Clot formation is the final result of interaction among multiple plasm
a proteins; after activation, it results in the conversion of fibrinog
en to fibrin and cross-linking of fibrin by activated factor XIII, whi
ch stabilizes the formed clot. Deficiency or functional abnormality of
the factors involved in these reactions causes bleeding disorders. Na
tural inhibitors of clotting factors include antithrombin III, protein
S, and protein C. When activated, these proteins inactivate specific
clotting factors, providing a regulatory mechanism that serves to cont
rol the coagulation response and limit the extension of the clot. Phys
iologic or natural inhibitors should not be confused with acquired inh
ibitors of coagulation factors, which are discussed in this review. In
hibitors to coagulation factors, also known as circulating anticoagula
nts, are antibodies that neutralize specific clotting proteins, thereb
y interfering with their normal function. Antibodies may be directed a
gainst isolated clotting factors, as is the case with factor VIII or I
X inhibitors. On the other hand, the antiphospholipid antibodies are k
nown to develop against multiple coagulation proteins. In contrast to
patients with antibodies against isolated clotting factors, who common
ly present with spontaneous bleeding, individuals with antiphospholipi
d antibodies may be asymptomatic or present with venous or arterial th
rombosis. In this article I refer to inhibitors developing in patients
with hemophilia A or other congenital factor deficiency as alloantibo
dies, and to spontaneous formation of antibodies in patients without p
rior history of hemorrhagic diathesis as autoantibodies. The antiphosp
holipid antibodies are discussed separately.