APC resistance in neonates and infants: Adjustment of the aPTT - based method

doi:10.1016/0049-3848(96)00043-6

Thrombosis Research

Volume 81, Issue 6, 15 March 1996, Pages 665-670

https://doi.org/10.1016/0049-3848(96)00043-6 Get rights and content

Abstract

Resistance to activated protein C (APCR) has emerged as the most important hereditary cause of venous thromboembolism. Using an aPTT-based method together with DNA technique we investigated 120 healthy neonates and infants < 12 months of age and 24 infants with septicaemia for the presence of this mutation. In addition, data of 11 neonates with vascular occlusion, heterozygous (+/−) for the Arg 506 Gln mutation were included. Results of an aPTT-based method (clotting time using the $APC CaCl1$ solution obtained in an undiluted, 1:5 and 1:11 dilution with factor V deficient plasma divided by clotting time with CaCl2 in the same plasma dilution) are shown: Whereas 7 (5.5%) out of 120 healthy neonates were (+/−) carriers for the factor V Arg 506 Gln mutation, concordance with the aPTT-based method (cut-off defined as ratio < 2) was found only when using the 1:11 plasma dilution. Six (four) out of 24 infants with sepsis, not carrying the factor V mutation, would have been classified as APC resistant when using the 1:1 (1:5) plasma dilution. Four (two) out of 18 patients, (+/−) for the Arg 506 Gln mutation showed APC ratios > 2 in the 1:1(1:5) plasma dilution.

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Cited by (29)

Laboratory Evaluation of Hypercoagulability
2009, Clinics in Laboratory Medicine
Citation Excerpt :
In newborns, a 1:11 dilution performed better than a 1:5 dilution. Furthermore, the 1:11 dilution results correlate with DNA analysis, whereas the 1:5 dilution results did not.75 Therefore, optimum assessment of activated protein C resistance in newborns may require a 1:11 dilution in factor V–deficient plasma.
This discussion considers several important hypercoagulable states that predispose patients to venous, and in some instances, arterial thrombosis, focusing on activated protein C resistance/factor V Leiden, prothrombin G20210A, deficiencies of protein C, protein S or antithrombin, and antiphospholipid antibodies. The discussion includes the incidence of each hypercoagulable condition, the magnitude of the thrombotic risk it poses and synergistic interactions among the various hypercoagulable conditions. Salient advances in understanding the molecular pathogenesis of each condition are presented and discussed in the context of the interpretation and clinical utility of current laboratory testing and identifying potential targets of future testing. Finally, recommendations for laboratory testing are summarized.
Hemostatic Disorders of the Newborn
2005, Avery's Diseases of the Newborn
Hypercoagulability test strategies in the protein C and protein S pathway
2002, Clinics in Laboratory Medicine
Laboratory evaluation of hypercoagulable states
1998, Hematology/Oncology Clinics of North America
Venous thromboembolism affects 0.1% of the general population in the United States every year, resulting in more than 50,000 deaths annually. Common predisposing conditions include the postoperative state, trauma, pregnancy, oral contraceptives, obesity, immobility, and heparin-induced thrombocytopenia. A variety of medical conditions are associated with thrombosis and are important to identify if present, including chronic disseminated intravascular coagulation, malignancy, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, polycythemia vera, and essential thrombocythemia. In addition, the number of well-characterized hereditary and acquired hypercoagulable conditions is increasing. A hypercoagulable condition is now identifiable by the laboratory in many cases, particularly in young individuals or those with a positive family history and/or recurrent thrombosis. This review describes the currently known hypercoagulable states that predispose patients to venous, and in some instances, arterial thrombosis. For each condition the discussion includes the incidence, the magnitude of the thrombotic risk in the general population in comparison to symptomatic families, synergistic interactions among the various hypercoagulable conditions, the molecular pathogenesis, and interpretation of laboratory test results. In addition, recommendations for laboratory testing are summarized.
Factor V Leiden, protein C, and lipoprotein (a) in catheter-related thrombosis in childhood: A prospective study
1997, Journal of Pediatrics
Objective: To determine the association between catheter-related thromboses and hereditary causes of thrombophilia, including the factor V Leiden mutation, deficiencies of protein C or protein S, or increased lipoprotein (a).
Study design: To evaluate the incidence of genetic risk factors for familial thrombophilia in catheter-related thrombosis, 163 consecutively admitted infants and children (cardiac disease and catheter placement [C] n = 140; Broviac catheter [B] n = 23) were prospectively investigated. In addition, an age-matched, healthy control group undergoing elective surgery (S: n = 155) was investigated.
Results: Heterozygous factor V Leiden mutation was diagnosed in 20 of the 318 study subjects (C: n = 5; B: n = 4; S: n = 11), homozygous factor V Leiden mutation was found in two subjects (C: n = 1; S: n = 1), protein C deficiency type I was diagnosed in nine subjects (C: n = 4; B: n = 1; S: n = 4), and five subjects showed increased lipoprotein (a) (C: n = 3; S: n = 2). The frequency of thrombosis (C: n = 13; B: n = 5) in patients with familial thrombophilia was significantly higher ( p < 0.0001; chi square: 27.79) in the catheter groups (15 of 17 subjects) than in control subjects after minor elective surgery (none of 18). Fifteen of the 18 infants with thrombosis had congenital thrombophilia; two children with congenital thrombophilia did not have documented thrombosis, and three infants with vascular occlusion had no inherited predisposition to thrombophilia.
Conclusions: Genetic risk factors for familial thrombophilia play an important role in the manifestation of catheter-related thromboembolism in children. (J Pediatr 1997;131:608-12)
Thromboembolism and resistance to activated protein C in children with underlying cardiac disease
1996, Journal of Pediatrics
OBJECTIVES: In the majority of cases, resistance to activated protein C is caused by the point mutation Arg⁵⁰⁶ to Gln in the factor V gene and has emerged as the most important hereditary cause of thromboembolism. METHODS: To determine to what extent resistance to activated protein C was present in children with thromboembolism and underlying cardiac disease, its occurrence was retrospectively investigated. By using a method based on activated partial thromboplastin time, with DNA technique derived from the polymerase chain reaction, we investigated nine children with underlying cardiac disease in whom thromboembolism had previously occurred. RESULTS: Heterozygous Arg⁵⁰⁶-to-Gln mutation in the factor V gene was diagnosed in five of the nine children investigated. In addition, protein C type I deficiency w as found in three patients, and two of the nine children showed increased lipoprotein (a) plasma values. Risk factors were present in all children with symptoms. CONCLUSIONS: These data indicate that deficiencies in the protein C anticoagulant pathway are likely to play an important role in the early manifestation of thromboembolism in children with underlying cardiac disease. (J Pediatr 1996;129:677-9)

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PaperAPC resistance in neonates and infants: Adjustment of the aPTT - based method

Abstract

Thromb Res

Lancet

Lancet

Lancet

Thromb Res

Factor VIII defect associated with familial thrombophilia

Thromb Haemostas

Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C

Mutation in blood coagulation factor V associated with resistance to activated protein C

Nature

Paper
APC resistance in neonates and infants: Adjustment of the aPTT - based method