Klodiana Mrishaj
Introduction
Neonatal purpura fulminans describes a clinico-pathological entity of dermal microvascular thrombosis associated with coagulazione intravascolare disseminata. (DIC) and perivascular hemorrhage, occurring in the newborn period. The clinical presentation is that of acute DIC and hemorrhagic necrosis of the skin. This is a rare condition, but it is often fatal if it is not treated early and effectively. Therefore early recognition with promp investigation and treatment is of paramount importance
Diagnosis and management of neonatal purpura fulminans, 2011.
Etiology of neonatal purpura fulminans
Purpura fulminans was first described in a neonate in 1962 and the etiology was presumed an inherited disorder as three siblings had similar skin lesions. It was only in 1983 that a possible link between the clinical findings of purpura fulminans and Protein C deficiency was described in a child, and soon after this the first child with confirmed homozygous protein C deficiency was successfully treated with protein C replacement therapy. The first association of homozygous . Protein S deficiency and purpura fulminans was reported in 1990. There are both congenital and acquired causes of neonatal purpura fulminans. Inherited causes are due to a homozygous protein C or S deficiency; compound heterozygosity and co-inheritance with other inherited thrombophilias have been described. Acquired causes are more common and often associated with severe infection causing a consumptive coagulopathy and a relative deficiency of protein C and/or S. Protein C is a vitamin K-dependent coagulation protein that is synthesized in the liver. Plasma protein C is activated by complex formation with thrombin bound to an endothelial cell surface receptor, thrombomodulin ™. TM and endothelial protein C receptor (EPCR) are both expressed on endothelial cells and regulate the protein C pathway. Thrombin binds TM and acts as a catalyst for the activation of protein C by thrombin. EPCR binds to protein C and enhances the activation of protein C by TMethrombin complexes by 10-fold. Activated protein C (APC) inactivates factor (F)Va and FVIIIa by limited proteolysis, resulting in a downregulation of thrombin generation. APC activity is enhanced by protein S. Therefore, protein C or S deficiency predisposes to a decreased capacity to reduce thrombin generation and
hypercoagulable state
Protein C deficiency, 2008
Protein S defiency: a clinical perspective, 2008
Protein C and Protein S deficiency – practical diagnostic issues, 2013
Diagnosis
Clinical presentation
Neonatal purpura fulminans usually presents with a rapid onset of cutaneous purpuric lesions after birth and DIC. If the condition is not recognized and treated promptly, it is usually fatal. The clinical severity may vary depending on the underlying cause, e.g. genetic variability of severe congenital protein C and S
deficiencies. The onset of symptoms is usually within 2e12 h after birth. However, infants presenting with a delayed onset of purpura fulminans, between 6 and 12 months of age, are reported. The skin lesions initially appear dark red and then become purple-black and indurated; they occur at previous sites of trauma, e.g. intravenous cannula insertion sites, and they may initially be mistaken as bruising. There is a predilection for the limbs, although buttocks and thighs are often affected. In time the areas may become necrotic and gangrenous resulting in loss of extremities. Severe protein C deficiency is often associated with thrombosis of the cerebral vasculature and ophthalmologic complications including vitreous hemorrhage
and retinal detachment that may result in partial or complete blindness. These two complications can occur as antenatal events. Large vessel venous thromboses may also occur, e.g. renal vein thrombosis. Similar vitreoretinal findings have been described in neonatal purpura fulminans due to severe congenital protein S deficiency. The diagnosis of homozygous protein C or S deficiency is based on the clinical findings of purpura fulminans, undetectable levels of protein C or protein S, a heterozygous state in the parents, and, if
possible, identification of the molecular defect. There may be no family history of thrombosis as there is wide variability in heterozygous phenotype. Both homozygous and compound heterozygous states have been associated with neonatal purpura fulminans. A history of consanguineous parents may point towards a homozygous state while compound heterozygous gene mutations may be found in neonates born to
unrelated parents. Acquired causes of neonatal purpura fulminans are mainly due to severe infections of which the most commonly associated pathogen in the neonatal period is group B streptococcus
Neonatal purpura fulminans secondary to group B streptococcal infection.
Laboratory diagnosis
During the acute phase, the laboratory findings are that of DIC: thrombocytopenia, hypofibrinogenemia, increased fibrin degradation products and prolonged prothrombin (PT) and activated partial thromboplastin (aPTT) times. There are reports of associated microangiopathic anemia. Distinction between congenital and acquired causes of protein C and S deficiency is often challenging in the setting of
acute thrombosis. Genetic testing of the child and family members can be useful to confirm the diagnosis, but it is not readily available in most centers, and the results would not be timely enough to guide management of these critically ill neonates. Testing of a citrated plasma sample, collected prior to initiation of treatment, is therefore crucial for accurate diagnosis. Functional (activity) assays are recommended for initial screening. Antigen levels may be contributory if interfering factors (e.g. factor V Leiden mutation, antiphospholipid antibodies, direct thrombin inhibitors) are present. Unlike testing in adults, the interpretation of protein S levels in neonates Is not complicated by binding to C4b, which is present at very low levels at birth. Protein C and S activity levels are undetectable in homozygote
Pregnancy has an unpredictable effect on protein C levels; in fact, diagnosis of an affected infant was delayed by an initial low e normal result in the mother. Protein S activity is predictably decreased in states of elevated estrogen, and there is difficulty distinguishing heterozygous carriers from normal pregnant women based on standard reference ranges. Acute inflammation also lowers protein S activity due to binding with C4b. Finally, treatment with oral vitamin K antagonists is a wellknown acquired cause of both protein C and S deficiency. Given these issues, abnormal results should be confirmed by repeat assays, and testing of extended family may be necessary to demonstrate the inherited nature of the deficiency. Experts have recommended testing of siblings and grandparents.
Diagnosis and management of neonatal purpura fulminans, 2011.
Purpura fulminans:recognition, diagnosis and management.
Prenatal diagnosis of severe protein C or S deficiency
If the causative mutation of protein C or S deficiency within a family is known, prenatal diagnosis is available for women at risk of having a child with homozygous deficiency. This requiresé "Chorionic villus sampling": http://en.wikipedia.org/wiki/Chorionic_villus_sampling that is associated with a 1% risk of fetal loss. Despite the identification of almost 200 unique mutations in the protein C gene and 131 in the protein S gene, the underlying defect is not always identified. Fetal blood sampling offers an alternative method; however, fetal protein C levels in the second trimester may be as low as 8% and the detection limit for many of the commercially available assays is 3%. This, combined with the risk of sample contamination with maternal blood, makes the distinction between heterozygous and homozygous states challenging. As complications of congenital protein C deficiency in the central nervous system may occur in the third trimester, antenatal diagnosis may provide an opportunity for early intervention, through timely delivery and initiation of replacement therapy, and prevention of devastating consequences of severe protein C deficiency
Treatment of neonatal purpura fulminans
Management of DIC should be based on the clinical and associated laboratory findings. The platelet count should be maintained >50,000_109/L and the fibrinogen level >1 g/L. If the etiology is secondary to severe infection, appropriate intravenous antibiotics should be administered.
Early stage sepsis-associated purpura fulminans may be reversible with quick therapeutic intervention. Treatment is mainly removing the underlying cause and degree of clotting abnormalities and with supportive treatment (antibiotics, volume expansion, tissue oxygenation, etc.). Thus, treatment includes aggressive management of the septic state.
Purpura fulminans with disseminated intravascular coagulation should be urgently treated with fresh frozen plasma (10–20 mL/kg every 8–12 hours) and/or protein C concentrate to replace pro-coagulant and anticoagulant plasma proteins that have been depleted by the disseminated intravascular coagulation process
Protein C in plasma in the steady state has a half life of 6- to 10-hour, therefore, patients with severe protein C deficiency and presenting with purpura fulminans can be treated acutely with an initial bolus of protein C concentrate 100 IU/kg followed by 50 IU /kg every 6 hours. A total of 1 IU/kg of protein C concentrate or 1 mL/kg of fresh frozen plasma will increase the plasma concentration of protein C by 1 IU/dL. Cases with comorbid pathological bleeding may require additional transfusions with platelet concentrate (10–15 mL/kg) or cryoprecipitate (5 mL/kg)
Treatment of neonatal purpura fulminans
If the infant has the classical signs of purpura fulminans, blood samples of the infant and parents should be drawn into citrated tubes for antigen and activity levels of protein C and protein S, before replacement therapy is commenced. There is no protein S concentrate available. FFP/FP (10e20 mL/kg every 12 h) or cryoprecipitate is used as replacement therapy. The mainstay of management of severe acquired, transient
deficiencies of protein C or S is aggressive treatment of the underlying cause, although replacement therapy has been used in such cases.
Fresh (frozen) plasma
Protein C replacement should be commenced promptly using FFP/FP, or a human plasma-derived, viral inactivated protein C concentrate. FFP/FP should be given at a dose of 10e20 mL/kg every 6e12 h until a protein C concentrate is available. The most common associated side-effect is fluid overload. Exposure to large numbers of donors potentially increases the risk for exposure to blood-borne pathogens and allergic reactions to donor proteins in FFP/FP. The use of solvent detergent-treated plasma may avoid this, but it is not universally available. There is evidence that the haemostatic qualities of solvent detergent-treated plasma and FFP/FP are similar, but the protein S activity may be lower in solvent detergent-treated plasma and the relevance of this is unclear when considering this product for replacement therapy. A total of 1mL/kg of FFP/FP will increase the plasma protein C concentration by 1 IU/dL. The aim is to have a troughprotein C activity of >10 IU/dL while awaiting the protein C concentrate.
Protein C concentrates
There are two human plasma-derived, viral-inactivated protein C concentrates available: Ceprotin (Baxter Bioscience, Glendale, CA,USA) is licensed for use in congenital protein C deficiency in the USA and Europe; and Protexel (LFB, Lille, France) is licensed for use in Europe. Unfortunately, these products are not widely available in many countries. The dose for both products is an initial 100 U/kg followed by 50 U/kg every 6 h.19 The dosing is based on the fact that 1 IU/kg of protein C concentrate increases plasma protein C by 1 IU/ dL and the half-life of plasma protein C is 6e10 h. The target protein C activity is a trough level of 50 IU/dL. Although both products are licensed for use for replacement of protein C in congenital deficient states, both have been used off label in the management of severe acquired protein C deficiency. Recombinant activated protein C (APC) is not recommended to treat neonatal purpura fulminans due to the possible increased risk of bleeding that was reported in a randomized controlled trial of APC in children with sepsis. In this study, there was a trend to increased major bleeding particularly in infants. However, there are reports of its use in the management of neonatal purpura fulminans. The treatment during the acute phase should continue until all lesions, including skin, CNS and ocular lesions, have resolved. Reliable venous access may be difficult and there are reports of protein C concentrate administered subcutaneously. Early referral to an ophthalmologist for management and follow-up of the ocular lesions is recommended.
Purpura fulminans
Liver transplant
Liver transplant has been performed as a successful treatment of homozygous protein C deficiency when replacement therapy was not readily available
Prophylaxis for surgical procedures
Protein C concentrate: 100 U/kg as an initial bolus, then 30e50 U/kg every 12e24 h with a target therapeutic range (trough level) for protein C activity of 20e50 IU/dL.
Anticoagulation
Initial therapy
Anticoagulation therapy should be initiated with administration of protein C replacement therapy (protein C concentrate or FFP/FP) and is an effective long term secondary prophylaxis. Initial anticoagulation consists of either unfractionated heparin (UFH) or low molecular weight heparin (LMWH). UFH should be administered at a dose of 28 U/kg/h with a target anti-Xa level of 0.3e0.7 U/mL. The recommended dose of LMWH is 1.0e1.5 mg/kg/dose every 12 h with a therapeutic target anti-Xa level of 0.5e1 U/mL.17,19,52 Initiation of warfarin therapy should overlap and only commence after several days of anticoagulation with UFH/LMWH to avoid warfarininduced skin necrosis and other thrombotic complications.
Warfarin is a vitamin K antagonist and therefore, on initiation of therapy, protein C levels are decreased, increasing the risk of thrombosis.
Rivaroxaban may be considered as a valid anticoagulant alternative in patients with severe inherited protein S deficiency and warfarin-induced skin necrosis.
Anticoagulant treatment with rivaroxaban in severe protein S
Maintenance
Warfarin therapy is recommended. If protein C concentrate is not concurrently administered as prophylaxis, the aim of an international normalized ratio (INR) is between 2.5 and 3.5. A smaller dose of warfarin, to maintain a target INR of 1.5e2.5, is recommended with protein C replacement therapy.
Monitoring of therapy
The therapeutic target activity levels for monitoring of protein C replacement therapy as well as anticoagulation therapy are mentioned above. Due to the risk of bleeding or recurrent purpura fulminans, INRs often need to be monitored on a weekly basis. Point-of-care testing for INR enables such patients to be monitored at home. D-Dimer is a useful marker for activation of the coagulation cascade and has been a helpful indicator both of adequate replacement and anticoagulation therapy in neonates. A rising or elevated D-dimer may be the first sign of recurrent purpura fulminans.
Conclusion
Neonatal purpura fulminans, whether caused by congenital or acquired deficiencies of protein C or S, remains a life-threatening condition. Fortunately it is a rare disorder. Early recognition of the clinical symptoms, prompt diagnosis and judicious replacement therapy decreases both the morbidity and mortality associated with this condition. Every effort should be made to increase awareness of this rarely diagnosed condition and its treatment, so that affected infants and their families will derive maximum benefit, even if replacement therapy with protein C concentrate is not widely available.
