Bleeding and its Assessment
Edmunds Transfusion Therapy and Blood Conservation
Recombinant Factor VII for massive haemorrhage
|
|
History, both personnel and family of excessive bleeding following minor trauma or following tooth extraction or surgical procedures.
Laboratory FBC, and clotting screen are usually sufficient, to confirm platelet number and soluble coagulation factor adequacy.
Withholding aspirin, clopidogrel and warfarin are also important factors to limit post operative bleeding.
Standard laboratory tests are usually too slow. Thromboelastography may play a role in this situation, however this is debated.
Standard laboratory tests and clinical acumen are the standard options here.
Fibrinogen, especially if less than 1.0 is a common cause of bleeding post extensive aortic surgery involving a lot of cell salvage and blood transfusion. Cryoprecipitate is the product of choice to replete fibrinogen.
Bed side ACT monitoring can play a role for treating cases of heparin rebound with extra doses of protamine.
Thromboelastography may play a role in this situation, however this is debated. (Tutorial).
Recombinant Factor VII for massive haemorrhage
Use of the cardiopulmonary bypass (CPB) apparatus generates varying degrees
of coagulopathic bledding in all patients. In addition, open-heart procedures
provide ample opportunity for incomplete mechanical hemostasis. These two
factors lead to an often realized potential for increased bleeding during the
postoperative period [1]. Although practically all patients have a normal
clotting mechanism before surgery, postoperative bleeeding is a threat in all
open-heart operations. The magnitude of the defect in particular components of
the hemostatic mechanism correlates poorly with the severity of the hemorrhagic
syndrome observed. Massive transfusion of banked blood not rarely compounds to
the acquired bleeding disorder.
Nontransfusion strategies for the control of postoperative bleeding fall under
four general categories, (1) prevention of the development of coagulopathyc
bleeding through appropriate technical and pharmacologic intervention, (2)
normalization of homeostatic and hemostatic function through immediate and
optimal application on nontranfusion supportive measures, (3) tolerance to
bleeding that does not exceed normla limits by adhering to appropriate
transfusion guidelines, and (4) delineation and timely correction of inadequate
mechanical hemostasis [1].
Intractable hemorrhage is a dreaded complication after cardiovascular surgery
tha often requires reexploration and the administration of large quantities of
blood products. Despite a meticulous surgical technique, an acellular prime and
the use of systemic agents to promote hemostasis a few patients will present a
refractory bleeding associated with a complex and intractable coagulopathy that
persists irrespective of surgical reexploration, massive transfusion of blood
products and the administration of hemostatic agents [2,3].
COAGULATION FACTOR VII
Factor VII is a vitamin K–dependent coagulation factor synthesized in the
liver. It occurs in the plasma in low concentrations, such as 0.5 mcg/mL and it
also has a short circulating half-life of 3-4 hours. Plasma FVII predominantly
exists in the form of the inactive single-chain zymogen, but approximately 1%
circulates in the activated form (FVIIa). The activation of FVII is the
initiating event of in vivo coagulation. The ability of FVIIa to cleave other
clotting factors depends on binding to its cofactor tissue factor (TF), which is
expressed on the surface of endothelial cells and monocytes in response to
injury or inflammation. With formation of the TF/VIIa complex, FVIIa rapidly
activates clotting factors VII, IX, and X, initiating the coagulation cascade
[4]. Maintaining FVII levels of at least 15-25% provides adequate hemostasis
levels for most surgical procedures.
Hemophilia A is a deficiency in factor VIII caused by a genetic mutation on the
X chromosome. Hemophilia B is a deficiency in factor IX, and is clinically
indistinguishable from hemophilia A. Factor assays are used to confirm a
diagnosis.
Recombinant Factor VIIa is used for the prevention and control of hemorrhagic
episodes in certain patients with Hemophilia A (antihemophilic factor
deficiency, classic hemophilia) or Hemophilia B (factor IX deficiency, Christmas
disease) who have developed inhibitors (alloantibodies) to antihemophilic factor
or factor IX [5].
RECOMBINANT FACTOR VII POSTCARDIOPULMONARY BYPASS
Irrespective of a more complete understanding of risk factors associated with
excessive bleeding after cardiopulmonary bypass, intractable postoperative
hemorrhage remains a risk for patients after complex operations, prolonged
bypass time, excessive intraoperative hemorrhage, reoperations, and blood
coagulation and platelet defects.
Success with the use of rFVIIa in patients with hemophilia and antibodies to
factor VIII and IX has resulted in the application of this agent in other
settings of uncontrollable hemorrhage related to postsurgical coagulopathy [3].
Halkos et al [3] reported a series of 9 patients with a a voluminous chest tube
drainage output after routine cardiopulmonary bypass with the adjunct of
aprotinin and total heparin reversal. Five patients were reexplored for
mediastinal hemorrhage and 2 patients were reexplored twice with no mechanical
bleeding identified. All patients continued to bleed after receiving an average
of 9 U of packed red blood cells, 7 U of plasma, 22 U of platelets, and 19 U of
cryoprecipitate. DiDomenico [7] reported two patients operated for correction of
aortic aneurysms secondary to Marfan´s syndrome with copious postoperative
bleeding and described a total of 20 reported cases with similar clinical
pictures.
Recombinant FVIIa was administered as a single intravenous bolus over 15 minutes
at 68 to 120 mcg/kg (4.8 to 9 mg) or divided into 2 doses withe the second bolus
given within 1 hour after the initial bolus. There were no additional infusions
after the bolus treatment. At the time of rFVIIa administration, chest tube
drainage averaged 640 mL/h. In all patients, bleeding dramatically reduced to
less than 100 mL/h within 5 hours after administration and post-rFVIIa
transfusions requirements were modest and only to restore red cell mass.
One patient presented multisystem-organ failure and another presented
overwhelming sepsis and both died.
PEDIATRIC PATIENTS AND rFVIIa
Tobias [8] et al evaluate the efficacy of rFVIIa in the treatment of bleeding
following cardiac surgery with CPB in pediatric patients. The authors compared
chest tube drainage before and after the administration of rFVIIa. The study
included patients with chest tube output of 4 mL/kg/h for the initical 3
postoperative hours who received rFVIIa. Recombinant factor VII was administered
to 9 children (age 9 +/- 4 years). Chest tube output for the initial 3
postoperative hours prior to the administration of rFVIIa was 5.8 +/- 2.8 mL/kg/h
and decreased to 2.0 +/- 1.3 mL/kg/h for the 3 hours following the
administration of rFVIIa. The control group without rFVIIa treatment presented a
chest tube output for the first 3 postoperative hours of 1.6 +/- 0.9 mL/kg/h and
1.2 +/- 0.6 mL/kg/h for the next 3 hours.
The recombinant factor VII has demonstrated to be an important adjuvant to treat
postcardiopulmonary bypass excessive bleeding when all conventional measures
fail. Further investigations will be necessary to determine the efficacy of this
agent in cardiovascular surgery patients with intractable postoperative
hemorrhage. Recombinant factor VIIa decreased chest tubing bleeding following
cardiac surgery in children. Given its potential therapeutic impact, rFVIIa also
warrants further investigation in the pediatric cardiac population.
REFERENCES:
1. Helm RE and Krieger KH. Assessment and control of postoperative bleeding. In
Krieger KH, Isom OW: Blood Conservation in Cardiac Surgery. Springer, New York,
1998.
2. de Leval MR, Hill JD and Mielke CH. Haematological aspects of extracorporeal
circulation. In Ionescu MI. Techniques in Extracororeal Circulatin. Second
Edition. Butterworths, London, 1981.
3. Halkos ME, Levy JH, Chen E, Reddy VS et al. Early experience with activated
recombinant factor VII for intractable hemorrhage after cardiovascular surgery.
Ann Thorac Surg 2005;79:1303-6.
4. Israels SJ. Factor VII deficiency. E-Medicine. http://www.emedicine.com/ped/topic3041.htm
as posted in 06.28.2005.
5. Medical and Scientific Advisory Council (MASAC), National Hemophilia
Foundation. MASAC recommendations concerning the treatment of hemophilia and
other bleeding disorder (revised November 2002).
6. Baudo F, Redaelli R, Caimi TM. The continuous infusion of recombinant
activated factor VIIa (rFVIIa) in patients with factor VII inhibitors activates
the coagulation and fibrinolytic systems without clinical complications. Thromb
Res 2000;99:21-4.
7. Robert J. DiDomenico, PharmD; Malek G. Massad, MD; Jacques Kpodonu, MD; R.
Antonio Navarro, MD and Alexander S. Geha, MD. Use of Recombinant Activated
Factor VII for Bleeding Following Operations Requiring Cardiopulmonary Bypass.
Chest. 2005;127:1828-1835.
8. Tobias JD, Simsic JM, Weinstein S, Schechter W, Kartha V, Michler R.
Recombinant factor VIIa to control excessive bleeding following surgery for
congenital heart disease in pediatric patients. J Intensive Care Med. 2004
19(5):270-3.