Decreased mortality of ischaemic heart disease among carriers of haemophilia

Šrámek, A.; Kriek, Marjolein; Fr, Rosendaal

doi:10.1016/s0140-6736(03)14021-4

Cited by 117 publications

(48 citation statements)

References 20 publications

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“…The proportionate reductions in mortality from heart disease were virtually identical in severe and in moderate/mild hemophilia, at 38% and 37%, respectively (Table 4) and were similar to the value observed in a recent study of mortality from ischemic heart disease among carriers of hemophilia 25 (36%, based on 39 deaths). This argues against a gradually increasing protective effect as concentrations of factor VIII and IX decrease and in favor of a threshold effect.…”

Section: Mortality From Cardiovascular Diseasesupporting

confidence: 84%

Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV

Darby¹,

Kan

Spooner

et al. 2007

Blood

467

480

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Section: Mortality From Cardiovascular Diseasesupporting

confidence: 84%

Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV

Darby¹,

Kan

Spooner

et al. 2007

Blood

467

480

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“…In addition, mortality due to ischemic heart diseases (but not cerebral stroke) in both hemophilia A (FVIII deficiency) and hemophilia B (FIX deficiency) patients is actually lower compared with the general male population. 31,32 Data from the present study indicate that PAI-1 is also essential in maintaining cardiac homeostasis and microvascular integrity. Indeed, interstitial hemosiderin deposition, near the pericardium, as revealed by Prussian blue staining, was detected in younger PAI-1 Ϫ/Ϫ hearts, but not in WT hearts.…”

Section: Org Frommentioning

confidence: 66%

Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture

Castellino

Ploplis

2010

Blood

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Although the involvement of plasminogen activator inhibitor-1 (PAI-1) in fibrotic diseases is well documented, its role in cardiac fibrosis remains controversial. The goal of this study was to determine the effect of a PAI-1 deficiency (PAI-1−/−) on the spontaneous development of cardiac fibrosis. PAI-1−/− mice developed pervasive cardiac fibrosis spontaneously with aging, and these mice displayed progressively distorted cardiac architecture and markedly reduced cardiac function. To mechanistically elucidate the role of PAI-1 in cardiac fibrosis, 12-week-old mice were chosen to study the biologic events leading to fibrosis. Although fibrosis was not observed at this early age, PAI-1−/− hearts presented with enhanced inflammation, along with increased microvascular permeability and hemorrhage. A potent fibrogenic cytokine, transforming growth factor-β (TGF-β), was markedly enhanced in PAI-1−/− heart tissue. Furthermore, the expression levels of several relevant proteases associated with tissue remodeling were significantly enhanced in PAI-1−/− hearts. These results suggest that PAI-1 is cardioprotective, and functions in maintaining normal microvasculature integrity. Microvascular leakage in PAI-1−/− hearts may provoke inflammation, and predispose these mice to cardiac fibrosis. Therefore, a PAI-1 deficiency contributes to the development of cardiac fibrosis by increasing vascular permeability, exacerbating local inflammation, and increasing extracellular matrix remodeling, an environment conducive to accelerated fibrosis.

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“…On the other hand, there were no major differences between siRNA and pharmacological modalities applied to fIXa as both could mimic the human hemophilia B observations (Sramek et al. 2003; Darby et al. 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In one example, it has been reported that approximately 99–50% reduction in levels of fIX (as observed in moderate, mild hemophilia B patients and carriers of hemophilia B) are associated with a reduced risk of thrombosis (Sramek et al. 2003; Darby et al. 2007) for acceptable levels of bleeding.…”

Section: Introductionmentioning

confidence: 99%

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

Ankrom

Wood

et al. 2016

Pharmacology Res & Perspec

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The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (C min) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An I max and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA‐mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban.

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Decreased mortality of ischaemic heart disease among carriers of haemophilia

Cited by 117 publications

References 20 publications

Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV

Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV

Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

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