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Coagulation Disorders

prophylaxis treatment with rFVIIa in both treatment groups compared to the three-month pre-prophylaxis period. The median target joint bleeds before and during prophylaxis were respectively 11.5 versus 4 at 90µg/kg and 9 versus 2.5 at 270µg/kg (both p<0.001).15

Secondary prophylaxis appears to be a promising alternative to on-demand therapy in haemophilia patients without inhibitors.23,24 Despite this, apart from the RCT included in this review,15

the scientific

level of evidence using such therapy in secondary prophylaxis compared with on-demand treatment is low.

As outlined above, there is considerable difficulty in evaluating rFVIIa in haemophilia patients with inhibitors due to the apparent lack of standardisation in how haemostatic efficacy should be evaluated. In the home-treatment studies, efficacy was evaluated by the patients themselves12–14,17

or by the investigators.8 Different time-points for

evaluation of haemostatic efficacy were used as primary end-points in the studies. There was also considerable heterogeneity in how haemostatic efficacy should be assessed and at what time-points haemostasis was assessed between RCTs and non-randomised studies.7,18,19,22,25–31

and the importance of platelets for intact haemostasis.37,38 Furthermore,

it was recognised that the kinetics of the thrombin burst has a separate influence on the strength and stability of the clot compared with the cleaving fibrinogen to fibrin. Thrombin also activates FXIII to XIIIa and TAFI to TAFIa in a concentration-dependent manner.39

It is well recognised in the scientific community that the coagulopathy of haemophilia relates to impaired thrombin generation. It is therefore surprising that assays only reflecting the first 2–3% of the patient’s ability to generate thrombin, such as activated partial thromboplastin time and prothrombin time, are employed. This is despite the fact that such assays have consistently been shown to correlate poorly with clinical bleeding conditions.40–49

Obviously, this constitutes a significant problem for the interpretation and comparison of results from studies of haemophilia patients.

Risk of Thromboembolic Events

Concern in terms of the potential risk of developing thromboembolic events secondary to administration of rFVIIa has been raised.32,33


the studies reviewed herein there are two reports of thromboembolic events.11,16

Shapiro et al.11 reported that one patient in the 35µg/kg

group developed thrombosis of the right internal jugular vein on the second day following central venous catheter placement. In the study by Pruthi et al.,16

one patient in the BI group developed

thrombosis of the popliteal vein and proximal peroneal vein on day 10 after surgery.

Two reviews have reported 55 thromboembolic events in approximately 1.5 million standard doses (90µg/kg for a 40kg individual),34


must be considered low. Consequently, the administration of rFVIIa in haemophilia inhibitor patients appears safe, with lower incidences of thromboembolic events than reported for other clotting factor concentrates.34,35

Safety and Efficacy in Congential Platelet Disorders No RCTs reporting on the safety and efficacy of rFVIIa in patients with congenital platelet disorders exist. A number of reports suggest that administration of rFVIIa to patients with Glanzmann’s thrombastenia and Bernard-Soulier syndrome may be beneficial, whereas other observations do not support its use.36

Taking into account that in

patients with congenital platelet disorders rFVIIa administration is only considered when other treatment options fail, this may justify its use despite the lack of scientific evidence.

Use of Assays

The cell-based model of haemostasis was introduced in 1994, emphasising the importance of tissue factor in initiating coagulation

1. Oldenburg J, Dolan G, Lemm G, Haemophilia care then, now and in the future, Haemophilia, 2009;15(Suppl. 1):2–7.

2. Dimichele D, Inhibitors: resolving diagnostic and therapeutic dilemmas, Haemophilia, 2002;8:280–7.

3. Morfini M, Haya S, Tagariello G, et al., European study on Conclusion

In conclusion, the systematic use of viscoelastic whole-blood assays may have the potential to significantly improve the treatment of haemophilia patients with inhibitors. Instead of administering rFVIIa in doses related to patient weight, an individual dosing regimen based on the amount rFVIIa needed to establish maximal thrombin generation and, hence, clot strength and stability seems reasonable. n

orthopaedic status of haemophilia patients with inhibitors, Haemophilia, 2007;13:606–12.

4. Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP, et al., The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A

and antibodies to factor VIII. A double-blind clinical trial, N Engl J Med, 1981;305:717–21.

5. Hedner U, Mechanism of action, development and clinical experience of recombinant FVIIa, J Biotechnol, 2006;124:747–57. 6. Pan-Petesch B, Laguna P, Mital A, et al., Single-dose (270

Coagulation factor deficiency and/or thrombocytopenia/pathy may result in impaired thrombin generation and, hence, impaired clot generation with reduced clot stability, as evidenced by an abnormal TEG tracing.44–47,50–60,63,64

Given this, it seems rational to monitor

haemostasis in haemophilia patients with inhibitors using TEG or ROTEM, as suggested by Yoshioka et al. more than 10 years ago63 Sørensen et al. more recently.64

and This view is supported by Bassus et al.,65

who found that administration of FVIII concentrate in patients with haemophilia A correlated linearly with increased FVIII activity, as evaluated by activated partial thromboplastin time. Thrombin generation and maximal clot strength, evaluated by thrombin generation test (TGT) and TEG, showed no such correlation. Instead, substituting whole-blood samples ex vivo with 1U/ml FVIII resulted in maximal haemostatic effect of FVIII, as evaluated by both TGT and TEG maximal clot strength. It also became evident that 30% FVIII activity was sufficient to produce >90% of the maximal thrombin generation and maximal clot strength and that FVIII substitution up to a plasma activity of >90% did not further enhance the haemostatic effect.

Furthermore, in terms of inhibitor patients, Trowbridge et al.66 reported

on the successful use of TEG to guide the administration of rFVIIa in haemophilia patients who were difficult to manage.

Whole-blood viscoelastic assays, such as thrombelastography (TEG) and thromboelastometry (ROTEM) have been consistently shown to be superior to conventional plasma-based coagulation assays in predicting the need for blood transfusion in actively bleeding patients. They have also provided guidance for treatment with plasma and platelets in non-haemophilia patients.44–47,50–61 this superiority was delineated by Rivard et al.62

The scientific rationale for who demonstrated a

correlation between total thrombus generation over time, as evaluated by TEG, and the concentration of generated thrombin-antithrombin (TAT) complexes.



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