C‐reactive protein‐induced activated partial thromboplastin time prolongation in heparinized samples is attenuated by elevated factor VIII

Abstract

Introduction Activated partial thromboplastin time (aPTT) and antifactor Xa (anti‐Xa) activity are used to monitor unfractionated heparin therapy in children on extracorporeal membrane oxygenation (ECMO). Elevated C‐reactive protein (CRP) can prolong aPTT and cause discrepancy between these two assays. We aimed to evaluate CRP effect on aPTT and anti‐Xa assays in the presence of heparin and to determine whether elevated CRP affects laboratory monitoring in pediatric ECMO patients. Materials and methods Citrated normal specimens were spiked with CRP, heparin, and recombinant factor VIII (FVIII) and followed by measurement of aPTT and anti‐Xa activity. Additionally, aPTT, anti‐Xa activity, FVIII, fibrinogen, and CRP were measured in 18 ECMO specimens. Results Elevated CRP prolonged aPTT in normal specimens with or without heparin, but did not affect anti‐Xa assay. In contrast, ECMO specimens showed similar aPTT and anti‐Xa values regardless of CRP level. Elevated CRP in specimens was accompanied by increased fibrinogen and FVIII activity. Additional in vitro experiments confirmed that FVIII spiked simultaneously with CRP attenuated CRP‐induced aPTT prolongation in heparinized specimens. Conclusion In vitro CRP‐induced aPTT prolongation is not observed in pediatric ECMO samples due to concomitant FVIII increase. Discordant changes of CRP and FVIII in plasma could contribute to aPTT/anti‐Xa discrepancies observed during heparin therapy in the pediatric population. The anti‐Xa assay is preferable for heparin monitoring in pediatric ECMO settings.

Is it time to switch to bivalirudin for ECMO anticoagulation?

“…Heparinase-treated aPTT (HPTT) helps to eliminate the heparin effect and reveal the underlying coagulable state, yet HPTT is still rarely used in most institutions due to its cost. It is also important to note that phospholipid-binding proteins such as lupus anticoagulant and C-reactive protein (CRP) may also prolong aPTT and HPTT ( 7 , 28 ) and this effect must be considered when assessing aPTT and anti-Xa in gaging anticoagulation with heparin.…”

Novel Coagulation Test Detects Anticoagulation Resistance and Is Associated With Thrombotic Events in Pediatric Patients Requiring Extracorporeal Membrane Oxygenation

“…aPTT and/or anti-Xa are most commonly used to assess adequate UFH-related anticoagulation given that ACT is unreliable in the pediatric ECMO setting and viscoelastic testing is not broadly available (11)(12)(13)(14). However, aPTT is effected by other factors such as presence of lupus anticoagulant, elevated C reactive protein, and increased factor VIII level (15)(16)(17)(18). Anti-Xa assays use platelet-poor-plasma (PPP) and are not functional clot time-based tests as they do not account for thrombin, fibrinogen, and other blood cells, which contribute to coagulation.…”

Heparin – Messias or Verschlimmbesserung?

“…APTT readings may be falsely shortened in patients receiving UFH with an elevated C‐reactive protein, dependent upon the chosen assay or high FVIII levels 49 . Anti‐Xa monitoring may therefore be preferable in these patients, which is of relevance to a significant proportion of COVID‐19 patients 50 . A pre‐COVID study of 539 hospitalized patients receiving UFH found that patients with disproportionately prolonged APTT readings compared with anti‐Xa values had worse clinical outcomes.…”

“… 49 Anti‐Xa monitoring may therefore be preferable in these patients, which is of relevance to a significant proportion of COVID‐19 patients. 50 A pre‐COVID study of 539 hospitalized patients receiving UFH found that patients with disproportionately prolonged APTT readings compared with anti‐Xa values had worse clinical outcomes. The authors suggested that concurrent measurement of both readings could be useful in stratifying bleeding risk and determining dose.…”