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A Practical Guide to Haemostasis


Heparin Cofactor II [HCII]


Introduction

Heparin cofactor II (HCII) is a member of the SERPIN family of SERine Protease INhibitors and a specific inhibitor of Thrombin [Factor IIa].  The inhibitory activity of HCII is accelerated by Glycosaminoglycans [GAGs] including Dermatan Sulphate, Heparin and Heparan Sulphate.
HCII is synthesised primarily in the liver and the mature protein has a MW of 66.5 kDa, a half-life of ~ 2.5 days and a plasma concentration of 85 µg/mL. The gene for HCII, SERPIND1 maps to the long arm of chromosome 22 [ 22q11 ] and consists of 499 amino acids comprising a mature protein on 480 amino acids and a19 amino acid signal peptide.  Clearance of HCII is via the low-density lipoprotein receptor-related protein.

The physiological role of HCII is still unclear but a number of possibilities have been proposed:
  - HCII II may regulate extravascular Thrombin
  - HCII may have a role in the in regulation of acute inflammation and wound healing
  - Heparin cofactor II may also have a role in protection from thrombosis during pregnancy
  - Mice that lack HCII develop carotid arterial thromboses more rapidly than wild-type mice after oxidative damage to the endothelium. HCII may, therefore have a role in regulating the physiological response to arterial trauma/injury.

Inherited deficiencies of HCII have been reported and although in some cases it may be associated with an increased risk of venous thrombosis this is not always the case.


Principles & Methodology

Several approaches exist for the measurement of HCII.

i. ELISA Assay
A microtitre plate is coated with a a polyclonal antibody to HCII.  The diluted plasma sample is added and after washing bound HCII is detected using a horseradish peroxidase-conjugated antibody to HCII.

ii. Dermatan Sulphate HCII Assays
In the Dermatan Sulphate HCII Assay, Dermatan Sulphate is added to a plasma sample.  The Dermatan Sulphate binds specifically to HCII increasing its inhibitory activity to Thrombin.  Thrombin is added to the sample and the residual thrombin, after inactivation by HCII, is measured by means of a chromogenic substrate.  By comparison against a series of standards and test sample dilutions the HCII concentration in the plasma sample can be calculated. 

Reference Ranges

The normal range of HCII is 0.7-1.5 U/ml, as compared to a normal plasma pool containing by definition 1 U/ml.