Low Levels Of Factor Research Articles

Management of Inherited von Willebrand Disease in 2006

The aim of treatment of von Willebrand disease (VWD) is to correct the dual defect of hemostasis (i.e., the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor [VWF] and the abnormal coagulation expressed by low levels of factor [F] VIII). Desmopressin acetate (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD types 1 and 2 are in progress to explore its benefits and limits as a therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective, and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep the FVIII level between 50 and 150 IU/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long-term prophylaxis for recurrent bleedings.

Detection and identification of intestinal pathogens in clinical specimens using DNA microarrays

The detection and identification of intestinal pathogens is critical for clinical patient diagnosis and antimicrobial therapy. No currently available assays with DNA microarrays can simultaneously detect and identify multiple intestinal pathogens, because there is no appropriate method for choosing target probes. To solve the problem we have experimented for facilitating screening of specific probes and developed a rapid (<3h) and reliable assay for simultaneous detection of intestinal pathogens using two universal PCR primers to amplify two variable regions of bacterial 16S and 23S ribosomal DNA (rDNA) genes, and then applied to DNA microarrays, hybridization between probes and amplicons occurred. Through this idea for screening of probes the assay was successful in discriminating 15 genera or species of intestinal pathogens. The limit of detection was approximately 10(3)CFU/mL for one species of pathogen and 10(5)CFU/mL for six species pathogens existing simultaneously in stool. When this assay was applied directly to identify 99 clinical specimens, 80(80.8%) were correctly analyzed, including four with mixed pathogens; 8(8.08%) received negative results due to no corresponding probes in this array and 11(11.11%) belonging to our targets were misidentified due to low-level pathogens and other factors. This approach is also convenient to obtain specific and proper probes while establishing assays for the applications in other aspects using DNA microarrays. In addition, the more species may be added to this system easily and endlessly by screening of candidate target probes in order to increase the power of simultaneous detection.

Refractory hematuria from amyloidosis successfully treated by splenectomy

Systemic amyloidosis can result in a coagulopathy that is associated with low levels of factor X. We present a case of intractable, life-threatening hematuria that was successfully managed with activated recombinant human factor VII and splenectomy.

Von Willebrand's disease: clinical management

The aim of treatment of von Willebrand's disease (VWD) is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor (VWF) and the abnormal coagulation expressed by low levels of factor VIII (FVIII). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD type 1 and 2 are in progress to further explore its benefits and limits as therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep FVIII level between 50 and 150 U/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long term prophylaxis for recurrent bleedings.

A modified chromogenic assay for the measurement of very low levels of factor VIII activity (FVIII:C)

A precise and sensitive chromogenic assay for the measurement of very low levels of factor VIII (FVIII) in plasma has been developed. The assay is based on modifications of a commercially available chromogenic assay. The modifications include reduction of sample final dilution factor and prolongation of the development period. The modified assay allows accurate and precise measurement of FVIII in the range of 0.001-0.02 IU mL(-1). The detection limit is 0.0005 IU mL(-1) and the quantitation limit is 0.0015 IU mL(-1). This assay can be used in research and to study the clinical efficacy of low circulating levels of FVIII in haemophilia A patients.

Patterns of fMRI Activity Dissociate Overlapping Functional Brain Areas that Respond to Biological Motion

Accurate perception of the actions and intentions of other people is essential for successful interactions in a social environment. Several cortical areas that support this process respond selectively in fMRI to static and dynamic displays of human bodies and faces. Here we apply pattern-analysis techniques to arrive at a new understanding of the neural response to biological motion. Functionally defined body-, face-, and motion-selective visual areas all responded significantly to "point-light" human motion. Strikingly, however, only body selectivity was correlated, on a voxel-by-voxel basis, with biological motion selectivity. We conclude that (1) biological motion, through the process of structure-from-motion, engages areas involved in the analysis of the static human form; (2) body-selective regions in posterior fusiform gyrus and posterior inferior temporal sulcus overlap with, but are distinct from, face- and motion-selective regions; (3) the interpretation of region-of-interest findings may be substantially altered when multiple patterns of selectivity are considered.

Cross-Cultural Adaptation and Evaluation of a Home-Based Program for Alcohol Use Prevention among Urban Youth: The “Slick Tracy Home Team Program”

The current study describes the extensive cross-cultural adaptation of a brief home-based alcohol prevention program for racially and ethnically diverse sixth grade students and their families, using a randomized controlled trial design involving 60 public schools in the city of Chicago (N = 3,623 students). The adapted program achieved high participation levels (73%) overall, as well as in single parent families, non-English homes, and low-income students, among other at risk groups. Lower levels of factors associated with the onset of alcohol use (i.e., normative expectations and outcome expectations) were achieved in the intervention group compared to the control group. However, no differences were observed for several other protective factors or alcohol use.

Estimation of temporal resolution of object identification in human vision

The purpose of the study was to estimate the temporal processing capacity of human object identification under different stimulus conditions. Objects, either facial images or characters, were shown in a rapid sequence on a computer display using a rapid serial visual presentation (RSVP) method. One of the images was a target and the other images were distracters. The task of the observer was to identify the target. A staircase algorithm was used to determine the threshold frequency of image presentation in the RSVP sequence. The threshold frequency was determined as a function of image contrast, size, and mean luminance. The results showed that the threshold frequency, around 10 Hz for faces (100 ms per face) and about 25 Hz for characters (40 ms per character), was independent of contrast and size at medium and high contrast values, medium and large sizes, and high luminances, but decreased at very low contrasts or small sizes and medium or low levels of luminance. Computer simulations with a model, in which temporal integration limited perceptual speed, suggest that the experimentally found difference in processing time for faces and characters is not due to the physical differences of these stimulus types, but it seems that face-specific sites in the brain process facial information slower than object-specific areas process character information. Contrast, size, and luminance affect the signal-to-noise ratio and the temporal characteristics of low-level neural signal representation. Thus, the results suggest that at low contrasts, low luminances and small sizes, the processing speed of object identification is limited by low-level factors, while at high contrasts and luminances, and at large sizes, processing speed is limited by high-order processing stages. Processing speed seems to depend on stimulus type so that for faces processing is slower than for characters.

Representational masking and the attentional blink

After successful detection of a target item within a stream of rapidly displayed visual stimuli, subsequent detection of an additional target is impaired for roughly 500 ms. This impairment is known as the “attentional blink” (AB). Previous studies have found that if either the first (Tl; Raymond, Shapiro, & Arnell, 1992) or second target (T2; Giesbrecht & Di Lollo, 1998) is not followed by a mask, the AB impairment is significantly reduced. Whereas low-level perceptual factors have been found to influence the efficacy of masking in the AB (e.g., Seiffert & Di Lollo, 1997), the current experiment used a higher level (representational) manipulation, i.e., repetition blindness to reduce the efficacy of target masking in the AB. These findings contribute to the growing literature suggesting that masking plays more than a perceptual role in the AB phenomenon.

The procoagulant effects of factor V Leiden may be balanced against decreased levels of factor V and do not reflect in vivo thrombin formation in newborns

Thrombin regulation in newborns remains incompletely understood. We studied tissue factor-initiated thrombin formation in cord plasma in vitro, and the effects of Factor V(Leiden) (FVL) heterozygosity on thrombin regulation both in vitro and in vivo in newborns. Pregnant women with known thrombophilia (n=27) were enrolled in the study. Cord blood and venous blood at the age of 14 days were collected from 11 FVL heterozygous newborns (FVL-positive) and from 16 FVL-negative newborns. Prothrombin fragment F1 +2 and coagulation factors were measured. Tissue factor-initiated thrombin formation was studied in cord platelet-poor plasma (PPP) of FVL-negative and -positive newborns, and in both PPP and platelet-rich plasma (PRP) of healthy controls. The endogenous thrombin potential (ETP) in cord PPP or PRP was approximately 60% of that in adult plasma, while thrombin formation started approximately 55% and approximately 40% earlier in cord PPP and PRP, respectively. Further, in FVL-positive newborns thrombin formation started significantly earlier than in FVL-negative newborns. Exogenous activated protein C (APC) decreased ETP significantly more in cord than in adult PRP. In FVL-negative cord plasma 5 nM APC decreased ETP by 17.4+/-3.5% (mean+/-SEM) compared with only 3.5+/-3.8% in FVL-positive cord plasma (p=0.01). FVL-positive newborns showed similar levels of F1 +2 but significantly decreased levels of factorV compared with FVL-negative newborns both in cord plasma (FV 0.82+/-0.07 U/ml vs. 0.98+/- 0.05 U/ml, p=0.03) and at the age of two weeks (FV 1.15+/-0.04 U/ml vs. 1.32+/- 0.05 U/ml, p=0.03). In conclusion, newborn plasma showed more rapid thrombin formation and enhanced sensitivity to APC compared with adult plasma. FVL conveyed APC resistance and a procoagulant effect in newborn plasma. Lack of elevated F1+2 levels in FVL-positive infants, however, suggested the existence of balancing mechanisms; one could be the observed lower level of factor V in FVL heterozygous newborns.

Local advantage in the visual processing of hierarchical stimuli following manipulations of stimulus size and element numerosity in monkeys ( Cebus apella)

Previous studies suggest that monkeys process local elements of hierarchical visual patterns more quickly and more accurately than they process the global shape. These results could be indicative of differences between relatively high visual functions of humans and non-human primates. It is, however, important to rule out that relatively low-level factors can explain these differences. We addressed this issue with two experiments carried out on capuchin monkeys ( Cebus apella) using matching-to-sample tasks featuring hierarchical stimuli. The first experiment assessed whether manipulations of stimulus size can affect the local advantage so far observed in this New World monkey species. An overall local versus global advantage still emerges in capuchins, irrespectively of the amplitude of the visual angle subtended by the hierarchical shapes. Moreover, a local-to-global interference, indicative of a strong local advantage, was observed for the first time. In the second experiment, we manipulated size and numerosity of the local elements of hierarchical patterns, mimicking procedures that in human perception relegate the local elements to texture and enhance a global advantage. Our results show that in capuchin monkeys, a local advantage emerges clearly even when these procedures are used. These results are of interest since extensive neurophysiological research is carried out on non-human primate vision, often taking for granted a similarity of visual skills in human and non-human primates. These behavioural results show that this assumption is not always warranted and that more research is needed to clarify the differences in the processes involved in basic visual skills among primates.

On second glance: Still no high-level pop-out effect for faces

A recent article in this journal (Hershler, O., & Hochstein, S. (2005). At first sight: A high-level pop out effect for faces. Vision Research, 45(13), 1707–1724) reported, in contradiction to several earlier studies, that photographs of human faces can be searched for efficiently (i.e., “pop out”) among photographs of other objects (as long as these objects are not “too similar” to faces). An apparent search asymmetry between faces and other categories (houses, cars) pointed to the existence of a specialized “face map”. Findings of impaired performance for scrambled images were presented as evidence that this face pop out is a high-level, “holistic” effect. While the main pop-out effect cannot be disputed, several choices made in that study in terms of experiment design, analysis and interpretation are questionable. After discussing these issues, I report novel experiments which show that (i) the face pop-out effect can be replicated, but under controlled conditions there is no asymmetry between faces and other objects (cars); (ii) inverting pictures and hence disrupting holistic face processing has only a minor effect on search performance; (iii) finally, search becomes inefficient when Fourier amplitude information (which carries global low-level statistical properties of images) is made irrelevant, and only phase information (carrying contour localization) can be used to detect faces. These results imply, contrary to the target article, that the face pop-out effect is mostly based on low-level factors.

Prolongation of the prothrombin time and activated partial thromboplastin time in children with sickle cell disease

Patients with sickle cell disease (SCD) have high rates of perioperative complications, including bleeding 1,2. We conducted a retrospective review of pre-operative coagulation studies in pediatric patients with SCD followed by a prospective study of 100 well children with SCD to determine the prevalence of abnormal coagulation screening tests, and to evaluate potential etiologies. In the retrospective study, 32/84 (38.1%) had a prolonged prothrombin time (PT), compared to 8/100 in the prospective study. Prolongations of the activated partial thromboplastin time (aPTT) were less common. Children in the prospective study with prolonged PTs had significantly lower levels of Factor V and VII compared to those with normal PTs. Factor VII levels were <50% in 4/8 with long PTs, compared to 3/92 with normal PTs, P=0.001. Though retrospectively, several patients had normalization of their PT with vitamin K, there was no laboratory evidence of vitamin K deficiency in the prospective study. In the retrospective analysis, six of seven children who had pre-operative coagulation studies and significant intraoperative blood loss had prolonged PTs (P=0.04). Children with SCD admitted for surgical procedures were more likely to have prolonged PTs than those tested at a well visit. There was intra-patient variability in coagulation studies that may be related to clinical status, hepatocellular dysfunction, and/or increased clotting factor consumption. Future well-designed prospective studies to determine whether abnormal coagulation studies are associated with an increased risk of perioperative bleeding in children with SCD are necessary.

Low prevalence of high-density lipoprotein cholesterol level &lt; 1 mmol/L in non-nucleoside reverse transcriptase inhibitor recipients

Our objective was to compare the prevalence of high-density lipoprotein-cholesterol (HDL-c) level < 1 mmol/L in non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) recipients in an unselected HIV-positive population. All HIV-positive patients living in Oslo who attended our outpatient clinic from April 1, 2000 to April 1, 2001 were invited to a study of cardiovascular risk factors. In this substudy, 40 NNRTI recipients and 124 PI recipients were included. Prevalence of HDL-c <1 mmol/L was 7.5% in the NNRTI recipients compared with 35.5% in the PI recipients (P <0.001). In the multivariate analyses, use of NNRTI was a significant protective factor (odds ratio [OR] 0.17; 95% confidence interval [CI] 0.05-0.66; P = 0.01) and elevated triglycerides a significant risk factor (OR 3.40; 95% CI 1.47-7.86; P = 0.004) for low HDL-c level. Our study shows that NNRTI recipients have a more favourable HDL-c profile than PI recipients, even when possible confounding factors are taken into account.

Predictive factors of low HCO3– levels in peritoneal dialysis patients

Metabolic acidosis is a major metabolic abnormality in end-stage renal disease (ESRD) and alkali is provided with dialysis treatment to patients on chronic peritoneal dialysis (CPD) to keep their acid-base balance within normal serum HCO3- levels. We examined the levels of venous serum HCO3- in 163 patients on CPD and the predictive factors for HCO3- levels low enough to indicate metabolic acidosis. The mean value for HCO3- was 26+/-2.4 mmol/l and for anion gap was 13.1+/-3.1 mEq/l. A serum bicarbonate concentration of less than 24 mmol/l, compatible with metabolic acidosis, was observed in 13.5% of the patients. In a multivariate analysis HCO3- levels were directly correlated with older age and use of CaCO3- as phosphate binders, and inversely associated with serum potassium, the use of sevelamer and low lactate dialysis solutions. Higher serum urea levels, the use of low lactate solutions and sevelamer instead of CaCO3 were significantly predictive factors for HCO3- levels < 24 mmol/l. Venous HCO3- and anion gap values were within the normal ranges in stable CPD patients. In 13.5% of them, however, chronic metabolic acidosis was observed based on venous HCO3- levels < 24 mmol/l. Dietary protein intake, the use of sevelamer and low (35 mmol/l) concentration of lactate in dialysis solutions are important predictive factors for chronic metabolic acidosis in these patients.

Thawed Plasma an Alternative to Fresh Frozen Plasma

Thawed plasma contains all of the clotting factors that Fresh Frozen Plasma contains with the exception of lower levels of Factor V and Factor VIII. Thawed plasma still has significant levels of factors to enhance coagulation. The purpose of our review was to decrease wastage and cost of fresh frozen plasma by utilizing thawed plasma and to encourage use of thawed plasma in place of fresh frozen plasma. Sources of information included our Blood Bank wastage data and cost analysis per unit. By educating the Trauma Service and Anesthesia and Emergency Services regarding the availability of thawed plasma versus fresh frozen plasma, the University Medical Center significantly decreased wastage of fresh frozen plasma after the program was initiated.

Co-existence of Bernard Soulier syndrome and factor XI deficiency in a family: A unified pathology?

Bernard Soulier syndrome (BSS) is an autosomal recessive disorder of platelet function. Factor XI deficiency leads to a variable bleeding tendency and the defect is also inherited in an autosomal recessive manner. In this paper we describe a case of BSS with severe deficiency of factor XI. The patient had both BSS and factor XI deficiency. The sister and both the parents were heterozygous for BSS and had factor XI deficiency. The brother is normal for both BSS and factor XI levels. Apart from the patient, no other family members had any history of bleeding in spite of having a deficiency of factor XI, which suggests that low level of factor XI in this family was not responsible for bleeding. Curiously, although the index patient inherited both Bernard Soulier syndrome and factor XI deficiency (FXI: C = 1.3%), he had mild bleeding symptoms restricted only to ecchymoses and petechiae. Detailed review of the pedigree showed that all the members who inherited the BSS phenotype, also inherited abnormal factor XI gene. Karyotype of the affected members of the family using standard Giemsa banding technique showed a normal picture. Considering the fact that the genes causing both BSS and factor XI are both on widely different chromosomes, their coinheritance in four members of the family without any unusual translocation suggest a unified pathology probably on the basis of a common transcription factor defect or a common post translational processing defect. This is the first case of coinheritance of BSS and factor XI deficiency reported in the English literature.

Complement factor I deficiency associated with recurrent infections, vasculitis and immune complex glomerulonephritis

Here we report complement factor I deficiency in an 11-y-old girl from a consanguineous Turkish family, who presented with recurrent pyogenic infections, vasculitic eruptions and immune complex glomerulonephritis. A moderately low C3 level together with the clinical picture suggested a deficiency affecting regulation of complement activation. Analysis of haemolytic activity revealed absence of alternative pathway activity and subsequent analysis showed no detectable factor I (<2%) together with a low level of factor B and a moderately low level of factor H, indicating consumption secondary to the factor I deficiency. Factor I inhibits complement activation beyond C3 by cleavage of C3b in the presence of cofactors. Complement factor I deficiency is frequently associated with recurrent pyogenic infections mainly affecting the upper and lower respiratory tract, or presenting as meningitis or septicaemia, while rheumatic disorders have not been a prominent feature. The patient's sister also suffered from recurrent pyogenic infections and had a low C3 level clearly suggesting the same deficiency.

Treatment of von Willebrand's Disease.

von Willebrand's disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of therapy is to correct the dual defects of haemostasis, i.e. abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand's disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with Type 1 von Willebrand's disease, who account for approximately 80% of cases. The pharmacological compound raises endogenous factor VIII and von Willebrand factor and corrects the prolonged bleeding time in most patients. In Type 3 and in the majority of Type 2 patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are currently effective and quite safe, even though the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time is associated with continued bleeding.

Successful Treatment of Life-Threatening Postpartum Hemorrhage With Recombinant Activated Factor VII

In Brief BACKGROUND Postpartum hemorrhage is one of the most common causes of maternal mortality and morbidity worldwide. The aims of treatment are to maintain the circulation and to stop the bleeding. The latter is achieved by either medical or surgical management. In intractable bleeding, emergency hysterectomy is usually required. CASE A 30-year-old nullipara presented with major postpartum hemorrhage due to uterine atony and vaginal lacerations. The patient developed hemorrhagic shock, resulting in prolonged prothrombin time, prolonged activated partial thromboplastin time, and low levels of factor VIII and fibrinogen. Treatments with uterotonic drugs, suturing, ligation of internal iliac arteries, subtotal hysterectomy, packing of the pelvis, and blood transfusion failed to control diffuse pelvic and vaginal bleeding. Recombinant activated factor VIIa (60-μg/kg intravenous bolus injection) was given as a final attempt to control the bleeding. The bleeding was successfully controlled within 10 minutes after administration. No side effects were noted. CONCLUSION Recombinant factor VIIa may be an alternative hemostatic agent in a patient with life-threatening postpartum hemorrhage unresponsive to conventional therapy. A successful treatment of life-threatening postpartum hemorrhage with recombinant factor VIIa is described.