Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand’s disease (VWD) has limited value in dosing for surgery

Summary. Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate‐P^®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg^?1 VWF: RCo. Median plasma levels, half‐life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time‐concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL^?1 (range, 6–124); with a mean change from baseline >100 IU dL^?1 immediately after the infusion, decreasing to 10 IU dL^?1 at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL^?1 per IU kg^?1, for VWF:Ag 2.3 IU dL^?1 kg^?1 and for FVIII:C was 2.7 IU dL^?1 per IU kg^?1. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra‐individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri‐operative infusions.     

von Willebrand factor/factor VIII concentrate (Humate‐P) for management of elective surgery in adults and children with von Willebrand disease

Summary. von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open‐label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate‐P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4‐point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half‐life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL^?1 per IU kg^?1 infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg^?1 (oral surgery) to 61.2 IU VWF:RCo kg^?1 (major surgery), with a median of 10 (range, 2–55) doses administered per subject. Adverse events considered possibly treatment‐related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD.     

Critical von Willebrand factor A1 domain residues influence type VI collagen binding

Summary. Background: von Willebrand factor (VWF) binds to subendothelial collagen at sites of vascular injury. Laboratory testing for von Willebrand disease (VWD), however, does not always include collagen binding assays (VWF:CB) and standard VWF:CB assays use type I and/or type III collagen rather than type VI collagen. Objectives: We report here on several mutations that exclusively alter binding to type VI collagen. Patients/methods: Healthy controls and index cases from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen. VWF gene sequencing was performed for all subjects. Results: Two healthy controls and one type 1 VWD subject were heterozygous for an A1 domain sequence variation, R1399H, and displayed a selective decreased binding to type VI collagen but not types I and III. Expression of recombinant 1399H VWF resulted in absent binding to type VI collagen. Two other VWF A1 domain mutations, S1387I and Q1402P, displayed diminished binding to type VI collagen. An 11 amino acid deletion in the A1 domain also abrogated binding to type VI collagen. Conclusions: VWF:CB may be useful in diagnosis of VWD, as a decreased VWF:CB/VWF:Ag ratio may reflect specific loss of collagen binding ability. Mutations that exclusively affect type VI collagen binding may be associated with bleeding, yet missed by current VWF testing.     

Holter Monitoring vs Tilt Testing in the Investigation of Suspected Vasovagal Syncope

The aim of this study was to compare the diagnostic yield of 48-hour Holter monitoring with head-up tilt (HUT) test in patients presenting with blackouts suggestive of vasovagal syncope. One hundred and eighteen consecutive patients, 68 women, aged (mean [SD])   50 ± 20  years   (range 16–88 years), underwent 48-hour Holter monitoring and 60° HUT test within 3 months. Endpoints were symptom-ECG correlation during Holter monitoring and positive HUT test. Syncope occurred in 3 (3%) patients during Holter monitoring, the rhythm being sinus tachycardia in all. Presyncope was reported in 22 (19%), the rhythm being sinus tachycardia in 6, persistent atrial fibrillation in 2, and normal sinus rhythm in the remainder. Asymptomatic arrhythmias were recorded in 103 (87%) patients. Positive HUT tests occurred in 39 (33%), the pattern being mixed (VASIS type 1) in 14 (36%), cardioinhibitory (VASIS type 2) in 3 (8%), and vasodepressor (VASIS type 3) in 22 (56%). Change in patient management occurred in 3 (3%) patients following Holter monitoring and 39 (33%) patients following HUT test. Holter monitoring produces a low yield of clinically useful information in the investigation of suspected vasovagal syncope. An HUT test should be considered the primary investigation of choice in such patients. (PACE 2003; 26[Pt. I]:1523–1527)     

ROLE OF CARBON MONOXIDE DIFFUSING CAPACITY IN THE EARLY DETECTION OF MAJOR BLEOMYCIN-INDUCED PULMONARY TOXICITY

Fifteen patients with malignant teratoma and twelve with squamous cancer of the head and neck received treatment with bleomycin. Routine measurements of carbon monoxide diffusing capacity (DL₀₀) were performed. Both groups showed a gradual fall of similar magnitude in their DL₀₀ measurements during treatment. No patient in the group with squamous cancer developed clinical or radiological evidence of major pulmonary toxicity.
Two of the teratoma patients suffered fatal pulmonary toxicity and their DL_CO measurements before any signs of major pulmonary toxicity were no different from the measurements of those patients who remained free of major clinical toxicity.
The two patients who died both showed a sustained reduction in renal function during chemotherapy which may have been a major risk factor in the development of severe clinical toxicity.
The magnitude of the decline in DL_CO in this series was not a useful predictor of those patients who developed severe and radiological toxicity.     

Neurological outcome of severe cystic periventricular leukomalacia

Objective : To determine the neurological outcome of a cohort of premature babies having ultrasound diagnoses of severe cystic periventricular leukomalacia.
Methodology : All neonatal intensive care unit admissions born at less than 35 weeks gestation or weighing less than 1500 g underwent serial cranial ultrasounds. Those developing severe bilateral cystic periventricular leukomalacia (12 patients) were then followed clinically to a mean age of 27.3 months.
Results : Ten of the 12 patients fulfilling strict ultrasound criteria survived. All had a major neurological handicap, all having spastic quadriparesis and visual impairments, with most suffering global developmental delay and epilepsy.
Conclusions : Severe bilateral cystic periventricular leukomalacia results in major permanent handicap. It is currently impossible to identify most patients with this condition while they are being ventilated. Non-ultrasound techniques are needed to diagnose the condition earlier, and to give guidance to management.