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during CPB. Previous reports have described a variety of techniques for managing anticoagulation of FXII deficient patients undergoing CPB. Reports of empiric heparin dos- ing without anticoagulation monitoring or by observing for visible clot in-vitro without anticoagulation monitoring presented an unacceptable risk to our patient.6,8–10 Similarly, in a paediatric patient with severe FXII deficiency, heparin concentration was monitored without measurement of heparin response.7 Alternatively, modification of the ACT using in-vitro donor FFP and calcium has been described in the FXII deficient patient, though this technique induces haemodilution and does not accurately reflect the composi- tion of plasma circulating in the extracorporeal circuit.11,12 Heparin resistance or antithrombin III deficiency may also be concealed by this method.
Preservation of the extracorporeal circuit during CPB is critical. Thus, we made the decision to replace FXII by transfusing FFP prior to surgery. Our approach was con- sistent with techniques previously reported, allowing for direct measurement of heparin induced anticoagulation rather than an assumption of anticoagulation.5,13,14
On the other hand, thrombin time is unaffected by alterations in the intrinsic and the extrinsic coagulation pathway but reflects heparin effect via the common pathway of the coagulation cascade. Thrombin time reflected the baseline, heparin effect and protamine reversal and was not altered by FXII levels in our patient (Table 1). The use of chromogenic anti-Xa assay to monitor anticoagulation has also been described; how- ever, protamine reversal is less reliably measured because protamine completely neutralises the anti-IIa activity of heparin but not anti-Xa activity. Both throm- bin time and anti-Xa assays are unable to be used as point of care tests and are not currently standardised for CPB.11,15
In our case, ACT-HR provided appropriate results pre- and post-FFP transfusion, tracked thrombin time at all stages of surgery and correctly reflected the state of heparinisation without being affected by FXII defi- ciency. Negatively charged surface activators such as kaolin, celite, dextran sulphate and sulphatides are known to be strong stimulants of the activation of FXII by kallikrein.16 Kaolin and negatively charged silica are present in the ACT-HR cartridge but absent in the ACT-LR, which contains celite. It is possible that the patient had sufficient residual FXII activity to elicit clot formation in the presence of both kaolin and silica. This was unexpected and in retrospect it would have been beneficial to delay FFP transfusion until after heparini- sation to observe a change in ACT-HR.
One other option is to use confirmation of a normal antithrombin level in combination with kaolin ACT monitoring and maintain the target heparin concentra- tion using heparin-protamine titration.17 However, while heparin-protamine titration indicates the presence of
heparin, it does not indicate a heparin response. Both tests are not commonly available as point-of-care tests. Additionally, the use of ACT alone remains the most commonly utilised method to monitor anticoagulation with heparin during cardiopulmonary bypass and in this sense our approach is low-risk and avoids utilising an unfamiliar strategy.18
FXII levels have not been previously reported over a 48-hour period following FFP transfusion in a severely deficient patient (Table 1). The half-life of FXII is 40 to 50 hours.3 Heparin contamination and dilution whilst on CPB distorts FXII levels post-heparin and on CPB and these results should be interpreted with caution. Burman et al.7 have previously reported a 12-year-old child with FXII <1% though they did not monitor hep- arin response.
There are two reports of thrombosis following antifi- brinolytic administration in FXII deficient patients.3,19 Our patient did not receive any antifibrinolytic medica- tion during her admission.
In conclusion, FXII deficient patients requiring CPB can be safely managed by perioperative transfusion with FFP. This is a simple and effective method, allowing anaesthesia and surgery to proceed in an otherwise standard fashion. We recommend using ACT-HR pre- and post-FFP transfusion as it utilises kaolin and silica as contact reagents and is more reliable in the presence of FXII deficiency.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics statement
This case report was written with the approval of the Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee.
Informed consent
Written informed consent was obtained from the child’s mother and father.
ORCID iD
Nicole Shrimpton
References
https://orcid.org/0000-0002-4046-8770
1. Stavrou E, Schmaier AH. Factor XII: what does it con- tribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res 2010; 125: 210–215.
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