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An evolutionary conserved, immobility associated antithrombotic mechanism

ABSTRACT: Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a main cause of morbidity and mortality that causes tremendous health care costs. Short term immobility related conditions arising from hospitalization, acute trauma and forced bed rest are major risk factors for the development of VTE. In contrast, chronically paralyzed patients with post-spinal cord injury are protected from VTE despite immobilization. Similarly, free-ranging brown bears (Ursus arctos) that hibernate (immobilize) have adapted to this threat through yet to be discovered mechanisms and do not develop VTE. This suggests that long-term immobility can induce antithrombotic mechanisms that are evolutionarily conserved. Here we aimed to identify these adaptive mechanisms of VTE protection in a cross-species approach. Mass spectrometry-based proteomics identified platelet expressed heat shock protein 47 (Hsp47) as the most substantially downregulated protein during brown bear hibernation. In a clinical bed rest study and in spinal-cord injured humans, we likewise observed drastic reduction of platelet-expressed Hsp47. Genetic ablation and pharmaceutical inhibition of platelet Hsp47 attenuates deep vein thrombosis and thromboinflammatory responses in mice and human blood cells. This suggests that Hsp47 downregulation is an evolutionarily conserved mechanism that also protects immobilized patients from VTE. Our translational approach thus identified an antithrombotic signature that may give rise to novel antithrombotic therapeutics and prognostic markers.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet, Platelet

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD031521 | Pride | 2023-04-14

REPOSITORIES: Pride

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Project description:Antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis. The unfavorable fibrin clot phenotype, including formation of dense and poorly lysable clots, has been reported both in thrombotic APS and venous thromboembolism (VTE). The presence and amount of different proteins within a plasma clot, not only associated with the coagulation system, may influence clot properties. To our knowledge, there is a lack of data on plasma fibrin-clot bound proteins in patients with thrombotic APS or VTE. The aim of our study was to perform a quantitative proteomic analysis of fibrin clots prepared from citrated plasma from subjects with thrombotic APS and prior VTE, along with fibrin clot permeability (Ks) and clot lysis time (CLT) assessed ex vivo. We investigated 23 consecutive patients with APS, 18 with a history of first-ever VTE, and 20 age and sex matched healthy subjects. A multiple enzyme digestion filter aided sample preparation and a multienzyme digestion (MED) FASP method combined with LC-MS/MS analysis performed on a Proxeon Easy-nLC System coupled to the Q Exactive HF mass spectrometer were used. The proteomic analysis revealed that clot composition regarding 117 proteins in APS patients and 48 proteins in VTE patients was changed as compared to healthy controls, while 72 clot-bounded proteins differed between APS and VTE subjects. In healthy controls, Ks was associated with fibrinogen alpha and gamma chains (r=0.46 and r=0.46, both p<0.05, respectively) or apolipoprotein B-100 (r=-0.53, p<0.05), while CLT correlated with annexin A2 (r=-0.58, p<0.05), apolipoportein(a) (r=0.47, p<0.05), or platelet glycoprotein 4 (r=0.59, p<0.05). In VTE patients correlations of Ks with complement C1q and histone H2B, as factors closely linked with thrombosis, were observed (r=-0.52 and r=-0.47, both p<0.05, respectively). In patients with thrombotic APS all above-mentioned associations were not found. This study is the first to show that different proteins are able to influence the clot formation, structure, and properties. Since, prothrombotic conditions abolished associations observed in healthy subjects fibrin clots, differences in protein clot components might explain the links between prothrombotic fibrin clot phenotype and thromboembolic events.

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An evolutionary conserved, immobility associated antithrombotic mechanism

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