الفهرس 
Anatomy & Pathophysiology of Haemostasis
Inherited Bleeding DisordersOnly 14 pages are availabe for public view
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Abstract
Recombinant FVIIa is a vitamin-K dependent glycoprotein
that is structurally similar to human plasma-derived factor
VIIa. No human serum or proteins are used in the production of
rFVIIa. It is manufactured by cloning of the human factor VII
gene and is expressed in baby hamster kidney cells, then
cultured in bovine albumin. This process eliminates the risk of
human blood-borne infection.
Recombinant FVIIa is a recombinant human coagulation
factor that is intended for promoting hemostasis through
activation of the extrinsic pathway of the coagulation cascade.
It does this by bypassing the coagulation cascade and creating a
―thrombin burst‖, thereby leading to a stable fibrin clot.
There are numerous theories about the exact
mechanism of rFVIIa in vivo. In hemophilia A and B (factor
VIII and IX deficiencies), it has been shown that factor VIIa
will bind to platelets and activate factor X to factor Xa,
resulting in thrombin generation, despite deficiencies in the
intrinsic pathway. There has also been shown to be a doseresponse
relationship between the amount of rFVIIa and
thrombin formation, so increasing doses of rFVIIa can
increase thrombin generation even in the absence of factor
VIII and IX. In addition to upregulation of thrombin
formation, it has also been shown that rFVIIa inhibits
fibrinolysis by activation of thrombin activatable fibrinolytic
inhibitor in factor VIII-deficient plasma.rFVIIa was originally developed as a bypassing agent
for the treatment of bleeding in hemophilia A and hemophilia
B patients with inhibitors to replacement factor VIII and
factor IX. However, recent research has supported its use in
numerous other hematological conditions. Its safety and
efficacy in congenital factor VII deficiency has been shown,
and it has been used as prophylaxis for bleeding associated
with surgery as well as used in the management of acute
bleeding episodes as in severe postpartum hemorrhage, DIC,
traumatic bleeding, drug induced coagulopathy, acute
intracerebral hemorrhage. Also, it can be used in bleeding
due to liver disease, renal failure & platelet disorders.
It has been reported that in patients with congenital
factor VII deficiency and hemophilia, the half-life of rFVIIa is
2.96 (2.82–3.11) and 2.3 (1.7–2.7) hours, respectively, and
therefore it needs to be dosed frequently. According to current
recommendations, when used in patients with factor VII
deficiency, the doses range from 15 to 30 μg/kg every 4–6
hours, but higher doses may be required for life-threatening
hemorrhage.
Effective treatment requires at least three doses to be
administered for adequate hemostasis. These dosage
recommendations vary dramatically from the dosing guidelines
for patients with hemophilia, in which rFVIIa is currently
recommended at 90 μg/kg every 2 hours until hemostasis is achieved. It has been suggested by Tran et al that continuous
infusion of rFVIIa during surgery results in the desired
hemostasis as well as requiring a significantly reduced amount
of rFVIIa, when compared with bolus injections. Such infusional
dosing has not become regarded as standard and therefore bolus
dosing remains recommended.
There have been several case reports which address
safety concerns and administration both in the setting of
bleeding prophylaxis as well as the complications that may
occur. Although bleeding improved in all patients, there are
also reports of rFVIIa causing significant side effects. Due to
the fact that rFVIIa is a potent thrombin generator,
thrombosis resulting in serious events should be of concern
to the prescribing physician. Review of the literature reveals
reports of cerebral infarction, cerebral ischemia, angina
pectoris, myocardial infarction, pulmonary embolism, and
deep vein thrombosis. In 2011, Girolami et al reported a
series of patients who developed significant thrombotic
events after factor replacement, emphasizing that although
these patients have severe clotting defects, there is still a risk
of thrombosis.