Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile

Santagostino, Elena; Mancuso, Maria Elisa; Tripodi, Armando; Chantarangkul, Veena; Clerici, Marigrazia; Garagiola, Isabella; Mannucci, Pier Mannuccio

doi:10.1111/j.1538-7836.2010.03767.x

Cited by 188 publications

(242 citation statements)

References 28 publications

Supporting

Mentioning

226

Contrasting

Unclassified

Order By: Relevance

“…There are in vitro and ex vivo observations showing that thrombin generation is a more sensitive parameter than factor VIII. For instance, Santagostino et al (39 ) showed that patients classified as severe hemophiliacs (factor VIII Ͻ1 IU/dL) may display different hemorrhagic phenotypes; some bleed more than others in spite of having identical levels of factor VIII. These different phenotypes were, however, distinguished by the TGA: the nonbleeders generated more thrombin than the bleeders (39 ).…”

Section: Application Of Tga To Manage Patients With Hemorrhagic Coagumentioning

confidence: 99%

“…For instance, Santagostino et al (39 ) showed that patients classified as severe hemophiliacs (factor VIII Ͻ1 IU/dL) may display different hemorrhagic phenotypes; some bleed more than others in spite of having identical levels of factor VIII. These different phenotypes were, however, distinguished by the TGA: the nonbleeders generated more thrombin than the bleeders (39 ). The logical conclusion is that thrombin generation in these patients is a more sensitive parameter than factor VIII.…”

Section: Application Of Tga To Manage Patients With Hemorrhagic Coagumentioning

confidence: 99%

See 1 more Smart Citation

Thrombin Generation Assay and Its Application in the Clinical Laboratory

2016

View full text Add to dashboard Cite

BACKGROUND A gap exists between in vivo and ex vivo coagulation when investigated by use of the coagulation tests prothrombin time (PT) and activated partial thromboplastin time (APTT). The thrombin generation assay (TGA) has been developed to fill this gap. CONTENT TGA evaluates thrombin generation (resulting from the action of the procoagulant driver) and decay (resulting from the action of the anticoagulant driver), thus assessing the balance between the two. Coagulation of the test plasma (platelet poor or platelet rich) is activated by small amounts of tissue factor and phospholipids, and the reaction of thrombin generation is continuously monitored by means of a thrombin-specific fluorogenic substrate. Among the parameters derived from the thrombin-generation curve, the most important is the endogenous thrombin potential, defined as the net amount of thrombin that test plasmas can generate on the basis of the relative strength of the pro- and anticoagulant drivers. TGA is therefore the candidate assay to investigate hypo- or hypercoagulability. SUMMARY From my analysis of the literature, I draw the following conclusions. There is strong evidence that TGA is helpful to elucidate coagulation mechanisms in various clinical conditions that until recently were poorly understood (chronic liver disease; diabetes; inflammatory bowel disease, myeloproliferative neoplasms, nonalcoholic fatty liver disease). TGA is a promising laboratory tool for investigating hemorrhagic coagulopathies and monitoring replacement therapy in hemophiliacs, predicting the risk of recurrent venous thromboembolism after a first event, and monitoring patients on parenteral or oral anticoagulants. These applications require clinical trials in which TGA results are combined with specific clinical end points.

show abstract

Section: Application Of Tga To Manage Patients With Hemorrhagic Coagumentioning

confidence: 99%

Section: Application Of Tga To Manage Patients With Hemorrhagic Coagumentioning

confidence: 99%

Thrombin Generation Assay and Its Application in the Clinical Laboratory

2016

View full text Add to dashboard Cite

show abstract

“…This view is supported by the association between detectable FVIII antigen and NNAs. Measurable FVIII antigen in plasma, 38 potential contamination with maternal blood during delivery, 39 and the presence of milk fat globule epidermal growth factor-FVIII (a glycoprotein with a strong homology with circulating FVIII in breast milk) might all be examples of early exposure. 40 The presence of NNAs before any specific treatment may be the expression of a natural anti-FVIII B-cell clone that exists independently of any environmental FVIII exposure.…”

Section: Discussionmentioning

confidence: 99%

Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A

Cannavó

Valsecchi

Garagiola

et al. 2017

Blood

View full text Add to dashboard Cite

Key Points• Nonneutralizing antibodies against FVIII are detected in untreated or minimally treated patients with hemophilia A.• The presence of nonneutralizing antibodies is associated with a substantially increased risk of inhibitor development.The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors. (Blood. 2017;129(10):1245-1250

show abstract

“…4 Thrombin generation assays (TGAs) measure the total amount of thrombin that can be generated in a volume of platelet-rich or plateletpoor plasma (PRP or PPP). It has been shown to be able to differ between severe and mild bleeding phenotypes, both in mild and severe haemophilia, 5,6 as well as being useful in monitoring the haemostatic effect of bypassing agents in haemophilia patients with inhibitors. 7 In this study, the response to prophylaxis was evaluated with TGA, To avoid unspecific contact activation it has been suggested that corn trypsin inhibitor (CTI) should be added on blood sampling.…”

mentioning

confidence: 99%