Assessment Of The Validation and Performance Of The Cone and Plate(let) Analyzer (CPA) In The Diagnosis Of Von Willebrand's Disease

Von Willebrand disease (VWD) is the most common significant bleeding disorder in the western world. VWD presents with a wide spectrum of clinical manifestations, ranging from totally asymptomatic individuals to severe, occasionally life-threatening bleeding episodes and hence early and accurate diagnosis is crucial for starting treatment.

Diagnosis of VWD requires specialized laboratories with skilled personnel and the testing process itself is time and labor consuming, and is costly. In recent years several methods for VWD diagnosis were developed including several flow bedside instruments which test whole blood coagulation following shear stress activation of clotting. One such tool is the cone and plate(let) analyzer (CPA). In the CPA test whole blood is activated by a rotating conical disc on a polystyrene surface at high shear rate. The test result is expressed as the % of the plastic surface covered with adherent platelets (SC- surface coverage %) and the average size of the platelet aggregates (average size- AS μm²).

The aim of the current study was to test the properties of the CPA as a diagnostic tool for VWD in a non-selected group of patients, to compare its diagnostic abilities with current methods of diagnosis, and to test for presence of (patient and physician) bias in the diagnostic process.

Patients referred for evaluation of bleeding symptoms, post-surgical bleeding, abnormal coagulation tests or with a known familial bleeding disorder were compared to a group of healthy controls and warfarin treated patients. Diagnosis of VWD and all other bleeding disorders was achieved by standard clinical and laboratory methods and in the final analysis VWD patients were compared to all other non VWD groups. The CPA was tested in all patients and controls, first on an inception cohort (268 subjects) and results from that sample were then applied to a validation cohort (221 subjects). The optimal SC and AS values were determined by ROC analysis in each sample and both samples overall. Sensitivity, specificity and likelihood ratios (likelihood of having (LR+) or not having (LR-) VWD given a specific cut-off value) were computed for each cut-off value. ROC method was also applied to test whether age, gender, severity of VWD, presence of bleeding symptoms, genetic/familial diagnosis of VWD and comorbidity of patients had any effect on CPA's testing accuracy.

During a 10 year period 489 consecutive patients referred to Sheba medical Center were studied. Following a complete workup we diagnosed (in both cohorts) 149 patients with VWD (type 1-72, type 2-42, type 3+acquired VWD- 35), that were compared to 217 healthy controls, 35 VKA treated patients, and 88 patients with other bleeding disorders (hemophilia A/B – 39, Factor II, VII, XI deficiencies – 49). The surface coverage was found as the best CPA diagnostic parameter for diagnosis of VWD, with an optimal cut-off value of 8.3% in the inception cohort and 6.9 % (but with better sensitivity) in the validation cohort (table and figure). In all of the study cohorts SC optimal cut-off maintained its high specificity with an improved sensitivity and a cut-off value of 7.1%. Age, sex, severity of VWD, or additional genetic/familial diagnosis of VWD had no effect on CPA's testing accuracy. However, patients tested soon after a bleeding event or during hospitalization (originated mainly from the validation cohort) were older, had higher levels VW activity and higher levels of SC and therefore different SC cut-off value with different test characteristics (table).

In this relatively large and representative cohort of healthy volunteers and patients with various bleeding disorders the CPA test was found sensitive and highly specific in the diagnosis of VWD. The test was robust to patient's age, sex, and VWD severity but a mild spectrum bias cannot be ruled out (as found in the validation cohort) deriving mainly from patient's comorbidity and recent bleeding. This highly specific test may prove its utility in preliminary or urgent diagnosis of VWD before a complete clinical and laboratory workup is done.

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