Activated protein C resistence screening

Screening for activated protein C resistance (APCR ) consists of measuring paired APTT clotting times for test plasma, one with and the other without exogenous activated protein C (APC). An index of in vitro APCR is obtained by dividing the clotting time of the APTT with APC by that of the APTT without APC, a reduced ratio being indicative of APCR. This ‘Classic’ APCR method is sensitive to acquired and hereditary APCR but prone to interference by other causes of elevated clotting times. Our laboratories additionally employ the ‘Modified’ APCR, which is performed similarly except that the test plasma is diluted 1+4 in FV deficient plasma and coagulation is triggered by the addition of noscarin. Noscarin is a FVa-dependent and phospholipid & calcium ion independent prothrombin activator from Tiger snake (Notechis scutatus) venom, making the assay almost 100% sensitive & specific for FV mutations conferring ACPR whilst rendering it largely insensitive to acquired APCR. All abnormal APCR results are accompanied by an interpretive report.
Clinical details: 
Down-regulation of blood coagulation within a forming clot is accomplished by the protein C anticoagulant pathway. The essential co-factors FVa and FVIIIa are degraded through proteolytic cleavage by activated protein C (APC). Protein C is activated by thrombin in complex with thrombomodulin, a transmembrane endothelial cell protein.Activated protein C resistance (APCR) is defined as a poor anticoagulant response of plasma to APC and has both hereditary and acquired causes. More than 90% of hereditary cases are due to the FV Leiden (FVL) point mutation which results in an impaired inactivation rate of FVa due to alteration of a protein C cleavage site. Native FVa is an important procoagulant co-factor to FXa in the prothrombinase complex and the result of the mutation is that thrombin formation will not be stopped as efficiently as in the case of inactivation of native FVa. Compared to individuals with a normal FV genotype, heterozygosity for the mutation confers about a 5 – 10 fold higher thrombotic risk. Other FV mutations conferring at least in vitro APCR include FV Cambridge and FV Hong Kong. No mutations in the FVIII gene conferring APCR have been described. Acquired APCR has been described in association with pregnancy, high FVIII levels, antiphospholipid antibodies and use of the oral contraceptive pill.
Reference range: 

Classic APCR reference ranges are sex & reagent batch specific. For modified APCR Ratio >3.0

Sample type and Volume required: 
External requests: Citrated platelet poor plasma
800µL x 2 aliquots
Internal requests: please refer to EPR label
Turnaround time: 
7 - 12 days
Special sample instructions: 

The sample should be analysed or processed & stored within 4 hours of venepuncture. Please ensure sample tubes are filled exactly to the fill-line as underfilling or overfilling creates a dilution error and leads to inaccurate results.

Storage and transport: 
It is advised that citrated plasma is frozen prior to transport and sent to the laboratory on dry ice to maintain sample quality and integrity.
Diagnostic Haemostasis and Thrombosis Department
020 7188 2797
St Thomas' Hospital
North Wing - 4th and 5th Floors
Westminster Bridge Road
London SE1 7EH

Laboratory opening times
For clinical advice or interpretation of results, please contact the laboratory in the first instance.

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Last updated: 09/07/2021