Thromboelastography in children with coagulation factor deficiencies.

Hemophilia is traditionally classified according to the levels of the deficient coagulation factor as Severe (<1%), Moderate (1-5%) or Mild (>5%). However, it is well known that the factor activity does not necessarily correspond to the clinical bleeding manifestations. As prophylactic therapy is the best method of prevention of serious complications such as hemophilic arthropathy, a test that may predict the bleeding pattern would be extremely beneficial. Thromboelastography (TEG) uses whole blood to determine clot formation characteristics, such as initiation, propagation as well as strength of the clot, and is now being extensively studied in bleeding and thrombophilia. This study attempted to determine the TEG characteristics in 47 children with moderate hemophilia (MH) and severe hemophilia with (SHI) and without inhibitors (SH) and tried to retrospectively correlate them to the clinical bleeding patterns. TEG showed evidence of faster and better clot formation, as evidenced by a higher maximum thrombin/fibrin generation, in those with mild bleeding manifestations compared to those with severe bleeding tendency, in addition to the expected prolongation in time to formation of clot related to factor deficiency. This may be a potentially useful tool to evaluate the bleeding tendency and determine need for prophylaxis in children with hemophilia.

Bleeding and coagulation changes during spinal fusion surgery: a comparison of neuromuscular and idiopathic scoliosis patients.

OBJECTIVE: Major blood loss is common during spinal fusion surgery. We have previously demonstrated that patients with neuromuscular scoliosis have more blood loss and greater transfusion requirement than those with idiopathic scoliosis. Our objective is to study the relationships between etiology of scoliosis, blood loss, and coagulation changes in children and adolescents undergoing spinal fusion surgery. DESIGN: Prospective, observational study. SETTING: University teaching hospital. PATIENTS: A total of 25 patients, 11 with neuromuscular and 14 with idiopathic scoliosis, undergoing spinal fusion surgery. INTERVENTIONS: Blood was obtained preoperatively, 2 and 4 hrs intraoperatively, and 2 and 24 hrs postoperatively for prothrombin time, partial thromboplastin time, thrombin time, platelet count, D-dimer, factor VII and VIII activity, thrombin-antithrombin III complex, and protein induced by vitamin K absence. Changes in coagulation over time were analyzed by repeated-measures analysis of variance. Comparisons between groups were made using independent t-tests. RESULTS: Neuromuscular scoliosis patients had significantly greater blood loss than idiopathic scoliosis patients (median blood loss, 78% of total blood volume; range, 25-127% vs. 20%, 2-82%; p < .001). Prothrombin time increased over time in both groups and was higher in the neuromuscular than the idiopathic group both preoperatively and postoperatively (p < .05). Factor VII activity decreased over time in both groups (p < .001) and was lower in the neuromuscular than the idiopathic group during surgery (p < .05). No changes in partial thromboplastin time, thrombin time, or factor VIII activity were observed. D-dimers were present in both groups by 4 hrs intraoperatively. Protein induced by vitamin K absence was not detected in any patient. CONCLUSIONS: Neuromuscular scoliosis patients have more blood loss during spinal fusion surgery than idiopathic scoliosis patients. The prolongation of prothrombin time and decrease in Factor VII activity suggest activation of the extrinsic coagulation pathway. Depletion of clotting factors during scoliosis surgery occurs to a greater extent in patients with underlying neuromuscular disease.

Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.

In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain-deleted human factor VIII (hFVIII) gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (PCR) analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one-stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3% to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P <.02) and area under the curve (AUC, P <.04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than a year in peripheral blood mononuclear cells, with measurable factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.