Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications

Figures & data

Table 1 Different manifestations of congenital protein C deficiency

Zygosity	Frequency
Type I heterozygous	76%
Type II heterozygous	12%
Type I homozygous	5%
Type II homozygous	0.6%
Type I mixed heterozygous	3%
Type II mixed heterozygous	0.6%
Type I/II mixed heterozygous	1.5%
Unknown	1.3%

Note: Analysis of 320 patients.

Table 2 Types of mutations in the protein C gene causing protein C deficiency

Mutation	Frequency n (%)
Missense/nonsense	170 (72.0)
Splicing	22 (9.3)
Regulatory	11 (4.7)
Small deletions	20 (8.5)
Small insertions	10 (4.2)
Small indels	1 (0.4)
Gross deletions	2 (0.8)
Gross insertions	0
Complex rearrangements	0
Repeat variations	0
Total	236

According to the Human Gene Mutation Database at Institute of Medical Genetics in Cardiff (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PROC).

Table 3 Types and diagnosis of protein C deficiency

Deficiency	Protein C activity (function)	Protein C antigen (proteinconcentration)
Heterozygous
Type I	decreased (about 0.5 IU/mL)	decreased (about 0.5 IU/mL)
Type II	decreased (about 0.5 IU/mL)	normal
Homozygous
Type I	severely decreased (<0.02 IU/mL)	severely decreased (<0.02 IU/mL)
Type II	severely decreased (<0.02 IU/mL)	normal/moderately decreased

Figure 1a Five-day-old newborn with homozygous protein C deficiency and purpura fulminans. Irregularly formed hypoperfused or necrotic skin lesions surrounded by an inflammatory border.

Figure 1b The same child 6 days after beginning of protein C replacement with Ceprotin®.

Figure 1c The same child 2 months later. All figures from Dreyfus M, Masterson M, David M, et al 1995. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Haemost, 21:371–81. Copyright © 1995. Reprinted by permission Thieme Publishers.

Table 4 Therapeutic options for severe (homozygous or mixed heterozygous) protein C deficiency

• Plasma-derived protein C zymogen concentrates

(Ceprotin®, Protexel®)

60–80 IU/kg body weight slow i.v. bolus every 6 hours

(maximum rate 2 mL/min in adults or 0.2 ml/min in children <10 kg)

Target: post-infusion plasma protein C activity 1.0 IU/mL, pre-infusion plasma protein C activity >0.25 IU/mL

Alternative regimen:

100 U/kg slow i.v. bolus, followed by 10 IU/kg/h continuous infusion

Target: plasma protein C activity 1.0 IU/mL

• Fresh frozen plasma

20–30 mL/kg i.v. every 6 hours

• Activated human protein C – drotrecogin alpha activated (Xigris^®)

20 μg/kg/hour for >10 hours?

not approved for substitution therapy of congenital protein C deficiency

After symptoms have resolved:

Vitamin K antagonist therapy – warfarin

Slow initiation, overlapping with protein C substitution

Table 5 Therapeutic options for heterozygous protein C deficiency

Asymptomatic carrier

No long-term therapy

Prolonged / intensified prophylaxis of thromboembolic events (with LMWH) in risk situations

Patients with first thromboembolic event

Therapeutic (full-dose) anticoagulation with LMWH

Overlapping slow initiation of warfarin (target INR 2.0–3.0) for 6–12 months

Recurrent thromboembolic events

Therapeutic (full-dose) anticoagulation with LMWH

Overlapping slow initiation of long-term warfarin therapy (target INR 2.0–3.0)

Cases of coumarin-induced skin necrosis

Therapeutic (full-dose) anticoagulation with LMWH or UFH

Protein C concentrate (Ceprotin^® initial dose 60 IU/kg every 6 h)

Target plasma protein C activity: post-infusion 1.0 IU/mL and pre-infusion

>0.25 IU/mL

Drotrecogin alpha activated (not approved)

overlapping slow initiation of warfarin therapy (target INR 2.0–3.0)

Abbreviations: INL, international normalized ratio; LMWH = low molecular weight heparin; UFH = unfractionated (standard) heparin.

DreyfusMMastersonMDavidM1995Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiencySemin Thromb Hemost21371818747700

 PubMed Web of Science ®Google Scholar