Reference Intervals for Coagulation Parameters in Developmental Hemostasis from Infancy to Adolescence

Abstract

Background: The objective of this study was to establish the age and sex-dependent reference intervals for coagulation assays evaluated in healthy children, ranging from 0 days to 16 years old. Methods: PT, aPTT, Fibrinogen (functional), Antithrombin activity, Protein C anticoagulant activity, Protein S free antigen, Thrombin time, D-Dimer, Von Willebrand Factor antigen, Lupus anticoagulant (screening), extrinsic and intrinsic pathway factors, and activated Protein C resistance were evaluated using STA-R Max². Results: A total of 1280 subjects (671 males and 609 females) were divided into five groups, according to their age: 0-15 days (n = 280, 174 M and 106 F), 15-30 days (n = 208, 101 M and 107 F), 1-6 months (n = 369, 178 M and 191 F), 6-12 months (n = 214, 110 M and 104 F), and 1-16 years (n = 209, 108 M and 101 F). The 95% reference intervals and the 90% CI were established using the Harrell-Davis bootstrap method and the bootstrap percentile method, respectively. Conclusions: The present study supports the concept that adult and pediatric subjects should be evaluated using different reference intervals, at least for some coagulation tests, to avoid misdiagnosis, which can potentially lead to serious consequences for patients and their families, and ultimately the healthcare system.

Keywords: coagulation; pediatrics; reference interval.

Figure 1

Reference intervals for PT ratio (A), aPTT ratio (B), Fibrinogen (C), TT (D), and D–Dimer (E) in the subjects subgrouped by sex and age. The horizontal segments represent the RIs, while the vertical segments indicate the limits of the 90% confidence interval of the RIs. For each class, RIs are reported combining males and females (red) or, respectively, only in females (green) or males (blue). The last three RIs are calculated without taking into account age, in females, males, or in the whole sample. d = days, m = months, y = years, F = females, M = males.

Figure 2

Reference intervals for FII (A), FV (B), FVII (C), and FX (D) in the subjects subgrouped by sex and age. The horizontal segments represent the RIs, while the vertical segments indicate the limits of the 90% confidence interval of the RIs. For each class RIs are reported combining males and females (red) or, respectively, only in females (green) or males (blue). The last three RIs are calculated without taking into account age, in females, males, or in the whole sample. d = days, m = months, y = years, F = females, M = males.

Figure 3

Reference intervals for FVIII (A), FIX (B), FXI (C), FXII (D), and FXIII (E) in the subjects subgrouped by sex and age. The horizontal segments represent the RIs, while the vertical segments indicate the limits of the 90% confidence interval of the RIs. For each class, RIs are reported combining males and females (red) or, respectively, only in females (green) or males (blue). The last three RIs are calculated, without taking into account age, in females, males, or in the whole sample. d = days, m = months, y = years, F = females, M = males.

Figure 4

Reference intervals for Antithrombin (A), Protein C (B), and Protein S (C) in the subjects subgrouped by sex and age. The horizontal segments represent the RIs, while the vertical segments indicate the limits of the 90% confidence interval of the RIs. For each class, RIs are reported combining males and females (red) or, respectively, only in females (green) or males (blue). The last three RIs are calculated without taking into account age, in females, males, or in the whole sample. d = days, m = months, y = years, F = females, M = males.

Figure 5

Reference intervals for VWF: Ag (A), VWF: RCO (B), PTT-LA ratio (C), DRVV Screening ratio (D), and APCR ratio (E) in the subjects subgrouped by sex and age. The horizontal segments represent the RIs, while the vertical segments indicate the limits of the 90% confidence interval of the RIs. For each class, RIs are reported combining males and females (red) or, respectively, only in females (green) or males (blue). The last three RIs were calculated without taking into account age, in females, males, or in the whole sample. d = days, m = months, y = years, F = females, M = males.

Figure 5

Reference intervals for VWF: Ag (A), VWF: RCO (B), PTT-LA ratio (C), DRVV Screening ratio (D), and APCR ratio (E) in the subjects subgrouped by sex and age. The horizontal segments represent the RIs, while the vertical segments indicate the limits of the 90% confidence interval of the RIs. For each class, RIs are reported combining males and females (red) or, respectively, only in females (green) or males (blue). The last three RIs were calculated without taking into account age, in females, males, or in the whole sample. d = days, m = months, y = years, F = females, M = males.