Linda J. Jacobson

University of Colorado, Denver, Colorado, United States

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Publications (43)267.19 Total impact

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    ABSTRACT: Adults with von Willebrand Disease (VWD) are known to have a ratio of factor VIII activity (FVIII:C) to von Willebrand factor antigen (VWF:Ag) greater than 1. We, however, noted healthy children with ratios that are unexpectedly high. Though the FVIII:C/VWF:Ag ratio differs significantly between healthy children and VWD patients in some age groups, the substantial overlap of observed ranges suggests that a ratio threshold-based screening approach alone cannot reliably discriminate between these groups. The diagnostic performance of this ratio is poor for VWD in children, which may decrease its value as a screening tool in the pediatric population. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    No preview · Article · May 2014 · Pediatric Blood & Cancer
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    ABSTRACT: BACKGROUND: Lipoprotein(a) [Lp(a)] is a risk factor for adult cardiovascular events, in which the apolipoprotein(a) [apo(a)] component is thought to promote atherogenesis and impair fibrinolysis. OBJECTIVE: We investigated whether elevated plasma Lp(a) concentration and small predominant apo(a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. METHODS: Childhood arterial ischemic stroke cases (29 days-<21 years at onset; n=43) and healthy controls (n=127) were recruited for plasma sampling and laboratory determinations. Cases were followed for recurrence via a prospective cohort study. RESULTS: Median Lp(a) concentration did not differ between groups (cases: median 18.0 nmol/L [7.5 mg/dL] and observed range 0.9-259 nmol/L [0.38-108.0 mg/dL], controls: 20.4 nmol/L [8.5 mg/dL] and 0.2-282 nmol/L [0.08-117.5 mg/dL]; P=0.62). While odds of incident stroke were not significantly increased, risks of recurrent arterial ischemic stroke were each more than ten-times increased for Lp(a) >90th percentile of race-specific reference values and apo(a) <10th percentiles (odds ratio=14.0 [95% confidence interval: 1.0-184], P=0.05)] and odds ratio=12.8 [1.61-101], P=0.02). Statistically significant but weak correlations were observed for euglobulin lysis time with both Lp(a) level (r=0.18, P=0.03) and apo(a) size (r= -0.26, P=0.002). CONCLUSIONS: Elevated Lp(a) and small apo(a) potently increase the risk of recurrent AIS in children, the mechanism for which is only partially attributable to impaired fibrinolysis. Collaborative studies are warranted to further investigate these findings, and more broadly to establish key risk factors for incident and recurrent arterial ischemic stroke in children.
    Full-text · Article · Jan 2013 · Haematologica
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    ABSTRACT: Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.
    No preview · Article · Jun 2011 · Gene therapy
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    ABSTRACT: Thrombin and plasmin are the key enzymes involved in coagulation and fibrinolysis, respectively. Plasma coagulative and fibrinolytic potentials in normal children and adults, and in representative pathologically altered hemostatic states, were evaluated via simultaneous assessment of thrombin and plasmin generation. An assay of Simultaneous Thrombin and Plasmin generation (STP) was developed to measure thrombin and plasmin in plasma using individual fluorometric substrates. Coagulation is initiated with dilute tissue factor, phospholipid, and calcium in platelet-poor plasma; fibrinolysis is accelerated via tissue plasminogen activator (tPA). Abnormal states of hemostasis were investigated. STP assay reproducibility and normal adult and pediatric values for measured and calculated parameters have been established. Onset of both thrombin and plasmin generation was significantly delayed in children relative to adults (p<0.001) and the maximum amplitudes of thrombin and plasmin generation were less in children than adults (p<0.01). No significant differences were measured among pediatric age groups. The most profound impairments in thrombin generation were observed for extrinsic and common pathway factor deficiencies, with the exception of afibrinogenemia. Plasmin generation was severely impaired in deficiencies of fibrinogen and plasminogen as well as with decreased tPA reagent concentration and addition of aminocaproic acid. Plasmin generation was greatly enhanced by alpha-2-antiplasmin deficiency and excess tPA reagent. Simultaneous assessment of thrombin and plasmin generation in plasma shows promise for affording an enhanced understanding of overall coagulative and fibrinolytic functions in physiological and pathologically altered states of hemostasis in children and adults.
    No preview · Article · Feb 2011 · Thrombosis Research
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    ABSTRACT: The preterm infant is at risk for consumptive coagulopathy and thrombosis due to late maturation of coagulation regulatory proteins. Replacement proteins are available, but neonatal pharmacokinetic data are lacking. The objective was to determine the pharmacokinetic properties of antithrombin (AT) and protein C (PC) in order to provide data for estimating doses in human infants. A catheterized ovine model was used to determine pharmacokinetic properties of AT and PC, including plasma recovery, volume of distribution (V(d)), clearance (Cl) and half-life (t((1/2))), in the fetal lamb relative to the ewe. AT studies showed statistically significant differences between ewes and fetuses in recovery (p < 0.0001), V(d) (p = 0.0002) and Cl (p < 0.0001). The AT t((1/2)) was significantly shortened among fetuses (5.55 h, 95% CI: 4.01-7.08) compared to ewes (18.7 h, 95% CI: 11.6-25.8). PC recovery (p < 0.0001), V(d) (p < 0.0001) and Cl (p = 0.004) differed significantly between ewes and singleton fetuses as did the t((1/2)): 3.86 h (95% CI: 3.35-4.36) and 11.9 h (95% CI: 10.9-12.9) in the singletons and ewes, respectively. All PC parameters were significantly different for twins compared to ewes. AT and PC show decreased recovery and t((1/2)) in the fetal lamb. These data can be used to estimate dosing for human neonates in comparison with human adult dosing recommendations.
    No preview · Article · Dec 2008 · Neonatology
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    ABSTRACT: The low-molecular-weight heparin (LMWH) dalteparin is approved by the Food and Drug Administration for prophylaxis of venous thromboembolism (VTE) in adults and has recently received an indication for acute VTE therapy in adults with cancer. Published reports of experience with dalteparin use in European children suggest that this LMWH agent is safe and effective in the prophylaxis and treatment of VTE in the pediatric population. However, dalteparin is commonly available in the US in a concentrated form that requires dilution for accurate administration in infants and young children. To investigate the in vitro stability of diluted dalteparin for pediatric use, as measured by serial anti-Xa activity assays over the course of 4 weeks. At 2 clinical research pharmacies, dalteparin multidose vials (anti-Xa concentration 25,000 U/mL) of the 2 distinct lots presently available for clinical use were diluted 1:10 with preservative-free NaCl 0.9% and maintained in tuberculin syringes at 4 degrees C. Syringes were then sampled for anti-Xa activity by chromogenic assay at baseline and weekly over the course of 4 weeks. For each lot of dalteparin, there was strong agreement in anti-Xa activity between corresponding diluted syringes prepared at the 2 pharmacy sites. No statistically significant difference in anti-Xa activity was detected from baseline to any time point, nor was a trend of change detected in anti-Xa activity with time for either lot of dalteparin. These data indicate that the anti-Xa activity of diluted dalteparin for pediatric use is stable over the course of 4 weeks.
    Full-text · Article · May 2008 · Annals of Pharmacotherapy
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    ABSTRACT: We sought to determine the influence of factor IX (FIX) deficiency upon overall coagulative and fibrinolytic capacities in plasma using the clot formation and lysis (CloFAL) assay, and to investigate the role of this global assay as an adjunctive monitoring tool in haemophilia B. CloFAL assay parameters were measured in vitro in platelet-poor plasma in relation to FIX activity and antigen (FIX:Ag), and were determined ex vivo among FIX-deficient patients (n = 41) in comparison to healthy individuals (n = 48). Supplementation of FIX-deficient plasma with FIX in vitro demonstrated a non-linear concentration dependence of FIX upon overall plasma coagulability. Ex vivo, coagulability was significantly decreased in FIX-deficient vs. healthy subjects among adults [median coagulation index (CI): 4% vs. 104% respectively; P < 0.001] and children (median CI: 9% vs. 63%; P < 0.001). Fibrinolytic capacity was increased in adult FIX-deficient vs. healthy subjects (median fibrinolytic index: 216% vs. 125%, respectively, P < 0.001), and was supported by a trend in shortened euglobulin lysis time (ELT). Severe haemophilia B patients showed heterogeneity in aberrant CloFAL assay waveforms, influenced partly by FIX:Ag levels. Patients with relatively preserved FIX:Ag (i.e. dysfunctional FIX) exhibited a shorter time to maximal amplitude in clot formation than those with type I deficiency. During patient treatment monitoring, markedly hypocoagulable CloFAL assay waveforms normalized following 100% correction with infused FIX. The CloFAL global assay detects FIX deficiency, demonstrates differences in coagulability between dysfunctional FIX and type I deficiency, and appears useful as an adjunctive test to routine FIX measurement in monitoring haemophilia B treatment.
    No preview · Article · Jan 2008 · Haemophilia
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    ABSTRACT: Effective ways to prevent arthropathy in severe hemophilia are unknown. We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI). Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. ( number, NCT00207597 [].).
    Full-text · Article · Aug 2007 · New England Journal of Medicine
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    Full-text · Article · Dec 2006 · Thrombosis Research
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    ABSTRACT: The objectives of the present study were to evaluate the analytical sensitivity of the recently developed Clot Formation and Lysis (CloFAL) global assay for factor VIII (FVIII) deficiency, both in vitro and ex vivo, to determine whether this global assay is influenced by FVIII inhibitors, and to investigate the coagulative response to FVIII replacement in haemophilia A patients using the CloFAL assay in comparison with FVIII activity. Among adults and children alike, the CloFAL assay coagulation index (CI) was significantly decreased in FVIII-deficient vs. healthy subjects (adults median CI: 2% vs. 94% respectively; children median CI: 3% vs. 63%; P < 0.001 for each), and correlated significantly with activated partial thromboplastin time-based FVIII activity across all individuals (r = 0.78; P < 0.001). The CloFAL assay was analytically sensitive to deficient FVIII activity and also influenced by the presence of von Willebrand factor. Severe haemophilia A patients without inhibitory antibodies to FVIII showed considerable heterogeneity in CloFAL assay waveforms, despite a uniformly diminished CI of 0-1%. During FVIII infusion half-life studies in patients with severe haemophilia A, the CloFAL assay demonstrated a marked rise in coagulability 30 min following infusion, with progressive decrease in coagulability towards baseline over the ensuing 48-h period. In each case, the profile of coagulative response to FVIII infusion as determined by CloFAL assay CI differed qualitatively from that measured by FVIII activity. These findings indicate that the CloFAL assay may be useful as an adjunctive test to FVIII activity measurements in the therapeutic monitoring of haemophilia A.
    No preview · Article · Dec 2006 · Haemophilia
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    ABSTRACT: Global clotting assays may reflect an individual's net hemostatic balance and could contribute to prothrombotic and hemorrhagic risk assessment. In this research, a global assay that measures both coagulation and fibrinolytic capacities was developed and investigated. In the Clot Formation and Lysis (CloFAL) assay, a buffered reactant solution containing trace amounts of calcium, tissue factor, and tissue-type plasminogen activator is added to plasma samples on a 96-well microplate in an automated, thermoregulated (37 degrees C) spectrophotometer. Clot formation and lysis are monitored as continuous changes in absorbance over the course of 3 h. Measurements include maximum amplitude (MA), times to maximum absorbance (T1) and completion of the first phase of decline in absorbance (T2), and area under the curve (AUC), from which a coagulation index (CI) and various fibrinolytic indices (FI) may be calculated. MA, T1, and CI were principally influenced by fibrinogen and procoagulant factors. FI was found to be altered by inhibiting activation of plasminogen or thrombin activatable fibrinolytic inhibitor. Median CI was significantly decreased, while FI was markedly increased, in term neonates as compared to healthy adults (CI: 58% vs. 115%, FI: 210% vs. 90%; P<0.001 for each). By contrast, median CI was notably increased, and FI decreased, in healthy pregnant women when compared to adults (CI: 239% vs. 115%, FI: 59% vs. 90%; P<0.001 for each). The CloFAL global assay is analytically sensitive to several key components in the coagulation and fibrinolytic systems, as well as to physiologic alterations in hemostasis.
    No preview · Article · Dec 2005 · Thrombosis Research
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    ABSTRACT: Despite a paucity of evidence, clinicians routinely advise that patients discontinue using nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, at least 1 week before most surgical procedures. To define the duration of ibuprofen-induced platelet dysfunction. Prospective cohort study. Denver/Aurora, Colorado. 11 healthy adult volunteers. Individuals were tested at baseline and serially after completion of a 7-day course of ibuprofen (600 mg orally every 8 hours). The platelet function analyzer (PFA-100, Dade Behring, Newark, Delaware), a test that has replaced the bleeding time in many clinical settings, was used. All participants exhibited normal platelet function before starting ibuprofen. Platelet dysfunction was apparent after completion of the ibuprofen course in 7 of the 11 participants and normalized by 24 hours after the last ibuprofen dose. The sample size in this study was small, and no participants had a major illness. Correlation between PFA-100 results and clinical bleeding has not been established. Platelet function seems to normalize within 24 hours after cessation of regular ibuprofen use in healthy individuals. Further studies are warranted to provide a rational basis for timing of NSAID withdrawal in a range of patients undergoing surgery.
    No preview · Article · May 2005 · Annals of internal medicine
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    ABSTRACT: Plasma fibrinolytic activity has been measured by the euglobulin clot lysis time (ELT) since the late 1950s. The euglobulin clot lysis assay (ECLA) method has been modified using a computerized kinetic spectrophotometric microtiter plate reader and measures optical density changes of recalcified euglobulin fraction of plasma samples over time. This method has been applied to normal healthy adults, children, pregnant women and newborn infants, which represent physiologic extremes of the ELT. The ECLA method adds measurements of maximum absorbance (Max Abs), area under the curve (AUC) and mean velocity to the standard clot lysis time. The resulting curves are unique to this method and have been analyzed and compared in order to establish normal ranges. Fibrinogen levels, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity and thrombin activatable fibrinolytic inhibitor (TAFI) antigen levels were measured in each individual of the four groups. Each protein measured within each study group except TAFI correlated with the lysis time, maximum absorbance and area under the curve. Considering all four groups together, PAI correlates most highly with lysis time, fibrinogen correlates the highest with Max Abs; fibrinogen and PAI-1 antigen have equally high correlations to AUC. Area under the curve is highly correlated with all coagulation parameters measured; the most significant contributor is fibrinogen. These observations are interesting, but at this time, it cannot be said that any of the test parameters are better than lysis time in distinguishing between these normal physiologic states.
    No preview · Article · Feb 2003 · Thrombosis Research
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    ABSTRACT: To investigate the development of coagulation regulatory proteins-protein C (PC), protein S (PS), and antithrombin (AT)-in relationship to the procoagulant protein factor X (FX), a chronically catheterized fetal ovine model was used. Infusion and sampling catheters were placed into pregnant ewes and their fetuses and maintained from mid-gestation. From a total of 110 fetuses, 17 lambs, and 63 ewes that were studied on one to 15 occasions, 212 fetal, 88 neonatal, and 157 maternal samples were obtained. Liver tissue was obtained from 31 fetuses and 15 ewes. Plasma levels of all proteins studied were higher in the ewe than in the fetus (p < 0.0001). Plasma levels of FX, PC, and PS achieved neonatal levels by mid-gestation with mild but significant decreases during mid- and late gestation. Fetal and early neonatal plasma concentrations of these vitamin K-dependent proteins fit a model with both quadratic (p < 0.01) and linear (p < 0.01) components. The discrepant levels in mRNA relative to plasma concentration were consistent with regulatory control beyond the level of transcription. In contrast, a simple linear increase in plasma protein levels was determined for the vitamin K-independent coagulation regulatory protein, AT (p for quadratic component > 0.05). This study suggests that fetal regulation of coagulation proteins follows characteristic patterns relative to the vitamin K dependence of the protein rather than its role as a procoagulant versus regulatory protein.
    Preview · Article · Nov 2002 · Pediatric Research
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    ABSTRACT: This cross-sectional study was conducted to determine the incidence of autoantibodies to phospholipids and coagulation proteins in children with acute varicella zoster virus (VZV) infection. Study groups included children with VZV alone or complicated by purpura fulminans and/or thromboembolism. VZV naïve children and children who had VZV >1 y before sample collection formed a control group. Blood was assayed for the following: free protein S (PS), protein C, antithrombin, and prothrombin; antibody binding to these proteins; lupus anticoagulant; anticardiolipin antibody; antiphospholipid antibodies; and prothrombin fragment 1+2. Data regarding coinfections was collected. Forty-three VZV-infected children showed an increased frequency of lupus anticoagulant, anticardiolipin antibody, antiphospholipid antibodies, and autoantibodies to PS, protein C, prothrombin, and antithrombin in comparison to 52 children without acute VZV (p < 0.0001). Seventeen children with VZV and purpura fulminans and/or thromboembolism showed a statistically significant decrease in free PS, significantly increased PS IgG antibody, and significantly increased prothrombin fragment 1+2 (p < 0.0001) compared with the group without acute VZV and the group with uncomplicated VZV. Twenty-six children with uncomplicated VZV showed increased PS IgG antibody (p < 0.001) compared with the children without acute VZV. For all groups combined, elevated PS IgG antibody showed negative correlation with free PS (p < 0.0001) and positive correlation with prothrombin fragment 1+2 (p = 0.0002). Autoantibodies were transient. Transient antiphospholipid and coagulation protein autoantibodies were common with VZV infection, but were not predictive of thrombotic complications.
    Full-text · Article · Oct 2001 · Pediatric Research
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    ABSTRACT: Hemophilia B is a sex-linked recessive bleeding disorder characterized by the presence of either a decreased amount of normal factor IX (FIX) or the presence of a dysfunctional FIX. We have identified a unique mutation in a family with mild hemophilia B. DNA analysis of family members revealed a single base transition in the 8th exon of the FIX gene predicting an amino acid change of Asn 346-->Asp in the catalytic domain. The FIX variant, named FIX Denver, was purified from proband plasma. Kinetic studies of factor X (FX) interactions with normal FIXa or FIXa Denver and phospholipid (PL) showed little difference in kcat but a significant difference when factor VIIIa (FVIIIa) was included in the reaction. Using kinetic assays to infer the Kd of FIXa for FVIIIa, normal FIXa had a Kd of 0.095 nM while that of FIXa Denver was 9.85 nM. The major defect caused by this point mutation is a marked decrease in the affinity of FIXa Denver for factor VIIIa.
    No preview · Article · Sep 2001 · Thrombosis and Haemostasis
  • Marilyn J. Manco-Johnson · Rachelle Nuss · Linda J. Jacobson
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    ABSTRACT: The purpose of this study was to determine the prevalence and effect of heparin contamination in samples drawn from implanted venous access devices (VADs, ports) on factor VIII activity and Bethesda inhibitor assay (BU) and the efficacy of heparinase to neutralize heparin. Plasma samples containing 85, 45, and 2 U/dL factor VIII were spiked in vitro with heparin from 0 to 3 U/mL. Factor VIII activity was assayed with a one-stage clotting assay on paired samples before and after heparinase, 25 mg/mL plasma. Paired patient samples drawn from VADs were assayed for heparin concentration, factor VIII, and BU before and after heparinase. At all three concentrations of factor VIII in vitro, the addition of heparin at 0.12 to 0.25 U/mL decreased assayed factor VIII activity. Heparinase neutralized up to 2 U/mL heparin and resulted in accurate factor VIII determination. Of 105 VAD samples, 47 (45%) had heparin contamination >0.05 U/mL. Of 47 heparin-contaminated samples, 42 showed decreased factor VIII activity in before/after comparisons. False-positive BU results were detected in 6 of 47 heparin-contaminated samples. Heparin contamination occurs frequently in samples drawn from VADs and could increase costs through excessive factor concentrate use. We recommend that all VAD samples be pretreated with heparinase before the assay of factor VIII activity or Bethesda inhibitor titers.
    No preview · Article · Aug 2000 · Journal of Laboratory and Clinical Medicine
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    ABSTRACT: Dysprothrombinaemia is a rare, congenital cause of bleeding. Fewer than 25 families who express a functional prothrombin (factor II) defect have been reported. The original patient with prothrombin Denver had a severe haemophilia-like bleeding disorder treated with weekly prophylactic factor replacement. Analysis of factor II activity and antigen in the patient showed a factor II activity of 5 units/dl and factor II antigen of 21 units/dl. Genomic DNA from the patient, mother and brother was obtained from peripheral blood white cells. Oligonucleotides were constructed, and prothrombin exons were amplified via polymerase chain reaction (PCR). The entire sequence of the thrombin portion of the molecule (exons VIII-XIV) and that of exons I-II and IV-VII was determined. This moderately severe dysprothrombinaemia was found to be associated with compound heterozygosity for two different Glu-->Lys point mutations, at amino acid positions 300 and 309. Assays of plasma from the prothrombin Denver proband suggested that the functional defect was in the activation of zymogen to enzyme.
    Preview · Article · Feb 2000 · British Journal of Haematology
  • R Nuss · L Jacobson · W E Hathaway · M Manco-Johnson

    No preview · Article · Dec 1999 · Thrombosis and Haemostasis
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    ABSTRACT: A flock of Rambouillet sheep experienced unexpected lamb mortality associated with excessive bleeding at the time of parturition. Most lambs died of blood loss through the umbilicus or into subcutaneous tissues. Subsequently, nine ewes which had previously delivered lambs that bled to death were bred to the suspected sire of the previous bleeding lambs. Fifteen lambs were born alive the following Spring, and three males and one female bled clinically. These lambs had markedly decreased factor IX (< 16%) and factor X (< 4%) activities, with variably decreased factor II (11-36%) and factor VII (20-37%) activities. Protein C chromogenic activity was also markedly decreased (< 1%) in these lambs. The results from crossed immunoelectrophoresis and 'protein-induced-in-vitamin-K-absence' determination of the plasma of affected lambs, with antiserum directed against coagulation factor X, protein C or proteins S, suggested that these proteins were not carboxylated normally. Examination of liver from one lamb in the first batch and the four subsequent lambs did not reveal a known vitamin K antagonist. The breeding data suggested that the coagulopathy in these sheep was inherited as an autosomal recessive trait. The genetic or molecular defect that exists in these lambs is unknown, but possibilities include abnormal gamma-glutamyl carboxylase activity or abnormal metabolism of vitamin K.
    No preview · Article · Mar 1999 · Blood Coagulation and Fibrinolysis

Publication Stats

2k Citations
267.19 Total Impact Points


  • 2001-2014
    • University of Colorado
      • • Department of Pediatrics
      • • Hemophilia and Thrombosis Center
      • • Department of Pathology
      Denver, Colorado, United States
  • 2011-2013
    • Children's Hospital Colorado
      • Department of Pediatrics
      Aurora, Colorado, United States
  • 2000
    • University of Colorado at Boulder
      Boulder, Colorado, United States
  • 1985-2000
    • University of Colorado Hospital
      • Department of Pediatrics
      Denver, Colorado, United States
  • 1996
    • The Scripps Research Institute
      لا هویا, California, United States
  • 1990-1991
    • Mahidol University
      Siayuthia, Bangkok, Thailand