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.

Related Information

Activated Partial Thromboplastin Time
Coagulation Factor Assays
Mixing Studies
Prekallikrein

Synonyms HMWK, Fitzgerald Factor; HMW Kininogen; Williams-Fitzgerald-Flaujeac Factor

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.

Specimen Plasma

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).

Footnotes

1. Andrew M, Paes B, and Johnston M, “Development of the Hemostatic System in the Neonate and Young Infant,”Am J Pediatr Hematol Oncol, 1990,12(1):95-104.

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.

References

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.