Thrombin generation as objective parameter of treatment response in patients with severe haemophilia A and high-titre inhibitors.

In Mexico, 15% of haemophilia A (HA) patients develop inhibitory alloantibodies in response to replacement therapy with factor VIII (FVIII), requiring bypass therapy such as activated prothrombin complex concentrate (APCC). Because bypass therapy has not been broadly available in Mexico even in recent years, this study aimed to evaluate the thrombin generation assay (TGA) in assessing the response to FVIII or APCC treatment in patients with severe HA positive to inhibitors. We studied 189 patients with severe HA. Clinical severity was verified by one-stage APTT-based clotting assay. Inhibitors to FVIII were investigated by the Nijmegen-Bethesda (N-B) method, and type of inhibition was assessed through serial plasma dilutions. Thrombin generation was measured with the calibrated automated thrombogram in inhibitor-positive plasmas previously spiked and incubated with FVIII or APCC. Data were analysed using anova, Student or Fisher's exact tests. We detected 47 (24.9%) subjects with high-titre (5-1700 N-B U mL(-1)) and 25 (13.2%) subjects with low-titre inhibitor antibodies (0.6-4.7 N-B U mL(-1)). We found an association between kinetic behaviour and clinical response to FVIII (P = 0.0049) or vs. FVIII response evaluated with TGA (P = 0.0007). Global concordance between clinical and in vitro response was 70%. By evaluating the capacity of thrombin formation in a plasma sample, TGA predicts the response to FVIII or APCC therapy and allows individual optimization of resources in patients with severe HA and high-titre inhibitors. The inhibition pattern of the antibodies to FVIII:C correlated with the TGA parameters and showed an association with the clinical response to FVIII.

Kinetics of factor VIII:C inhibitors and treatment response in severe hemophilia A patients.

Severe hemophilia A (HA) patients develop inhibitory alloantibodies to factor VIII:C and therefore require bypass agents that are scarce, expensive and may provoke secondary effects. Twenty-three severe HA patients who were high-responders to FVIII inhibitors were studied. FVIII:C activity in plasma was measured by one-stage activated partial thromboplastin time method, and the quantification of FVIII:C inhibitors was carried out by the Nijmegen-Bethesda method. Inhibition kinetics was assessed through serial plasma dilutions. FVIII:C activity was <1% in all patients. Kinetics behavior of the inhibitors was classified as type I in 14 patients, type II in four and an intermediate pattern that we named type III in one case. We were unable to apply the regression model to the remaining four of 23 patients in the study because of their low inhibitory titer (<3 Nijmegen-Bethesda units per ml). Seventy-eight percent of the patients with inhibitor type I did not respond to high doses of FVIII therapy, whereas 50% of patients with type II kinetics did (P = 0.5323). Generally, patients belonging to the same family had similar kinetics behavior as well as concordant treatment response. Although nonsignificant, our results suggest an association between kinetics behavior and treatment response that may be a valuable prognostic parameter for the management of these patients.

[Usefulness of prothrombin fragment 1 + 2 and fibrin dimer in the detection of hypercoagulation in obstetrical patients with thrombosis risk factors]. / Utilidad del fragmento 1 + 2 de protrombina y del dímero de fibrina en la detección de hipercoagulabilidad en pacientes obstétricas con factores de riesgo de trombosis.

We measured prothrombin 1 + 2 fragment (f1 + 2p) and dimer D (dD) in plasma from 100 pregnant women at high risk for thromboembolic disease (TED) and in 23 non-pregnant control. Measures of f1 + 2p were made by immunoassay analysis in 75 patients and dD by semiquantitative analysis of plate agglutination in 97 cases. F1 + 2p was significantly elevated in 85% of cases, but its levels was not predictive value for TED. Dimer D was not found in 40 cases, in 33 patients its values were between 500 and 1000 ng/ml. and in the other 24 cases were higher than 2000 ng/ml. Values higher than 1000 ng/ml. were founded in 78% of patients with history of TED, in 60% of cesarean section patients, in 37% of hypertensive patients and in the 23% of diabetic patients. Dimer D, that was higher than 500 ng/ml. in 59% of pregnant and puerperal patients, have predictive value for TED, because 25% of 24 patients that had dD higher than 2000 ng/ml. developed TED and/or coagulation anomalies suggestive of thrombotic activity. These findings were not found in the rest of patients (n 73) which had negative dD or less than 1000 ng/ml.