Desmopressin in haemophilia: The need for a standardised clinical response and individualised test regimen.

INTRODUCTION: Due to interindividual variation in desmopressin response, non-severe haemophilia A patients require desmopressin testing prior to therapeutic treatment. However, adequate response or frequency of blood sampling is not standardised in international guidelines. Consequently, various definitions and blood sampling protocols are currently applied. Interestingly, sustainability of desmopressin response is not incorporated into these definitions. AIM: To study desmopressin response rates in a cohort of non-severe haemophilia A patients using currently accepted desmopressin response definitions. This, in order to formulate a standardised, uniform response which includes information on sustainability and to design a standardised blood sampling protocol. METHODS: Currently used desmopressin responses in non-severe haemophilia A patients were derived from a literature search. Actual desmopressin response rates were individualised in 105 non-severe HA patients from the Erasmus University Medical Centre and classified according to current varying definitions. RESULTS: Five response definitions were evaluated, three of which included only factor VIII (FVIII):C cut-off levels and two also incorporated FVIII:C-fold increase over baseline. FVIII: C-fold increase showed no association with desmopressin response sustainability. FVIII: C 1 hour after infusion (<0.30, ≥0.30-0.49, ≥0.50-0.79 and ≥0.80 IU/mL) was, however, indicative of desmopressin response after 6 hours. CONCLUSION: We suggest standardised desmopressin response based on clinically relevant FVIII:C levels, e.g. 0.30 and 0.50 IU/mL. In addition, patients with <0.30 IU/mL FVIII:C after 1 hour (non-responder) or ≥0.80 IU/mL (sustained responder) do not require subsequent blood sampling. However, patients with ≥0.30-0.79 IU/mL FVIII:C after 1 hour should undergo blood sampling after 6 hours to additionally determine response sustainability.

Tachyphylaxis and reproducibility of desmopressin response in perioperative persons with nonsevere hemophilia A: implications for clinical practice.

Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose. Objectives: To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A. Methods: We studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test. Results: The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients. Conclusion: Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.

Lengths of hamstrings and psoas muscles during crouch gait: effects of femoral anteversion.

Recent studies of muscle lengths measured by means of gait analysis data and musculoskeletal models have suggested that in many cases of crouch gait in patients with cerebral palsy, the hamstrings are of normal length and the psoas muscles are short. In these studies, however muscle lengths were calculated by applying kinematic data from a child's joint to a normal adult model. Children with cerebral palsy and other disorders generally do not have normal bone architecture but instead have muscle attachment points and muscle paths altered by osseous deformities. In this study, we explored the consequences of using normal adult musculoskeletal models to calculate hamstring and psoas lengths for children with cerebral palsy. Specifically, for a group of subjects with cerebral palsy who walk with a crouch gait, we investigated the changes in muscle lengths that arise when a patient-specific representation of clinically measured femoral anteversion was added to a model of normal musculoskeletal geometry. The calculation of psoas muscle length was found to be very sensitive to femoral anteversion whereas the calculation of hamstrings length was found to be relatively insensitive to this osseous deformity.

An index for quantifying deviations from normal gait.

A method is derived to calculate the amount by which a subject's gait deviates from an average normal profile, and to represent this deviation as a single number. The method uses principal component analysis to derive a set of 16 independent variables from 16 selected gait variables. The sum of the square of these 16 independent variables is interpreted as the deviation of the subject's gait from normal. Statistical tests of the method's validity and an initial demonstration of its clinical utility are included. It is found that using this index, increasing clinical involvement corresponds to increasing index score.

The use of inverse dynamics solutions in direct dynamics simulations.

Previous attempts to use inverse dynamics solutions in direct dynamics simulations have failed to replicate the input data of the inverse dynamics problem. Measurement and derivative estimation error, different inverse dynamics and direct dynamics models, and numerical integration error have all been suggested as possible causes of inverse dynamics simulation failure. However, using a biomechanical model of the type typically used in gait analysis applications for inverse dynamics calculations of joint moments, we produce a direct dynamics simulation that exactly matches the measured movement pattern used as input to the inverse dynamic problem. This example of successful inverse dynamics simulation demonstrates that although different inverse dynamics and direct dynamics models may lead to inverse dynamics simulation failure, measurement and derivative estimation error do not. In addition, inverse dynamics simulation failure due to numerical integration errors can be avoided. Further, we demonstrate that insufficient control signal dimensionality (i.e., freedom of the control signals to take on different "shapes"), a previously unrecognized cause of inverse dynamics simulation failure, will cause inverse dynamics simulation failure even with a perfect model and perfect data, regardless of sampling frequency.