What are the implications of elevated prothrombin time (PT) and international normalized ratio (INR) in children?

From the Guidelines

Elevated PT and INR in children should be managed with immediate treatment using vitamin K and fresh frozen plasma (FFP) for significant bleeding or severely elevated INR (>8), as recommended by the American College of Chest Physicians evidence-based clinical practice guidelines 1. The initial approach should focus on assessing the severity and identifying the underlying cause of the elevated PT and INR. Common causes include vitamin K deficiency, liver disease, disseminated intravascular coagulation (DIC), warfarin therapy, or inherited coagulation disorders.

• For significant bleeding or severely elevated INR (>8), immediate treatment with vitamin K and FFP is recommended.
• Vitamin K can be administered at 0.5-1 mg/kg IV slowly (maximum 10 mg) for severe cases, or 1-5 mg orally for less urgent situations, as suggested by the American College of Chest Physicians 1.
• FFP dosing is typically 10-15 mL/kg.
• For children on warfarin with elevated INR but no bleeding, dose adjustment or temporary discontinuation may be sufficient, as recommended by the American Heart Association 1.
• In vitamin K deficiency, which is common in newborns, prophylactic vitamin K (1 mg IM) is given at birth.
• For chronic liver disease, regular monitoring and vitamin K supplementation may be needed.
• Prompt consultation with pediatric hematology is advised for complex cases or when the cause is unclear, with the goal of preventing serious hemorrhagic complications while addressing the root cause. Key considerations in managing elevated PT and INR in children include:
• The presence of bleeding
• The degree of elevation
• The underlying condition
• The need for prompt intervention to prevent serious hemorrhagic complications. The American College of Chest Physicians evidence-based clinical practice guidelines 1 provide the most recent and highest quality guidance on managing elevated PT and INR in children, and should be followed in clinical practice.

From the FDA Drug Label

Safety and effectiveness in pediatric patients below the age of 18 have not been established, in randomized, controlled clinical trials. However, the use of warfarin sodium tablets in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements. The use of warfarin in children may lead to difficulty achieving and maintaining therapeutic PT/INR ranges. To manage this, more frequent PT/INR determinations are recommended due to possible changing warfarin requirements in pediatric patients 2.

From the Research

Elevated PT and INR in Children

• Elevated prothrombin time (PT) and international normalized ratio (INR) in children can be an indicator of coagulopathy, which may require correction with plasma transfusion 3.
• However, a study found that plasma transfusion is ineffective in correcting mildly elevated PT-INR in critically ill children, with no significant difference in PT-INR values pre- and post-transfusion 3.
• The study also found that only 15.4% of patients showed post-transfusion normalization of PT-INR, and these patients were not different from the remaining 85% in terms of age, plasma dose, or bleeding status 3.

Standardization of PT/INR

• The PT/INR test is widely used to monitor oral anticoagulant therapy, but its results can vary between laboratories due to differences in thromboplastin reagents and coagulometers 4, 5.
• The international normalized ratio (INR) is calculated from the PT result and allows for worldwide standardization of results, but its accuracy can be affected by various factors, including the type of thromboplastin used and the coagulometer's sensitivity index (ISI) 4, 5.
• A study found that INR values obtained from the same patient plasma sample using different thromboplastins can be significantly different, even when the thromboplastins have nearly the same ISI values 5.

Relationship between INR and Vitamin K-Dependent Clotting Factors

• The INR value is related to the levels of vitamin K-dependent clotting factors, such as factor II (FII), factor VII (FVII), and protein C (PC) 6.
• A study found that the changes in INR values during oral anticoagulant treatment are related to the changes in FII and PC levels, and that FII levels are independent predictors of the variation in prothrombin activation 6.
• The study also found that in vivo prothrombin activation is a function of the balance between FII and PC levels, and is not significantly prevented until nadir levels of FII are obtained 6.

PT/INR Test Principle

• The PT/INR test is based on the principle that in citrated plasma, the addition of a thromboplastin and CaCl2 allows for formation of a stable clot, and the time required for the formation of a stable clot is recorded in seconds 7.
• The INR is calculated from the PT result and allows for worldwide standardization of results, making it a useful tool for monitoring oral anticoagulant therapy and diagnosing the risk of bleeding 7.