Aaron Lubetsky

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.

Factor V Leiden and Antiphospholipid Antibodies in Either Mothers or Infants Increase the Risk for Perinatal Arterial Ischemic Stroke

Background and Purpose— The objective was to investigate the role of infant and maternal thrombophilia in a cohort of mothers and infants presenting with perinatal arterial ischemic stroke. Methods— Forty-seven infants with clinically and radiologically confirmed perinatal arterial ischemic stroke underwent thrombophilia workup: factor V Leiden (FVL), PII20210A mutation, Methylene-tetrahydrofolate reductase 677T polymorphism, protein C, protein S, antithrombin, FVIII, and antiphospholipid antibodies. Thrombophilia data were available for 23 mother–infant pairs and compared with control populations to evaluate the risk for PAS. Results— Thirty of 47 (64%) infants and 15 of 22 mothers (68%) had evidence of thrombophilia. In 18 of 23 (78%) mother–infant pairs, there was at least 1 thrombophilic risk factor, but 15 pairs were mismatched in pathology. Among infants, FVL, protein C deficiency, and presence of antiphospholipid antibodies prevailed (OR, 4.2; 95% CI, 1.5–11.3; OR, 12.2; 95% CI, 2.5–59.9; OR, 4.1; 95% CI, 1.4–12.2, respectively). Interestingly FVL prevailed in almost one-third of mothers (OR, 8.5; 95% CI, 4.1–17.5) and 18% of mothers had antiphospholipid antibodies (OR, 3.8l; 95% CI, 1.5–10.0). Conclusions— Maternal and neonatal thrombophilia, especially presence of FVL or antiphospholipid antibodies, may be important in the pathogenesis of perinatal arterial ischemic stroke. The nature of thrombophilic mother–infant risk potential interactions warrants further investigation.

Phase I/II, open-label, multicenter, safety, efficacy and PK study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in subjects with hemophilia B

Recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) is a novel recombinant albumin fusion protein designed to extend the half-life of recombinant factor IX (rFIX), which is used in the management of hemophilia B. Clinical evaluation of rIX-FP in humans is underway, including a recently completed phase I/II, open-label, multicenter, study that assessed the safety, pharmacokinetics, and efficacy of rIX-FP in patients with severe hemophilia B. A total of 17 patients received rIX-FP (25 IU/kg) as either on-demand therapy (n = 4) for 20 weeks or weekly prophylaxis (n = 13) for up to 44 weeks. Preliminary results confirm that rIX-FP has an excellent safety profile and a pharmacokinetic profile highlighted by a marked extended half-life, suggesting that weekly prophylaxis with rIX-FP at a dose of 25 IU/kg may be appropriate in patients with severe hemophilia B, and that extended dosing intervals (10-14 days) may be feasible in some patients. A phase II/III study evaluating the safety and efficacy of rIX-FP in patients with hemophilia B is underway.

Risk factors for failure of heparin thromboprophylaxis in patients with acute traumatic spinal cord injury

UNLABELLED Venous thromboembolism (VTE) is a well-recognized complication of Acute Traumatic Spinal Cord Injury (ATSCI). Despite prophylaxis by heparins, VTE occurs in a substantial number of ATSCI patients without an obvious explanation. In this matched case-control study we examined whether thrombophilia and other risk factors are associated with failure of thromboprophylaxis. Cases and controls receiving heparin thromboprophylaxis were selected from consecutively admitted ATSCI patients. Patients who developed a new, objectively confirmed, symptomatic VTE despite prophylaxis at hospital were matched by gender, age, level and mechanism of ATSCI with 2-3 controls without VTE. Patients were interviewed about VTE risk factors and tested for factor V Leiden (FVL), prothrombin G20210A (PT), methylenetetrahydrofolate reductase C677T homozygosity (MTHFR), lupus anticoagulant, homocysteine (Hcy) and plasma factor VIII (FVIII) levels. Twenty-two patients with new VTE episodes and 64 controls were ascertained. The total number of gene alterations for MTHFR, FVL and PT or elevated levels of Hcy or FVIII was significantly more common in patients compared to controls (82% vs. 48%, p=0.006). Multiple logistic regression proved the PT mutation, a positive family history of thrombosis and elevated levels of either FVIII or Hcy to be predictors of thrombosis. CONCLUSION A positive family history of VTE, carriership of the prothrombin mutation and elevated FVIII or Hcy levels were significantly associated with failure to prevent VTE by heparin therapy following ATSCI. Testing for thrombophilia in patients with ATSCI and possibly a more intense thromboprophylactic regimen seem desirable but need to be verified by a prospective study.

Superficial abdominal thrombophlebitis (Mondor's disease) presenting as loss of response to adalimumab in a Crohn's disease patient

Dear Editor, Multiple etiologies should be considered in Crohns disease (CD) patients experiencing worsening symptoms while treated with anti-TNFs.1 We describe an unusual case of seeming loss of response to adalimumab. A 39 year-old man was hospitalized due to worsening right lower abdominal pain lasting for three days prior to presentation. The patient was inflicted by fibro-stenotic Crohns ileo-colitis for the last three years. He has been treated during the last two years by adalimumab 40 mg bi-weekly, and 6-mercaptopurine at 1.3 mg/kg. The patient underwent four endoscopic balloon dilations of 2 colonic strictures during the course of his disease, but has enjoyed near complete remission in the prior eleven months with a Harvey–Bradshaw index of 4 …

The Impact of Genetic and Environmental Factors on Homocysteine Levels in Preterm Neonates

Hyperhomocysteinemia may be associated with vascular complications in adults. Whereas pediatric thrombosis risk peaks in neonates, data on homocysteine (Hcy) levels assessed in term and preterm infants during the perinatal period are scarce. In the present study, we aimed to establish Hcy reference values for preterm infants and study their potential associations with the early post‐natal health status. Plasma Hcy and hematocrit levels and MTHFR polymorphisms (C677T and A1298C substitution) were studied in a large cohort of preterm infants in a tertiary referral medical center during an 18‐month period. Data were collected on maternal history and delivery as well as on post‐natal complications.

Effect of Enoxaparin on Homocysteine Concentration in Warfarin-Treated Patients

BACKGROUND: Elevated plasma total homocysteine (tHcy) concentration is an emerging independent risk factor for hypercoagulability states and cardiovascular diseases. Many disease states and various drug treatment regimens are known to affect plasma tHcy concentration. OBJECTIVE: To examine the effect of short-term treatment with the low-molecular-weight heparin enoxaparin on plasma tHcy concentrations. METHODS: A prospective study was conducted in an outpatient anticoagulation clinic set in a tertiary care referral medical center. Subjects included twenty-four consecutive patients treated with warfarin who were scheduled for short-term enoxaparin treatment. Fasting plasma tHcy concentrations were measured before and after 3 days of enoxaparin treatment in patients who began short-term therapy with enoxaparin because of temporary inadequate anticoagulation (international normalized ratio <1.5). The main outcome measures were the difference in tHcy concentration between baseline and after enoxaparin treatment. RESULTS: tHcy plasma concentrations decreased in most patients (n = 21), did not change in 2, and increased in 1 patient after 3 days of enoxaparin treatment. The decline of tHcy was statistically significant: from 9.8 ± 3.4 to 7.6 ± 2.6 μmol/L (mean ± SD; p < 0.005). This decline was more prominent in patients with baseline tHcy plasma concentrations above the normal range compared with patients with normal baseline concentrations. Six patients in whom a third sample was obtained 15–30 days after the last enoxaparin injection developed decreased mean tHcy plasma concentrations: from 9.1 ± 3.0 μmol/L at baseline to 6.4 ± 2.0 μmol/L on day 3 and further to 5.7 ± 1.8 μmol/L on days 15–30. No relation was found between age, gender, treatment indication, and average weekly dose of warfarin to the presence or magnitude of tHcy plasma concentration decline. CONCLUSIONS: Short-term treatment with enoxaparin reduces plasma tHcy concentrations. Further studies are needed to clarify the mechanism and the clinical significance of enoxaparins effect.