Test Details
Methodology
Factor prekallikrein activity is determined utilizing an aPTT-based one-stage clotting time assay. Factor prekallikrein-depleted plasma is used as the substrate, and the clotting time with the patient plasma is compared to the clotting time of normal pooled plasma.
Result Turnaround Time
4 - 8 days
Turnaround time is defined as the usual number of days from the date of pickup of a specimen for testing to when the result is released to the ordering provider. In some cases, additional time should be allowed for additional confirmatory or additional reflex tests. Testing schedules may vary.
Use
This test is used for the measurement of prekallikrein factor activity.
Limitations
Plasmas deficient in FXII may give falsely low results. Lupus anticoagulants and other non-specific factor inhibitors may also interfere with this assay. Heparin, direct Xa or thrombin inhibitor therapy may have an effect on factor assays.
This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.
Custom Additional Information
The contact system is a group of plasma proteins that responds to the presence of pathophysiological materials and invasive pathogens. This system consists of three serine proteinases: coagulation factors XII (FXII) and XI (FXI), plasma prekallikrein (PK) and the nonenzymatic cofactor high molecular weight kininogen (HMWK).1 The contact system plays a role in coagulation, fibrinolysis, complement activation, inflammation and blood pressure regulation. HMWK is a multi-domain glycoprotein2-5 that circulates in plasma either in free form or in non-covalent complexes with the zymogens prekallikrein (PK) or factor XI (FXI).6,7 HMWK and PK, together with factor XII (FXII), comprise the kallikrein-kinin system (KKS).4,5,8 In plasma9,10 or on vascular endothelial cells,11,12 PK and FXII reciprocally convert each other to the proteases plasma kallikrein (PKa) and FXIIa. PKa cleaves HMWK at two sites, liberating the peptide bradykinin, which contributes to regulation of vascular permeability and tone by binding to specific receptors.2,3,5 When KKS proteins assemble on macro-molecules or surfaces, FXII undergoes autocatalytic activation and reciprocal activation with PK is enhanced in a process called contact activation.8,9,13 During contact activation, HMWK facilitates PK binding to the surface, in addition to serving as a PKa substrate.5,8,13 Contact activation-induced bradykinin production at injury sites likely contributes to swelling and pain sensation.14,15 Accelerated PKa and FXIIa generation in the disorder hereditary angioedema triggers episodes of bradykinin-induced soft tissue swelling.4,16-20
Prekallikrein (PK) is a glycoprotein involved in the intrinsic pathway of the coagulation system.21 PK is a glycoprotein synthesized in the liver with its gene located on chromosome 4.22 It circulates in the plasma bound to high molecular weight kallikrein (HMWK) with only 20% in free form. The inactive PK is converted to the active kallikrein by factor XIIa and also by the proteins derived from the endothelial cells.21 Kallikrein, in turn, regulates activation of factor XII to XIIa and the formation of bradykinin from HMWK before it is rapidly degraded in plasma by alpha-2 microglobulin and C1 esterase. Although not well characterized, PK is also believed to be implicated in the activation of plasminogen, decreasing blood pressure and increasing capillary permeability. There is data on both decreased and normal fibrinolytic activity with PK deficiency, but no clinically significant effects have been reported so far on blood pressure or capillary permeability.22
PK deficiency is an autosomal recessive disorder with more than seven different types of mutation identified by molecular genetic analysis.23 PK deficiency has been classified as type I and type II based on the level of activity and antigen. Type I, seen in 80% of cases, exhibits deficiency in both activity and antigen, whereas type II is associated with deficient activity and normal antigen levels. The exact prevalence of PK deficiency is unknown. Less than 100 cases have been reported in the literature.24 It is likely that it is underreported as it is not associated with bleeding, thrombosis or any other severe clinical symptoms.
In the majority of cases that have been reported, patients underwent numerous procedures without any bleeding complications.25,26 Although case reports exist where patients with bleeding were found to have PK deficiency, almost all of them are more than 20 years old when coagulation testing may have been incomplete. Some other case reports have also attributed PK deficiency to cases with arterial and venous thrombosis, but recent studies have suggested that most of these patients had other risk factors for thrombosis.25
PK deficiency largely presents as a marked elevation in aPTT with a normal PT/INR and thrombin time (TT).27 Bleeding, however, is not seen as factors downstream (factor XII, factor XI, etc.) can be auto-activated or activated by other factors like thrombin or factor II.28 Additionally, variation in PTT prolongation may be seen depending on the type of reagent used, (i.e., silica, ellagic acid or kaolin reagent).29
The prognosis of a patient with PK deficiency is the same as the normal patient population25; therefore, they do not require specific therapy. Its clinical significance is in patients on heparin treatment being monitored with the PTT since PK deficiency falsely elevates the PTT. Thus, anti-Xa level monitoring is recommended. Those with thrombosis are treated according to the guidelines for normal patients with similar thrombosis or thrombosis risk.
Recently, interest in contact phase defects has increased as plasma prekallikrein (PK), the main HMWK cleaving protease zymogen, represents a therapeutic target in hereditary angioedema.30,31
Specimen Requirements
Specimen
Plasma, frozen
Volume
1 mL
Container
Blue-top (sodium citrate) tube
Collection Instructions
Citrated plasma samples should be collected by double centrifugation. Blood should be collected in a blue-top tube containing 3.2% buffered sodium citrate.32 Evacuated collection tubes must be filled to completion to ensure a proper blood to anticoagulant ratio.33,34 The sample should be mixed immediately by gentle inversion at least six times to ensure adequate mixing of the anticoagulant with the blood. A discard tube is not required prior to collection of coagulation samples, except when using a winged blood collection device (i.e., "butterfly"), in which case a discard tube should be used.35,36 When noncitrate tubes are collected for other tests, collect sterile and nonadditive (red-top) tubes prior to citrate (blue-top) tubes. Any tube containing an alternate anticoagulant should be collected after the blue-top tube. Gel-barrier tubes and serum tubes with clot initiators should also be collected after the citrate tubes. Centrifuge for 10 minutes and carefully remove 2/3 of the plasma using a plastic transfer pipette, being careful not to disturb the cells. Deliver to a plastic transport tube, cap, and recentrifuge for 10 minutes. Use a second plastic pipette to remove the plasma, staying clear of the platelets at the bottom of the tube. Transfer the plasma into a Labcorp PP transpak frozen purple tube with screw cap (Labcorp No. 49482). Freeze immediately and maintain frozen until tested. To avoid delays in turnaround time when requesting multiple tests on frozen samples, please submit separate frozen specimens for each test requested.
Please print and use the Volume Guide for Coagulation Testing to ensure proper draw volume.
Reference Range
Adults: 50%−200%
Mild deficiency: 5−49
Severe deficiency: <5
Storage Instructions
Freeze. Stable at room temperature for four hours.
Patient Preparation
Do not draw from an arm with a heparin lock or heparinized catheter.
Footnotes
1. Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood. 1997 Nov 15;90(10):3819-3843. PubMed 9354649
2. Ponczek MB. High molecular weight kininogen: a review of the structural literature. Int J Mol Sci. 2021 Dec 13;22(24):13370. PubMed 34948166
3. Ponczek MB, Shamanaev A, LaPlace A, et al. The evolution of factor XI and the kallikrein-kinin system. Blood Adv. 2020 Dec 22;4(24):6135-6147. PubMed 33351111
4. Kaplan AP, Joseph K, Ghebrehiwet B. The complex role of kininogens in hereditary angioedema. Front Allergy. 2022 Aug 3;3:952753. PubMed 35991308
5. Sainz IM, Pixley RA, Colman RW. Fifty years of research on the plasma-kallikrein system: from protein structure and function to cell biology and in vivo-pathophysiology. Thromb Haemost. 2007 Jul;98(1):77-83. PubMed 17597995
6. Mandle RJ, Colman RW, Kaplan AP. Identification of prekallikrein and high-molecular-weight kininogen as a complex in human plasma. Proc Natl Acad Sci U S A. 1976 Nov;73(11):4179-4183. PubMed 1069308
7. Thompson RE, Mandle R, Kaplan AP. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest. 1977 Dec;60(6):1376-1380. PubMed 915004
8. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost. 2016 Jan;14(1):28-39. PubMed 26565070
9. Shamanaev A, Litvak M, Gailani D. Recent advances in factor XII structure and function. Curr Opin Hematol. 2022 Sep 1;29(5):233-243. PubMed 35916558
10. Ivanov I, Matafonov A, Sun MF, et al. Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood. 2017 Mar 16;129(11):1527-1537. PubMed 28069606
11. Joseph K, Nakazawa Y, Bahou WF, Ghebrehiwet B, Kaplan AP. Platelet glycoprotein Ib: a zinc-dependent binding protein for the heavy chain of high-molecular-weight kininogen. Mol Med. 1999 Aug;5(8):555-563. PubMed 10501658
12. Mahdi F, Madar ZS, Figueroa CD, Schmaier AH. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood. 2002 May 15;99(10):3585-3596. PubMed 11986212
13. Naudin C, Burillo E, Blankenberg S, Butler L, Renne T. Factor XII contact activation. Semin Thromb Hemost. 2017 Nov;43(8):814-826. PubMed 28346966
14. Margaglione M, D’Apolito M, Santocroce R, Maffione AB. Hereditary angioedema: Looking for bradykinin production and triggers of vascular permeability. Clin Exp Allergy. 2019 Nov;49(11):1395-1402. PubMed 31574187
15. Brusco I, Fialho MFP, Becker G, et al. Kinins and their B1 and B2 receptors as potential therapeutic targets for pain relief. Life Sci. 2023 Feb 1;314:121302. PubMed 36535404
16. Craig TJ, Reshef A, Li HH, et al. Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Apr 1;401(10382):1079-1090. PubMed 36868261
17. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020 Mar 19;382(12):1136-1148. PubMed 32187470
18. Cao H, Biondo M, Lioe H, et al. Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation. J Allergy Clin Immunol. 2018 Oct;142(4):1355-1358. PubMed 29936101
19. Banerji A, Busse P, Shennak M, et al. Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med. 2017 Feb 23;376(8):717-728. PubMed 28225674
20. Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol. 2010 Mar;104(3):192-204. PubMed 20377108
21. Riano I, Prasongdee K. A Rare Cause of Isolated Prolonged Activated Partial Thromboplastin Time: An Overview of Prekallikrein Deficiency and the Contact System. J Investig Med High Impact Case Rep. 2021 Jan-Dec;9:23247096211012187. PubMed 33940978
22. Bojanini EU, Loaiza-Bonilla A, Pimentel A. Prekallikrein deficiency presenting as recurrent cerebrovascular accident: case report and review of the literature. Case Rep Hematol. 2012;2012:723204. PubMed 22953077
23. Nakao T, Yamane T, Katagami T, et al. Severe prekallikrein deficiency due to a homozygous Trp499Stop nonsense mutation. Blood Coagul Fibrinolysis. 2011 Jun;22(4):337-339. PubMed 21415712
24. Dasanu CA, Alexandrescu DT. A case of prekallikrein deficiency resulting in severe recurrent mucosal hemorrhage. Am J Med Sci. 2009 Nov;338(5):429-430. PubMed 19773642
25. Girolami A, Rolland C, Sexton D, Vardi M, Bernstein JA. Long-term safety outcomes of prekallikrein (Fletcher factor) deficiency: A systematic literature review of case reports. Allergy Asthma Proc. 2020 Jan 17;41(1):10-18. PubMed 31888778
26. Unal S, Jariwala PD, Mahoney DH, Teruya J. A challenging diagnosis of homozygous prekallikrein deficiency during the preoperative evaluation of an infant with intractable seizures: a literature review of surgical management in this disorder. Lab Med. 2010;41:271-274.
27. Kamal AH, Tefferi A, Pruthi RK. How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults. Mayo Clin Proc. 2007 Jul;82(7):864-873. PubMed 17605969
28. Asmis LM, Sulzer I, Furlan M, Lammle B. Prekallikrein deficiency: the characteristic normalization of the severely prolonged aPTT following increased preincubation time is due to autoactivation of factor XII. Thrombosis Res. 2002 Mar 15;105(6):463-470. PubMed 12091043
29. LaDuca FM, Tourbaf KD. Fletcher factor deficiency, source of variations of the activated partial thromboplastin time test. Am J Clin Pathol. 1981 Apr;75(4):626-628. PubMed 6908796
30. Martello JL, Woytowish MR, Chambers H. Ecallantide for treatment of acute attacks of hereditary angioedema. Am J Health Syst Pharm. 2012 Apr 15;69(8):651-657. PubMed 22472866
31. Fijen LM, Riedl MA, Bordone L, et al. Inhibition of prekallikrein for hereditary angioedema. N Engl J Med. 2022 Mar 17;386(11):1026-1033. PubMed 35294812
32. Adcock DM, Kressin DC, Marlar RA. Effect of 3.2% vs 3.8% sodium citrate concentration on routine coagulation testing. Am J Clin Pathol. 1997;107(1):105-110. PubMed 8980376
33. Reneke J, Etzell J, Leslie S, Ng VL, Gottfried EL. Prolonged prothrombin time and activated partial thromboplastin time due to underfilled specimen tubes with 109 mmol/L (3.2%) citrate anticoagulant. Am J Clin Pathol. 1998 Jun;109(6):754-757. PubMed 9620035
34. National Committee for Clinical Laboratory Standardization. Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline. 5th ed. Villanova, Pa: NCCLS; 2008. Document H21-A5:28(5).
35. Gottfried EL, Adachi MM. Prothrombin time and activated partial thromboplastin time can be performed on the first tube. Am J Clin Pathol. 1997 Jun;107(6):681-683. PubMed 9169665
36. McGlasson DL, More L, Best HA, Norris WL, Doe RH, Ray H. Drawing specimens for coagulation testing: Is a second tube necessary? Clin Lab Sci. 1999 May-Jun;12(3):137-139. PubMed 10539100
LOINC® Map
| Order Code | Order Code Name | Order Loinc | Result Code | Result Code Name | UofM | Result LOINC |
|---|---|---|---|---|---|---|
| 086075 | Prekallikrein Factor | 52759-8 | 086076 | Prekallikrein Factor | % | 52759-8 |
| Order Code | 086075 | |||||
| Order Code Name | Prekallikrein Factor | |||||
| Order Loinc | 52759-8 | |||||
| Result Code | 086076 | |||||
| Result Code Name | Prekallikrein Factor | |||||
| UofM | % | |||||
| Result LOINC | 52759-8 |