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
High-Molecular Weight Kininogen [CO002500]
Synonyms HMWK, Fitzgerald Factor; HMW Kininogen; Williams-Fitzgerald-Flaujeac
Abstract High molecular weight kininogen (HMWK) is a coagulation
protein involved in the early stages of intrinsic pathway activation.
HMWK deficiency can cause a marked prolongation of the PTT, but
it does not cause bleeding. The same is true for factor XII deficiency
and prekallikrein deficiency.
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 test 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)
Special Instructions Patients cannot be on hirudin or argatroban
anticoagulation, which can interfere with mixing studies and HMWK
assays. Danaparoid may also interfere with these assays. If heparin
is present, notify the laboratory because heparin must be removed
prior to testing.
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 assay for HMWK (and prekallikrein) can be considered
when the following findings are present: 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.
Methodology A factor assay for HMWK can be performed which
is similar to other coagulation factor assays. Patient plasma is
mixed with HMWK-deficient plasma and a PTT is performed on the mixture.
The amount of HMWK in the patient plasma is determined from a standard
curve that plots known amounts of HMWK against PTT values.
Additional Information HMWK 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.
HMWK deficiency is rare and does not cause bleeding, despite PTT
prolongations. 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.2,3 Thus, factor XI can be activated
without the need for HMWK, prekallikrein, 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 HMWK may be found in liver disease
or disseminated intravascular coagulation (DIC).
1. Andrew M, Paes B, and Johnston M, "Development of the Hemostatic
System in the Neonate and Young Infant,"Am J Pediatr Hematol
2. Gailani D and Broze GJ, "Factor XI Activation in a Revised Model
of Blood Coagulation,"Science, 1991, 253(5022):909-12.
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.
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.