Case Study: Protein C and S

Case Study: Protein C and S
Aug 29, 2010 7:58pm

A 17-month old child suffered a stroke in July of 2010. The results of a specimen collected ten days after the event showed that his protein C and protein S activities were 54% and 40%. Reference intervals for a child over 1 year old are the same as adults: 65% to 140% for protein C and 70% to 140% for protein S. An MRI revealed a previous stroke and the neurologist concluded the child had combined inherited protein C and protein S deficiencies. However, repeat assays performed one month after the stroke were 79% and 74%. What happened?

The prevalence of hereditary protein C deficiency in the community is 1 in 300, and protein S, 1 in 1000, so the likelihood of a patient possessing both deficiencies is 1 in 300,000. In 2004, however, Dr. Marisa Marques and I reviewed five years of laboratory data and found that nearly 20% of thrombophilia profiles turn up a combined protein C and protein S deficiency. This is an error of timing, and illustrates the need for education that helps us avoid an erroneous diagnosis. Laboratory practitioners know that proteins C and S are vitamin K-dependent, and that their activity is reduced in warfarin therapy. They also drop during or following a thrombotic event, and protein S activity at least, is low during inflammation and pregnancy.

laboratory directors regularly remind physicians that specimens for proteins C and S and for antithrombin activity and antigen assays must be collected at least ten days after warfarin is discontinued and at least ten days after resolution of a clotting episode to accurately identify a genetic deficiency. Positive results should be repeated once after a period of several weeks, and first-degree relatives should be tested to confirm the deficiency is hereditary.

Can you provide anecdotes about situations you have experienced in which a patient believes they have a combined protein C and S deficiency? Please respond in our comments section. Geo.

 

6 Comments

A 17-month old child suffered a stroke in July of 2010. The results of a specimen collected ten days after the event showed that his protein C and protein S activities were 54% and 40%. Reference intervals for a child over 1 year old are the same as adults: 65% to 140% for protein C and 70% to 140% for protein S. An MRI revealed a previous stroke and the neurologist concluded the child had combined inherited protein C and protein S deficiencies. However, repeat assays performed one month after the stroke were 79% and 74%. What happened?

The prevalence of hereditary protein C deficiency in the community is 1 in 300, and protein S, 1 in 1000, so the likelihood of a patient possessing both deficiencies is 1 in 300,000. In 2004, however, Dr. Marisa Marques and I reviewed five years of laboratory data and found that nearly 20% of thrombophilia profiles turn up a combined protein C and protein S deficiency. This is an error of timing, and illustrates the need for education that helps us avoid an erroneous diagnosis. Laboratory practitioners know that proteins C and S are vitamin K-dependent, and that their activity is reduced in warfarin therapy. They also drop during or following a thrombotic event, and protein S activity at least, is low during inflammation and pregnancy.

laboratory directors regularly remind physicians that specimens for proteins C and S and for antithrombin activity and antigen assays must be collected at least ten days after warfarin is discontinued and at least ten days after resolution of a clotting episode to accurately identify a genetic deficiency. Positive results should be repeated once after a period of several weeks, and first-degree relatives should be tested to confirm the deficiency is hereditary.

Can you provide anecdotes about situations you have experienced in which a patient believes they have a combined protein C and S deficiency? Please respond in our comments section. Geo.

 

By MR VILAS HIREMATH
Aug 29, 2010 10:18pm
Dear Geo,
PC and PS are both low by clot based assay as they are influenced by acute phase. So repeat PC by chromogenic assay will overcome false underestimation. PS is very notorious test to do no matter which kit used. Free PS should be choice of test.

with regards

Vilas Hiremath,
Bangalore India

Hello, Vilas Hiremath, let me expand on this question. Actually, both the chromogenic and the clot-based protein C and protein S are reduced in acute phase, meaning they are likely to be low when measured during or within a few days after a thrombotic event. Likewise, PC and PS antigens, when measured by immunoassay techniques, are reduced. For an accurate PC and PS, the specimen should be collected at least 14 days following resolution of the thrombotic event and at a time that the patient is not receiving warfarin anticoagulant therapy, if deemed safe by the physician.

By the way, you will find there are some clot-based protein C and protein S assays that generate acceptable percent coefficient of variation (%CV) values when performed on an automated instrument. For instance, CryoCheck Protein S from Precision Biologic generates an inter-assay CV% of 6.7% in the normal range and 7.9% among abnormals. These %CVs closely approximate those of chromogenic substrate techniques.
By Dr Emmanuel Favaloro
Sep 1, 2010 8:06am
In addition to 'acute phase' events, there are many alternate possibilities and preanalytical issues to consider. Congenital Protein C deficiencies are rare; Congenital Protein S deficiencies are rare; I couldn't guess at the likelihood of a combined congenital Protein C and S deficiency. Combined Protein C and S deficiency events are much more likely to be acquired events or caused by preanalytical variables; apart from acute phase/consumption events, did you rule out a liver dysfunction or vitamin K deficiency? An underfilled coag tube (very common in paediatric collections) would also generate a false low Protein C and S event.
By MR VILAS HIREMATH
Sep 4, 2010 3:12am
Dear George,
APCR :whether PT based or APTT based better.
when both PC and APCR are both abnormal off anticoagulation.how do you interprete.
please comment

with regards
Vilas Hiremath
By Sosier
Sep 29, 2010 5:01am
How about coumadin toxicity (i.e.overdose)?
By POWENS
Oct 6, 2010 8:32am
Geo et al,
We would disagree with the statement that Protein C levels in infants and children up to 1 year old are the same as adults. The sources we have read state that PC levels do not reach adult levels until puberty. The latest we have seen is from Haemophilia 2008;14,1214-1221 by NA Goldberg and MJ Manco-Johnson. We caution our clinicians against making a diagnosis of deficiency in infants and children. We would appreciate your comments. Thanks, Pam and Kelly, TriCore Reference Labs.
By George Fritsma
Oct 11, 2010 2:02pm
My thanks to Pam Owens and Kelly Townsend. The article they reference contains this statement, "Levels of protein C mature later than many other coagulation proteins. The mean plasma concentration of protein C in a healthy term infant is 40 Units/dL... Protein C concentration increases from birth until 6 months of age when the 50th percentile of pediatric levels is equivalent to the 10th percentile of healthy adults (approximately 60 Units/dL). Protein C concentration remains slightly low through childhood and achieves the adult range after puberty."

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