Thrombospondin-1 inhibits ADAMTS13 activity in sickle cell disease

Novelli, Enrico M.; Kato, Gregory J.; Hildesheim, Mariana; Barge, Suchitra; Meyer, Michael; Lozier, Jay N.; Hassett, Andrea Cortese; Ragni, Margaret V.; Isenberg, Jeffrey S.; Gladwin, Mark T.

doi:10.3324/haematol.2013.092635

Cited by 38 publications

(56 citation statements)

References 15 publications

(16 reference statements)

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“…In patients with SCD, reduced ADAMTS13 activity may account, at least in part, for the increased circulating levels of vWF, especially the ultra-large multimer forms (100,101), and subsequent elevation of plasma level of FVIII. However, in one study, plasma vWF level was not significantly different in SCD patients with and without undetectable ADAMTS13 activity, suggesting that ADAMTS13 activity is not the sole regulatory determinant of vWF levels in SCD (98). …”

Section: Hemostatic Alterations Of Scdmentioning

confidence: 95%

“…FVIII also strongly correlates with von Willebrand factor antigen (vWF:Ag) and markers of hemolysis, but not with high-sensitivity C-reactive protein, suggesting a role for hemolysis in the elevation of plasma levels of FVIII in SCD (94). Reduced ADAMTS13 activity has been reported in patients with SCD at “steady state” (97,98). Other studies have reported similar ADAMTS13 activity in SCD patients and controls, but reduced ADAMTS13 activity/vWF:Ag ratio in patients at “steady state,” with further reduction during pain crisis (99,100).…”

Section: Hemostatic Alterations Of Scdmentioning

confidence: 99%

“…In vitro studies demonstrate that cell-free hemoglobin released during intravascular hemolysis can bind the A2 domain of the von Willebrand molecule and prevent its cleavage by ADAMTS13 (97). In addition, high plasma levels of thrombospondin-1 have been observed in some SCD patients with undetectable levels of ADAMTS13 activity, suggesting an inhibitory effect of thrombospondin-1 on enzyme activity (98). In patients with SCD, reduced ADAMTS13 activity may account, at least in part, for the increased circulating levels of vWF, especially the ultra-large multimer forms (100,101), and subsequent elevation of plasma level of FVIII.…”

Section: Hemostatic Alterations Of Scdmentioning

confidence: 99%

See 2 more Smart Citations

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

2016

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Sickle cell disease (SCD) is a hypercoagulable state. Patients exhibit increased platelet activation, high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis “steady state.” Furthermore, SCD is characterized by an increased risk of thrombotic complications. The pathogenesis of coagulation activation in SCD appears to be multi-factorial, with contributions from ischemia-reperfusion injury and inflammation, hemolysis and nitric oxide deficiency, and increased sickle RBC phosphatidylserine expression. Recent studies in animal models suggest that activation of coagulation may contribute to the pathogenesis of SCD, but the data on the contribution of coagulation and platelet activation to SCD-related complications in humans are limited. Clinical trials of new generations of anticoagulants and antiplatelet agents, using a variety of clinical endpoints are warranted.

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Section: Hemostatic Alterations Of Scdmentioning

confidence: 95%

Section: Hemostatic Alterations Of Scdmentioning

confidence: 99%

Section: Hemostatic Alterations Of Scdmentioning

confidence: 99%

See 1 more Smart Citation

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

2016

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“…Although no haemodynamic impairment was reported in its original description [18], the occurrence of shock is not uncommon and probably accounts for most of the deaths during SMOF [15 & ,16,17].The absence of haemodynamic impairment might explain the discrepancy between the low mortality rate reported in the original case series [18] and the fact that SMOF appears to be a major cause of death [14,15 & ,16]. A large number of clinical, biological, and autopsy findings highlight many overlaps between SMOF and other non-SCD conditions such as fat embolism and thrombotic microangiopathy syndromes [35][36][37][38][39][40][41][42], especially in patients who worsen despite aggressive and effective transfusion [14, 36,37]. Thus, SMOF better meets the definition of a syndrome that we name 'catastrophic sickle cell syndrome'.…”

Section: Key Pointsmentioning

confidence: 89%

“…Thus, SMOF better meets the definition of a syndrome that we name 'catastrophic sickle cell syndrome'. However, stigmata of fat embolism or thrombotic microangiopathy syndromes are inconstantly associated with SMOF, and vice versa [35,39,43]. It is more likely that each of these mechanisms act in a various combination and whether they play a real pathogenic role or just reflect a severe and diffuse vaso-occlusive phenomenon is unknown.…”

Section: Key Pointsmentioning

confidence: 92%

Sickle cell disease in the ICU

Cecchini

Fartoukh

2015

Current Opinion in Critical Care

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Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease

et al. 2016

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A growing body of evidence suggests a role for platelets in sickle cell disease (SCD). Despite the pro-inflammatory, occlusive nature of platelets, a role for platelets in acute chest syndrome (ACS), however, remains understudied. To provide evidence and potentially describe contributory factors for a putative link between ACS and platelets, we performed an autopsy study of 20 SCD cases – 10 of whom died from ACS and 10 whose deaths were not ACS-related. Pulmonary histopathology and case history were collected. We discovered that disseminated pulmonary platelet thrombi were present in 3 out of 10 of cases with ACS, but none of the matched cases without ACS. Those cases with detected thrombi were associated with significant deposition of endothelial vWF and detection of large vWF aggregates adhered to endothelium. Potential clinical risk factors were younger age and higher platelet count at presentation. However, we also noted a sharp and significant decline in platelet count prior to death in each case with platelet thrombi in the lungs. In this study, neither hydroxyurea use nor perimortem transfusion was associated with platelet thrombi. Surprisingly, in all cases, there was profound pulmonary artery remodeling with both thrombotic and proliferative pulmonary plexiform lesions. The severity of remodeling was not associated with a severe history of ACS, or hydroxyurea use, but was inversely correlated with age. We thus provide evidence of undocumented presence of platelet thrombi in cases of fatal ACS describe clinical correlates. We also provide novel correlates of pulmonary remodeling in SCD.

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Thrombospondin-1 inhibits ADAMTS13 activity in sickle cell disease

Cited by 38 publications

References 15 publications

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

Sickle cell disease in the ICU

Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease

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