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Klinisk Biokemi i Norden · 2 2017
Fiix-ing the prothrombin time to improve warfarin
anticoagulation
Pall T. Onundarson, M.D.
1,2
and Brynja R. Gudmundsdottir, M.S.1
1Landspitali National University Hospital of Iceland, Reykjavik, Iceland;
2University of Iceland, Faculty of Medicine, Reykjavik, Iceland.
Abstract
The Fiix-prothrombin time (Fiix-PT, Fiix-test) is a
new prothrombin time variant that is only affected
by reduced coagulation factor II and X activity but
not by the activity of factors VII, I or V.
Monitoring warfarin with the Fiix-PT stabilizes
warfarin anticoagulation, reduces dose adjustment
need and reduces thromboembolism compared to
PT/INR monitoring without increasing bleeding.
The results suggest that replacing the PT with a
test that is not sensitive to factor VII, such as the Fiix-
test, can improve warfarin anticoagulation stability
and outcome.
Background
The Quick prothrombin time (PT, Quick-PT) was
described in year 1935. It has remained an important
coagulation test ever since (1). The PT initially con-
sisted of adding tissue thromboplastin (consisting of
tissue factor and phospholipids derived from human
or animal brain, lung or placenta) and calcium chlo-
ride to a citrated plasma sample from a patient to
induce clotting and measuring the consequent clot-
ting time. Today, the thromboplastin is most com-
monly made from rabbit brain or it is replaced by a
mix of recombinant human tissue factor and natural
or synthetic phospholipids. Vitamin K antagonist
(VKA) anticoagulation, e.g. warfarin, is managed
by measuring the PT that is sensitive to reductions
in coagulation factors (F) II, VII and X activities
induced by the drug. The rationale is historical but
not biological.
When the PT was invented, deficiency in FI (fibri-
nogen) or FII (prothrombin) were found to explain its
prolongation as other coagulation factor deficiencies
had not been discovered. Accordingly, when the first
VKA, dicoumarol, was discovered in Wisconsin in
the United States of America in the early 1940´s, its
potency causing severe bleeding in cattle and pro-
longation of the PT was found to be consequent to
acquired severe deficiency of FII. Later in the 1940´s
other factors affecting the PT were described, i.e the
non-VKD factor V (2) and the vitamin K dependent
(VKD) FVII (3), followed in the 1950´s by the VKD
FX (4). Gradually it was realized that the VKA inhibit
liver gamma carboxylation of four vitamin K depen-
dent coagulation factors, i.e. (F) II, VII, IX and X (5).
Despite its importance for coagulation, FIX does not
affect the undiluted PT.
By purposely overdosing VKA and inducing fatal
hemorrhage, VKAs were initially used only as roden-
ticides. Soon, however, it became evident that the
VKA effect could measured and managed using the
Quick PT (1) or its later modification invented by Paul
Owren in Norway, the prothrombin-proconvertin
time (P&P test, Owren´s PT, also known as proth-
rombin complex test) (6). Consequently these tests
became the cornerstones of long-term anticoagula-
tion with VKA and have remained so for over six
decades. The PT and the P&P test are interchangea-
ble for the purpose of managing VKA although the
P&P test has advantages such as being less sensitive
to lupus anticoagulant and not beeing sensitive to
