Abnormal fibrinolysis recognized by thromboelastography in a case of severe bleeding with normal coagulation and platelet function, leads to detection of a novel <i>SERPINF2</i> variant causing severe alpha‐2‐antiplasmin deficiency

Egan, Grace; Pluthero, Fred G.; Bouskill, Vanessa; Hilliard, Pamela; Drury, Luke J.; Carção, Manuel; Kahr, Walter H A

doi:10.1111/bjh.16077

Cited by 3 publications

(3 citation statements)

References 9 publications

(17 reference statements)

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“…Many PAI‐1 function assays were designed to detect elevated, and not low, levels of PAI‐1, and the assays that lack a quantifiable lower reference range limit are not suitable to diagnose PAI‐1 deficiency. Thromboelastography findings (for samples taken while not on therapy) have only been described for a few cases with PA1‐1 or α2AP deficiency, and accelerated lysis is evident in tests with added tPA, 43,44 a protocol modification that has not been validated for diagnostic purposes. Increased lysis with added tPA is only seen in QPD samples with a low platelet count, as the detection of increased lysis by thromboelastography requires more uPA than is present in QPD blood 45 and low platelet count samples (due to many different causes) show accelerated lysis.…”

Section: Inherited Disorders Of Fibrinolysismentioning

confidence: 99%

“…Many PAI-1 function assays were designed to detect elevated, and not low, levels of PAI-1, and the assays that lack a quantifiable lower reference range limit are not suitable to diagnose PAI-1 deficiency. Thromboelastography findings (for samples taken while not on therapy) have only been described for a few cases with PA1-1 or α2AP deficiency, and accelerated lysis is evident in tests with added tPA, 43,44 a protocol modification that has not been validated for diagnostic purposes.…”

Section: Inherited Disorders Of Fibrinolysismentioning

confidence: 99%

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Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Mathews

Tasneem

Hayward

2023

Int J Lab Hematology

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Background Coagulation factors, anticoagulants, and fibrinolytic proteins are important for hemostasis, and mutations affecting these proteins causes some rare inherited bleeding disorders that are particularly challenging to diagnose. Aims This review provides current information on rare inherited bleeding disorders that are difficult to diagnose. Material & Methods A review of the literature was conducted for up to date information on rare and difficult to diagnose bleeding disorders. Results Some rare bleeding disorders cause an inherited deficiency of multiple coagulation factors (F), such as combined FV and FVIII deficiency and familial vitamin K‐dependent clotting factor deficiency. Additionally, congenital disorders of glycosylation can affect a variety of procoagulant and anticoagulant proteins and also platelets. Some bleeding disorders reflect mutations with unique impairments in the procoagulant/anticoagulant balance, including those caused by F5 mutations that secondarily increase the plasma levels of tissue factor pathway inhibitor as well as THBD mutations that increase functional thrombomodulin in plasma or cause a consumptive coagulopathy due to thrombomodulin deficiency. Some bleeding disorders accelerate fibrinolysis due to loss‐of‐function mutations in SERPINE1 and SERPINF2 or in the case of Quebec platelet disorder, a duplication mutation that rewires PLAU and selectively increases expression in megakaryocytes, resulting in a unique platelet‐dependent gain‐of‐function defect in fibrinolysis. Discussion Current information on rare and difficult to diagnose bleeding disorders indicates they have unique clinical and laboratory features, and pathogenic characteristics to consider for diagnostic evaluation. Conclusion Laboratories and clinicians should consider rare inherited disorders, and difficult to diagnose conditions, in their strategy for diagnosing bleeding disorders.

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Section: Inherited Disorders Of Fibrinolysismentioning

confidence: 99%

Section: Inherited Disorders Of Fibrinolysismentioning

confidence: 99%

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Mathews

Tasneem

Hayward

2023

Int J Lab Hematology

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“…The potential complexity of hypercoagulability in SCD patients has prompted the application of global assays of hemostasis, such as thromboelastography (TEG), which allows ex vivo monitoring of coagulation in whole blood [ 14 , 15 ]. As with CAT, a variety of clinical and laboratory variables can influence TEG results [ 16 ], and in several studies employing these assays, we have minimized these factors by having tests performed by a single operator under consistent conditions [ [17] , [18] , [19] , [20] , [21] , [22] ]. TEG has been employed (along with CAT) to assess chronic hypercoagulability in adult SCD patients of HbSS and HbSB°–thalassemia genotypes, where TEG results were consistent with hypercoagulability relative to normal healthy controls (NC) [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Constitutive hypercoagulability in pediatric sickle cell disease patients with hemoglobin SS genotype

Sussman,

Mburu,

Steele

et al. 2024

Research and Practice in Thrombosis and Haemostasis

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Inherited Disorders of the Fibrinolytic Pathway: Pathogenic Phenotypes and Diagnostic Considerations of Extremely Rare Disorders

Al-Ghafry,

Abou-Ismail,

Acharya

2024

Semin Thromb Hemost

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Fibrinolysis is initiated by the activation of plasminogen to plasmin via tissue-plasminogen activator (tPA) and urokinase-plasminogen activator (uPA); plasmin then converts fibrin to fibrin degradation products (FDPs). The antifibrinolytics counterbalancing this system include plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA and uPA, α-2 antiplasmin (α2AP), which inhibits plasmin, and thrombin activatable fibrinolysis inhibitor, which inhibits the conversion of fibrin to FDP. Inherited disorders of the fibrinolytic pathway are rare and primarily have hemorrhagic phenotypes in humans: PAI-1 deficiency, α2AP deficiency, and Quebec platelet disorder. Patients with these disorders are usually treated for bleeds or receive prophylaxis to prevent bleeds in the surgical setting, with pharmacological antifibrinolytics such as aminocaproic acid and tranexamic acid. Disorders of the fibrinolytic pathway with fibrin deposition are extremely rare, mostly noted in patients with plasminogen deficiency, who have more recently benefited from advances in human plasma-derived plasminogen concentrates administered intravenously or locally. These disorders can be very difficult to diagnose using conventional or even specialized coagulation testing, as testing can be nonspecific or have low sensitivity. Testing of the corresponding protein's activity and antigen (where applicable) can be obtained in specialized centres, and routine laboratory measures are not diagnostic. Genetic testing of the pathogenic mutations is recommended in patients with a high suspicion of an inherited disorder of the fibrinolytic pathway.

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Abnormal fibrinolysis recognized by thromboelastography in a case of severe bleeding with normal coagulation and platelet function, leads to detection of a novel SERPINF2 variant causing severe alpha‐2‐antiplasmin deficiency

Cited by 3 publications

References 9 publications

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

Constitutive hypercoagulability in pediatric sickle cell disease patients with hemoglobin SS genotype

Inherited Disorders of the Fibrinolytic Pathway: Pathogenic Phenotypes and Diagnostic Considerations of Extremely Rare Disorders

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