Biomedical subjects

A J Reininger

Publications and source records attributed to A J Reininger.

At least 19 recordsLinked to original sources

PubMed2006

Primary haemostasis and its assessment by laboratory tests.

Platelets constantly patrol the inner surface of blood vessels searching leaks to be sealed, in order to prevent blood loss. When they detect a vessel injury their action can be divided into three phases. ADHESION: The platelets adhere to the injured blood vessel wall via their receptors glycoprotein (GP) Ib and integrin alpha2bbeta3 (GPIIb/IIIa) mediated by the ligands von Willebrand factor (VWF), fibrinogen and others. AGGREGATION: Platelets stick to each other through fibrinogen bridging integrin alpha2bbeta3 (GPIIb/IIIa) on adjacent platelets. SECRETION: During activation the content of platelet granules is released by exocytosis, thus augmenting and propagating formation of a haemostatic plug or thrombus. Laboratory tests mimic one or several aspects of these three phases to obtain reliable data on a patients platelet function. In this overview assays, test principles, and pitfalls are presented.

Bleeding Time↗

PubMed2001

Shear stress decreases endothelial cell tissue factor activity by augmenting secretion of tissue factor pathway inhibitor.

Monolayers of human umbilical vein endothelial cells were activated with 50 U/mL interleukin-1alpha (IL-1alpha) for 3 hours and simultaneously conditioned with shear stresses of 0, 0.68, or 13.2 dyne/cm(2) in a parallel-plate flow chamber. In the presence of an inflow buffer containing 100 nmol/L factor X and 10 nmol/L factor VII, production of factor Xa, a measure of functional tissue factor (TF), was determined as the product of outflow concentration of factor Xa (chromogenic assay performed under quasi-static flow conditions after the shear period) and flow rate. Similarly, production of TF pathway inhibitor (TFPI) was estimated as the product of antigenic TFPI (by enzyme-linked immunosorbent assay) in the supernatant and flow rate. In parallel experiments, total RNA was isolated for determination of amplification products of TF mRNA by reverse transcription-polymerase chain reaction. We found that shear stress reduced factor Xa production (mean+/-SE; n=number of experiments) from 13.33+/-1.14 (n=16) fmol/minxcm(2) at 0 shear stress to 5.70+/-2.51 (n=5) and 0.54+/-0.54 (n=4) fmol/minxcm(2) at shear stresses of 0.68 and 13.2 dyne/cm(2), respectively. At the same time, immunogold labeling showed that TF antigen on the endothelial surface increased >5-fold with shear stress, whereas TFPI antigen on the surface increased 2-fold. The secretion of TFPI (appearance of new supernatant TFPI) rose from 7.4+/-2.4 (n=12) x10(-)(3) fmol/minxcm(2) at 0 shear stress to 23.7+/-7.3 (n=9) and 50.2+/-14.3 (n=4) x10(-)(3) fmol/minxcm(2) at 0.68 and 13.2 dyne/cm(2), respectively. TF mRNA amplification products were not markedly changed by shear stress. We conclude that acute application of shear stress reduces functional, but not antigenic, expression of TF by intact, activated endothelial cell monolayers in a manner associated with shear stress-augmented endothelial cell secretion of TFPI.

Antigens↗

PubMed2000

Mildly oxidized low density lipoprotein rapidly stimulates via activation of the lysophosphatidic acid receptor Src family and Syk tyrosine kinases and Ca2+ influx in human platelets.

In contrast to native low density lipoprotein (LDL), mildly oxidized LDL (mox-LDL) induced platelet shape change and stimulated during shape change the tyrosine phosphorylation of specific proteins including Syk; the translocation of Src, Fyn, and Syk to the cytoskeleton; and the increase of cytosolic Ca(2+) due to mainly Ca(2+) entry. The stimulation of these early signal pathways by mox-LDL was inhibited by desensitization of the lysophosphatidic acid (LPA) receptor and specific LPA receptor antagonists, was independent of the alpha(IIb)beta(3)-integrin, and was mimicked by LPA. Stimulation of tyrosine phosphorylation and Syk activation were independent of the increase of cytosolic Ca(2+) and were suppressed by genistein and two specific inhibitors of the Src family tyrosine kinases, PP1 and PD173956. In contrast to PP1 and PD 173956, genistein prevented shape change by mox-LDL. The results indicate that mox-LDL, through activation of the LPA receptor, stimulates two separate early signal pathways, (a) Src family and Syk tyrosine kinases, and (b) Ca(2+) entry. The activation of these early signaling pathways by mox-LDL probably plays a role in platelet responses subsequent to shape change. The inhibition of mox-LDL-induced platelet activation by LPA receptor antagonists or dietary isoflavonoids such as genistein could have implications in the prevention and therapy of cardiovascular diseases.

Blood Platelets↗

PubMed2000

c7E3 Fab inhibits low shear flow modulated platelet adhesion to endothelium and surface-absorbed fibrinogen by blocking platelet GP IIb/IIIa as well as endothelial vitronectin receptor--results from patients with acute myocardial infarction and healthy controls.

The c7E3 Fab reduces ischemic complications in patients undergoing high-risk coronary angioplasty or atherectomy. The present study investigated how c7E3 Fab inhibition of the platelet receptor glycoprotein IIb/IIIa and the endothelial vitronectin receptor affected platelet adhesion to endothelium and surface adsorbed fibrinogen under flow conditions. Platelet adhesion was examined using a stagnation point flow device with shear stress and shear rates up to 2.2 dynes/cm2 and 170 s(-1), respectively. Ex vivo adhesion was compared between two groups of patients with acute myocardial infarction (AMI) treated with angioplasty and stent implantation and a group of healthy controls. Only one AMI group received c7E3 Fab therapy. Patients in both groups were administered acetyl salicylic acid (ASA) and heparin. In AMI patients c7E3 Fab reduced platelet adhesion to adsorbed fibrinogen by 79% compared to AMI patients without c7E3 Fab treatment and by 74% compared to healthy controls. Thirty hours after termination of c7E3 Fab infusion adhesion had slightly recovered with an inhibition of 61% and 52% still present, respectively. Additionally, in vitro platelet adhesion to intact endothelium and to adsorbed fibrinogen was measured during superfusion with ADP stimulated platelet rich plasma of healthy controls to which c7E3 Fab was added at a final concentration fc of 20 microg/ml. In spite of ADP stimulation c7E3 Fab completely blocked platelet adhesion to adsorbed fibrinogen and, moreover, to intact endothelium. Preincubation of endothelial cells with c7E3 (fc = 20 [microg/ml) blocked adhesion of ADP-stimulated platelets by approximately 50%. Apart from the inhibition of platelet aggregation, c7E3 Fab added in vitro and given therapeutically in patients effectively blocks platelet adhesion to components of the injured as well as intact vessel wall under stagnation point flow conditions.

Abciximab↗

PubMed1998

Cardiovascular risk profile after simultaneous pancreas and kidney transplantation.

The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the development of diabetic microvascular lesions is well established. On the other hand, little is known on its impact on diabetic macrovascular disease, which is still the major cause of death in diabetes, including patients after PKT. In order to evaluate the influence of PKT on the cardiovascular risk profile, we performed a cross-sectional study on 55 patients. Special attention was given to the hemorheological parameters fibrinogen and plasma viscosity, two important cardiovascular risk factors, which so far have found no attention in the field of PKT research. The patients were subdivided into three groups according to their graft function: group 1-26 patients after successful PKT (no insulin dependency, serum creatinine <2 mg%), group 2-23 patients after PKT and rejection of the pancreas graft (insulin dependency, serum creatinine <2 mg%), group 3-6 patients after PKT with pancreas rejection and renal insufficiency (insulin dependency, serum creatinine >2 mg%, no dialysis). There was a high prevalence of arterial hypertension after PKT (group 1: 65%, group 2: 70%, group 3: 100%). Serum lipids were in the normal range as long as renal function was intact. In renal insufficiency, however, LDL-cholesterol and triglycerides were significantly elevated (p < 0.05). Fibrinogen was significantly raised after PKT (p < 0.001), as was plasma viscosity when the pancreas graft was rejected (p < 0.02). There was a tendency towards elevated fibrinogen levels with decreasing graft function. In conclusion, a number of cardiovascular risk factors were identified in patients after PKT, predominantly arterial hypertension and impaired hemorheology, with elevated fibrinogen levels and plasma viscosity. There is a further enhancement with decreasing graft function.

Adult↗

PubMed1998

Spreading of platelets: a morphological marker for platelet reactivity in peripheral arterial occlusive disease.

Platelet-surface contact is the first step in thrombus formation. Platelet spreading makes this initial contact irreversible. On the other hand plasma lipids and fibrinogen have been described to activate platelets or promote adhesion. We therefore investigated whether platelet spreading under stagnation-point flow conditions correlated with plasma concentrations of cardiovascular risk factors such as fibrinogen and high density lipoprotein (HDL)-cholesterol. Platelet rich plasma (PRP) from patients with peripheral arterial occlusive disease and healthy controls was examined by means of the Stagnation-Point Flow Adhesio- Aggregometer (SPAA). The SPAA comprises a microscopic setup with a flow chamber that permits direct observation and quantitation of platelet deposition onto standardized surfaces. After the flow experiments the deposited platelets were analyzed morphometrically for the degree of spreading expressed as inverse circularity (1/C). 1/C was correlated over 2 X 2 tables of fibrinogen combined with plasma levels of HDL-cholesterol, each of which was divided into a low and high value group. The patient and control group differed significantly with regard to 1/C, i.e. patient platelets demonstrated more adhesive platelets with a more extensive degree of spreading. 1/C was inversely correlated with HDL-cholesterol and showed significant differences between the patient and the control group. Increased 1/C values were found when associated with high fibrinogen levels and simultaneously with low HDL-cholesterol concentrations. Platelet spreading shows a correlation with increased levels of independent plasmatic risk factors for thrombosis in PAOD patients. Obtained during stagnation-point flow, spreading seems to be a morphological marker for platelet hyperreactivity.

Journal Article↗

PubMed1998

Adhesion of ADP-activated platelets to intact endothelium under stagnation point flow in vitro is mediated by the integrin alphaIIbeta3.

As we demonstrated earlier, platelets adhere to intact endothelium provided they are activated and convectively transported against the endothelial surface. To identify the platelet receptors involved we superfused cultured endothelium with activated platelet rich plasma (PRP) by means of the Stagnation Point Flow Adhesio- Aggregometer while blocking various platelet receptors. Inhibition was performed with the tetrapeptide RGDS, the non-peptide Ro-43-8857, or a monoclonal antibody directed against integrin alphaIIbeta3. Platelet deposition was video-recorded and quantified by image analysis. Infusion of RGDS or Ro-43-8857 into ADP-stimulated PRP completely prevented adhesion as well as subsequent aggregation. Interrupting the inhibitor infusion while ADP stimulation persisted, prompted adhesion and aggregation, demonstrating the reversibility of the inhibition. Platelet adhesion was irreversibly blocked by preincubation of the PRP with the moab against alphaIIbeta3. Its specific binding was confirmed by immunoelectron microscopy. Our results suggest that platelet adhesion to intact endothelium is mediated via platelet integrin alphaIIbeta3.

Adenosine Diphosphate↗

PubMed1998

Impact of pancreas and kidney transplantation on determinants of blood and plasma viscosity.

Simultaneous pancreas and kidney transplantation (PKT) is associated with a deterioration of hemorheology. We investigated the determinants of plasma and blood viscosity (hct. 35%) after PKT (n = 49), in type 1 diabetes (n = 26) and in healthy controls (n = 24). Patients after PKT were subdivided due to their graft function (intact pancreas and kidney graft, n = 26; pancreas rejected, intact kidney graft, n = 23). We examined the correlations of total serum protein, albumin, fibrinogen, alpha 2-macroglobulin, total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides with plasma and blood viscosity (hct. 35%) measured at a continuous shear range of 600-0.2 s-1 with a rotational viscometer (Haake, Germany). Total protein was strongly associated with plasma viscosity in all examined groups (r > 0.5, p < 0.03), it determined blood viscosity over the whole shear range in type 1 diabetic patients, but only at high shear rates after PKT (> or = 100 s-1). The strong association of albumin and blood viscosity in type 1 diabetes and in healthy controls (shear rates > or = 10 s-1) was not found after PKT. Fibrinogen correlated with plasma and blood viscosity (> or = 25 s-1) after PKT (p < 0.03) but no in type 1 diabetic patients or healthy controls. Alpha 2-macroglobulin correlated with plasma and high shear blood viscosity after PKT only after pancreas rejection, no correlation was found after successful PKT. It also correlated with plasma and blood viscosity at low and high shear rates in type 1 diabetes. Total cholesterol and low shear blood viscosity correlated positively in successfully transplanted patients (r > 0.44), but negatively after pancreas rejection (r > -0.44). No correlation was found in type 1 diabetic patients, a positive association was found in healthy controls for plasma and low shear blood viscosity. LDL cholesterol correlated negatively (after pancreas rejection) or positively (healthy controls) with low shear blood viscosity (p < 0.03) and positively with plasma viscosity. HDL cholesterol was negatively associated with high shear blood viscosity in all groups (p < 0.05), except after successful PKT, where no association was found. It did not correlate with plasma viscosity in any group. Triglycerides did not contribute significantly to blood viscosity in the examined groups. The metabolic alterations after PKT influence plasma proteins, lipids and corpuscular elements of blood with regard to their effect on rheology.

Adult↗

PubMed1997

Formation of plasma advanced glycosylation end products (AGEs) has no influence on plasma viscosity.

Plasma viscosity is mainly determined by large non-spherical proteins. In Type 1 diabetes mellitus, plasma viscosity increases with deterioration of diabetic control. Since protein glycation and formation of advanced glycosylation end products (AGEs) alter the structural and functional properties of proteins, AGEs might influence the rheological properties of plasma proteins. Therefore, we investigated the influence of plasma-AGEs on plasma viscosity in 34 normoalbuminuric diabetic patients (17 Type 1, 17 Type 2) with normal renal and liver function. In an additional experiment, 6 ml plasma of 9 healthy volunteers were incubated under sterile conditions for 14 days at 37.5 degrees C in the presence of 5.2 and 32.9 mmol l(-1) glucose. In diabetic patients, plasma-AGE levels were not correlated with plasma viscosity. Plasma-AGE levels in healthy controls (246 +/- 37 U ml[-1], mean +/- SD) were raised significantly (p<0.001) after the incubation at 37.5 degrees C (392 +/- 57 U ml[-1] and 552 +/- 58 U ml[-1], respectively). However, no difference was found in plasma viscosity pre- and post-incubation (pre-incubation: 1.25 +/- 0.04 mPas, post-incubation: 1.23 +/- 0.03 and 1.24 +/- 0.03, respectively). We conclude that there is no influence of plasma-AGEs on plasma viscosity.

Adult↗

PubMed1996

Increased platelet and coagulatory activity indicate ongoing thrombogenesis in peripheral arterial disease.

In peripheral arterial disease (PAD) risk of thrombosis is high and systemic haemostatic derangement thought contributory. We investigated platelet and coagulatory activity in patients with PAD and sought to find the best disease indicator. Stagnation point flow adhesion-aggregometry (SPAA) enables real-time quantitative assessment of platelet adhesion and aggregation under well-defined flow conditions. SPAA and agonist-induced aggregometry (Born method) were performed and concentrations of fibrinogen, fibrin monomer (FM), D-dimer, and thrombin-antithrombin complex (TAT) measured in 92 PAD patients and 70 healthy volunteers. Agonist-induced aggregometry detected no differences between patients and controls. SPAA-measured platelet adhesion and spontaneous aggregation (p < 0.001), and concentrations of fibrinogen (p < 0.001), FM (p < 0.001), TAT (p < 0.02) and D-dimer (p < 0.001) were all significantly increased in patients. Neither platelet function nor coagulatory activity was altered in patients receiving aspirin. Sensitivity and specificity in detecting PAD were as follows: SPAA (95%, 93%), fibrinogen (36%, 91%), FM (48%, 84%), TAT (36%, 78%), D-dimer (73%, 80%). Our findings support the concept of ongoing thrombogenesis as being contributory to the progression and possibly to the initiation of PAD. Aspirin alone did not prevent haemostatic hyperreactivity in these patients and flow-mediated platelet function was the most sensitive and specific indicator of advanced disease. This technique thus appears to be valuable, not only for evaluating therapeutic strategies to prevent platelet activation, but also in elaborating platelet-related mechanisms involved in thrombogenesis and atheroma formation.

Adult↗

PubMed1996

Influence of glycemic control on viscosity and density of plasma and whole blood in type-1 diabetic patients.

The hemorheological properties of blood play an important role in determining blood flow. Blood inertia, as characterized by blood density, controls blood flow in the large arteries, whereas blood viscosity becomes increasingly important with decreasing vessel diameter. In order to evaluate the impact of glycemic control on the rheological properties of blood, we examined viscosity (shear range: 600-0.2 s-1) and density of plasma and whole blood in 26 Type-1 diabetic patients and in 24 healthy controls, matched for age and sex. The diabetic subjects were subdivided into two groups according to their degree of glycemic control: 14 patients with good (HbA1c = 7.1 +/- 0.6%), and 12 patients with poor control (HbA1c = 8.7 +/- 0.7%). Diabetic patients as a whole did not differ from healthy controls in any of the rheological parameters. Subdivision of the patients due to their degree of glycemic control led to a marked rheological separation of Type-1 diabetic subjects with significantly lower plasma (P < 0.008) and whole blood viscosity (P < 0.03 at 10 and 25 s-1), and plasma density (P < 0.05) in well controlled patients. Compared with healthy controls, well controlled diabetic patients had significantly lower values of viscosity (P < 0.005) and density (P < 0.05) of plasma. Poorly controlled patients, on the other hand, did not differ from healthy controls in the examined rheological parameters. There seems to be a positive influence of good glycemic control on hemorheology in Type-1 diabetic patients.

Adult↗

PubMed1996

Agglutination of isolated platelet membranes.

Platelet membrane glycoproteins play a central role in platelet aggregation and thus in primary hemostasis. To investigate mechanisms of platelet-platelet interaction in the absence of cellular activation events, we studied immunological and functional aspects of isolated platelet membranes. Platelet membranes contained significant amounts of the inducible fibrinogen receptor, glycoprotein (GP) IIb-IIIa, which exposes conformation-dependent LIBS1 and PMI-1 epitopes in response to fibrinogen-mimetic peptides GRGDSP and HHLG-GAKQAGDV. In the presence of soluble fibrinogen, membrane-coated latex beads showed Ca(2+)-dependent agglutination that could be partially inhibited by GRGDSP but not by the biologically inactive peptide GRGESP. Thrombospondin enhanced agglutination of membrane-coated beads, which could be inhibited by polyvalent anti-thrombospondin Fab fragments and anti-thrombospondin monoclonal antibody MA-II. Mg2+ inhibited both GPIIb-IIIa- and thrombospondin-mediated agglutination of membranes in a dose-dependent manner. The results of the present study indicate that isolated platelet membranes are a useful tool to study regulation of GPIIb-IIIa- and thrombospondin-mediated platelet-platelet interaction.

Agglutination↗

PubMed1996

Experimental infection with a persistent influenza C virus variant leads to prolonged genome detection in the chicken lung.

A persistent variant of influenza C virus was used to infect chickens by intraamniotic (i.a.) inoculation. The infected hatchings were analyzed for virus production in different tissues and for the continuous presence of viral RNA genomes. The permissiveness for infection was demonstrated primarily for the chicken lung, besides other organs. Viral antigens could be detected by indirect immunofluorescence staining for a period of 8 days and reisolates were obtained mainly at early time points post infection (p.i.). Nested reverse transcription-polymerase chain reaction (RT-PCR) directed to 3 genomic sequences was positive at least until day 53, whereby no distinct end point was determined. These experiments provide first evidence for the long-term stability of influenza C virus RNA segments in vivo.

Animals↗

PubMed1996

Increased platelet and coagulatory activity in peripheral atherosclerosis flow mediated platelet function is a sensitive and specific disease indicator.

The importance of flow in both athero- and thrombogenesis is well established. In peripheral arterial disease (PAD) atherosclerosis is disseminated, thrombosis risk high and systemic hemostatic derangement believed contributory. We studied platelet and coagulatory activity in PAD patients, thereby evaluating the clinical efficacy of Stagnation Point Flow Adhesio-Aggregometry (SPAA). SPAA provides real-time quantitative assessment of platelet adhesion and aggregation under convective, low-shear flow conditions. 62 nondiabetic PAD patients and 66 healthy volunteers were examined, whereby SPAA and conventional aggregometry were performed and circulating fibrinogen, fibrin monomer (FM), the fibrin degradation product D-Dimer and thrombin-antithrombin-complex (TAT) assessed. Conventional aggregometry detected no differences between patients and controls. SPAA-measured platelet function (p < 0.001), fibrinogen (p < 0.001), FM (p < 0.001), TAT (p < 0.02) and D-Dimer (p < 0.001) were significantly increased in patients and not effected by aspirin therapy. Respective sensitivity and specificity in detecting PAD was as follows: SPAA (96%/95%), fibrinogen (36%/92%), FM (46%/88%), TAT (40%/73%), D-Dimer (75%/80%). Increased platelet and coagulatory activity was verified in PAD, whereby flow-mediated platelet adhesion and aggregation proved the most sensitive and specific parameter. These findings indicate the usefulness of SPAA for delineating platelet-related disease mechanisms and evaluating therapeutic strategies to prevent platelet activation.

Antithrombin III↗

PubMed1995

Fluid mechanics of the stagnation point flow chamber and its platelet deposition.

The interaction of flow and thrombus generation often is a crucial question for the engineer working in the field of artificial organs. However, this interaction is only incompletely known, and quantitative data under well-defined experimental conditions are especially rare. These can be attained with the stagnation point flow chamber. This flow model applies platelet-rich plasma (PRP) as fluid. Its flow conditions are assessed with the help of computational fluid mechanics. In addition, the concept of the boundary layer is introduced, which permits assessment of the platelet flow along the wall. The results of the experiment indicate that platelets are deposited at a defined shear rate.

Animals↗

PubMed1995

Occlusive thrombus formation on indwelling catheters: in vitro investigation and computational analysis.

To determine the hydrodynamic parameters involved in thrombus formation on indwelling catheters, fibrin coagulation was investigated in an in vitro model and compared with the prevailing flow field. Computational analysis was used to simulate clot growth and identify the variables which determine its localization. The fibrin clot grew from the distal end of the catheter along the interface between the bulk stream and the annular vortex located immediately downstream of the catheter tip, finally filling the entire vortex. The calculations of flow parameters for three different growth stages showed that regions of clot formation always correlated with regions exhibiting the longest residence time. Fibrin clotting could be simulated by a mathematical model using residence time as the only variable parameter. Our results demonstrate that the residence time is the single most important flow factor for fibrin coagulation and thus probably for thrombus formation. When the residence time equals the clotting time for the fluid, thrombus formation is initiated. Conversely, it ceases when the area of long fluid residence times is replaced by a fibrin clot. Hence the fibrin clot represents a hydrodynamic optimization of the previously disturbed flow.

Animals↗

PubMed1995

Effect of fibrinogen substitution in afibrinogenemia on hemorheology and platelet function.

Fibrinogen substitution can correct bleeding in afibrinogenemia. We assessed the effect of fibrinogen substitution in a patient lacking immunoreactive fibrinogen. Fibrinogen and thrombin time were not measurable before, but became detectable within 30 min after substitution, parallelled by an increase in ADP-induced platelet aggregation from < 10% to 32%. Platelet adhesion, measured by Stagnation Point Flow Adhesio- Aggregometry, was not detectable prior to substitution but attained normal values thereafter. Scanning electron microscopy of adhering platelets revealed pseudopodia protrusion and spreading. Morphometry revealed two populations of spread platelets one of which demonstrated inhibited spreading as compared to healthy controls. Immunoelectron microscopy revealed normal GPIIb/IIIa receptor expression, both before and after substitution. Dynamic and kinematic viscosity of plasma and whole blood remained below the 99.9% confidence border of a healthy control group. In afibrinogenemia fibrinogen levels as low as 10% of normal concentration sufficed to normalize coagulation, platelet adhesion, and, partially, spreading.

Adult↗

PubMed1995

Residence time in niches of stagnant flow determines fibrin clot formation in an arterial branching model--detailed flow analysis and experimental results.

Deposition of blood components in branching flow has been investigated primarily with regard to platelets. We instead examined thrombin-induced fibrin clot formation in separated laminar as well as turbulent branching flow. The most rapid clot growth and largest clot was obtained at the lowest inflow rate. Increased inflow reduced the clot size and turbulence completely prevented clot formation. Examination of corresponding flow conditions revealed the recirculation zone in laminar flow to be characterized by two stationary, counterrotating vortices. Niches of stagnant flow, exhibiting long residence times, low wall shear rates and characterized by convergent flow, were spared between the bulk flow and these vortices. Here, fibrin clot growth continued even when shear rates were increased more than 100-fold. Our results indicate that, in branching flow, the long residence times and convergent flow characteristic of flow niches rather than shear rate are critical for fibrin clot formation.

Arteries↗