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CARDIOVASCULAR ANESTHESIOLOGY

Thrombelastography-Guided Factor VIIa Therapy in a Surgical Patient with Severe Hemophilia and Factor VIII Inhibitor

Evan G. Pivalizza, MB ChB, FFASA^*, and Miguel A. Escobar, MD

From the Departments of *Anesthesiology, Medicine and Pediatrics, University of Texas Health Science Center, and Department of Hematology and the Gulf States Hemophilia & Thrombophilia Center, Houston, Texas.

Address correspondence and reprint requests to Evan G. Pivalizza, MB ChB, FFASA, Department of Anesthesiology, University of Texas Health Science Center, Houston, MSB 5.020, 6431 Fannin St., Houston, TX 77030. Address e-mail to Evan.G.Pivalizza{at}uth.tmc.edu.

Abstract

A patient with hemophilia and factor VIII inhibitors required urgent evacuation of a spinal cord hematoma. Two large doses of recombinant factorVIIa (200 µg/kg followed by 300 µg/kg) were required for hemostasis. Traditional and rotational thrombelastography were used to guide dose and timing of rFVIIa therapy. With the limitations of prothrombin and partial thromboplastin times as perioperative monitors of rFVIIa efficacy, this description of thrombelastography supports reports of in vitro use, and may be helpful when large perioperative doses of rFVIIa are required.

There are reports of use of recommended doses (90–120 µg/kg) of recombinant factorVIIa (rFVIIa) in perioperative situations, including spinal surgery.1–3 Use in these situations is considered "off-label" as current United States Food and Drug Administration-approved indication is as a coagulation-inhibitor bypassing agent in hemophilia patients with significant factor VIII and IX inhibitors. Use of both rotational (ROTEM®, Pentapharm GMBH, Germany) and traditional (TEG®, Hemoscope Corp., Niles, IL) thrombelastography have been proposed as laboratory tools for monitoring rFVIIa therapy in hemophilia patients.4–6 We report a patient with severe hemophilia A and a high titer inhibitor requiring urgent spinal surgery in whom dosing and timing of rFVIIa was guided by use of both the TEG® and ROTEM®.

CASE REPORT

A 21-yr-old man with severe hemophilia A and high titer factor VIII inhibitor presented with an acute thoracic spinal cord hemorrhage and neurological deficit requiring urgent decompression. Simultaneous kaolin-activated TEG® in the operating room and tissue factor (TF)-activated ROTEM® in the hemophilia laboratory were used to document and guide rFVIIa therapy.

Thrombelastography monitors whole blood coagulation encompassing initial fibrin formation, clot strengthening, platelet function and fibrinolysis. In the traditional TEG®, the cuvette containing blood sample is stationary with a rotating piston and with the rotational device (ROTEM®), the pin is fixed on the tip of a rotating shaft guided by a ball bearing system. This report describes simultaneous use of both monitors. However, without consistent activation or citration, it is not intended to compare both monitors but to describe potential use.

Preoperative laboratory results included prolonged partial thromboplastin time (52.4 s), normal prothrombin time (PT) (5.9 s), thrombin time (16.2 s), fibrinogen (475 mg/dL) and D-dimers (0.72). Initial kaolin-activated TEG® parameters prior to rFVII were consistent with significantly delayed fibrin formation (prolonged split point [SP] and R time) and decreased clot strength (prolonged K time, decreased angle), although platelet function (maximum amplitude, G) approached normal (Fig. 1, Table 1). Velocity of thrombus generation parameters (first derivative of the TEG®) showed decreased maximum rate of thrombus generation (MRTG), increased time to MRTG, and decreased total thrombus generated (Table 2). Preoperative ROTEM® assay with calcium and TF (Innovin, Dade Behring, Germany) added to a citrated sample showed prolonged clotting time (CT, analogous to the TEG® R time), clot formation time (CFT, analogous to the TEG® K time), and clot formation rate (analogous to the TEG® angle) (Fig. 2). The first derivative of the ROTEM® clot signal is presented, calculated using DyCoDerivAn^TM software.5 With these data, a large bolus of rFVIIa (200 µg/kg) was infused after anesthetic induction.

View larger version (14K): [in this window] [in a new window]   Figure 1. Superimposed TEG® traces.

View larger version (40K): [in this window] [in a new window]   Figure 2. Summary of RoTEM® traces during rFVIIa administration.

TEG® variables 45 min later showed improvement, although SP, R, K time, angle, MRTG, and time to MRTG remained abnormal (Tables 1 and 2). After 2 h, continued surgical bleeding, correlating with prolonged CT and CFT on the ROTEM® prompted an additional 300 µg/kg rFVIIa dose. There was subsequent significant shortening of CT and CFT (not completely normalized) (Fig. 1) and continued improvement of traditional and velocity-based TEG® variables (Tables 1 and 2). Hemostatic control was achieved and surgery completed.

Postoperatively, the patient received 3 hourly rFVIIa (100 µg/kg) based on anticipated duration of action with improved indices of fibrin formation in the 24 h postoperative TEG® (Tables 1 and 2). The patient did not regain full neurological function with a protracted clinical course before discharge.

DISCUSSION

Perioperative rFVIIa use in urgent off-label surgical situations has been described.1–3 Extremely large rFVIIa doses are often required in hemophiliac patients with factor VIII or IX inhibitors. The PT (abnormally short) and activated partial thromboplastin time have limitations as monitors of rFVIIa therapy and may not correlate with the clinical picture.4 We describe a case where thrombelastography (traditional [TEG®] and rotational [ROTEM®]) were used to monitor intraoperative response to large rFVIIa doses. Previous reports have discussed perioperative use of these devices using lower doses of rFVIIa.

TEG® and ROTEM® have been suggested for use in laboratory monitoring of hemophilia patients treated with FVIIa, where changes in profiles have correlated with outcome.5,6 In vitro ROTEM® measures of rFVIIa showed shortening of CT without complete normalization.5 Others have reported TEG® use in von Willebrand's disease7,8 and in patients receiving rFVIIa during liver transplantation.9 One report described sequential thrombelastography to monitor poor hemostatic response to activated prothrombin complex concentrate and rFVIIa in a bleeding, nonsurgical hemophiliac, despite normal plasma-based clotting assays.10

All TEG® indicators showed substantial change over the 2 rFVIIa doses (SP 30%–40%, R 35%–40%, K 62%–65%, angle 109%–125%, maximum amplitude 26%–53%, G 82%–222%). However, the magnitude of the abnormal baseline may have masked the "" of these changes. We anticipated a major change in the indices of fibrin formation (SP, R time), mirroring the dramatic shortening of PT with rFVIIa. However, with the baseline prolongation, improvement in these subsequently affected the K time and angle. Given the role of thrombin on platelet function, significant changes occurred in platelet function indices. It is difficult to isolate the most sensitive variable in this case, underscoring the value of the TEG® as a monitor of the continuum of coagulation rather than isolated measures.

Dose requirements for rFVIIa in hemophilia patients with inhibitors undergoing surgery are greater than those reported in nonhemophilia patients.11 Although hematologists should be involved in the perioperative care of these patients, anesthesiologists should be aware that higher doses than the approved 90–120 µg/kg every 2 h may be required to achieve hemostasis.12 Given such large doses (200 + 300 µg/kg in this case), an on-site monitor of therapeutic response would be useful.

Velocity profiles of thrombus generation with the first derivative of the TEG profile have been described.13 These measures reflect thrombus generation (MRTG, mm/min, time to MRTG [s], and thrombus generated [mm/min]) and thrombus disintegration (maximum rate of lysis [mm/min] and time to maximum rate of lysis [s]), although the latter indices were not measurable in this case due to prolonged clot initiation times. In this patient with delayed thrombus formation, changes in response to therapy were evident, although addition of TF would have facilitated velocity analysis.

This initial report suggests that thrombelastography (TEG® and ROTEM®) may be useful in monitoring the dosing and timing of rFVIIa. Although corroborating recent in vitro use, additional experience and investigations will further delineate the role of thrombelastography in surgical hemophiliac patients with inhibitors.

Footnotes

Accepted for publication April 1, 2008.

REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pivalizza, E. G. Articles by Escobar, M. A. Search for Related Content PubMed PubMed Citation Articles by Pivalizza, E. G. Articles by Escobar, M. A. Related Collections Cardiovascular Monitoring (Cardiac) Coagulation