title: Platelet Control of Fibrin Distribution and Microelasticity in Thrombus Formation Under Flow.
abstract: OBJECTIVE
  Platelet- and fibrin-dependent thrombus formation is regulated by blood flow and exposure of collagen and tissue factor. However, interactions between these blood-borne and vascular components are not well understood.
  
  
  RESULTS
  Here, we developed a method to assess whole-blood thrombus formation on microspots with defined amounts of collagen and tissue factor, allowing determination of the mechanical properties and intrathrombus composition. Confining the collagen content resulted in diminished platelet deposition and fibrin formation at high shear flow conditions, but this effect was compensated by a larger thrombus size and increased accumulation of fibrin in the luminal regions of the thrombi at the expense of the base regions. These thrombi were more dependent on tissue factor-triggered thrombin generation. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminal-oriented fibrin. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Studies with blood from patients with distinct hemostatic insufficiencies indicated an impairment in the formation of a platelet-fibrin thrombus in the cases of dilutional coagulopathy, thrombocytopenia, Scott syndrome, and hemophilia B.
  
  
  CONCLUSIONS
  Taken together, our data indicate that (1) thrombin increases the platelet thrombus volume; (2) tissue factor drives the formation of fibrin outside of the platelet thrombus; (3) limitation of platelet adhesion redirects fibrin from bottom to top of the thrombus; (4) a lower shear rate promotes thrombus coverage with fibrin; (5) the fibrin distribution pattern determines thrombus microelasticity; and (6) the thrombus-forming process is reduced in patients with diverse hemostatic defects.
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Frauke
authors: F
authors: Swieringa
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Constance C F M J
authors: CC
authors: Baaten
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Remco
authors: R
authors: Verdoold
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Tom G
authors: TG
authors: Mastenbroek
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Niek
authors: N
authors: Rijnveld
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Koen O
authors: KO
authors: van der Laan
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Ernst J
authors: EJ
authors: Breel
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Peter W
authors: PW
authors: Collins
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Marcus D
authors: MD
authors: Lancé
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Yvonne M C
authors: YM
authors: Henskens
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Judith M E M
authors: JM
authors: Cosemans
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Johan W M
authors: JW
authors: Heemskerk
authors: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (F.S., C.C.F.M.J.B., R.V., T.G.M., J.M.E.M.C., J.W.M.H., P.E.J.v.d.M.); Research and Development, Optics11, Amsterdam, The Netherlands (N.R., K.O.v.d.L., E.J.B.); Arthur Bloom Haemophilia Centre, Cardiff Institute of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom (P.W.C.); and Central Diagnostic Laboratory (Y.M.C.H.), Departments of Anaesthesiology (M.D.L.) and Internal Medicine (Y.M.C.H.), Maastricht University Medical Center, Maastricht, The Netherlands. p.vandermeijden@maastrichtuniversity.nl.
authors: Paola E J
authors: PE
authors: van der Meijden
mesh_terms: D001777:Blood Coagulation; D001778:Blood Coagulation Disorders / Q000097:blood / Q000503:physiopathology; D001780:Blood Coagulation Tests; D001783:Blood Flow Velocity; D001792:Blood Platelets / Q000378:metabolism*; D016022:Case-Control Studies; D003094:Collagen / Q000097:blood; D004548:Elasticity; D005337:Fibrin / Q000378:metabolism*; D002836:Hemophilia B / Q000097:blood / Q000503:physiopathology; D006801:Humans; D012039:Regional Blood Flow; D013921:Thrombocytopenia / Q000097:blood / Q000503:physiopathology; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D005337:Fibrin; D003094:Collagen; D013925:Thromboplastin
keywords: blood platelet; elasticity; fibrin; thrombin; thrombosis