Blood product support for delivery in severe factor X deficiency: the use of thrombin generation to guide therapy

Abstract

Background: Severe FX deficiency is a rare disorder with a variable bleeding tendency but spontaneous life threatening haemorrhage can occur. Treatment for invasive procedures and spontaneous bleeding is with prothrombin complex concentrates (PCC). When used in large or repetitive doses these are associated with a thrombotic tendency. FX:C levels of 0.15 - 0.30 IU/ mL are thought to be haemostatic during surgery . There is only limited information on the outcome and management of pregnancy in severe FX deficiency. Caesarean section is suggested as delivery mode to reduce the risk of intracranial/abdominal neonatal haemorrhage, but successful vaginal deliveries are also described. The calibrated automated thrombin generation assay (CAT) is a global coagulation test that measures the time course of thrombin generation. It has been reported to correlate with prothrombotic states and the severity of bleeding in rare coagulation disorders. The variability in phenotype, the uncertainty of the minimal haemostatic FX:C concentration and the association of PCC's with thrombosis make thrombin generation of interest in the management of FX deficient patients.

Patient: We describe the use of CAT as a possible means to monitor treatment with PCC (Beriplex) in a patient with severe FX deficiency (FX:C < 0.01 IU/mL) during successful vaginal delivery and epidural anaesthesia.

Results: Thrombin generation was normal at FX:C 0.80 IU/mL but only borderline normal at FX:C 0.25 IU/mL. Repetitive doses over 3 days increased thrombin generation to the upper limit of normal at FX:C 0.25 IU/mL consistent with a prothrombotic tendency after multiple doses. The increase in thrombin generation was not related to prothrombin levels.

Conclusion: The data suggest that CAT may be used to monitor treatment with PCC in FX deficiency. Higher levels than previously thought may be needed to normalize thrombin generation. Further studies into the correlation with bleeding or thrombosis are needed before the approach can be accepted in clinical practice.

Keywords: FX deficiency; endogenous thrombin potential; pregnancy; prothrombin complex concentrate; thrombin generation.

Figure 1

The response of A) ETP, B) peak thrombin generation, C) lag time and D) time to peak to in vitro spiking with increasing concentrations of Beriplex^® . The horizontal grey lines represent the normal range for women

Figure 1

The response of A) ETP, B) peak thrombin generation, C) lag time and D) time to peak to in vitro spiking with increasing concentrations of Beriplex^® . The horizontal grey lines represent the normal range for women

Figure 1

The response of A) ETP, B) peak thrombin generation, C) lag time and D) time to peak to in vitro spiking with increasing concentrations of Beriplex^® . The horizontal grey lines represent the normal range for women

Figure 1

The response of A) ETP, B) peak thrombin generation, C) lag time and D) time to peak to in vitro spiking with increasing concentrations of Beriplex^® . The horizontal grey lines represent the normal range for women

Figure 2

Response of thrombogram parameters to treatment with Beriplex^® . The solid black lines indicate the normal ranges for women. Note absent thrombin generation prior to treatment, normal ETP and peak after treatment to FX=0.80 IU/mL and increased thrombin generation on day 3 with comparable FX levels to day -1. No samples for thrombin generation were taken on day 1 and day 2. No lag time or ttpeak were reached

Figure 2

Response of thrombogram parameters to treatment with Beriplex^® . The solid black lines indicate the normal ranges for women. Note absent thrombin generation prior to treatment, normal ETP and peak after treatment to FX=0.80 IU/mL and increased thrombin generation on day 3 with comparable FX levels to day -1. No samples for thrombin generation were taken on day 1 and day 2. No lag time or ttpeak were reached

Figure 2

Response of thrombogram parameters to treatment with Beriplex^® . The solid black lines indicate the normal ranges for women. Note absent thrombin generation prior to treatment, normal ETP and peak after treatment to FX=0.80 IU/mL and increased thrombin generation on day 3 with comparable FX levels to day -1. No samples for thrombin generation were taken on day 1 and day 2. No lag time or ttpeak were reached

Figure 2

Response of thrombogram parameters to treatment with Beriplex^® . The solid black lines indicate the normal ranges for women. Note absent thrombin generation prior to treatment, normal ETP and peak after treatment to FX=0.80 IU/mL and increased thrombin generation on day 3 with comparable FX levels to day -1. No samples for thrombin generation were taken on day 1 and day 2. No lag time or ttpeak were reached