Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

XXIst Congress of the International Society on Thrombosis and Haemostasis

Geneva, Switzerland / July 6-12, 2007

Protocols have long been established regarding control of hemostasis in surgery and trauma, including surgical correction of the bleeding source. Nevertheless, achievement of hemostasis, especially in trauma patients where the “lethal triad” of coagulopathy, hypothermia and acidosis often exists, remains particularly challenging and new strategies are needed to provide rapid and effective hemostasis when traditional approaches fail.

During a discussion on the issue of avoiding thromboembolic complications in surgical patients, Dr. Pierre Albaladejo, Centre hospitalier universitaire Henri Mondor, Créteil, France, reminded delegates that ASA may increase bleeding but not necessarily the need for transfusion and many invasive procedures can be carried out in patients on ASA. ASA also needs to be in place during certain surgical procedures such as carotid endarterectomy; otherwise, platelet activation will occur and increase the risk of thromboembolic events. He cited an example of patients in whom ASA had been withdrawn about 12 days prior to hospital admission for suspected acute coronary syndromes. They had higher 30-day death and myocardial infarction (MI) rates and higher bleeding rates than those on chronic ASA therapy (Circulation 2004;110(16):2361-7).

ASA withdrawal has also been identified as an independent risk factor for perioperative MI in noncardiac surgery, Dr. Albaladejo added. When bare-metal stents are added to the equation, the risk of stent thrombosis is unacceptably high in patients undergoing non-cardiac surgery an average two weeks after coronary stent placement, and it is now accepted that non-cardiac surgery should be delayed for at least six weeks’ postpercutaneous coronary intervention (PCI) with baremetal stents.

Drug-eluting stents (DES) in turn have been associated with a 1.3% to 1.7% risk of stent thrombosis at about nine months of follow-up in real-world patients, according to Iakovou et al. (JAMA 2005; 293(17):2126-30). Hard clinical end points including death, MI or stent thrombosis at 30 days are higher with off-label use of DES than when used as indicated but as Dr. Albaladejo noted, almost half of patients in one recent US study had received stents for off-label or untested indications, suggesting off-label/untested DES use may have important clinical implications (JAMA 2007;297(18):1992-2000).

Based on advice from a French Working Group led by Dr. Albaladejo ( Br J Anaesth 2006;97(4):580-2), perioperative management of antiplatelets in patients with coronary stents includes the following suggestions:

• Withdrawing antiplatelet therapy is a major risk factor for thrombosis for all types of stents, especially for late stent thrombosis.

• If surgery is to be done within six to 12 months, a bare metal stent is the preferred option.

• Antiplatelet treatment should be resumed as soon as possible after surgery. (Recommended loading dose of at least 300 mg of clopidogrel on resumption)

• Following DES positioning: If patients are at major risk for stent thrombosis, postpone surgical intervention for six months to one year. If this is not possible, stop ASA or clopidogrel for five days if patients are at high risk.

• If bleeding risk is intermediate, stop clopidogrel for five days but maintain ASA.

• Both ASA and clopidogrel should be continued in minimal-risk patients.

Massive Hemorrhage

Presenters reminded delegates that trauma patients are at high risk for coagulopathy and the higher the injury severity score, the more likely the coagulopathy and the more likely the patient will die. As noted by Dr. Donat Spahn, University Hospital Zurich, Switzerland, the more fluids are administered to the patient pre-operatively, the greater the likelihood of coagulopathy. Given the complex factors that drive the “lethal triad” of coagulopathy, hypothermia (<34ºC) and acidosis (pH<7.10), Spahn et al. developed guidelines for the management of bleeding following major trauma (Crit Care 2007;11(1):R17). Key recommendations include the following:

• Apply measures to reduce heat loss early and warm hypothermic patients to achieve and maintain normothermia.

• Target hemoglobin to between 7 and 9 g/dL.

• Treat massively bleeding patients complicated by coagulopathy (prothrombin time [PT] or an activated partial thromboplastin time [aPTT] >1.5 times normal) with fresh frozen plasma (FFP). Initial dose: 10 to 15 mL/kg.

• Platelets should be given to maintain a count >50 x 109/L, and >100 x 109/L in patients with multiple trauma who are severely bleeding. Initial suggested dose: 4 to 8 platelet concentrates.

• Treat with fibrinogen concentrate or cryoprecipitate when bleeding is accompanied by a plasma level of <1 g/L. Initial dose: 3 to 4 g of fibrinogen concentrate or 50 mg/kg of cryoprecipitate—approximately equivalent to 15 to 20 units in a 70-kg adult.

• Consider rFVIIa if major bleeding in blunt trauma persists despite standard attempts to control bleeding. Initial dose: 200 µg/kg followed by two doses of 100 µg/kg given one and three hours after the first dose. (Editor’s comment: This recommendation was based on evidence graded as “2C”; as such, one may consider the doses to be fairly high compared with North American recommendations)

Hemostatic Strategies with rFVIIa: A Review

Several case series presented here suggest that rFVIIa can safely be used in a variety of minor or major surgical settings. Preliminary results from Laurian et al., for example, demonstrated that hemophilia patients with inhibitors can undergo knee arthroplasties using rFVIIa as first-line therapy. The investigators continue to collect data from additional cases in order to confirm the hemostatic agent’s role in this setting.

Rodríguez-Merchan et al. evaluated outcomes following 91 surgical procedures, all of them undertaken with either rFVIIa or activated prothrombin complex concentrate factor eight inhibitor bypassing activity (FEIBA) support. Of the 11 major procedures, seven incorporated rFVIIa administration and four were carried out with FEIBA. Hemostatic control was achieved in all but one patient, who developed an arterial pseudoaneurysm, which was resolved with arterial embolization. The experience of these centres suggests that hemophilia patients with inhibitors can safely undergo both orthopedic and other types of surgery with the help of novel hemostatic agents.

Reduction in hematoma growth, reduced functional disability and a lower mortality risk were all seen with the use of rFVIIa in patients with intracranial hemorrhage (ICH) compared with placebo in the phase IIb study. In the phase III, rFVIIa in Acute Hemorrhage Stroke Treatment (FAST) trial, ICH patients with a history of ischemia received one of two doses of rFVIIa or placebo. Treatment with either 20 µg/kg or 80 µg/kg was associated with a significant change in ICH volume at 24 hours vs. placebo. As Steiner et al. reported, those receiving treatment within two hours experienced the largest absolute reduction in ICH volume. Surprisingly, however, reduction in ICH growth did not translate into either a functional or mortality advantage in either rFVIIa group compared with placebo.

In a small registry series of 45 patients with massive bleeding, Koscielny et al. reported that actual mortality rates were substantially lower following rFVIIa use compared with predicted mortality rates using two validated scoring systems. These observations suggest that the use of rFVIIa is associated with a reduction in blood loss which in turn may confer a mortality advantage in surgical and trauma patients, although it is plausible that other factors were equally responsible for reduced mortality.

In a single centre experience, establishing strict protocol for off-label rFVIIa use resulted in significantly better outcomes when patients met protocol criteria. As reported by López-Fernández et al., hemostasis was achieved in almost three-quarters of patients treated within protocol guidelines compared to only about half when rFVIIa was used off protocol. These findings suggest that appropriate usage of rFVIIa is associated with better outcomes than when it is used outside of established criteria, even though there are inherent limitations in a study such as this.

In Australia and New Zealand, 59 hospitals are currently reporting data to the Haemostasis Registry on the use of rFVIIa in non-hemophilia patients with critical bleeds. As Dunkley et al. report, overall response to rFVIIa has been very high—69% for the overall cohort and 84% for cardiac surgery patients. Patients who responded to treatment were also more likely to survive than non-responders and the adverse event rate has been acceptable at about 5%.

Dager et al. in turn reported their experience with low-dose rFVIIa (1.2 mg) in patients who have a major bleed while on warfarin. At a mean dose of 16.3 µg/kg, mean international normalized ratios (INRs) in this small series of critically ill patients were significantly reduced, and onset of hemostasis was rapid in patients who were evidently bleeding. With further experience, low-dose rFVIIa may emerge as an important adjuvant to FFP and intravenous vitamin K in patients requiring pharmacological reversal of vitamin K antagonists.

According to Lak et al., increasing thrombin generation with rFVIIa in Glanzmann’s thrombasthenia appears to provide good hemostatic control in patients whose bleeding proves intractable to all other coagulation protocols. Finally, an in vitro study by Kjalke et al. demonstrated the potential of combining rFVIIa with rFXIII for enhanced hemostatic efficacy.