From: Elizabeth M. Van Cott, M.D., and Michael Laposata, M.D., Ph.D., "Coagulation." In: Jacobs DS et al, ed. The Laboratory Test Handbook, 5th Edition. Lexi-Comp, Cleveland, 2001; 327-358.
Index of Tests
Synonyms Fletcher Factor
Applies to Kallikrein
Abstract Prekallikrein is a coagulation protein involved
in the early stages of intrinsic pathway activation. Prekallikrein
deficiency can cause a marked prolongation of the PTT, but it does
not cause bleeding. The same is true for factor XII deficiency and
high-molecular weight kininogen (HMWK) deficiency.
Patient Preparation Patients cannot be on hirudin or argatroban
anticoagulation, which can interfere with mixing studies and PTT-based
prekallikrein assays. Danaparoid may also interfere with these assays.
If heparin is present, notify the laboratory because heparin must
be removed prior to testing.
Container One blue top (sodium citrate) tube
Collection Routine venipuncture. If multiple tests are being
drawn, draw blue top tubes after any red top tubes but before any
lavender top (EDTA), green top (heparin), or gray top (oxalate/fluoride)
tubes. Immediately invert tube gently at least 4 times to mix. Tubes
must be appropriately filled. Deliver tubes immediately to the laboratory.
Storage Instructions Separate plasma from cells as soon as
possible. If assay is not performed within 4 hours, freeze plasma
Causes for Rejection Specimen received more than 4 hours
after collection, tubes not filled, clotted specimens
Turnaround Time Less than 1 day (longer if test is a send-out)
Reference Interval 60% to 140% of normal. Newborns have lower
levels than adults; the values increase to near adult normal range
by age 6 months.1
Use May be performed when a routine prolonged PTT evaluation
finds no explanation for the prolongation (see Mixing
Studies). The PTT is normal in the mixing study; factors VIII,
IX, XI, and XII are normal; the PT and fibrinogen are normal; and
lupus anticoagulant assays are negative. If prekallikrein assays
are normal, HMWK assays may be considered.
Screening assay: Preincubate a PTT test sample for 10 minutes
prior to adding calcium. A prolonged PTT that shortens after the
10-minute incubation is suspicious for a prekallikrein deficiency.
In addition, if a PTT is performed with ellagic acid as the intrinsic
pathway activator, the PTT will usually be normal in prekallikrein
Specific factor assay for prekallikrein: Can be performed
similar to other coagulation factor assays. Patient plasma is mixed
with prekallikrein-deficient plasma and a PTT is performed on the
mixture. The amount of prekallikrein in the patient plasma is determined
from a standard curve that plots known amounts of prekallikrein
against PTT values. Note: PTT tests are normally incubated
for 3 minutes prior to adding calcium. When using the PTT in a prekallikrein
factor assay, the incubation period is shortened to 1 minute.2 A chromogenic prekallikrein assay is also available.
Additional Information Prekallikrein is one of the contact
factors that participates in the activation of the intrinsic pathway
of coagulation when blood is exposed to a negatively charged foreign
surface. With contact activation, activated factor XII (XIIa) converts
prekallikrein into kallikrein. Kallikrein then activates more factor
XII. HMWK acts as a cofactor in both of these reactions. HMWK also
acts as a cofactor in the activation of factor XI by factor XIIa.
Kallikrein releases bradykinin from HMWK, which has vasoactive activities.
Fibrinolysis is also activated by contact activation. Recent evidence
suggests that, in vivo, activation of prekallikrein occurs
before activation of factor XII.
Prekallikrein deficiency is rare and does not cause bleeding, despite
prolongation of the PTT. The lack of bleeding is presumably because
the extrinsic pathway of coagulation, via factor VII and tissue
factor, remains intact, and factor XI can be activated by thrombin
generated from the extrinsic pathway.3,4 Thus, factor
XI can be activated without the need for prekallikrein, HMWK, or
factor XII. This is consistent with the observation that deficiencies
of the latter three factors are not associated with bleeding.
Acquired, usually mild-to-moderate decreases in prekallikrein may
be found in liver disease or disseminated intravascular coagulation
(DIC). Rarely, a prekallikrein inhibitor (antibody) has been reported.5
1. Andrew M, Paes B, and Johnston M, "Development of the Hemostatic
System in the Neonate and Young Infant,"Am J Pediatr Hematol
2. Sibley C and Evatt BL, "Laboratory Suggestions: Improving the
Sensitivity of the Fletcher Factor Assay,"Am J Clin Pathol,
3. Naito K and Fujikawa K, "Activation of Human Blood Coagulation
Factor XI Independent of Factor XII. Factor XIa Is Activated by
Thrombin and Factor XIa in the Presence of Negatively Charged Surfaces,"J
Biol Chem, 1991, 266(12):7353-8.
4. Gailani D and Broze GJ, "Factor XI Activation in a Revised Model
of Blood Coagulation,"Science, 1991, 253(5022):909-12.
5. Page JD, DeLa Cadena RA, Humphries JE, et al, "An Autoantibody
to Human Plasma Prekallikrein Blocks Activation of the Contact System,"Br
J Haematol, 1994, 87(1):81-6.
Sanfelippo MJ, Carafo AJ, and Hollister WN, "APTT Prolonged by
Prekallikrein Deficiency,"Lab Med, 1998, 29(5):274-6.
Schmaier AH, Rojkjaer R, and Shariat-Madar Z, "Activation of the
Plasma Kallikrein/Kinin System on Cells: A Revised Hypothesis,"Thromb
Haemost, 1999, 82(2):226-33.