, and improve the quality of life of patients. One study in 2017 followed patients for long term and found knee bracing to be more cost effective than total knee replacement, and could replace the need for surgery. Several minor complications were reported with bracing, like soft tissue irritation, which could be due to poor fitting. A management strategy for this could be regular follow-up at a nurse-led clinic.

Conclusions Unloader braces are an economical and effective treatment for unicompartmental knee osteoarthritis. They can significantly improve a patient's quality of life and potentially delay the need for surgery. Patients should be managed with a multidisciplinary approach with conservative management and knee bracing, before surgery is considered.
Pituitary Stalk Interruption Syndrome: Presentation of a Rare Case
Authors: Agridag Ucpinar Burcin , Ucar Ahmet , Ozmen Evrim
Published: July 2018

Pituitary stalk interruption syndrome is a congenital anomaly characterized by interrupted or thin pituitary stalk, hypoplastic or absent anterior pituitary, and an absent or ectopic posterior pituitary gland. The exact incidence rate of this syndrome is not known. However, the estimated incidence rate is 0.5/1,000,000 births. In this case report, we wanted to present a case of interrupted pituitary stalk syndrome, which presented with seizures and thyroid hormone deficiency. A 5-year-old female patient was admitted to our emergency department with vomiting, fever, and seizures with new onset. She had a twin who was ex-utero intrapartum in taken history. She was diagnosed with hypothyroidism and started on levothyroxine. Her height was in 25 to 50th percentile and her weight was in 10 to 25th percentile. She had mild mental retardation. On contrast-enhanced cranial magnetic resonance imaging scan, the pituitary stalk was absent, posterior pituitary was ectopic, and anterior pituitary was hypoplastic. The patient was diagnosed with interrupted pituitary stalk syndrome. After the symptoms were relieved, patient started on carbamazepine for epileptic seizures and hormone replacement therapy with levothyroxine and hydrocortisone. She was routinely followed up after the proper diagnosis. Leuprolide (gonadotropin-releasing hormone) and Norditropin (biosynthetic growth hormone) were added to medical therapy. Her height and weight were in 25th percentile after the long-term follow-up of approximately 10 years. On neurological examination, situation of mild mental retardation persisted. Pituitary stalk interruption syndrome is a very rare entity. However, radiologists should keep this syndrome in mind for patients who present with hypoglycemia, seizures, jaundice, cryptorchidism, and hypothyroidism in neonatal period and growth retardation with pituitary hormone deficiencies in childhood.
Ethische Betrachtungen zur Elternschaft psychisch Erkrankter
Authors: Jordan Wolfgang
Published: July 2018

Die ethische Diskussion einer Elternschaft psychisch Erkrankter wird auf der Individual-, Struktur- und Systemebene des deutschen Gesundheitssystems vorgenommen. Das „Konzept des ethischen Therapeuten“ bietet eine Lösungsperspektive für die Individualebene, wohingegen strukturelle und systemische Probleme institutionelle und politische Lösungen erfordern. Der „Ethische Kompass psychiatrischer Elternschaft“ bewegt sich zwischen den Dimensionen Selbst-, Fremdbestimmung, Eigen- und Gemeinsinn. Eine Reduktion psychosozialer Belastungen, eine altersabhängige differenzierte Prävention und eine frühzeitige Unterstützung können zu einer gelungenen Elternschaft psychisch Erkrankter beitragen.
Ist Glück „machbar“?
Authors: Birnbacher Dieter
Published: July 2018

Psychiatrie und Psychotherapie machen es sich u. a. zur Aufgabe, Menschen die Erfahrung von Glück zu ermöglichen. Insofern hängt ihre Existenzberechtigung an der – wie immer begrenzten – „Machbarkeit“ von Glück. Eine solche „Machbarkeit“ ist in der Geschichte der Philosophie und Psychologie immer wieder infrage gestellt worden. Der Beitrag diskutiert 4 Argumente, die gegen eine „Machbarkeit“ von Glück vorgebracht worden sind: das „Glücksparadox“, die irreduzible Subjektivität von Glück, die Variabilität der Glücksvorstellungen und die Theorie der vollständigen genetischen Determiniertheit des Glücksempfindens.
Das Glück des Psychotherapeuten
Authors: Kottje-Birnbacher Leonore
Published: July 2018

Berufsarbeit ermöglicht die Erfahrung von Selbstwirksamkeit, stabilisiert den Selbstwert und gewährleistet Zugehörigkeit. Wieweit erfüllt der Beruf des Psychotherapeuten diese Desiderate? Der Beitrag skizziert die Bedingungen, die zusammenkommen müssen, wenn Psychotherapeuten nicht nur anderen zum Glück verhelfen, sondern selbst ihre Tätigkeit als erfüllend empfinden sollen. Hinter der hohen durchschnittlichen Zufriedenheit der Therapeuten mit ihrem Beruf verbergen sich Unterschiede im Umgang mit der Arbeit und in der Zufriedenheit, die sich wesentlich auf den Therapieerfolg auswirken. Daher sollten Therapeuten im Eigeninteresse und im Patienteninteresse versuchen, durch Fortbildungen, Intervision und Supervision den eigenen Arbeitsstil möglichst gut zu gestalten.
Dimensionen von Glück und Zufriedenheit bei beruflich psychiatrisch Pflegenden und in der psychiatrischen Pflege
Authors: Hahn Birgit , Nienaber André , Schulz Michael
Published: July 2018

Ziel der Studie Ziel dieses Beitrags ist es, wesentliche Aspekte der Konzepte Glück und Zufriedenheit im Hinblick auf die Arbeit in der psychiatrischen Pflege zu diskutieren.

Methodik Aspekte der Persönlichkeit, des Arbeitsumfelds und der Charakter der Arbeit werden beschrieben und Fallbeispiele aus dem ortsansässigen psychiatrischen Krankenhaus diskutiert.

Ergebnisse Glück und Zufriedenheit sind bei psychiatrisch Pflegenden abhängig von Kontextfaktoren und ihren individuellen Erlebnissen in konkreten Pflegesituationen.

Schlussfolgerung Glück und Zufriedenheit beeinflussen die Pflege- und Behandlungsqualität. Darüber hinaus ist die empfundene Berufszufriedenheit ein wichtiger Faktor im Hinblick auf die Frage, ob sich Pflegende für die Arbeit in der Psychiatrie entscheiden und wie lange sie in dem Beruf bleiben.