A New Look into Childhood Acute ITP: The Relationship Between Thrombin Generation and Thrombocytopenia

Introduction: Immune thrombocytopenic purpura (ITP) is the most common cause of primary isolated thrombocytopenia of childhood.  Although ITP results in profound thrombocytopenia, the severity of bleeding in this disease does not correlate well with the platelet count suggesting a compensatory procoagulant state.  The primary aim of this study is to evaluate thrombin generation in childhood acute ITP patients compared to age-matched controls and examine procoagulant activity in relation to bleeding severity in childhood acute ITP.

Methods:  After IRB consent was approved, platelet poor plasma was isolated from acute ITP patients at the time of initial diagnosis and serially for up to 6 months post-diagnosis.  A single sample was obtained from age-matched controls.  Thrombin generation assays were run via the Calibrated Automated Thrombogram (CAT) using reagent containing 1pM tissue factor and 4uM phospholipid.   Peak thrombin levels were measured and compared to control samples using paired t-test analysis.  Clinical bleeding severity was assessed using a modified overall Buchanan bleeding score at each time point (0=no bleeding, 1=minor, 2=mild, 3=moderate, 4=severe, 5=life threatening bleeding).

Results: Samples from 19 childhood acute ITP patients, mean age 7 years, and 8 controls, mean age 5 years, were assessed.  The figure below demonstrates that despite profound thrombocytopenia, the peak thrombin values of acute ITP patients were higher than controls throughout the first 3-4 months following diagnosis.  ITP assays were significantly different from controls at the following time-points: 1-2 weeks (p=0.001), 3-4 weeks (p =0.022), 5-8 weeks (p =0.0009), 9-12 weeks (p =0.004), and 13-16 weeks (p=0.006) post-diagnosis.  Peak thrombin values returned to values similar to controls 17 weeks from diagnosis.  With the onset of acute ITP, higher bleeding scores were related to more severe thrombocytopenia.  In ITP patients, thrombin peak values remained elevated regardless of resolving thrombocytopenia and improved bleeding scores (see figure).

Conclusion:  To our knowledge, this is the first study to assess longitudinal thrombin generation using the CAT in childhood ITP patients.  In a highly significant pattern, acute ITP patients demonstrated sustained elevated peak thrombin levels compared to controls, even at acute onset of disease.  Certainly, thrombin release, and subsequent thrombin generation play a compensatory role to decrease bleeding among childhood ITP patients when the platelet count remains in the 10-50,000 range.  But, based on bleeding scores, this elevated thrombin may not be able to overcome the bleeding phenotype at presentation when platelets are most profoundly decreased or absent.  Greater understanding of the etiology of this thrombin potential in childhood acute ITP is critical, as the thrombocytopenia in this disorder may be triggered or linked to a larger post infectious or inflammatory coagulopathy.