Comprehensive Pediatric Care of Rare Bleeding Disorders

Muriel Giansily-Blaizot; Jean-François Schved


Pediatr Health. 2010;4(2):209-217. 

In This Article

Biological Phenotype: Which Clotting Tests should be Conducted for a Quick Diagnosis?

In severe forms of RBDs, early diagnosis is crucial due to the risks associated with ICH. Since both age and sex have a profound influence on the hemostatic cascade, data from the results of the same tests conducted in age- and sex-matched healthy subjects should be made more easily accessible in order to accurately interpret the clotting test results. The hemostatic system matures during the first weeks and months following birth, with most hemostatic parameters reaching adult values by 6 months of age (meticulously reviewed in [15]). In the neonatal period, only RBD homozygotes can be diagnosed, whereas levels of the missing factor in heterozygotes may overlap with the normal range.[15] The first-line coagulation tests in common use are tests for the activated partial thromboplastin time, prothrombin time and thrombin clotting time or the fibrinogen measurement. Prolongation of these clotting tests, when they are corrected by the addition of an equal volume of normal plasma to that of the test plasma, is indicative of either a single factor or multiple factor deficiency.[15] The tests generally allow the screening of all RBDs except FXIII deficiency ( Table 1 ). Severe FXIII (fibrin-stabilizing factor) deficiency differs as it leads to impaired fibrin cross-linking and the production of defective and unstable blood clots that do not affect the clotting end point of routine coagulation tests. Therefore, specific screening tests, including the urea clot solubility test or, even more easy to conduct, specific FXIII activity assays, should be performed in patients who are suspected of having FXIII deficiency.[7]

The vast majority of bleeding problems encountered in the neonatal period are due to acquired hemostatic defects including vitamin K deficiency or disseminated intravascular coagulation.[15] Inherited bleeding disorders are rare. Acquired clotting factor deficiencies owing to the presence of inhibitors are unlikely to occur in children. As soon as a rare inherited bleeding disorder is suspected, specific factor assays should be performed to identify the corresponding RBD. From a clinical stand point, the factor activity level is sufficient to make a correct diagnosis. For a more detailed biological phenotype, the factor antigen level may be assessed, thus allowing the classification of the deficiency. Type I is usually caused by defects in the expression and/or secretion of the protein, and in type II, the factor is present but not functioning. In type I deficiencies, factor coagulant activity and antigen levels decrease in parallel, whereas in type II deficiencies, there is a discrepancy betweent the reduced factor coagulant activity levels and up to normal antigen levels. A more detailed protein characterization may require a full spectrum of tests to be conducted, which can only be performed in specialized laboratories.

Certain phenotypic characteristics are required to be mentioned that may require further investigation. First, levels of FVIII should be tested in individuals with reduced FV levels to exclude the possibility of combined FV plus FVIII deficiency. In these cases, FV and FVIII levels are usually within the mild ranges although levels below 10% have been reported.[16] Second, some FVII variants (R304Q, FVII Padua, R79Q and G331D) display different FVII coagulant activities depending on the species-derived thromboplastin preparation used. The most common example concerns FVII Padua (R304Q), which frequently occurs in southern Europe and Africa. When present in the homozygous state, this variant may exhibit activity levels as low as 2% when rabbit tissue factor is used, whereas levels can reach 30–35% with recombinant human tissue factor.[17] Therefore, recombinant human tissue factor preparations and highly sensitive clotting assays are recommended for the correct assignment of FVII:coagulant activity (compared with the levels of antigen) in these cases.[18]


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