scholarly journals Case Report: Successful Long-Term Management of a Low-Birth Weight Preterm Infant With Compound Heterozygous Protein C Deficiency With Subcutaneous Protein C Concentrate Up to Adolescence

2021 ◽  
Vol 9 ◽  
Author(s):  
Johannes Pöschl ◽  
Wolfgang Behnisch ◽  
Bernd Beedgen ◽  
Navina Kuss
Keyword(s):  
Cesarean Section ◽  
Vitamin K ◽  
Protein C ◽  
Vitamin K Antagonists ◽  
Compound Heterozygous ◽  
Protein C Deficiency ◽  
Protein C Concentrate ◽  
Protein C Activity ◽  
Heterozygous Protein C Deficiency

Homozygous/compound heterozygous forms of congenital protein C deficiency are often associated with severe antenatal and postnatal thrombotic or hemorrhagic complications. Protein C deficiency frequently leads to severe adverse outcomes like blindness and neurodevelopmental delay in children and may even lead to death. The most widely used long-term postnatal treatment consists of oral anticoagulation with vitamin K antagonists (e.g., warfarin), which is supplemented with protein C concentrate in acute phases. Subcutaneous infusions have been described in infants mostly from 2 months of age after severe postnatal thrombosis, but not in newborns or premature infants without thromboembolism. We report the first case of a compound heterozygous protein C-deficient preterm infant, born at 31+5 weeks of gestation to parents with heterozygous protein C deficiency (protein C activity 0.9% at birth). We focus on both prenatal and perinatal management including antithrombotic treatment during pregnancy, the cesarean section, and continuous postnatal intravenous and consecutive subcutaneous therapy with protein C concentrate followed by a change of therapy to direct oral anticoagulants (DOACs) (apixaban). We report successful home treatment with subcutaneous protein C concentrate substitution overnight (target protein C activity >25%) without complication up to 12.5 years of age. We propose that early planned cesarean section at 32 or preferably 34 weeks of gestation limits potential maternal side effects of anticoagulation with vitamin K antagonists and reduces fetal thromboembolic complications during late pregnancy. Intravenously administered protein C and early switch to subcutaneous infusions (reaching about 3 kg body weight) resulted in sufficient protein C activity and has guaranteed an excellent quality of life without any history of thrombosis for 13 years now. In older children with protein C deficiency, as in our case, DOACs could be a new therapeutic option.

scholarly journals Fetal Effects of Coumadin Administered During Pregnancy

Blood ◽  
1970 ◽  
Vol 36 (5) ◽  
pp. 623-627 ◽  
Author(s):  
J. HIRSH ◽  
J. F. CADE ◽  
A. S. GALLUS
Keyword(s):  
Cesarean Section ◽  
Vitamin K ◽  
Early Pregnancy ◽  
Vitamin K Antagonists ◽  
Practical Method ◽  
Coagulation Factors ◽  
Coagulation Defect ◽  
In Pregnancy

Abstract The safest and most practical method of administering long-term anticoagulants in pregnancy is uncertain because treatment of the mother with vitamin K antagonists may be complicated by hemorrhage in the fetus. The effects on the fetus of giving coumadin in pregnancy was evaluated in rabbits. When coumadin was given from early pregnancy until term, all of the fetuses were stillborn with widespread hemorrhages. However, the fetuses were born alive and without hemorrhage when (1) coumadin was stopped 4-5 days before delivery, at which time the level of coagulation factors had almost returned to normal and (2) when delivery was performed by cesarean section at a time when the fetal coagulation defect was severe. It is suggested that the risk of fetal hemorrhage is high only when fetuses with a severe coagulation defect are exposed to the trauma of delivery.

Compound Heterozygous Protein C Deficiency Caused by Two Mutations, Arg-178 to Gin and Cys-331 to Arg, Leading to Impaired Secretion of Mutant Protein C

1994 ◽  
Vol 72 (06) ◽  
pp. 814-818 ◽  
Author(s):  
Yuichi Sugahara ◽  
Osamu Miura ◽  
Shinsaku Hirosawa ◽  
Nobuo Aoki
Keyword(s):  
Disulfide Bond ◽  
Protein C ◽  
Catalytic Domain ◽  
Point Mutations ◽  
Expression Vectors ◽  
Compound Heterozygous ◽  
Protein C Deficiency ◽  
Peptide Cleavage ◽  
Mutant Proteins ◽  
Heterozygous Protein C Deficiency

SummaryThe protein C gene in a patient apparently homozygous for protein C deficiency was analyzed. Two different point mutations, each located in a different allele, were detected to reveal that the patient is a compound heterozygote. Mutation of Arg-178 (CGG) to Gin (CAG) [mutation I] was detected in exon VII, in the vicinity of activation peptide cleavage site by thrombin. Mutation of Cys-331 (TGC) to Arg (CGC) [mutation II] was found in exon IX, at one of the sites involved in disulfide bond formation in the catalytic domain of the heavy chain. The alteration of Cys-331 to Arg disables the formation of the disulfide bond and would alter the protein conformation. Transient expression assays using COS-7 cells transfected with protein C expression vectors containing each one of these two mutations suggested that each of the two mutations would lead to the protein C deficiency by an impairment of secretion of the respective mutant proteins.

scholarly journals Different impact of two mutations of a novel compound heterozygous protein C deficiency with late onset thrombosis

2014 ◽  
Vol 13 (2) ◽  
pp. 2969-2977 ◽  
Author(s):  
L.-H. Yang ◽  
M.-S. Wang ◽  
F.-X. Zheng ◽  
J. Li ◽  
Y. Chen ◽  
...  
Keyword(s):  
Protein C ◽  
Late Onset ◽  
Compound Heterozygous ◽  
Protein C Deficiency ◽  
Heterozygous Protein C Deficiency

scholarly journals Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1159-1164 ◽  
Author(s):  
J Conard ◽  
KA Bauer ◽  
A Gruber ◽  
JH Griffin ◽  
HP Schwarz ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Purpura Fulminans ◽  
Coagulation Activation ◽  
Protein C Deficiency ◽  
Protein C Concentrate ◽  
System Activation ◽  
Heterozygous Protein C Deficiency ◽  
Sustained Increase

Homozygous or double heterozygous protein-C deficiency can present at birth with purpura fulminans or later in life with venous thrombosis. Two homozygous patients who had previously sustained thrombotic episodes were investigated at a time when they were asymptomatic and not receiving antithrombotic therapy. The plasma levels of protein-C antigen and activity in both individuals were approximately 20% of normal. We administered a highly purified plasma-derived protein C concentrate to these individuals and monitored levels of several markers of in vivo coagulation activation. Assays for protein-C activation (activated protein C and protein C activation peptide) showed a sustained increase from reduced baseline levels, whereas thrombin generation (as measured by prothrombin fragment F1 + 2) gradually decreased over about 24 hours into the normal range. These investigations provide direct evidence that protein C is converted to activated protein C in vivo, and that the protein-C anticoagulant pathway is a tonically active mechanism in the regulation of hemostatic system activation in humans.

scholarly journals Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1159-1164 ◽  
Author(s):  
J Conard ◽  
KA Bauer ◽  
A Gruber ◽  
JH Griffin ◽  
HP Schwarz ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Purpura Fulminans ◽  
Coagulation Activation ◽  
Protein C Deficiency ◽  
Protein C Concentrate ◽  
System Activation ◽  
Heterozygous Protein C Deficiency ◽  
Sustained Increase

Abstract Homozygous or double heterozygous protein-C deficiency can present at birth with purpura fulminans or later in life with venous thrombosis. Two homozygous patients who had previously sustained thrombotic episodes were investigated at a time when they were asymptomatic and not receiving antithrombotic therapy. The plasma levels of protein-C antigen and activity in both individuals were approximately 20% of normal. We administered a highly purified plasma-derived protein C concentrate to these individuals and monitored levels of several markers of in vivo coagulation activation. Assays for protein-C activation (activated protein C and protein C activation peptide) showed a sustained increase from reduced baseline levels, whereas thrombin generation (as measured by prothrombin fragment F1 + 2) gradually decreased over about 24 hours into the normal range. These investigations provide direct evidence that protein C is converted to activated protein C in vivo, and that the protein-C anticoagulant pathway is a tonically active mechanism in the regulation of hemostatic system activation in humans.

Idiopathic venous thrombosis

2006 ◽  
Vol 26 (01) ◽  
pp. 52-54 ◽  
Author(s):  
P. A. Kyrle
Keyword(s):  
Chronic Disease ◽  
Venous Thrombosis ◽  
Vitamin K ◽  
Clinical Benefit ◽  
Plasma Levels ◽  
Vitamin K Antagonists ◽  
Antithrombin Deficiency ◽  
Optimal Duration ◽  
Risk Of Treatment

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

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