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Haemostasis in Subjects Undergoing Spine Surgery
Figure 1: Time to Haemostasis
21
Table 1: Development of Antibodies Against Thrombin
21
Cumulative per cent achieving haemostasis
Anti-bThrombin Anti-rThrombin p value*
100 n/N (%) n/N (%)
90
Anti-product 3/60 (5) 0/60 (0) –
80
rThrombin (n=61)
antibodies, baseline
70
bThrombin (n=61) Anti-product 9/60 (15) 2/60 (3.3) 0.05
antibodies, day 29
60
50
* Fisher’s exact test, analysis pre-specified.
n = incidences of antibody formation; N = sample number.
40
30
(1.5%) developed antibodies to the protein, compared with 43 of the 200
20
patients (21.5%) treated with bThrombin (p<0.0001). Baseline levels of
10
antibodies were similar between groups. Samples from the three subjects
0
0 12345678 910
Time (minutes)
treated with rThrombin who seroconverted did not neutralise the activity of
native human thrombin. The incidence of adverse events was similar
Recombinant Thrombin between rThrombin and bThrombin in the phase III clinical trial, and the
A set of comparative analytical studies between rThrombin and plasma- severity of adverse events was generally similar between treatment groups
derived human thrombin was performed to assess the structural, and as expected for post-operative patients.
functional and biological properties for pharmacological equivalency.
The primary sequence of rThrombin was found to be identical to that of An analysis of the 122 patients undergoing spine surgery from the phase
plasma-derived human thrombin by amino acid analysis, with minor III clinical trial was presented in abstract form, with 98% of each
differences in sialylation and fucosylation. Regardless, circular dichroism treatment group achieving haemostasis within 10 minutes (see Figure
showed that the proteins possessed comparable secondary and tertiary 1).
21
Both bThrombin and rThrombin were well tolerated, with the latter
structures. When assaying the clotting and cleavage abilities of treatment demonstrating superior immunogenicity through a lower
rThrombin and human thrombin, the proteins exhibited enzymatic incidence of antibody formation following exposure to thrombin
activities that were indistinguishable.
19
(15 versus 3.3%; p=0.05; see Table 1).
1
Using a rabbit liver injury model, the time to haemostasis (TTH) was The studies suggest that bThrombin and rThrombin have comparable
evaluated in a randomised blind study using rThrombin and bThrombin. A efficacy in eliciting haemostasis in vivo, with little difference in terms
statistically significant reduction (t-test: p<0.05) in TTH was observed when of adverse events and complications following treatment. However,
the thrombin products were compared with a saline control. Results also the most notable difference is that of antibody development against the
showed no difference in TTH between rThrombin and bThrombin when bThrombin and rThrombin products. As expected, rThrombin did not
administered in equivalent doses.
19
Consistent with empirical data showing elicit a strong antibody response, as the protein is consistent with human
that TTH by thrombin depends on the amount of equivalent units used in plasma thrombin in terms of sequence, structure, biology and
treatment, equal dosage amounts of rThrombin and bThrombin were physiochemistry. As bThrombin is commonly used as a haemostatic agent
expected to yield similar haemostatic results. Phase II clinical trials have in surgery, a comparison between bThrombin and rThrombin in a surgical
suggested that rThrombin is safe during surgery as a topical haemostatic setting was appropriate in studying the efficacy and safety of rThrombin.
agent.
20
A subsequent phase III trial investigated the use of rThrombin With bThrombin associated with impurities, antibody development and
versus bThrombin in surgical haemostasis. In a blinded, randomised study related coagulopathies, the potential for rThrombin to perform as a pure
of 401 patients undergoing liver, spine or vascular procedures, the efficacy, haemostatic agent with a reduced risk of antigenicity has immense
safety and antigenicity of the thrombin proteins were compared.
1
implications on surgery and improved patient post-operative health.
The efficacy of the haemostatic agents was found to be similar, as analysed As spine surgeries have a high propensity for blood loss, a haemostatic
by TTH. Following surgery, the patients were monitored for one month to agent such as rThrombin with efficacy equal to that of bThrombin may
evaluate safety. Both treatment groups reported a similar incidence of well reduce blood loss during surgery, with an improved risk
adverse events. Blood samples were collected from 398 patients prior to management profile. Furthermore, the superior immunogenicity profile
and one month after their surgeries to test the presence of antibodies in of rThrombin may reduce the bThrombin post-operational risks, therefore
plasma. Of the 198 subjects who received rThrombin treatment, only three enhancing patient recovery. ■
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2007;205:256–65. 9. Gailani D, Renné T, Arterioscler Thromb Vasc Biol, 16. Winterbottom N, Kuo JM, Nguyen K, et al., J Applied Res,
2. Erstad BL, Eur Spine J, 2004;13:S28–S33. 2007;27:2507–13. 2002;2:1–11.
3. Sabel S, Stummer W, Eur Spine J, 2004;13:S97–S101. 10. Mann KG, Thomb Haemost, 1999;82:165–74. 17. Streiff MB, Ness PM, Transfusion, 2002;42:18–26.
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5. Shapiro F, Sethna N, Eur Spine J, 2004;13(Suppl. 1):6–17. 13. Schoenecker JG, Hauck RK, Mercer MC, et al., J Clin Immunol, 19. Bishop PD, Lewis KB, Schultz J, et al., Semin Thromb Hemost,
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2002;3:364–9. 14. Savage WJ, Kickler TS, Takemoto CM, Pediatr Blood Cancer, 20. Chapman WC, LockStadt H, Singla N, et al., J Thromb Haemost,
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EUROPEAN MUSCULOSKELETAL REVIEW 41
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