Antithrombin III Deficiency and Thromboembolism

Thaler, Erica R.; Lechner, Klaus

doi:10.1016/s0308-2261(21)00229-0

Cited by 353 publications

(15 citation statements)

References 105 publications

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“…Antithrombin III deficiency causes thrombosis by reducing the anticoagulant activity of plasma. Many families with ATIII deficiency and hereditary thrombosis have been described [see Thaler and Lechner (1981) for review]. Inheritance of this condition is autosomal dominant, and affected individuals (who are heterozygous for the trait) may experience recurrent episodes of deep vein thrombosis and pulmonary embolism during adult life.…”

mentioning

confidence: 99%

Antithrombin III Utah: proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site

Bock¹,

Marrinan²,

Radziejewska³

1988

Biochemistry

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A dysfunctional antithrombin III (ATIII) gene encoding a qualitatively and quantitatively abnormal anticoagulant molecule is responsible for hereditary thrombosis in a Utah kindred [Bock et al. (1985) Am. J. Hum. Genet. 37, 32-41]. Nucleotide sequencing of the entire protein-encoding portion of the cloned ATIII-Utah gene revealed a C to T transitional mutation which converts proline-407 to leucine. Proline-407 is located 14 amino acids C-terminal to the reactive site arginine of ATIII in a core region of the molecule that has been highly conserved during evolution of the serine protease inhibitor (serpin) gene family. The location of this proline in the crystal structure of the homologous serpin alpha 1-antitrypsin suggests that the leucine substitution in ATIII-Utah may interfere with correct folding of the mutant gene product, leading to its rapid turnover and the low antithrombin levels observed in patient plasmas. The Pro-407 to Leu mutation does not interfere with binding of antithrombin III to heparin. Patient antithrombin III, isolated by affinity chromatography on heparin-Sepharose, was reacted with purified thrombin. ATIII encoded by the patient's normal gene formed protease-inhibitor complexes with thrombin, whereas the product of the ATIII-Utah gene did not. The Pro-407 to Leu mutation destroys a restriction site for the enzyme StuI, permitting rapid diagnosis of affected members of the Utah kindred by Southern blotting of genomic DNA.

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mentioning

confidence: 99%

Antithrombin III Utah: proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site

Bock¹,

Marrinan²,

Radziejewska³

1988

Biochemistry

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“…The presence of a hereditary or acquired prothrombotic state significantly increases the risk of VTE. Antithrombin III, protein C and S deficiencies are associated with a 7-8-fold increase in the risk of venous thromboembolic events [120][121][122]. The presence of FV Leiden causes a 7-fold increase in the risk of deep venous thrombosis in heterozygotes [123] and an 80-fold increase in homozygotes [124].…”

Section: Discussionmentioning

confidence: 99%

Osteonecrosis of the Femoral Head in Patients with Hypercoagulability—From Pathophysiology to Therapeutic Implications

Rezuş

Tamba

Bădescu

et al. 2021

IJMS

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Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly in the early stages, ONFH has devastating consequences and leads to mandatory total hip arthroplasty. The pathophysiology of non-traumatic ONFH is very complex and not fully understood. While multiple risk factors have been associated with secondary ONFH, there are still many cases in which a clear etiology cannot be established. Recognition of the prothrombotic state as part of the etiopathogeny of primary ONFH provides an opportunity for early medical intervention, with implications for both prophylaxis and therapy aimed at slowing or stopping the progression of the disease. Hereditary thrombophilia and hypofibrinolysis are associated with thrombotic occlusion of bone vessels. Anticoagulant treatment can change the natural course of the disease and improve patients’ quality of life. The present work focused on highlighting the association between hereditary thrombophilia/hypofibrinolysis states and ONFH, emphasizing the importance of identifying this condition. We have also provided strong arguments to support the efficiency and safety of anticoagulant treatment in the early stages of the disease, encouraging etiological diagnosis and prompt therapeutic intervention. In the era of direct oral anticoagulants, new therapeutic options have become available, enabling better long-term compliance.

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“…ATIII is deficient in many hypercoagulative pathologies [19]. This model predicts [ATIII] 0 /[II] 0 ≥ 1 (for [II] 0 = 1400 nM, [ATIII] 0 = 1400 nM or 41% of physiological mean [11]) to avoid hypercoagulation.…”

Section: To Terminate or To Propagate?mentioning

confidence: 99%

“…ATIII deficiency could be due to faulty synthesis, increased consumption, loss (such as filtration in kidneys), etc. [19]. The proteins not explicitly accounted for in this model would precisely determine the threshold value of the ratio.…”

Section: To Terminate or To Propagate?mentioning

confidence: 99%