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AT III Barcelona: a familial quantitative-qualitative AT III deficiency
E Grau1, J Fontcuberta, J Félez
1Servei d'Hematologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Insights
A Spanish family exhibited a dual deficiency in antithrombin III (ATIII), impacting both quantity and quality. This genetic condition, ATIII Barcelona, results in reduced heparin cofactor activity and impaired blood clotting.
Area of Science:
- Biochemistry
- Genetics
- Hematology
Background:
- Antithrombin III (ATIII) is a crucial protein regulating blood coagulation.
- Deficiencies in ATIII are linked to an increased risk of thrombosis.
- Familial thrombotic tendencies warrant investigation into underlying genetic defects.
Observation:
- Four members of a Spanish family presented with a history of thrombotic events.
- Affected individuals showed approximately 50% reduction in both ATIII antigen and heparin cofactor activity.
- Abnormal ATIII behavior was detected using crossed immunoelectrophoresis (CIE) with heparin.
Findings:
- Crossed immunoelectrofocusing (CIEF) revealed normal ATIII migrating between pH 4.9-5.3, while affected individuals had an abnormal ATIII population.
- The abnormal ATIII exhibited asymmetric distribution across pH ranges (4.9-5.3 and 4.6-4.8) and lacked heparin affinity.
- Affinity chromatography confirmed the presence of a heparin-deficient ATIII variant in affected family members.
Implications:
- The study identified a novel quantitative-qualitative ATIII deficiency, termed ATIII Barcelona.
- This deficiency, present in a heterozygous state, impairs ATIII's ability to bind heparin.
- Understanding ATIII Barcelona provides insights into thrombotic disorders and potential therapeutic targets.
Abstract:
A quantitative and qualitative deficiency of antithrombin III (ATIII) was found in four members of a Spanish family with thrombotic tendency. In all affected members, levels of ATIII antigen and activity (heparin cofactor activity) were reduced to 50% of the normal range. When crossed immunoelectrophoresis (CIE) was performed in the presence of heparin, an abnormal slow-moving peak was found. Crossed immunoelectrofocusing (CIEF) from normal and affected individuals showed that normal ATIII migrated between pH 4.9-5.3 while the ATIII under study was asymmetrically distributed between two pH ranges: 4.9-5.3 and 4.6-4.8. Affinity adsorption of affected members' plasma to heparin-sepharose beads revealed one population of ATIII in the supernatant corresponding to the abnormal ATIII, devoid of heparin cofactor activity and showing a peak between pH range: 4.6-4.8 in CIEF. Our data supports the view that a quantitative-qualitative deficiency was present in the heterozygous state in all the affected family members. Both normal and abnormal ATIII were present in plasma of the affected individuals. This abnormal ATIII was characterized by a lack of affinity for heparin. This familial ATIII deficiency was named ATIII Barcelona.