Fetal stroke and congenital parvovirus B19 infection complicated by activated protein C resistance

Parvovirus B19 infection in gestation has been associated with severe fetal complications such as anaemia, hydrops and fetal demise. Fetal infection in the first trimester poses the greatest risk for these complications, but infection during the third trimester is more common than previously appreciated and can be associated with severe complications, i.e. fetal death, in the absence of hydrops or classical clinical symptoms. Parvovirus B19 infection has been associated with vasculitis and pathological changes in the central nervous system, which may cause stroke. We report a newborn infant with a rare combination of a recent central nervous system infection with parvovirus B19 and a factor V Leiden mutation, who developed fetal stroke. Conclusion: Factor V Leiden mutation leads to activated protein C resistance and increases the risk of thromboembolism. Thromboembolism occurs rarely in newborns with activated protein C resistance, but can be precipitated by dehydration, asphyxia and infection. Although parvovirus B19 infection of the central nervous system may be a precipitant in neonatal and/or fetal stroke, it can also cause stroke independent of a thrombophilic mutation. In this case, both causative factors may have coincided.     

Fulminant sepsis/meningitis due to Haemophilus influenzae in a protein C-deficient heterozygote treated with activated protein C therapy

A 13-month-old Japanese female with Haemophilus influenzae type b meningitis presented with unusually severe septic shock and cerebral infarction in half a day of fever. The initial therapy of plasma-derived activated protein C (Anact C) led to an impressive effect on the aggressive condition. However, purpura fulminans and the consistent decline of plasma protein C activity (<20%) required prolonged activated protein C therapy and gene analysis. The patient carried a novel heterozygous mutation of PROC (exon 4; 335 GAC>TAC, Asp46Tyr). This is the first report of infectious purpura fulminans in a protein C-deficient heterozygote. The clinical onset and treatment course adequately corroborated the aggravated immune/hemostatic reactions and the cytoprotective effects of activated protein C replacement in human heterozygous protein C deficiency. The monitoring of plasma protein C activity and sufficient administration of activated protein C product could improve the outcome of severe sepsis in children.     

Paediatric thrombo-embolism: the influence of non-genetic factors and the role of activated protein C resistance and protein C deficiency

 In many children, the pathogenesis of thrombo-embolism remains unexplained. This study examines the role of non-genetic risk factors in 37 children with venous or arterial thrombosis. Included were 17 patients with portal vein thrombosis following umbilical vein catheterisation, 6 with portal vein thrombosis and an uneventful neonatal period, 4 with deep vein␣thrombosis, 4 with renal vein thrombosis after kidney transplantation, 1 haemodialysis patient with thromboses of arteriovenous shunts, and 5 with arterial thromboses at various sites. In 25 of these 37 patients (68%) exogenic risk factors and particularly vascular manipulations (24/37) were related to the thrombotic event. Resistance to activated protein C was identified in 5 patients and protein C deficiency in 2 (7/37; 19%). This prevalence was significantly higher than that of the control group (14/243; 5.8%; χ², P < 0.008). Conclusion Our data show that non-genetic and particular iatrogenic risk factors can often be identified in children with thrombosis, but activated protein C resistance and protein C deficiency are significant genetic risk factors in this age group. Received: 23 April 1996 / Accepted: 1 August 1996     

白血病患儿并发急性肺损伤时血浆活化蛋白C的变化及意义

目的 采用前瞻、对照的方法明确白血病患儿并发急性肺损伤(acute lunginjuny,ALI)时血浆活化蛋白C(activated protein C,APC)的变化及其与预后的关系.方法2009年1月至12月收入我院PICU的急性淋巴细胞白血病(ALL)合并ALI患儿17例,其中粒细胞缺乏组10例,粒细胞正常组7例.比较两组患儿发生ALI时的基础资料(年龄、性别、危重病例评分、是否合并休克、化疗阶段、机械通气时间、ICU住院时间),在发生ALI的第1天和第4天检测血气和血浆APC水平.结果 与粒细胞正常组相比,粒细胞缺乏组患儿机械通气时间更长[(16.60±10.83)d vs(3.79±4.08)d,P=0.0096],其发生ALI第1天的PaO2更低[(54.90±17.05)mm Hg vs(92.70±27.53)mm Hg,P=0.0097],第4天的APC水平更低[(193.06±63.19)pg/ml vs(286.28±25.12)pg/ml,P=0.007 7].结论 白血病患儿存在粒细胞缺乏合并ALI时,其产生APC的能力严重受损,机械通气时间更长,氧合更差,预后更差.监测APC水平对此类患儿的预后有一定提示作用,也为将来行APC的替代治疗提供了依据.     

Inherited defects of the protein C anticoagulant system in childhood thrombo-embolism

Childhood thrombo-embolism is mostly the result of inherited thrombophilia or vascular insults combined with risk factors such as peripartal asphyxia, fetopathia diabetica, exsiccosis, septicaemia, central lines, congenital heart disease, cancer, trauma, surgery or elevated antiphospholipid antibodies. Inherited thrombophilia includes mainly defects of the protein C pathway, resistance to activated protein C, protein C or protein S deficiency. Resistance to activated protein C, in the majority of cases caused by the point mutation Arg 506 Gln of the factor V gene, has emerged as the most important hereditary cause of thrombo-embolism in adults and children. However, since an acquired risk of thrombo-embolic complications frequently masks the inherited deficiency in affected children, children with thrombo-embolism should have adequate laboratory evaluation for inherited coagulation disorders, especially the protein C pathway. Until more data on childhood thrombo-embolism are available, treatment recommendations will continue to be extrapolated from guidelines for adults.     

Recombinant human activated protein C, heparin and melagatran in umbilical cord versus adult plasma

Aim: We investigated the anticoagulant effects of recombinant human activated protein C (rhAPC), unfractionated heparin (UH) and melagatran (a new direct thrombin inhibitor [DTI]), when administered individually and in combinations of rhAPC with either UH or melagatran, in umbilical cord and adult plasma. rhAPC is a promising candidate treatment to improve the outcome of severe sepsis in neonates and adults; the DTI melagatran represents a potential advance in antithrombotic therapy. Methods: The anticoagulant efficacy of these drugs was measured using the standard coagulation assays activated partial thromboplastin time (aPTT) and prothrombin time (PT). Results: Administered individually, rhAPC, UH and melagatran dose-dependently prolonged aPTT to a significantly greater extent in umbilical cord than in adult plasma. Melagatran alone, but not rhAPC or UH alone, dose-dependently prolonged the PT in both umbilical cord and adult plasma. Combining rhAPC with either UH or melagatran significantly augmented aPTT prolongation in both umbilical cord and adult plasma.

Conclusion: Our results, which facilitate estimation of rhAPC and melagatran dose requirements in umbilical cord plasma, may be of benefit in critically sick newborns with severe sepsis.     

Arterial ischaemic stroke in childhood

Stroke in childhood is poorly recognised amongst the public and healthcare professionals. Stroke in any age group should be considered a medical emergency and yet in children the diagnosis is often delayed with subsequent doubt regarding optimal management or treatment. Adult management protocols have been applied to children with limited evidence and uncertain success. This review looks at childhood arterial ischaemic stroke in the non-neonatal age group i.e. 1 month-16 years and summarises current guidelines and literature. The investigation and management of suspected and confirmed arterial ischaemic stroke, and stroke due to venous sinus thrombosis is discussed. Although thrombolysis is well-established in adult ischaemic stroke care, more studies are required to definitively guide the safe use of this medical therapy in the acute phase in children.     

Arterial ischaemic stroke in children

OBJECTIVE: Arterial ischaemic stroke (AIS) in childhood is a serious disorder about which little is published. The aim of this study is to determine the epidemiology and outcome of AIS in Australian children. METHODS: Cases of childhood AIS occurring at the Royal Children's Hospital, Melbourne 1993-2001, were identified by medical record search using International Classification of Disease Codes. Information was collected on demographics, risk factors, arterial distribution, results of thrombophilic testing, management and outcome. RESULTS: During the 8 years of review 95 patients presented with 98 cases of AIS calculating an incidence of 1.8 per 100000 children per year. Children less than 12 months of age represented greater than one third of all cases. Identifiable risk factors were present in 64% of cases with congenital heart disease the major risk factor. Thrombophilic testing was incomplete with initial abnormalities present in 18% of cases tested. The estimated stroke-related mortality was 8.4%. Of the patients who survived and who had follow-up details available, 78% had a neurological deficit. Twenty-six patients (26%) received anticoagulation. There was no statistically significant association between treatment with anticoagulation and normal neurological outcome. CONCLUSION: AIS is over-represented in children under 12 months of age and results in death or residual neurological impairment in the majority of cases. Further prospective studies are needed to identify risk factors for poor outcome. The recently established Australian and New Zealand Stroke and Thrombophilia Registry should provide important information on clinical and laboratory based risk factors and create a basis for international clinical trials to improve the outcome of childhood AIS.     

Inherited resistance to activated protein C in a boy with multiple thromboses in early infancy

Resistance to activated protein C is a recently discovered genetic defect with a high prevalence in adult patients with thromboembolic disease. It is an autosomal dominant disorder and is ten times more common in these patients than antithrombin III-, protein C- and protein S deficiency together. In spite of this high prevalence among adults with thromboembolic disease no clinical manifestation in infancy so far has been reported. We describe a 4-year-old boy with a complex cardiac malformation and inherited resistance to activated protein C, who developed multiple thromboses after cardiac catheterization in early infancy.Conclusion Resistance to activated protein C can cause thrombosis in infants and children if additional risk factors for the development of thrombosis are present.     

Intracardiac thrombus causing systemic embolism in a child with idiopathic ventricular tachycardia and heterozygous activated protein C resistance

Systemic embolism in childhood is rare but often disastrous. Most often the concomitant occurrence of more than one prothrombotic factor is responsible for the acute event. We report on a child in whom an intracardiac thrombus embolized into the descending aorta resulting in subtotal occlusion. Causative for thrombus formation was an idiopathic ventricular tachycardia and a heterozygous activated protein C resistance, both previously unknown. Immediate surgical thrombectomy was successful without sequelae. Antithrombotic and antiarrhythmispioproptylactic treatment was started afterwards. We suggest that in cases of longstanding or repeated tachycardia and in children after thromboembolic events diagnostic work-up for thrombophilia should be undertaken.     

Long-term follow-up after stroke in childhood

Over the last few years, the importance of paediatric stroke has become more and more evident; however, there is still little known about long-term neurological and especially neuropsychological outcome of these children. By retrospective chart review, questionnaire and clinical examination with structured interview, we analysed initial presentation, aetiology and long-term outcome of children suffering ischaemic childhood stroke between 1985 and 1999. A total of 20 children (13 boys) suffered acute arterial ischaemic events. Aetiology was detected in 14, and suspected in another five. Follow-up after 1–15 years (mean 7 years) was possible for 16 children; two had died and two were lost to follow-up. Only two were completely healthy, five suffered mild, six moderate, and three severe handicap. Eleven children presented with combined neurological and neuropsychological problems. Neurological problems were mild to moderate hemisyndrome in 11, dysphasia, epilepsy and other in six each. Mild to severe neuropsychological problems were detected in 13 children, school problems in eight, attention deficits in nine and behaviour problems in seven, increased fatigability and headache in six each. Recurrence was observed in three children, all due to progressive underlying disease. Outcome was most affected by the presence of combined cortical/subcortical and least affected by subcortical infarction. Epilepsy affected neuropsychological outcome. Conclusion: although prognosis of paediatric stroke is better than for adult stroke, neurological and especially neuropsychological long-term problems significantly influence the lives of these children. Careful long-term follow-up to support these children in their school career and integration into professional life is necessary. Future studies should evaluate whether specific treatments during the acute episode could improve outcome for these children.     

Role of protein C in childhood cerebrovascular occlusive accidents

A group of 23 children with cerebrovascular occlusion of unknown oetiology were re-evaluated 6 months-2 years later. Plasma protein C levels were determined with the coagulation method and were low in 10 cases. The role of this deficiency and the necessity of this test in cerebrovascular occlusion is discussed.     

儿童动脉缺血性脑卒中研究进展

很多全身性疾病可导致儿童动脉缺血性脑卒中(AIS),如脑动脉病.轻微感染在短暂性脑动脉病(TCA)中起重要作用.由于儿童卒中表现的非特异性以及医师对儿童AIS认识不足常常延误诊断和治疗.目前儿童AIS的治疗国内外尚无统一标准,急性期处理以支持疗法为主.儿童AIS的二级预防大多参照成年人治疗方案,预后并不乐观,一旦患病往...     

儿童动脉缺血性脑卒中研究进展

儿童动脉缺血性脑卒中(AIS)是重要的全球健康问题。近年来多项国际合作研究的开展使儿童AIS的诊疗有了重要进展。文章对儿童AIS的诊疗新进展进行综述,主要内容包括脑动脉病的分类和诊治进展、AIS相关基因及再灌注治疗三个方面。     

Prognostic value of protein kinase C,proto-oncogene products and resistance-related proteins in newly diagnosed childhood acute lymphoblastic leukemia

In this investigation, untreated non-B-type acute lymphoblastic leukemia (ALL) of 104 children was analyzed using immunocytochemistry for expression of protein kinase C, proto-oncogene products (Fos, Jun, Ras) and resistance-related proteins (topoisomerase II, P-glycoprotein, glutathione S-transferase-π, metallothionein, dihydrofolate-reductase, thymidylate-synthase). The aim of the analysis was to find out whether combining those factors with the most important clinical prognostic factor (blast cell count) can improve the prognostic value (relapse-free interval). Univariate analysis shows that protein kinase D (PKC), Fos, P-glycoprotein (P-170) and glutathione S-transferase-π (GST-π) are significant prognostic factors independent of blast cell count (PBC) for the relapse-free intervals of children with ALL. The presence of the proteins Fos, PKC, P-1.70 and GST-π was not independent within the patient population. The multivariate analysis showed that in combination with PBC and PKC, both P-170 and GST-π have only limited prognostic influence. Combining the factors PKC, Fos and GST-π as a categorial variable showed that this variable is a strong prognostic factor in addition to PBC. Med. Pediatr. Oncol. 28:117–126 © 1997 Wiley-Liss, Inc.     

Purpura fulminans in severe congenital protein C deficiency: Monitoring of treatment with protein C concentrate

This report describes the successful use of protein C concentrate to treat severe purpura fulminans in a homozygous protein C-deficient infant for 8 months until oral anticoagulation was initiated. While fresh frozen plasma was previously used in such cases to replace protein C in the acute phase, the availability of a monoclonal antibody purified protein C concentrate now allows specific replacement of protein C, avoiding problems of fluid overload. An occlusive-hydrocolloid bandage proved to be effective in local treatment of skin lesions. D-dimer, fibrin monomer, thrombin-antithrombin complex and prothrombin fragment 1+2 were useful markers in monitoring and optimizing protein C replacement therapy.