bluuebunny/crossref_metadata_2025_split huggingface dataset:
Titration of Antiplatelet Treatment in Pregnant Women at Risk of Preeclampsia
Authors: Clark N. A. C. , Swiet M. de , Nelson-Piercy C. , Elder M. G. , Sullivan M. H. F. 
Published: March 2018

SummaryWe recruited 111 patients who were considered to be at significantly increased risk of preeclampsia on the basis of previous obstetric history or preexisting medical disorders. All patients were treated with low dose aspirin (75 mg/day) from the first occasion the patient attended the antenatal clinic, regardless of gestational age. If the maternal mean platelet volume (MPV) increased significantly (by >0.8 fl) from the baseline, antiplatelet treatment was increased. Five pregnancies were lost during the second trimester and 106 of the treated patients had live infants. The incidence of neonatal death (3/106 infants) was much lower than in the previous pregnancies in these patients (32/134 infants). Patients who were treated from the first trimester of pregnancy (group A, 89 patients) did substantially better than those treated from the second trimester (group B, 17 patients) as assessed by the incidence of pre-eclampsia or intrauterine growth restriction (IUGR), gestational age and birthweight at delivery. These data suggest that longitudinal monitoring of the MPV may identify the women who could benefit from increased antiplatelet treatment, and that antiplatelet treatment may be more effective when initiated in the first trimester rather than later in pregnancy.
Factor VIII Inhibitors in Mild and Moderate-severity Haemophilia A
Authors: Ludlam C.A. , Colvin B.T. , Hill F.G.H. , Preston F.E. , Wasseem N. , Bagnall R. , Peake I.R. , Berntorp E. , Bunschoten E.P. Mauser , Fijnvandraat K. , Kasper C.K. , White G. , Santagostino E. , Hay C.R.M. ,   the UK Haemophilia Centre Directors Organisation
Published: March 2018

SummaryTwenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths.The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage.Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.
Simple and Reliable Factor V Genotyping by PNA-Mediated PCR Clamping
Authors: Behn Moira , Schuermann Marcus 
Published: March 2018

SummaryResistance to activated protein C (APC resistance) is the most common cause of thrombophilia and linked to a single point mutation in the factor V gene (G>A transition at nucleotide 1691). In the past, several PCR based methods have been proposed to determine the allelostatus of individual patients from small amounts of blood DNA including PCR followed by restriction fragment length polymorphism detection (PCR-RFLP), PCR using sequence-specific primers (PCR-SSP) and oligonucleotide ligation assay (OLA). Here, we present a novel approach based on the method of peptide nucleic acid(PNA)-mediated PCR clamping which is extremely sensitive to base pair mismatches. If PNAs specific for the two allelic variants are applied separately in each case a clear discrimination between a heterozygous or homozygous normal or homozygous Factor V Leiden status is possible and no further confirmation step is required. In a prospective study, 60 patients with suspected venous thrombosis events were tested and compared to the conventional PCR-RFLP technique. The concordance between both methods was 100%. PNA-based factor V genotyping, therefore, should be considered for large scale screening of those patients considered to be at risk for deep venous thrombosis.
Identification of Mutations in the Canine von Willebrand Factor Gene Associated with Type III von Willebrand Disease
Authors: Rieger M. , Schwarz H. P. , Turecek P. L. , Dorner F. , Mourik van , Mannhalter C. 
Published: March 2018

SummaryIn humans, type III von Willebrand disease is caused by deletions or nonsense mutations. In dogs, the underlying genetic defects have not been determined yet. We searched for the genetic defect in four related type III deficient Dutch Kooiker dogs obtained from one breeder. Mutation analysis was performed with total RNA isolated from platelets or whole blood. The complete coding region of the vWf gene was amplified by RT-PCR and sequenced by the cycle sequencing technique. Two homozygous mutations were found, a G→A transition at the first position of the donor splice site sequence of intron 16 (TGgtaagt→TGataagt) and a missense mutation at nt 208 (G→A) (1). The splice site defect resulted in the generation of a transcript containing 46bp of intron sequence and a stop codon at amino acid position 729 in the propeptide region of the vWf protein. This mutation seems to be causative for the type III phenotype. The effect of the missense mutation in exon 3 which causes a change of Val to Ile on the vWD phenotype is unclear. Probably, this transition represents a polymorphism occurring in Dutch Kooiker dogs. Both mutations were not present in 5 healthy mongrel dogs.Parts of this paper were presented at the 39th annual meeting of the American Society of Hematology (ASH), December 5-9, San Diego, USA
The Molecular Basis of Antithrombin Deficiency in Belgian and Dutch Families
Authors: Lissens W. , Seneca S. , Capel P. , Chatelain B. , Meeus P. , Osselaer J. C. , Peerlinck K. , Seghers J. , Slacmeulder M. , Stibbe J. , Loo J. van de , Vermylen J. , Liebaers I. , De Waele M. , Jochmans K. 
Published: March 2018

SummaryThe molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed.DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intronexon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect.
Effect of Cilostazol on Soluble Adhesion Molecules and Platelet-derived Microparticles in Patients with Diabetes
Authors: Shouzu Akira , Omoto Seitaro , Hayakawa Takashi , Kagawa Hideo , Nishikawa Mitsushige , Inada Mitsuo , Fujimura Yoshihiro , Ikeda Yasuo , Fukuhara Shirou , Nomura Shosaku 
Published: March 2018

SummaryWe evaluated the plasma concentrations of soluble adhesion molecules and platelet-derived microparticles (PMP) in patients with non-insulin dependent diabetes mellitus (NIDDM) and studied the effect of cilostazol on PMP generation. There were differences in the levels of soluble adhesion molecules between NIDDM patients (N = 43) and the control subjects (N = 30) (soluble thrombomodulin: 11.5 ± 5.3 vs. 7.0 ± 1.2 TU/ml, p<0.0001; soluble vascular cell adhesion molecule-1: 708 ± 203 vs. 492 ± 113 ng/dl, p<0.0001; soluble intercellular cell adhesion molecules-1: 274 ± 65 vs. 206 ± 48 ng/dl, p<0.0001; soluble P-selectin: 194 ± 85 vs. 125 ± 43 ng/dl, p<0.0001). There were also differences in the levels of PMP and platelet activation markers between NIDDM patients and the controls (PMP: 943 ± 504 vs. 488 ± 219/10 4 plt, p<0.0001; platelet CD62P: 9.2 ± 4.6 vs. 4.4 ± 4.3%, p<0.001; platelet CD63: 10.2 ± 4.5 vs. 4.5 ± 3.3%, p<0.0001; platelet annexin V: 9.1 ± 3.9 vs. 5.3 ± 3.8%, p<0.001). To study the release of PMP into plasma, a modified cone-and-plate viscometer was used. Increased release of PMP from platelets was observed in diabetic plasma compared to normal plasma under high shear stress conditions (2,672 ± 645 vs. 1,498 ± 386/104 plt, p<0.05). Therefore, one cause of PMP elevation in NIDDM may be high shear stress. The levels of PMP, activated platelets, and soluble adhesion molecules all decreased significantly after treatment with cilostazol. These results suggest that cilostazol may be useful for the inhibition of both PMP-dependent and -independent vascular damage in NIDDM.
Preinfarction Angina and Improved Reperfusion of the Infarct-related Artery
Authors: Sciahbasi Alessandro , De Marco Eugenia , Maseri Attilio , Andreotti Felicita 
Published: March 2018

SummaryPreinfarction angina and early reperfusion of the infarct-related artery are major determinants of reduced infarct-size in patients with acute myocardial infarction. The beneficial effects of preinfarction angina on infarct size have been attributed to the development of collateral vessels and/or to post-ischemic myocardial protection. However, recently, a relation has been found between prodromal angina, faster coronary recanalization, and smaller infarcts in patients treated with rt-PA: those with preinfarction angina showed earlier reperfusion (p = 0.006) and a 50% reduction of CKMB-estimated infarct-size (p = 0.009) compared to patients without preinfarction angina. This intriguing observation is consistent with a subsequent observation of higher coronary recanalization rates following thrombolysis in patients with prodromal preinfarction angina compared to patients without antecedent angina. Recent findings in dogs show an enhanced spontaneous lysis of plateletrich coronary thrombi with ischemic preconditioning, which is prevented by adenosine blockade, suggesting an antithrom-botic effect of ischemic metabolites. Understanding the mechanisms responsible for earlier and enhanced coronary recanalization in patients with preinfarction angina may open the way to new reperfusion strategies.A vast number of studies, globally involving ≈17,000 patients with acute myocardial infarction, have unequivocally shown that an infarction preceded by angina evolves into a smaller area of necrosis compared to an infarct not preceded by angina (Table 1) (1). So far, preinfarction angina has been thought to have cardioprotective effects mainly through two mechanisms: collateral perfusion of the infarctzone (2-4), and ischemic preconditioning of the myocardium (5-7). Here we discuss a further mechanism of protection represented by improved reperfusion of the infarct-related artery.
Thrombolysis in Newborns and Infants
Authors: Auberger K. , Halimeh S. , Junker R. , Klinge J. , Kreuz W. D. , Ries M. , Schlegel N. , Nowak-Göttl U. 
Published: March 2018

SummaryThis review analyses literature reports from 1970 to 1998 assessing the use of streptokinase (SK), urokinase (UK) or recombinant tissuetype plasminogen activator (rt-PA) for thrombolytic therapy in neonates and infants. From 1970 to 1998 182 infants were reported to have received SK (n = 54; 29.5%), UK (n = 41; 22.5%) or rt-PA (n = 87; 48%). During thrombolytic therapy no concomitant heparin administration or low dose heparin therapy (5 U/kg/h) were recorded. To perform reocclusion prophylactics heparin was reinitiated at the end of thrombolytic therapy usually in the recommended dosage of 20 U/kg/h. The overall thrombolytic patency rate in neonates varied from 39% to 86%. Besides bleeding from local puncture sites or recent catheterisation sites (10.4%), pulmonary embolism was reported in 1.1% of the 182 infants. Major bleeding complications, i.e. pulmonary bleeding (0.6%), gastrointestinal bleeding (0.6%) or intraventricular haemorrhage (IVH 2.7%) are rarely reported side effects and only 2 thrombolysis related deaths due to haemorrhage were mentioned. Bleedings reported in the central nervous system (n = 4) mainly occurred in preterm infants (n = 3). In conclusion, data of this preliminary analysis suggest that there is no big difference (p = 0.09; χ2-test) in the efficacy rate between the 3 thrombolytic agents used in the first year of life. In each case an assessment must be made with respect to the relative benefit conferred by thrombolytic therapy in preventing organ or limb damage versus the potential side effects, costs and inconvenience for the childhood patient. Controlled prospective multicentre studies on thrombolytic therapy in neonates and infants are recommended to evaluate patency rates and adverse effects for the different thrombolytic agents used.
Ultrasound Thrombolysis
Authors: Gaul Georg B. 
Published: March 2018

SummaryThe possibility of lysing clots by the direct intravascular application of ultrasound was described first in 1974 in an animal experiment. However research on therapeutic ultrasound for thrombolysis gained momentum in the early 1980s and is now divided into several directions: 1) pharmacological thrombolysis supported by externally applied ultrasound; 2) pharmacological thrombolysis accelerated by intravascular ultrasound; 3) lysis of intravascular clots by intravascular ultrasound applied as singular treatment; 4) facilitating angioplasty by intravascular ultrasound which may smoothen the rigid surface of calcified arteries by lysing calcified structures out of sclerotic plaques.In acute myocardial infarction first evidence of efficacy in lysing clots by ultrasound was described in two small series of 15 patients in 1997. Furthermore, ultrasound thrombolysis seems to be efficient also in occluded saphenous vein grafts and in completely obstructed peripheral arteries, where the latest clinical experience gives very promising results.
Depletion of Plasma Factor XIII Prevents Disseminated Intravascular Coagulation-induced Organ Damage
Authors: Lee Soo Young , Chang Sung Keun , Lee Il Ha , Kim Yu-Mie , Chung Soo Il 
Published: March 2018

SummaryThe impact of clot stability affecting the vasculopathy and tissue necrosis in Shwartzman reaction was investigated using plasma Factor XIII A2-depleted rabbit (FXIII-DR). Plasma Factor XIIIA2 (FXIIIA2) was depleted by infusion of the mono-specific goat anti-rabbit FXIIIA2 IgG. Generalized Shwartzman reaction (GSR) was induced by priming and challenged by i.v. injection of LPS and local Shwartzman reaction (LSR) was primed by intradermal injection of LPS and challenged by i.v. injection of LPS. Histological examination of the GSR animals showed, extensive thrombi accumulation in renal tubules and bilateral cortical necrosis of kidney in 8 out of 10 rabbits but none in the FXIIIDR. Fibrinogen levels were elevated to 3~4 fold at 24 h and lowered at 48 h whereas a steady rise was seen in the FXIII-DR. FDP levels in GSR animals were significantly elevated at 24 h and further increased at 48 h but only slightly elevated in the FXIII-DR. Examination of the LSR tissues after 48 h showed an acute onset of progressive cutaneous vascular thrombosis, purpura, and secondary hemorrhagic necrosis whereas neither fibrin deposit nor necrosis of tissue were detected in FXIII-DR despite of an early edema formation. Fibrinogen levels were also increased two fold at 24 h but returned to basal levels at 48 h in control LSR animals but not affected at all in FXIII-DR. These results suggest that during the severe inflammatory conditions such as sepsis, the fibrinolytic system is functionally sufficient to dissipate the pathogenic accumulation of disseminated intravascular clots and exudated fibrin clots if those clots were prevented from getting cross-linked in plasma.
Inhibition of Arterial Thrombosis by a Soluble Tissue Factor Mutant and Active Site-blocked Factors IXa and Xa in the Guinea Pig
Authors: Refino Canio , Burcklen Louis , Himber Jacques , Roux Sébastien , Kirchhofer Daniel 
Published: March 2018

SummaryThe substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulted in a mutant, hTFAA, which can bind factor VIIa but forms an enzymatically inactive complex. We found that hTFAA inhibits the activity of guinea pig factor VIIa, allowing us to evaluate hTFAAs effects on thrombosis and hemostasis in a guinea pig model of recurrent arterial thrombosis. In addition to heparin, the effects of hTFAA were compared to active site inhibited factor IXa (F.IXai) and factor Xa (F.Xai). We found that hTFAA, F.IXai and F.Xai were potent antithrombotics and may possess a decreased risk of hemorrhage when compared to unfractionated heparin. When administered at a dose that inhibited thrombosis by about 90%, hTFAA neither affected cuticle bleeding nor the activated partial thromboplastin time, and had only a modest effect on the prothrombin time. At equi-efficacious doses, F.IXai, F.Xai and heparin prolonged bleeding times by 20% (p >0.5), 50% (p <0.05) and 100% (p <0.01), respectively. In summary, our study demonstrates that, unlike heparin, specific inhibitors of factors VIIa, IXa and Xa can produce antithrombotic effects without or with only minimally disturbing normal hemostasis. The results further suggest that factor VIIa and factor IXa are especially promising targets for antithrombotic drug development.
Contribution of Platelet-derived Factor Va to Thrombin Generation on Immobilized Collagen- and Fibrinogen-adherent Platelets
Authors: Briedé Jacob , Heemskerk Johan , Cornelis van’t Veer , Hemker H. Coenraad , Lindhout Theo 
Published: March 2018

SummaryAdhesion of platelets to immobilized collagen induces the expression of anionic phospholipids, e. g. phosphatidylserine (PS), in the outer leaflet of the plasma membrane of these platelets. In contrast, of the platelets that adhere to immobilized fibrinogen only a small sub-population representing 10 ± 3% of the total population of the fibrinogen-adherent platelets has exposed PS as probed by annexin V binding. Although the presence of PS is thought to be critical for thrombin generation at the platelet surface, no information is available about the effect of this differential PS exposure on the ability of adherent platelets to support thrombin generation. Perfusion of the fibrinogen- or collagen-adherent platelets with solutions containing factor Xa and prothrombin resulted in thrombin generation that i) increased linear during the first perfusion minutes, ii) was about two-fold faster at collagen-adherent than at fibrinogen-adherent platelets and iii) was for more than 98% restricted to the surface of the adherent platelets. It appeared that the lower thrombin generating capacity of fibrinogen-adherent platelets is not due to a lower overall surface density of PS, but is caused by lower amounts of platelet-bound factor Va. Firstly, in both cases thrombin generation could be completely attenuated with antibodies against human factor Va, and secondly, in the presence of an excess of exogenous plasma-derived factor Va similar initial rates of thrombin formation were measured for collagen- and fibrinogen-adherent platelets. Our findings suggest a unique role for immobilized collagen in maintaining haemostasis.
Thrombopoietin: From Theory to Reality
Authors: Kaushansky Kenneth 
Published: March 2018

IntroductionThe term thrombopoietin (TPO) was first penned in 1958 to describe the primary regulator of platelet production. Multiple efforts to purify the hormone were unsuccessful throughout the 1970s and 1980s because the protein was scarce and starting materials for purification biochemically complex. Even purification of thrombocytopenic plasma, which is the richest source of TPO, was unsuccessful.1,2 However, the cloning of the proto-oncogene c-mpl
3 opened an alternative route to the identification of TPO. Detailed study of the c-mpl gene revealed that it encoded an orphan hematopoietic cytokine receptor. Its tissue distribution and experiments designed to eliminate its expression suggested that c-mpl encoded the TPO receptor.4,5 In 1994, using three distinct strategies, five separate groups either purified protein or cloned cDNA for TPO.6 This review will focus on the physiology of TPO production and function, concentrating on recent findings that help to explain platelet homeostasis and how our understanding of TPO can translate into better patient care for thrombocytopenic patients.
The Elegant Platelet: Signals Controlling Actin Assembly
Authors: Barkalow Kurt , Azim Anser , Italiano Joe , Hartwig John 
Published: March 2018

SummaryThe function of the blood platelet is defined by its two physical states. The platelet is born in the first state, in long cytoplasmic extensions from megakaryocytes, as a small disc of reproducible structure having an elegant, actin-based cytoskeleton. At rest, the platelet circulates through the vasculature in this form. In the second state, in response to vascular damage, the platelet rapidly converts into its active form with filopodia and lamellipodia that derive from a remodeled actin skeleton and a massive assembly of new actin filaments. In the last two decades, we have begun to understand the structural basis for these two platelet states, the role of specific proteins that define the architecture of both shapes, and the proteins and signals that drive this conversion of shapes.