A fusion protein comprising factor IX and the dimeric Fc domain of IgG1 has a half-life that is five times as long as that of native factor IX, allowing prophylactic injections to be spaced as far as ...2 weeks apart while maintaining levels of factor IX that are sufficient to prevent bleeding.
In patients with severe hemophilia B, recurrent bleeding leads to painful hemarthroses, disabling hemophilic arthropathy, and other sequelae.
1
,
2
Prophylactic replacement of coagulation factor IX is associated with improved clinical outcomes
3
–
7
; however, the relatively short half-lives of currently available factor IX products necessitate frequent intravenous injections (two or three times weekly) to maintain protective levels (at or above 1 IU per deciliter).
8
,
9
The frequency of injections is a considerable burden, cited by patients as a key deterrent to undertaking prophylactic treatment.
10
Various strategies to reduce this burden and improve the treatment of hemophilia B are under investigation, . . .
Lipoprotein (a) is a risk factor for adult cardiovascular events, in which the apolipoprotein (a) component is thought to promote atherogenesis and impair fibrinolysis. We investigated whether ...elevated plasma lipoprotein (a) concentration and small predominant apolipoprotein (a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. Patients who had had an arterial ischemic stroke in childhood (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 in a prospective cohort study. The median lipoprotein (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 lipoprotein(a) >90(th) percentile of race-specific reference values and apolipoprotein (a) <10(th) 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 between euglobulin lysis time and both lipoprotein (a) level (r=0.18, P=0.03) and apolipoprotein (a) size (r= -0.26, P=0.002). In conclusion, elevated lipoprotein (a) and small apolipoprotein (a) potently increase the risk of recurrent arterial ischemic stroke in children, with a mechanism only partially attributable to impaired fibrinolysis. Collaborative studies are warranted to investigate these findings further and, more broadly, to establish key risk factors for incident and recurrent arterial ischemic stroke in children.
von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of ...debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria. von Willebrand factor (VWF) laboratory testing and full-length VWF gene sequencing was performed for all index cases and healthy control subjects in a central laboratory. Bleeding phenotype was characterized using the International Society on Thrombosis and Haemostasis bleeding assessment tool. At study entry, 64% of subjects had VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity below the lower limit of normal, whereas 36% had normal VWF levels. VWF sequence variations were most frequent in subjects with VWF:Ag <30 IU/dL (82%), whereas subjects with type 1 VWD and VWF:Ag ≥30 IU/dL had an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study entry had a similar rate of sequence variations as the healthy controls (14%). All subjects with severe type 1 VWD and VWF:Ag ≤5 IU/dL had an abnormal bleeding score (BS), but otherwise BS did not correlate with VWF:Ag. Subjects with a historical diagnosis of type 1 VWD had similar rates of abnormal BS compared with subjects with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and bleeding symptoms are frequent in this population.
•Type 1 VWD in the United States is highly variable, including patients with very low VWF levels as well as those with mild or minimal VWF deficiency.•The frequency of sequence variants in the VWF gene increases with decreasing VWF level, but BS does not vary by VWF level.
Summary
Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often ...leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events coumarin-induced skin necrosis; CISN, 1 event; venous thrombosis, 5 events). Predefined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate–treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated
effective
and 5.3 %
effective with complications
(not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated
effective
(68.4 %
excellent
; 21.1 %
good
; 10.5 %
fair
). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated
excellent
and 20 % were rated
good
. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients.
Lemierre's syndrome, or jugular vein thrombosis (JVT) associated with anaerobic infection of the head and neck and frequently complicated by septic pulmonary embolism (PE), has historically been ...described as a disease of young adults. In recent years, an increasing number of case reports of childhood Lemierre's syndrome have been published, focusing mostly on the clinical and laboratory findings at disease presentation and the outcomes of infection. Given the potentially life-threatening thromboembolic complications of this disorder, we reviewed our single-institutional experience with pediatric Lemierre's and Lemierre's-like syndromes (LALLS) from within the context of a larger cohort study of thrombosis in children.
Children who were aged from birth to 21 years and had received a diagnosis of JVT and Lemierre's syndrome at the Children's Hospital (Denver, CO) between 2001 and 2005 were identified for inclusion. Case designation of LALLS required all the following: (1) radiologic confirmation of JVT, (2) clinical diagnosis of pharyngitis or other febrile illness, and (3) intraoperative evidence of loculated infection in the head and neck region or radiologic demonstration of bilateral pulmonary infiltrates. Isolation of a causative organism by microbiologic culture of blood, tissue, or purulent fluid was also a necessary diagnostic criterion among patients who had not been treated with antibiotics before culture. A designation of classic Lemierre's syndrome was reserved for documented cases of anaerobic infection. Children in whom JVT was associated with the presence of an ipsilateral central venous catheter were excluded from the analysis. Analysis included information on underlying medical conditions, microbiologic and radiologic findings, and comprehensive hypercoagulability testing results from the time of diagnosis, as well as antimicrobial and anticoagulant therapies administered. In addition, clinical outcomes were evaluated via serial follow-up and included bleeding complications, thrombus resolution on serial radiologic studies, symptomatic recurrent venous thromboembolism (VTE), and mortality.
From January 2001 to January 2005, 9 children with LALLS were identified. Median age was 15 years (range: 2.5-20 years). Clinical presentation was consistent with septic PE in 5 cases and septic shock in 2. Thrombophilia was present in 100% (7 of 7) of children tested, consisting principally of antiphospholipid antibodies and elevated factor VIII activity. Anticoagulation was given in 89% (8 of 9), for a median duration of 3 months (range: 7 weeks-1 year). After a median follow-up time of 1 year, all children had survived without recurrent VTE or anticoagulant-associated major hemorrhage. JVT failed to resolve at 3 to 6 months in 38% of anticoagulated children.
Our experience suggests that LALLS is an emerging pediatric concern with serious acute (eg, septic PE) and chronic (eg, persistent vascular occlusion) complications. Septic JVT may not be uniquely anaerobic, and the inflammatory prothrombotic state is often characterized by antiphospholipid antibodies and elevated factor VIII levels. Early diagnosis and aggressive antimicrobial and antithrombotic therapies in LALLS may be necessary for optimal long-term outcomes.
BACKGROUND: Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu‐like illness that occurs most frequently in childhood. The virus is resistant to current viral ...inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission.
STUDY DESIGN AND METHODS: Blood specimens obtained from participants of a surveillance system established in federally supported specialized bleeding disorders clinics were used in a B19V seroprevalence study.
RESULTS: A total of 1643 specimens from 1043 participants age 2 to 7 years born after B19V NAT screening was implemented were tested. Age‐specific prevalence rates were generally higher for subjects exposed to either plasma‐derived products alone or in combination with other products compared to subjects with no exposure to antihemophilic products. Overall, compared to participants unexposed to blood or blood products, those exposed to plasma‐derived products alone were 1.7 times more likely to have antibodies to B19V (p = 0.002).
CONCLUSION: These results are consistent with continued B19V transmission through plasma‐derived factor concentrates. Effective viral inactivation and detection processes are needed to protect users of these products from infection with B19V or other new or emerging viruses.
Young individuals with occlusive, proximal-limb deep vein thrombosis (DVT) who have acutely increased plasma levels of factor VIII and D-dimer are at high risk for postthrombotic syndrome (PTS) when ...treated with conventional anticoagulation alone. The present report is an evaluation of experience with adjunctive percutaneous mechanical thrombolysis (PMT) and/or percutaneous pharmacomechanical thrombolysis (PPMT) in such patients.
Among 95 children 11-21 years of age enrolled in a prospective cohort of venous thromboembolism between March 1, 2006, and November 1, 2009, 16 met eligibility criteria and underwent PMT/PPMT, typically with adjunctive catheter-directed thrombolytic infusion (CDTI) of tissue-type plasminogen activator given after the procedure.
Median age was 16 years (range, 11-19 y). Thirteen cases (81%) involved lower limbs. Underlying stenotic lesions were disclosed in 53%, with endovascular stents deployed in all cases of May-Thurner anomaly. There were no periprocedural major bleeding events and one symptomatic pulmonary embolism. Technical success rate was 94%. Early (< 30 days) locally recurrent DVT developed in 40% of cases, of which 83% were successfully treated with repeat lysis. Late recurrent DVT rate (median follow-up duration, 14 months; range, 1-42 mo) was 27%. Cumulative incidence of physically and functionally significant PTS at 1-2 years was 13%.
This experience provides preliminary evidence that PMT/PPMT with adjunctive CDTI can be used safely and effectively in adolescent subjects with DVT at high risk for PTS.
To evaluate the impact of early disseminated intravascular coagulation (DIC) on illness severity in children using a database of emergency department ED encounters for children with suspected sepsis, ...in view of similar associations in adults.
Laboratory and clinical data were extracted from a registry of emergency department encounters of children with suspected sepsis between April 1, 2012, and June 26, 2017. International Society of Thrombosis and Hemostasis DIC scores were calculated from laboratory values obtained within 24 hours of emergency department admission. Univariate logistic regression, multivariable logistic regression, and Cox regression were used to assess the influence of DIC scores on vasopressor use (primary outcome), mortality, ventilator requirement, pediatric intensive care unit admission, and hospital duration (secondary outcomes). The optimal DIC score cutoff for outcome prediction was determined.
Of 1653 eligible patients, 284 had DIC scores within 24 hours, including 92 who required vasopressors and 23 who died within 1 year. An initial DIC score of ≥3 was the most sensitive and specific DIC score for predicting adverse outcomes. Those with a DIC score of ≥3 vs <3 had increased odds of vasopressor use in both univariate (OR, 4.48; 95% CI, 2.63-7.62; P < .001) and multivariable (OR, 3.78; 95% CI, 1.82-7.85; P < .001) analyses. Additionally, those with a DIC score of ≥3 vs <3 had increased 1-year mortality with a hazard ratio of 3.55 (95% CI, 1.46-8.64; P = .005).
A DIC score of ≥3 was an independent predictor for both vasopressor use and mortality in this pediatric cohort, distinct from the adult overt DIC score cutoff of ≥5.
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