Neil A. Goldenberg

Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension A Scientific Statement From the American Heart Association

Venous thromboembolism (VTE) is responsible for the hospitalization of >250 000 Americans annually and represents a significant risk for morbidity and mortality. Despite the publication of evidence-based clinical practice guidelines to aid in the management of VTE in its acute and chronic forms, the clinician is frequently confronted with manifestations of VTE for which data are sparse and optimal management is unclear. In particular, the optimal use of advanced therapies for acute VTE, including thrombolysis and catheter-based therapies, remains uncertain. This report addresses the management of massive and submassive pulmonary embolism (PE), iliofemoral deep vein thrombosis (IFDVT),and chronic thromboembolic pulmonary hypertension (CTEPH). The goal is to provide practical advice to enable the busy clinician to optimize the management of patients with these severe manifestations of VTE. Although this document makes recommendations for management, optimal medical decisions must incorporate other factors, including patient wishes, quality of life, and life expectancy based on age and comorbidities. The appropriateness of these recommendations for a specific patient may vary depending on these factors and will be best judged by the bedside clinician.

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children. METHODS The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). CONCLUSIONS The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.

Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children A Systematic Review and Meta-Analysis of Observational Studies

Background— The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and Results— A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). Conclusions— The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review

Summary.  Background: Different rates of inhibitor development after either plasma‐derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta‐regression and analysis‐of‐variance were used to investigate the effect of covariates (testing frequency, follow‐up duration and intensity of treatment). Results: Two thousand and ninety‐four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4–19.4) for pdFVIII and 27.4% (23.6–31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2–13.7) for pdFVIII and 17.4% (14.2–21.2) for rFVIII. In the multi‐way anova study design, study period, testing frequency and median follow‐up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

Impact of Inherited Thrombophilia on Venous Thromboembolism in Children A Systematic Review and Meta-Analysis of Observational Studies

Background— The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. Methods and Results— A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). Conclusions— The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.

The Postthrombotic Syndrome: Evidence-Based Prevention, Diagnosis, and Treatment Strategies A Scientific Statement From the American Heart Association

The purpose of this scientific statement is to provide an up-to-date overview of the postthrombotic syndrome (PTS), a frequent, chronic complication of deep venous thrombosis (DVT), and to provide practical recommendations for its optimal prevention, diagnosis, and management. The intended audience for this scientific statement includes clinicians and other healthcare professionals caring for patients with DVT. Members of the writing panel were invited by the American Heart Association Scientific Council leadership because of their multidisciplinary expertise in PTS. Writing Group members have disclosed all relationships with industry and other entities relevant to the subject. The Writing Group was subdivided into smaller groups that were assigned areas of statement focus according to their particular expertise. After systematic review of relevant literature on PTS (in most cases, published in the past 10 years) until December 2012, the Writing Group incorporated this information into this scientific statement, which provides evidence-based recommendations. The American Heart Association Class of Recommendation and Levels of Evidence grading algorithm (Table 1) was used to rate the evidence and was subsequently applied to the draft recommendations provided by the writing group. After the draft statement was approved by the panel, it underwent external peer review and final approval by the American Heart Association Science Advisory and Coordinating Committee. External reviewers were invited by the American Heart Association. The final document reflects the consensus opinion of the entire committee. Disclosure of relationships to industry is included with this document (Writing Group Disclosure Table). View this table: Table 1. Classification of Recommendations and Levels of Evidence ### Background DVT refers to the formation of blood clots in ≥1 deep veins, usually of the lower or upper extremities. PTS, the most common long-term complication of DVT, occurs in a limb previously affected by DVT. PTS, sometimes referred to as postphlebitic syndrome or secondary venous stasis syndrome, is considered a …

Lemierre's and Lemierre's-like syndromes in children: survival and thromboembolic outcomes.

Objective. 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. Methods. 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. Results. 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. Conclusions. 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.

Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study

BACKGROUND For childhood-onset arterial ischaemic stroke (AIS), treatment trials are lacking and practices vary from country to country and centre to centre. We aimed to describe frequencies and predictors of acute treatments and early outcomes in the International Pediatric Stroke Study (IPSS), a large international series of childhood AIS. METHODS The IPSS has 33 centres enrolling children with stroke. Data for children aged 28 days to 19 years with AIS from Jan 1, 2003, to Oct 1, 2007, were collected with standardised case-report forms and analysed to identify factors associated with stroke treatment and early prognosis. FINDINGS Among 661 children with AIS (640 with acute treatment data, 612 with morbidity data, and 643 with mortality data), acute treatments included anticoagulation alone in 171 patients (27%), antiplatelet therapy alone in 177 (28%), antiplatelet and anticoagulation in 103 (16%), and no antithrombotic treatment in 189 (30%). After adjustment for significant covariates, subtypes associated with any use of anticoagulation were dissection (odds ratio 14.09, 95% CI 5.78-37.01; p<0.0001) and cardiac disease (1.87, 1.20-2.92; p=0.01). Factors associated with non-use of anticoagulation included sickle-cell disease subtype (0.12, 0.02-0.95; p=0.04) and the enrolment centre being located in the USA (0.56, 0.39-0.80; p=0.002). By contrast, antiplatelet use was associated with moyamoya (4.88, 2.13-11.12; p=0.0002), whereas non-use was associated with dissection (0.47, 0.22-0.99; p=0.047), low level of consciousness (0.45, 0.31-0.64; p<0.0001), and bilateral ischaemia (0.32, 0.20-0.52; p<0.0001). Outcomes at hospital discharge included neurological deficits in 453 (74%) patients and death in 22 (3%). In multivariate analysis, arteriopathy, bilateral ischaemia, and decreased consciousness at presentation were prognostic of adverse outcome. INTERPRETATION Acute anticoagulation is commonly prescribed in acute childhood-onset AIS although practice varies with AIS subtype and geographical region. Several factors are prognostic of adverse early outcome, and clinical trials are needed to determine the best treatment strategies.

Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors

Background Post-thrombotic syndrome is a manifestation of chronic venous insufficiency following deep venous thrombosis. This systematic review was conducted to critically evaluate pediatric evidence on frequency of occurrence, validity of outcome measures, and prognostic indicators of post-thrombotic syndrome. Design and Methods A comprehensive literature search of original reports revealed 19 eligible studies, totaling 977 patients with upper/lower extremity deep venous thrombosis. Calculated weighted mean frequency of post-thrombotic syndrome was 26% (95% confidence interval: 23–28%) overall, and differed significantly by prospective/non-prospective analysis and use/non-use of a standardized outcome measure. Results Standardized post-thrombotic syndrome outcome measures included an adaptation of the Villalta scale, the Clinical-Etiologic-Anatomic-Pathologic classification, and the Manco-Johnson instrument. Data on validity were reported only for the Manco-Johnson instrument. No publications on post-thrombotic syndrome-related quality of life outcomes were identified. Candidate prognostic factors for post-thrombotic syndrome in prospective studies included use/non-use of thrombolysis and plasma levels of factor VIII activity and D-dimer. Conclusions Given that affected children must endure chronic sequelae for many decades, it is imperative that future collaborative pediatric prospective cohort studies and trials assess as key objectives and outcomes the incidence, severity, prognostic indicators, and health impact of post-thrombotic syndrome, using validated measures.

Protein C deficiency.

Summary.  Severe protein C deficiency (i.e. protein C activity <1 IU dL−1) is a rare autosomal recessive disorder that usually presents in the neonatal period with purpura fulminans (PF) and severe disseminated intravascular coagulation (DIC), often with concomitant venous thromboembolism (VTE). Recurrent thrombotic episodes (PF, DIC, or VTE) are common. Homozygotes and compound heterozygotes often possess a similar phenotype of severe protein C deficiency. Mild (i.e. simple heterozygous) protein C deficiency, by contrast, is often asymptomatic but may involve recurrent VTE episodes, most often triggered by clinical risk factors. The coagulopathy in protein C deficiency is caused by impaired inactivation of factors Va and VIIIa by activated protein C after the propagation phase of coagulation activation. Mutational analysis of symptomatic patients shows a wide range of genetic mutations. Management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate while maintaining therapeutic anticoagulation; protein C replacement is also used for prevention of these complications around surgery. Long‐term management in severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen. Although many patients with severe protein C deficiency are born with evidence of in utero thrombosis and experience multiple further events, intensive treatment and monitoring can enable these individuals to thrive. Further research is needed to better delineate optimal preventive and therapeutic strategies.