Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency.

Protein C replacement therapy with a monoclonal antibody purified, virus inactivated protein C concentrate was carried out in nine infants (three male, six female) with severe congenital protein C deficiency and life-threatening purpura fulminans and/or thrombosis associated with disseminated intravascular coagulation (DIC). Eight infants were homozygous for protein C deficiency; one was a compound heterozygote. The treatment period varied from 22 days to three years. The half-life of protein C was found to be as short as two to three hours during activation of the coagulation system, increasing to approximately ten hours after stabilization. During the acute phase, protein C levels of 0.10 to 0.25 IU/mL were associated with elevated markers of coagulation activation indicating DIC, while protein C levels greater than 0.25 were associated with normalization of coagulation markers. No product-related side effects were reported. Episodes of bleeding or purpura recurred in all patients who were switched to oral anticoagulant therapy, necessitating reinstatement of protein C replacement therapy, either as needed to control symptoms, or on a long-term prophylactic schedule, alone or in addition to oral anticoagulation. Home treatment with protein C concentrate allowed a near-normal life-style for patients who otherwise would be hospitalized for long periods of time.

Homozygous type I protein C deficiency in two unrelated families exhibiting thrombophilia related to Ala136-->Pro or Arg286-->His mutations.

Separate single nucleotide mutations have been identified in two unrelated homozygous type I protein C deficient individuals suffering from thrombophilia. Each mutation, initially established by direct DNA sequencing of polymerase chain reaction amplification products, results in an amino acid substitution. The first mutation (PCClamart) results in an Ala136 to Pro substitution in the protein's second epidermal growth factor-like domain. The second mutation (PCMünchen) results in an Arg286 to His substitution in the serine protease domain. Comparison of the location of these two mutations and the relative conservation of the two regions in homologous vitamin K-dependent plasma proteins is consistent with the difference in severity of protein C deficiency and disease in the two individuals. Both mutations result in the abolition of a naturally occurring restriction endonuclease site, thereby allowing independent confirmation of the mutations and rapid and unambiguous genetic analysis of protein C deficiency in family members. In both families, the genetic analysis has proven useful in cases where an assignment of the protein C status based upon clinical laboratory measurements was either ambiguous or incorrect.

A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk pregnancy.

A novel homozygous mutation in the protein C (PROC) gene was detected in an individual with severe type I protein C deficiency who presented with neonatal Purpura fulminans. The deletion/insertion mutation found [3351del4, 3350insA] resulted in an Asn102-->Lys substitution and the removal of codon Gly103. First trimester prenatal diagnosis was performed in a subsequent pregnancy by chorionic villus sampling and PCR/direct sequencing; the foetus was shown to be heterozygous for the lesion. This diagnosis was confirmed phenotypically after the birth of a clinically healthy child.

A novel homozygous missense mutation (Val 325-->Ala) in the protein C gene causing neonatal purpura fulminans.

A novel homozygous GTG-->GCG (Val 325-->Ala) substitution was detected in the protein C gene of a newborn causing severe purpura fulminans post partum. In the consanguineous parents and two further infants a heterozygous type 1 protein C deficiency was found. Up to now the heterozygous individuals are clinically unaffected. The mutation co-segregates with the protein C deficiency state. It creates a restriction enzyme (Sac II) cleavage site.

Neonatal thrombocytopenia in HLA-DR, -DQ, -DP-typed mother due to rare anti-HPA-1b (PLA2) (Zwb) fetomaternal immunization.

A new case of rare neonatal alloimmune thrombocytopenia, due to an IgG anti-HPA-1b in a mother HPA-1 (a+, b-), was diagnosed using monoclonal antibody-specific immobilization of platelet antigens. Clinically, it was similar to the 2 previously reported observations and confirmed that, in this particular case of anti-HPA-1b, the treatment with random platelet pools may be as effective as selected single-donor platelet units when maternal platelets are unusable. The HLA-DR, -DQ, -DP genotypes of the family were obtained by PCR-SSO. The mother's typing, compared to the HLA-DR of the 6 similar cases reported in Europe, suggests that a combined effect of two rare HLA haplotypes might enhance this immunization.

Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies.

Homozygous protein C deficiency or homozygous protein S deficiency are rare genetic diseases with catastrophic and fatal purpura fulminans-like or thrombotic complications occurring during the neonatal period. These diseases can now be successfully treated. Purpura fulminans is at least in part a cutaneous manifestation of the syndrome of systemic DIC. It is characterized by microvascular thrombosis in the dermis followed by perivascular hemorrhage, necrosis, and minimal inflammation. Laboratory findings are consistent with DIC. Although the pathogenesis is not fully understood, the DIC in purpura fulminans appears to involve the skin selectively. The development of purpura fulminans from homozygous protein C or protein S deficiencies can be separated into the two distinct phases. The first phase is the time period when the initial reversible lesions develop and grow. This reversible progression can be halted and reversed with the administration of protein C or protein S. The second phase is the irreversible stage in which the lesion continues to develop into a necrotic lesion, whether or not treated with protein C. This irreversible lesion will ultimately develop into a large full-thickness necrotic injury of the skin. It is very similar to the lesions seen in idiopathic purpura fulminans, warfarin-induced skin necrosis, and acute infectious purpura fulminans. Unfortunately, our current understanding of the mechanism or mechanisms of the induction and propagation of the purpura fulminans-like lesions in homozygous protein C or protein S deficiencies is minimal, since it has never been studied. We can only speculate on the mechanism based on laboratory data and comparison with the little that is known about the other similar types of lesions.

[Congenital cytomegalovirus infection after maternal renal transplantation (author's transl)]. / Konnatale Zytomegalie des Kindes einer nierentransplantierten Mutter

A 34-year-old female gave birth to a 32 to 35 week-old girl one year after she had undergone renal transplantation. The child was dwarfed and microcephalic and also had congenital platelet deficiency and purpura. In addition it was anaemic and suffered from severe neonatal icterus. An initial hypogammaglobulinaemia disappeared except for low IgA levels. The immunoglobulin deficiency is probably correlated with the virologically and serologically proven cytomegalovirus infection. The incidence of this disease seems to be high in children of mothers with renal transplantations.

Congenital cytomegalovirus infection after maternal renal transplantation.

Congenital cytomegalovirus infection was found in an infant whose mother had a successful renal transplant and was treated with immunosuppressant therapy before and during pregnancy. Although so far not experiencing any untoward infections, the child had impaired T-lymphocyte function and subnormal serum-IgA.