Hemostasis in the Pregnant Woman, the Placenta, the Fetus, and the Newborn Infant.

The hemostasis system is composed of procoagulant, anticoagulant, and fibrinolytic proteins that interact with endothelial and blood cells and with each other in a complex system of checks and balances to maintain blood flow while preventing both hemorrhage and thrombosis. Pregnancy is a unique physiological state in which biological alterations predispose both mother and fetus to both bleeding and clotting. The placenta is a vascular interface for maternal and fetal blood exchange which predisposes the mother to hemorrhage. Maternal hemostasis presents a compensatory hypercoagulability including elevated factor VIII, von Willebrand factor, fibrinogen and thrombin generation, decreased thrombin regulation with resistance to activated protein C and decreased free protein S, and decreased fibrinolysis with increased plasminogen activator inhibitors. The placental vascular surface is of fetal trophoblastic origin that derives many characteristics of endothelium but differs in that tissue factor is constitutively expressed. Ontogeny of fetal hemostasis is characteristic. Platelets, von Willebrand factor, factor VIII, and fibrinogen are expressed and mature early in gestation, while vitamin K-dependent and contact factors exhibit delayed development. The fetal hemostatic system has a decreased capacity to generate or regulate thrombin, resulting in a fragile balance with little capacity to compensate under stress conditions, particularly in the infant born prematurely. Dysfunction of the maternal/placental/fetal unit gives rise to gestational disorders including preeclampsia, fetal growth restriction, placental abruption, and premature delivery. Knowledge of normal hemostasis levels and function are critical to evaluate bleeding or clotting syndromes in the pregnant woman and her fetus or newborn infant.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

Outcome measures in Haemophilia: Beyond ABR (Annualized Bleeding Rate).

Options for management of haemophilia are increasing rapidly with completely novel therapeutic approaches that cannot be compared using traditional factor assays. In addition, as prophylaxis regimens have improved, bleeding rates have decreased, and consequently, it is difficult to show an impact of novel therapies on rates of spontaneous bleeding. There is currently an urgent need for a panel of outcome measures to compare therapies that are dissimilar in many essential ways. Conventional objective outcome measures including joint physical examination and joint imaging continue to hold a central importance. Factor assays are essential for evaluation of products derived from native factor genes, but are not applicable to some extended half-life factors or non-factor bypassing agents. Global assays including thrombin generation and chromogenic assays of factor X activation are under investigation for their usefulness in haemophilia assessment. Bleeding rate is a conventional subjective patient-reported outcome that, while decreasing in frequency, is indispensable as an outcome given that the primary manifestation of haemophilia is bleeding. Other patient-reported outcomes such as pain intensity and interference, health-related quality of life and activities and participation are increasingly important to distinguish superior outcomes in comparative trials. This review of outcome measures for haemophilia presents examples of existing outcome measures with an emphasis on their strengths and limitations.

Disseminated Intravascular Coagulation Is an Independent Predictor of Adverse Outcomes in Children in the Emergency Department with Suspected Sepsis.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project.

This analysis of the US Hemophilia Treatment Center Network and the Centers for Disease Control and Prevention surveillance registry assessed trends in prophylaxis use and its impact on key indicators of arthropathy across the life-span among participants with severe hemophilia A. Data on demographics, clinical characteristics, and outcomes were collected prospectively between 1999 and 2010 at annual clinical visits to 134 hemophilia treatment centers. Trends in treatment and outcomes were evaluated using cross-sectional and longitudinal analyses. Data analyzed included 26 614 visits for 6196 males; mean age at first registry visit was 17.7 years; and median was 14 (range, 2 to 69). During this time, prophylaxis use increased from 31% to 59% overall, and by 2010, 75% of children and youths <20 years were on prophylaxis. On cross-sectional analysis, bleeding rates decreased dramatically for the entire population (P < .001) in parallel with increased prophylaxis usage, possibly because frequent bleeders adopted prophylaxis. Joint bleeding decreased proportionately with prophylaxis (22%) and nonprophylaxis (23%), and target joints decreased more with prophylaxis (80% vs 61%). Joint, total, and target joint bleeding on prophylaxis were 33%, 41%, and 27%, respectively, compared with nonprophylaxis. On longitudinal analysis of individuals over time, prophylaxis predicted decreased bleeding at any age (P < .001), but only prophylaxis initiation prior to age 4 years and nonobesity predicted preservation of joint motion (P < .001 for each). Using a national registry, care providers in a specialized health care network for a rare disorder were able to detect and track trends in outcomes over time.

Factor VIII prophylaxis effects outweigh other hemostasis contributors in predicting severe haemophilia A joint outcomes.

INTRODUCTION: The Joint Outcome Study (JOS) demonstrated that previously untreated children with severe haemophilia A treated with prophylactic factor VIII (FVIII) concentrate had superior joint outcomes at age 6 years compared to those children treated episodically for bleeding. However, variation in joint outcome within each treatment arm was not well explained. AIM: In this study, we sought to better understand variation in joint outcomes at age 6 years in participants of the JOS. METHODS: We evaluated the influence of FVIII half-life, treatment adherence, constitutional coagulant and anticoagulant proteins, and global assays on joint outcomes (number of joint bleeds, total number of bleeds, total MRI score and joint physical exam score). Logistic regression was used to evaluate the association of variables with joint failure status on MRI, defined as presence of subchondral cyst, surface erosion or joint-space narrowing. Each parameter was also correlated with each joint outcome using Spearman correlations. RESULTS: Prophylaxis treatment arm and FVIII trough were each found to reduce risk of joint failure on univariate logistic regression analysis. When controlling for treatment arm, FVIII trough was no longer significant, likely because of the high level of covariation between these variables. We found no consistent correlation between any laboratory assay performed and any joint outcome parameter measured. CONCLUSION: In the JOS, the effect of prescribed prophylactic FVIII infusions on joint outcome overshadowed the contribution of treatment adherence, FVIII half-life, global assays of coagulation and constitutional coagulation proteins. (ClinicalTrials.gov number, NCT00207597).

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States.

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.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.

Inter-Rater Reliability of the CASCADE Criteria: Challenges in Classifying Arteriopathies.

BACKGROUND AND PURPOSE: There are limited data about the reliability of subtype classification in childhood arterial ischemic stroke, an issue that prompted the IPSS (International Pediatric Stroke Study) to develop the CASCADE criteria (Childhood AIS Standardized Classification and Diagnostic Evaluation). Our purpose was to determine the CASCADE criteria's reliability in a population of children with stroke. METHODS: Eight raters from the IPSS reviewed neuroimaging and clinical records of 64 cases (16 cases each) randomly selected from a prospectively collected cohort of 113 children with arterial ischemic stroke and classified them using the CASCADE criteria. Clinical data abstracted included history of present illness, risk factors, and acute imaging. Agreement among raters was measured by unweighted κ statistic. RESULTS: The CASCADE criteria demonstrated a moderate inter-rater reliability, with an overall κ statistic of 0.53 (95% confidence interval [CI]=0.39-0.67). Cardioembolic and bilateral cerebral arteriopathy subtypes had much higher agreement (κ=0.84; 95% CI=0.70-0.99; and κ=0.90; 95% CI=0.71-1.00, respectively) than cases of aortic/cervical arteriopathy (κ=0.36; 95% CI=0.01-0.71), unilateral focal cerebral arteriopathy of childhood (FCA; κ=0.49; 95% CI=0.23-0.76), and small vessel arteriopathy of childhood (κ=-0.012; 95% CI=-0.04 to 0.01). CONCLUSIONS: The CASCADE criteria have moderate reliability when used by trained and experienced raters, which suggests that it can be used for classification in multicenter pediatric stroke studies. However, the moderate reliability of the arteriopathic subtypes suggests that further refinement is needed for defining subtypes. Such revisions may reduce the variability in the literature describing risk factors, recurrence, and outcomes associated with childhood arteriopathy.

Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B.

BACKGROUND: Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS: We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS: As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS: Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).

Inflammatory predictors of neurologic disability after preterm premature rupture of membranes.

OBJECTIVE: The maternal-fetal inflammatory response contributes to both preterm premature rupture of membranes (PPROM) and adverse neurological outcomes. Additionally, cytokines associated with fetal placental inflammation can be detrimental to brain development regardless of inciting infection. We investigated whether differential patterns of cytokine markers in maternal and fetal plasma samples reflect subtypes of placental inflammation and neurological outcomes at 6 months in infants born to mothers with PPROM. STUDY DESIGN: Within a prospective cohort study of 25 women with PPROM, plasma cytokines (interleukin [IL]-1ß, IL-6, IL-8, and tumor necrosis factor-α) were measured by enzyme-linked immunosorbent assay from maternal blood samples at rupture and delivery, and from fetal umbilical cord blood samples. Patterns of cytokine expression were correlated with specific placenta pathologies. Infants underwent cranial ultrasound after birth and standardized neurological examinations at 6 months' corrected gestational age. Predictors of inflammation and adverse neurological outcome were assessed by logistic regression, adjusting for gestational age at birth. RESULTS: Inflammation of the fetal side of the placenta was associated with elevated maternal IL-6 and IL-8 at delivery and fetal IL-1ß, IL-6, IL-8, and tumor necrosis factor-α. Worse neurological outcome at 6 months was associated with inflammation of the fetal side of the placenta and shorter duration from rupture of membrane to delivery, independent of gestational age at birth or cranial ultrasound results. CONCLUSION: Our findings support the connection between fetal inflammation with adverse neurological outcome with PPROM, regardless of cranial ultrasound results. Further longitudinal studies are needed to adequately examine these patterns, and will aid in risk assessment and intervention strategies.

Anticoagulation in Pediatric Patients.

The use of antithrombotic agents is increasing in infants, children and adolescents. The more recent routine inclusion of children in FDA-monitored clinical trials has propelled the rapid accumulation of safety and efficacy data on these agents in pediatric patients. Antithrombotic agents in current use include indirect or antithrombin-dependent anticoagulants, intravenous direct thrombin inhibitors, direct oral anticoagulants (DOACs) targeting thrombin or factor Xa, antiplatelet agents and thrombolytic therapies. Each class of antithrombotic agent has distinct mechanisms of action, clearance routes, half-lives, safety and dosing. Anticoagulant efficacy is dependent upon the specific clinical indication and stability of the pediatric patient. Duration of anticoagulant course is also dependent upon the clinical indication as well as rate of thrombus resolution. This manuscript reviews the mechanism of action, route of administration, route of clearance and plasma half-life for the antithrombotic agents in current use in children. Use of anticoagulation in the context of thrombolytic therapy is discussed.

Joint reaction and simulated muscle forces during squatting and walking in persons with hemophilia.

BACKGROUND: Persons with hemophilia experience joint bleeding that can lead to debilitating arthropathy, most commonly seen in ankles, knees, and elbows. Arthropathy can hinder participation in daily and athletic activities. We explored how hemophilic arthropathy impacts movement patterns in walking and bilateral squatting tasks in persons with hemophilia compared to healthy controls. METHODS: Persons with hemophilia and healthy controls completed walking and squatting tasks while kinematic and kinetic motion capture data were collected. The Hemophilia Joint Health Score exam was performed to measure hemophiliac arthropathy. OpenSim was used to model muscle and joint reaction forces and calculate moments and angles. Peak values were compared using Cohen's d to estimate effect sizes of hemophilia on movement parameters. FINDINGS: Nine persons with hemophilia and eight age-matched controls were analyzed. Temporal-spatial metrics were similar between hemophilia and control groups in both tasks. In walking, persons with hemophilia had higher peak ankle dorsiflexion angles, vertical ground reaction force weight acceptance peaks, and hip extension and flexion moments compared to controls. In squatting, persons with hemophilia had lower knee extension moments, ankle joint reaction force, and knee extensor forces, but had higher hip extension moments. INTERPRETATION: Temporal-spatial metric similarity between hemophilia and controls suggests that kinetic and kinematic analyses are needed to identify movement pattern differences. These data identify potential compensatory strategies at the hip that may be used by persons with hemophilia to mitigate impact on the knee and ankle. Future work will confirm these data in a larger sample size and be used to develop physical therapy strategies.

Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen.

Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal/fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.

Duration of Anticoagulation for Venous Thromboembolism in Pediatric Patients: Kids-DOTT Trial Outcomes at Two Years.

BACKGROUND: The Kids-DOTT multinational randomized clinical trial (RCT) revealed non-inferiority of a six-week versus three-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old, in regard to net clinical benefit at one year. OBJECTIVE: To evaluate non-inferiority at two years. PATIENTS/METHODS: Patients whose repeat imaging six weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation versus receive a total three-month course and followed for two years for the occurrence of symptomatic recurrent (SR-) VTE (efficacy outcome) and clinically-relevant bleeding (CRB, safety outcome). Outcomes were centrally adjudicated and net clinical benefit was compared between treatment arms via a pre-specified bivariate non-inferiority boundary, using 95% confidence intervals (CIs) in absolute risk differences (ARDs) between treatment arms. RESULTS: Kaplan-Meier estimates of two-year cumulative incidences in the six-week and three-months arms of the intention-to-treat (ITT) population (n=417) were 1.7% (95% CI: 0%, 3.7%) and 2.9% (95% CI: 0.3%, 5.4%) for SR-VTE and 1.1% (95% CI: 0%, 2.5%) and 3.2% (95% CI: 0.6%, 5.7%) for CRB. Bivariate analysis of the ARDs in the ITT population demonstrated that a six-week anticoagulation duration was non-inferior to a three-month course. CONCLUSIONS: These findings support durability of the Kids-DOTT RCT findings of net clinical benefit at two years.

Arteriopathy, D-dimer, and risk of poor neurologic outcome in childhood-onset arterial ischemic stroke.

OBJECTIVE: To assess whether acute findings of cerebral arteriopathy, large infarct, and acutely elevated plasma D-dimer levels are independently prognostic of poor long-term neurologic outcome as measured at ≥ 1 year post-event in children with arterial ischemic stroke (AIS). STUDY DESIGN: Sixty-one patients with childhood-onset (ie, >28 days of life) AIS were enrolled in a single-institution cohort study at Children's Hospital Colorado between February 2006 and June 2011. Data on demographic and diagnostic characteristics, antithrombotic treatments, and outcomes were systematically collected. RESULTS: Cerebral arteriopathy and D-dimer levels >500 ng/mL (a measure of coagulation activation) were identified acutely in 41% and 31% of the cohort, respectively. Anticoagulation was administered in the acute period post-event in 40% of the children, in the subacute period in 43%, and in the chronic period in 28%. When not receiving anticoagulation, patients were routinely treated with aspirin 2-5 mg/kg once daily for a minimum of 1 year. Death, major bleeding (including intracranial hemorrhage), and recurrent AIS were infrequent. The Pediatric Stroke Outcome Measure at 1 year demonstrated poor outcome in 54% of the children. Acute cerebral arteriopathy and elevated D-dimer level were identified as putative prognostic factors for poor outcome; after adjustment for D-dimer, arteriopathy was an independent prognostic indicator (OR, 19.0; 95% CI, 1.6-229.8; P = .02). CONCLUSION: Arteriopathy and coagulation activation are highly prevalent in the acute period of childhood AIS. Although recurrent AIS and intracranial hemorrhage were infrequent in our cohort, one-half of children experienced a poor neurologic outcome at 1 year, the risk of which was increased by acute arteriopathy. Substantiation of these findings in multi-institutional cohort studies is warranted, toward risk stratification in childhood-onset AIS.

Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children.

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.