Growth Hormone, Atherosclerosis and Peripheral Arterial Disease: Exploring the Spectrum from Acromegaly to Growth Hormone Deficiency.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are increasingly recognised for their role in cardiovascular (CV) physiology. The GH-IGF-1 axis plays an essential role in the development of the CV system as well as in the complex molecular network that regulates cardiac and endothelial structure and function. A considerable correlation between GH levels and CV mortality exists even among individuals in the general population without a notable deviation in the GHIGF- 1 axis functioning. In addition, over the last decades, evidence has demonstrated that pathologic conditions involving the GH-IGF-1 axis, as seen in GH excess to GH deficiency, are associated with an increased risk for CV morbidity and mortality. A significant part of that risk can be attributed to several accompanying comorbidities. In both conditions, disease control is associated with a consistent improvement of CV risk factors, reduction of CV mortality, and achievement of standardised mortality ratio similar to that of the general population. Data on the prevalence of peripheral arterial disease in patients with acromegaly or growth hormone deficiency and the effects of GH and IGF-1 levels on the disease progression is limited. In this review, we will consider the pivotal role of the GH-IGF-1 axis on CV system function, as well as the far-reaching consequences that arise when disorders within this axis occur, particularly in relation to the atherosclerosis process.

Endocrine Disorders and Peripheral Arterial Disease - A Series of Reviews Cushing Syndrome-Cortisol Excess.

Cushing syndrome (CS), characterised by endogenous or exogenous glucocorticoid hormone excess, is associated with several systemic complications, including impaired glucose metabolism, which often becomes clinically manifest as diabetes mellitus (DM). In addition, CS can harm the arterial wall because of hyperglycaemia, dyslipidaemia, hepatic steatosis, and central obesity. These metabolic disorders promote atherosclerosis by synthesising adipokines, leptin, and proinflammatory cytokines. Lower limb arterial complications in CS are common and significantly impact morbidity and mortality. Furthermore, CS, in combination with DM, is likely to cause more diffuse vascular disease that predominantly affects distal arterial beds. In conclusion, CS promotes atherosclerosis, including peripheral artery disease, by causing functional and morphological deterioration of the arterial vessel wall and increasing the presence of classical risk factors of atherosclerosis.

Clinical Exome Sequencing as a Novel Tool for Diagnosing Loeys-Dietz Syndrome Type 3.

OBJECTIVE/BACKGROUND: In rare genetic vascular syndromes the diagnosis may not be apparent from the phenotype, but might be important for proper management. METHODS: A previously healthy woman without dysmorphic features presented with pregnancy associated vascular dissections and aneurysms. Next generation clinical exome sequencing was performed. RESULTS: The differential diagnosis of spontaneous arterial dissection is outlined. The patient's diagnosis became evident after clinical exome sequencing detected a novel missense mutation in the evolutionary conserved region of SMAD3, confirming the diagnosis of Loeys-Dietz syndrome (LDS) type 3. A brief overview of the various types of LDS and their management is presented. CONCLUSION: Clinical exome sequencing proved useful in diagnosing LDS type 3 where detailed vascular surveillance and timely intervention with a low threshold is recommended.

Nurr1 haplotypes are associated with femoropopliteal restenosis/re-occlusion after percutaneous transluminal angioplasty.

Restenosis/re-occlusion remains a frequent complication in the first year after percutaneous transluminal angioplasty (PTA). In this study, association of nuclear receptor related 1 protein (Nurr1) haplotypes to the restenosis/re-occlusion rate after femoropopliteal PTA was investigated. Patients (n = 142) with disabling claudication or critical limb ischaemia, who had undergone technically successful femoropopliteal PTA, were prospectively followed up by vascular ultrasound imaging 12 months after the procedure. Nurr1 haplotypes 2 and 3 were associated significantly with the restenosis/re-occlusion rate (adjusted odds ratio 1.6, 95% confidence interval (CI) 1.1-2.3 and 2.0, 1.3-2.8, respectively) on univariate analysis.

Prevention of ischemic events in patients with peripheral arterial disease design, baseline characteristics and 2-year results an observational study.

AIM: Peripheral arterial disease (PAD) is associated with frequent cardiovascular ischemic events. We followed the survival of PAD patients and tested whether PAD remains an adverse prognostic indicator in spite of treatment according to the current European guidelines on cardiovascular disease prevention. METHODS: Eight hundred eleven patients with PAD and 778 control subjects, aged 65 (SD 9) years at inclusion, with a male/female ratio of 3/2 were treated according to the European guidelines on cardiovascular disease prevention and evaluated yearly for occurrence of death, non-fatal acute coronary syndrome, stroke or critical limb ischemia (major events) and revascularization procedures (minor events). At baseline, classical risk factors were significantly more prevalent in the PAD group and protective cardiovascular medication was prescribed to patients with PAD more frequently than to control subjects. RESULTS: In the PAD group, the 2-year Kaplan-Meier survival estimate was 96.7% (CI 95.4-97.9) vs. 98.2% (CI 97.2-99.1) in the control group, P=0.059. The groups differed in the 2-year major event-free survival: 93.5% (CI 92.7-95.3) in PAD vs. 97.1% (CI 95.9-98.4) in controls, P<0.017, as well as in event-free survival: 79.9% (CI 77.1-82.9) in PAD vs.96.4% (CI 95.0-97.9) in controls, P<0.001. CONCLUSION: Patients with PAD had a borderline higher risk of all-cause death and a significantly higher risk of major and minor non-fatal cardiovascular events compared to control subjects. However, treatment according to the European guidelines on cardiovascular disease prevention resulted in encouragingly low absolute mortality and morbidity. (ClinicalTrials.gov number NCT00761969.).

Infrapopliteal run-off and the outcome of femoropopliteal percutaneous transluminal angioplasty.

BACKGROUND: The outcome of percutaneous transluminal angioplasty (PTA) of peripheral arterial lesions is influenced by several factors, including the haemodynamic conditions. Our study tested: (a) whether infrapopliteal run-off after completed PTA influenced the time course of restenosis/reocclusion of the femoropopliteal arterial segment, and (b) whether worsening of infrapopliteal run-off influenced the long-term femoropopliteal patency after PTA. PATIENTS AND METHODS: Among 245 patients treated by femoropopliteal PTA we enrolled 176 patients who consented to regular follow-up. Concomitant infrapopliteal PTA was performed whenever feasible. The technical success of PTA and the patency of calf arteries were assessed by angiography. Infrapopliteal run-off was scored by a modification of the Society for Vascular Surgery criteria. The treated patients' limbs were divided into a group with good infrapopliteal run-off and a group with compromised run-off. Follow-up examination of the femoropopliteal arterial segment was performed by vascular ultrasonography (US) 1, 6 and 12 months after PTA, and an adverse outcome was defined by a > or = 50 % stenosis, i.e., at least doubling of the maximal systolic velocity, or occlusion - evidenced by the absence of flow. The patency of calf arteries was re-assessed by US 12 months after PTA. RESULTS: One month after femoropopliteal PTA 19 / 83 (23 %) of patients with compromised run-off developed the combined end-point of restenosis or reocclusion in comparison to 10 / 93 (11 %) with good run-off (p = 0.03). After 6 months the incidence of restenosis/reocclusion had increased in both groups at an approximately equal rate, but the differences were no longer significant: 39 / 80 (49 %) in the compromised run-off group vs. 36 / 83 (43 %) in the good run-off group after 6 months, p = 0.49, and 42 / 73 (57 %) vs. 38 / 73 (52 %) after 12 months, p = 0.51. However, in patients' limbs with good periprocedural run-off that deteriorated into compromised run-off in the year after PTA, femoropopliteal restenosis/reocclusion occurred more often than in limbs which retained good run-off: 10 / 14 (71 %) vs. 18 / 51 (35 %), p = 0.02. CONCLUSIONS: Compromised postprocedural infrapopliteal run-off predisposes to early restenosis/reocclusion after femoropopliteal PTA. Deterioration of infrapopliteal run-off in the year after femoropopliteal PTA is accompanied by worsening of long-term femoropopliteal patency.

A mathematical model for the dissolution of non-occlusive blood clots in fast tangential blood flow.

Our aim was to study the effect of an axially directed blood plasma flow on the dissolution rate of cylindrical non-occlusive blood clots in an in vitro flow system and to derive a mathematical model for the process. The model was based on the hypothesis that clot dissolution dynamics is proportional not only to the biochemical proteolysis of fibrin but also to the power of the flowing blood plasma dissipated along the clot. The predicted rate of thrombolysis is then proportional to the square of the average blood plasma velocity for laminar flow and to the third power of the average velocity for turbulent flow. To verify the model, the time dependence of the clot cross-sectional area was measured by dynamic magnetic resonance microscopy during fast (turbulent) and slow (laminar) flow of plasma through an axially directed channel along the clot. The flowing plasma contained a magnetic resonance imaging contrast agent (Gd-DTPA) and a thrombolytic agent (recombinant tissue-type plasminogen activator). The experimental data fitted well to the model, and confirmed the predicted increase in the dissolution rate when blood flow changed from a laminar to a turbulent flow regime.

Modelling the effect of laminar axially directed blood flow on the dissolution of non-occlusive blood clots.

Axially directed blood plasma flow can significantly accelerate thrombolysis of non-occlusive blood clots. Viscous forces caused by shearing of blood play an essential role in this process, in addition to biochemical fibrinolytic reactions. An analytical mathematical model based on the hypothesis that clot dissolution dynamics is proportional to the power of the flowing blood plasma dissipated along the clot is presented. The model assumes cylindrical non-occlusive blood clots with the flow channel in the centre, in which the flow is assumed to be laminar and flow rate constant at all times during dissolution. Effects of sudden constriction on the flow and its impact on the dissolution rate are also considered. The model was verified experimentally by dynamic magnetic resonance (MR) microscopy of artificial blood clots dissolving in an in vitro circulation system, containing plasma with a magnetic resonance imaging contrast agent and recombinant tissue-type plasminogen activator (rt-PA). Sequences of dynamically acquired 3D low resolution MR images of entire clots and 2D high resolution MR images of clots in the axial cross-section were used to evaluate the dissolution model by fitting it to the experimental data. The experimental data fitted well to the model and confirmed our hypothesis.

Pharmacological prevention of atherothrombotic events in patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is strongly associated with atherosclerosis in the coronary and carotid arteries, leading to a highly increased incidence of myocardial infarction, ischaemic stroke and cardiovascular death. Fortunately, pharmacological interventions in large clinical trials have been as effective in subgroups of patients with PAD as in subjects with other atherosclerotic disease. Antiplatelet treatment is indicated in virtually all patients with PAD. Aspirin 75-325 mg day(-1) is considered as first-line treatment, and clopidogrel 75 mg day(-1) is an effective alternative. Statin therapy is indicated to achieve a target low-density lipoprotein cholesterol level of < or = 2.5 mmol L(-1) in patients with PAD and there is emerging evidence that even lower levels are beneficial. Lowering of plasma homocysteine by supplementing folic acid, vitamin B(12) and vitamin B(6) is not recommended in patients with mild to moderate hyperhomocysteinaemia in the 12-25 micromol L(-1) range, since it does not reduce the incidence of cardiovascular events. Antihypertensive treatment is indicated to achieve a goal blood pressure of < or = 140/90 mmHg or < or = 130/80 mmHg in the presence of diabetes or chronic kidney disease. All classes of antihypertensive drugs are acceptable for treatment of hypertension in patients with PAD, but angiotensin-converting enzyme inhibitors ramipril or perindopril are especially appropriate because they reduce the incidence of cardiovascular events beyond their blood pressure-lowering effects. Beta-blockers should not be used as first-line antihypertensive treatment. Diabetic patients with PAD should reduce their glycosylated haemoglobin to < or = 7%. In conclusion, pharmacological secondary prevention of cardiovascular morbidity and mortality in patients with PAD should be as comprehensive as that in patients with established coronary or cerebrovascular disease.

Serum amyloid A in autoimmune thrombosis.

The objectives of this study were (1) to determine how levels of serum amyloid A (SAA), high sensitivity C-reactive protein (CRP) and interleukin-6 (IL-6) correlate to autoimmune diseases in patients with or without thrombosis, and (2) to discuss the parameters that influence the relative SAA values. SAA, CRP and IL-6 concentrations were determined by enzyme linked immunosorbent assay (ELISA). 84 patients with secondary antiphospholipid syndrome (SAPS), primary antiphospholipid syndrome (PAPS), systemic lupus erythematosus with antiphospholipid antibodies (SLE+aPL), SLE, venous thrombosis (VT), arterial thrombosis (AT) were compared to healthy donors (n=60). The percentages of patients above cut-off were highest in the SAPS, SLE and SLE+aPL groups. Significant differences were observed between healthy donors and inflammatory groups of patients (SAPS and SLE+aPL) in all three measured parameters. SAA and CRP were shown to be correlated to a greater extent in SAPS patients than SLE+aPL patients. In summary, this cross-sectional, retrospective, small study and accompanying clinical considerations limit the ability to make definite conclusions. SAA would not serve as a useful marker for venous, arterial thrombosis or PAPS (pro-coagulant events). It could however, be a good predictor of progression from a non-inflammatory thrombotic condition to an inflammatory one.

Lysability of arterial thrombi assessed by magnetic resonance imaging.

BACKGROUND: Intravascular thrombi change in time due to retraction and organization, which is reflected in the appearance of magnetic resonance images of clots. We have hypothesized that MRI has the potential to improve patient selection for thrombolytic treatment. The aim of our study was to analyze occlusive arterial thrombi with MRI, and to correlate the MRI parameters with the therapeutic outcome in patients with occlusive atherothrombotic disease of the superficial femoral artery who were treated with catheter-directed thrombolysis by streptokinase. PATIENTS AND METHODS: We included 13 patients with subacute (2 weeks to 3 months old) occlusive arterial thrombi and 4 patients with chronic (more than 6 months old) arterial occlusions. We measured the MRI signal intensity on gradient echo images of 98 axial slices of the subacute occlusive thrombi and in 45 slices of 4 chronic thrombi. Following MRI, the patients with subacute history were treated with catheter-directed thrombolysis. RESULTS: Thrombolysis was successful in 11/13 patients. The normalized MRI signal intensity was significantly higher in the unsuccessfully treated thrombi than in the successfully treated thrombi (1.10 +/- 0.08 vs. 0.72 +/- 0.17, p < 0.003), but the subacute and chronic thrombi did not differ in signal intensity. CONCLUSIONS: High signal intensity of arterial thrombi on gradient echo MRI might predict resistance to thrombolytic therapy.

Biochemical and biophysical conditions for blood clot lysis.

We have studied how pharmacological dissolution of blood clots was affected by clot retraction, the mode of transport of fibrinolytic agents into the clot and the thickness of the composite fibrin fibers. Retracted clots were resistant to fibrinolysis in a milieu without dissolved plasminogen, because the amount of fibrin-bound plasminogen in retracted clots was insufficient for successful clot lysis. In plasma containing plasminogen, retracted clots were successfully lysed with fibrin-specific plasminogen activators, but not with non-fibrin-specific activators. Preincubation of retracted clots in plasma increased their plasminogen content as well as their sensitivity to fibrinolysis. The rate of lysis was increased up to 100-times when plasminogen activator and plasminogen were introduced into cylindrical clots by pressure-induced bulk flow in comparison with diffusion alone. The magnitude of the increase was similar in retracted and nonretracted clots, but the absolute rate of lysis was faster in non-retracted clots. The influence of fibrin fiber thickness on fibrinolysis was studied by atomic force microscopy. The time to complete lateral section of fibers did not differ between thick and thin composite fibers, and the rate of diameter reduction was faster in thick fibers than in thin ones. Taken together our results suggest that lysis of retracted clots proceeds in circular stages: (a) activation of bound plasminogen followed by partial degradation of fibrin, (b) opening of new plasminogen-binding sites on partly degraded fibrin, (c) binding of plasminogen to the new binding sites which enhances the susceptibility of clots to lysis. Lysis is accelerated by bulk flow of plasminogen activator and plasminogen into clots in comparison to diffusion alone. Fibrinolysis of thick composite fibrin fibers proceeds more efficiently than lysis of thin fibers.

A case of pseudothrombocytopenia after infusion of abciximab in vivo and anticoagulant-independent platelet clumping after rechallenge with abciximab in vitro.

A 45-year old man was treated for unstable angina pectoris with percutaneous transluminal angioplasty and stenting of his left anterior descending coronary artery. The procedure was followed by infusion of abciximab. The patient's automated platelet count in an EDTA-anticoagulated blood sample at admission to the hospital was normal, but dropped to 5 x 10(9)/l three hours after the procedure. The infusion of abciximab was stopped and the patient received platelet transfusions although there were no signs of bleeding. Two days later his platelet count was still low (37 x 10(9)/l) in an EDTA-anticoagulated blood sample, but normal (193 x 10(9)/l) in a heparin-anticoagulated sample. Platelet clumps were present only in the sample anticoagulated with EDTA, and pseudothrombocytopenia was diagnosed. The patient's recovery was uneventful. At follow-up visits four months and one year after discharge from hospital, the patient's blood samples were anticoagulated with three different anticoagulants: EDTA, citrate and heparin. The platelet count was normal in all three samples but after mixing with abciximab in vitro it dropped profoundly due to platelet clumping, regardless of the choice of the anticoagulant. Our report raises two points: (a) one needs to consider the possibility of pseudothrombocytopenia in a patient with a low automated platelet count after infusion of abciximab but without signs of bleeding, and (b) the in vitro results suggest that our patient who had initially responded to abciximab with pseudothrombocytopenia could develop true thrombocytopenia after repeated exposure.

Transport processes in fibrinolysis and fibrinolytic therapy.

Transport of fibrinolytic agents into thrombi represents a rate limiting step in therapeutic thrombolysis. Mathematical modeling predicts and in vitro experiments demonstrate that effective delivery of fibrinolytic agents into clots is the most important determinant of fibrinolytic rate. Transport by diffusion is slow and limited by the need for a high concentration gradient. Transport by convection is more efficient and depends on both the intrinsic resistance of the thrombus and on the effective pressure gradient. Animal experiments indicate that delivery of activator into a thrombus accelerates fibrinolysis and that fibrinolytic rate is dependent on the pressure gradient to which the clot is exposed. Clinical observations are consistent with a dominant role of transport in determining thrombolytic efficacy. Systemic thrombolysis is most successful in short clots exposed to a high pressure gradient, such as coronary artery thrombi in normotensive or hypertensive patients. Rapid lysis is also achieved by intrathrombic delivery of plasminogen activator into peripheral arterial clots and thrombosed dialysis access fistulas. In contrast, systemic thrombolysis is much less successful in clots that are exposed to an insufficient pressure gradient, such as venous thrombi and coronary thrombi of patients in cardiogenic shock.

Subacute rupture of the left ventricular free wall after acute myocardial infarction. Three cases of long-term survival without emergency surgical repair.

Rupture of the left ventricular free wall after acute myocardial infarction (AMI) has been regarded as uniformly fatal unless emergency surgical repair is performed. Among 2,862 patients admitted with AMI to our ICU during the last 8 years, 107 patients developed rupture of the left ventricular free wall. Twenty-nine patients had a subacute course and three of them survived for prolonged periods without having to have emergency surgical repair. At the onset of rupture on day 1 through 7 after AMI, the three survivors developed sudden hypotension accompanied by a new pericardial effusion. They were initially managed with hemodynamic support. Two patients had elective open-heart surgery 2 to 3 months after AMI, whereas one patient did nt require surgery. All three survived 1 1/2 to 8 1/2 years after AMI. This report indicates that a small subset of patients with subacute ventricular free wall rupture has a benign course that may allow for prolonged survival without having to have emergency surgical repair.

Finger-like lysing patterns of blood clots.

One-dimensional modeling of fibrinolysis (Senf, 1979; Zidansek and Blinc, 1991; Diamond and Anand, 1993) has accounted for the dissolution velocity, but the shape of the lysing patterns can be explained only by two- or three- drug-induced blood clot dissolution patterns obtained by proton nuclear magnetic resonance imaging, which can be described by the enzyme transport-limited system of fibrinolytic chemical equations with diffusion and perfusion terms (Zidansek and Blinc, 1991) in the reaction time approximation if the random character of gel porosity is taken into account. A two-dimensional calculation based on the Hele-Shaw random walk models (Kadanoff, 1985; Liang, 1986) leads to fractal lysing patterns as, indeed, is observed. The fractal dimension of the experimental lysing patterns changes from 1.2 at the beginning of the experiments to a maximum of approximately 1.3 in the middle and then decreases toward one when the clot is recanalized.

Ultrasound increases flow through fibrin gels.

Ultrasound accelerates fibrinolysis in vitro and in animal models of thrombosis. Since transport of fibrinolytic enzymes into clots by permeation may be an important determinant of the rate of fibrinolysis, we examined the effect of ultrasound on permeation through fibrin gels in vitro. Gels of purified fibrin were prepared in plastic tubes, and the rate of pressure-mediated fluid permeation was measured. Exposure to 1 MHz ultrasound at 2 W/cm2 and a duty cycle of 5 msec on, 5 msec off resulted in a significant (p = .005) increase in flow through the gel of 29.0 +/- 4.2% (SEM). The ultrasound-induced flow increase was intensity-dependent, increasing from 17.0 +/- 1.2% at 1 W/cm2 to 30.1 +/- 1.9% at 2.3 W/cm2. Increased flow was not due to heating, detachment of fibrin from the tube wall or fragmentation of the gel resulting in channeling. However, degassing the fluid by autoclaving significantly reduced the ultrasound-induced increase in flow. We conclude that exposure of fibrin gels to ultrasound increases pressure-mediated permeation. This effect may be related to cavitation-induced changes in fibrin gel structure, and could contribute to the accelerated fibrinolysis observed in an ultrasound field.

Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots.

Fibrinolysis is accelerated in vitro in an ultrasound field, and externally applied high frequency ultrasound also accelerates thrombolysis in animal models. Although the mechanism of this effect is not known, ultrasound does not cause mechanical disruption of clots but rather accelerates enzymatic fibrinolysis. To determine if accelerated fibrinolysis could be related to increased transport of enzyme into clot, we have examined the effect of insonification on the distribution of plasminogen activator between clot and surrounding fluid in vitro. Plasma clots were overlayed with plasma containing 125I-radiolabeled, active-site-blocked recombinant tissue plasminogen activator (rt-PA) and incubated in the presence of 1-MHz ultrasound at 4 W/cm2 or in the absence of ultrasound. The rate of uptake of rt-PA was significantly faster in the presence of ultrasound, reaching 15.5 +/- 1.4% at 4 h compared to 8.2 +/- 1.0% in the absence of ultrasound (p < 0.0001). Similarly, ultrasound increased transport of enzyme from the clot into the surrounding fluid. To determine the effect of ultrasound on the spatial distribution of enzyme, plasma clots were overlayed with plasma containing radiolabeled rt-PA and incubated in the presence or absence of ultrasound. The clots were then snap-frozen, and the radioactivity in serial cryotome sections was determined. Exposure to ultrasound altered the rt-PA distribution, resulting in significantly deeper penetration of rt-PA into the clots. We conclude that exposure to ultrasound increases uptake of rt-PA into clots and also results in deeper penetration. These effects of ultrasound on enzyme transport may contribute to the accelerated fibrinolysis observed in an ultrasound field.

Acceleration of fibrinolysis by ultrasound in a rabbit ear model of small vessel injury.

High frequency ultrasound has been previously shown to accelerate fibrinolysis in vitro at intensities that are potentially applicable for noninvasive administration clinically. To extend these findings in vivo, we have investigated the effects of ultrasound on fibrinolysis induced by streptokinase in a rabbit model of small vessel injury. Full thickness puncture wounds were made in rabbit ears with a scalpel blade. The rabbits were rested for 2-3 hours after cessation of bleeding to allow maturation of hemostatic plugs. Saline or streptokinase was then infused intravenously, and ultrasound was applied to some lesions at 1 MHz with a 50% duty cycle at 1 W/cm2 net intensity. Ear lesions in rabbits treated with saline showed no bleeding after 30 minutes whether they were exposed to ultrasound or not. Streptokinase alone induced bleeding after 19.7 +/- 5.5 minutes. Application of ultrasound significantly reduced the time to bleeding in streptokinase treated rabbits to 7.5 +/- 3.9 minutes (p < .002). The times to bleeding with "sham" ultrasound (18.8 +/- 5.6 minutes) and heating of the ear (18.0 +/- 5.6 minutes) during streptokinase administration were not significantly different compared to streptokinase alone. Histologic examination revealed that application of ultrasound resulted in a mild increase in interstitial edema and accumulation of polymorphonuclear leukocytes but did not cause vascular or other tissue damage. We conclude that the noninvasive, percutaneous application of ultrasound significantly accelerated streptokinase-induced fibrinolysis in this rabbit model of small vessel injury.

Flow through clots determines the rate and pattern of fibrinolysis.

Thrombolytic therapy depends on penetration of plasminogen activator into clots which occurs through diffusion and flow. An in vitro system has been developed to characterize the rate and pattern of fibrinolysis in relation to flow through occlusive clots exposed to a pressure gradient. Whole blood clots formed in plastic tubes were perfused with plasma containing 1 microgram/ml tissue plasminogen activator (t-PA) and 0.5 or 1 mmol/l gadolinium-diethylentriamine pentaacetic acid (Gd-DTPA), a paramagnetic substance used as a contrast enhancer for magnetic resonance (MR) imaging. T1-weighted spin echo MR images were obtained during clot perfusion at 3-5 min intervals for 45 min. Characteristic signal intensities allowed identification of non-perfused, perfused but non-lysed, and completely lysed areas of clot. A spatially resolved time course of perfusion and subsequent lysis was constructed for 10 clots. Plasma flowed non-uniformly through clots forming asymmetric channels that left some areas non-perfused. The longitudinal velocity of flow through the dominant channel was 1.6 +/- 0.7 mm/min. The flow rate during the first five minutes was 7.5 +/- 6.5 microliters/min and 15.3 +/- 10 microliters/min between min 26-30 in clots that had not completely recanalized by that time. A sharp increase in flow was noted at the time of recanalization that occurred at 37 +/- 11 min. Clot lysis followed the pattern of perfusion through the dominant channel after a lag time of 13 +/- 4 min, representing the time required for enzymatic processes. The delay time between perfusion and lysis was longer in regions with slower flow indicating that the rate of t-PA delivery influenced the rate of fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)