Small Vessel Thrombosis Research Articles

Antithrombotic activity of BMY-43351, a new imidazoquinoline with enhanced aqueous solubility

BMY-43351 is a new broad-spectrum inhibitor of platelet aggregation with greater aqueous solubility than earlier analogs from the imidazoquinoline series. This report compares the antithrombotic activity of BMY-43351 to that of two other imidazoquinolines: BMY-20844, a simply-substituted compound, and BMY-21638, a more potent ether-linked side chain analog. All of these compounds act, at least in part, via inhibition of platelet low-Km cyclic AMP phosphodiesterase. Antithrombotic activity was assessed in the rabbit ear chamber-biolaser preparation, an animal model of small vessel thrombosis, and in the canine coronary artery stenosis-occlusion model of large vessel thrombosis. BMY-43351 was found to be remarkably potent in the biolaser model, with an ED 50 of 0.074 mg/kg p.o. In comparison, compounds such as aspirin, ticlopidine, sulfinpyrazone, and dipyridamole demonstrate little or no activity at much higher doses, (eg. 100 mg/kg p.o.). Other inhibitors of platelet low Km cyclic AMP phosphodiesterase are active but substantially weaker than BMY-43351. Similarly, in the coronary artery stenosis-occlusion model, BMY-43351 demonstrated impressive activity, significantly inhibiting arterial thrombosis at intraduodenal doses as low as 1 μg/kg. The potential use of BMY-43351 as adjunct therapy in thrombolysis was suggested in a series of experiments where this drug was used in combination with a thrombolytic regimen of stretokinase plus heparin. In this experimental setting, time to reperfusion was reduced from 42 ± 5 minutes to 11 ± 5 minutes, and reocclusion was totally inhibited.

Histopathology of prostatic tissue after transurethral hyperthermia

Histopathological changes were studied in four patients who had moderate to severe urinary outflow obstruction due to benign prostatic hyperplasia (BPH) and were treated with transurethral microwave hyperthermia (TUMH). All these patients received TUMH with a helical antenna using a BSD 300 unit. The temperature was controlled on the urethral surface at 45 degrees C +/- 1 degree C. Each treatment session lasted 70 min at this temperature. Histological changes were periurethral, extending up to 6 mm radially and 4-5 cm longitudinally. They were symmetrical and most severe in the immediate periurethral zone. The severity and distribution of these histological changes correlated well with the thermal profile of the helical antenna. Acute changes, observed 24-48 h following administration of a single TUMH session, consisted of periurethral oedema, parenchymal haemorrhages and occasional, partial small-vessel thrombosis. Selective coagulation necrosis of the parenchymal smooth muscles with sparing of smooth muscle fibres in the vessel walls was noted. Histopathological changes found in patients 7 or 26 days following the administration of 10 TUMH treatments given twice-weekly for 5 weeks showed more severe and deeper lesions. They consisted of interstitial haemorrhages, complete obliteration of blood vessel lumina due to thrombosis and further evidence of coagulation and haemorrhagic necrosis. Evidence of a reparative process with ingrowth of granulation tissue in various stages of organization was clearly demonstrated. The effect of TUMH on BPH-obstructed urethra is probably expressed through selective shrinking and retraction of the periurethral prostatic parenchyma due to organizing localized tissue necrosis and cicatrization. Details of this complex process will be presented.

The Surgical Implications of Purpura Fulminans

Purpura fulminans is an uncommon catastrophic syndrome that occurs in children, typically one to four weeks after a seemingly benign infectious process. The child usually presents with a high fever, purpuric ecchymosis, hypotension, disseminated intravascular coagulation, and gangrene of the extremities. We have recently treated six children, whose mean age was 22 months; three were male and three were female. Five of the six had a change of mental status upon initial examination. Their mean temperature was 104 degrees F. All six children had purpuric involvement of their extremities; three had involvement of their hands, two had involvement of their faces, and two had involvement of their trunks. All had absent palpable pulses and sluggish capillary refill in the involved hands and feet. Two patients died shortly after admission as a result of severe end-stage sepsis. The platelet counts in these two patients, and the white blood cell counts were markedly depressed. The mean platelet count of the survivors was 370,000 and the mean white blood cell count was 25,000. Lumbar punctures were positive for bacterial meningitis in five patients and viral meningitis in one patient. All patients were treated with intravenous heparin. Of the four survivors, two lost significant tissue and required multiple plastic reconstructive procedures, and two improved on heparin alone with no tissue loss. In addition to systemic support and intravenous antibiotics, the mainstay of treatment is one of immediate heparinization and a continuous heparin drip. Heparin prevents subsequent small vessel thrombosis and limits tissue loss due to ongoing purpura. Conservative management of the purpuric lesions is the treatment of choice until final demarcation occurs.

Pulmonary Capillary Density in Rats Given Monocrotaline: A Cast Corrosion Study

A mechanism for monocrotaline-induced pulmonary hypertension in experimental animals may be the loss of small blood vessels, but when pulmonary arteries have been studied, the results have been controversial. In this report, the density of the entire lung microvasculature as measured by gray-scale analysis of scanning electron microscopic images of corrosion casts is reported. In the first experiment, monocrotaline, 60 mg/kg, was injected intraperitoneally into Sprague-Dawley rats. After 16 days, the pulmonary vascular tree was cast with methylmethacrylate. The vascular density index of the casts at a magnification x 100 on the alveolar surface was 0.40 for the monocrotaline-treated animals and 0.48 for the saline-treated control animals (p less than 0.01). On the pleural surface, it was 0.51 for the monocrotaline animals and 0.67 for the saline animals (p less than 0.001). A second experiment found no significant difference in vascular density index between different doses of monocrotaline. Light and scanning electron microscopy suggest that capillary and small vessel thrombosis may account for the decrease in the density of vessels in pulmonary microvascular casts that occurs in response to monocrotaline.

The rationale for arterial and venous shunting in the management of limb vascular injuries

The duration of limb ischaemia following blunt or penetrating vascular injury is one of several factors influencing the incidence of compar tment syndromes, ischaemic contracture, muscle necrosis and amputation. These wide-ranging effects of arterial injury, haemorrhage and ischaemia emphasise the importance of speed in restoring flow. Despite all the advances made in the managemen t of vascular injuries through the main conflicts in recent decades, a small but measurable incidence of complications including amputat ion continues, mainly as a consequence of the complexity of the injury and the time taken to evacuate the victim to hospital. The rationale and importance of shunting injured limb arteries and veins can best be judged firstly by a clear understanding of the pathophysiological effects of vascular disruption, and secondly by an appreciation of the constraints and shortcomings in the customary management of vessel injuries. The effects of major vascular disruption are aggravated by hypovolaemic shock and this scenario may be further complicated by associated bone and major soft tissue injury. The acute impairment of tissue perfusion and the corresponding fall in tissue pO2 increase capillary permeability and exudation of fluid into the interstitial space creating high compartmental pressures which in turn elevate venous pressure to cause further exudation. Swollen muscle fibres confined within inelastic fascial compar tments offer resistance to arterial inflow, already attenuated by several factors such as the vasoconstrictive response to hypovolaemia, haematoma, concomitant vein injury and soft tissue damage. Robbed of any residual-blood supply the extremity undergoes widespread small vessel thrombosis. 1

Beneficial effects of intra-arterial reserpine after upper-extremity embolectomy: A prospective randomised trial

Persistent ischaemia occasionally follows technically-successful arterial embolectomy, and has generally been ascribed to small-vessel thrombosis in the distal vascular bed. Because of the possibility that distal vasospasm might be a contributory cause, we conducted a prospective randomised trial of vasodilator therapy in this setting. In 50 consecutive patients presenting with their first episode of upper-extremity arterial embolism, we compared the results of the intra-arterial instillation of 0.5 mg reserpine with those of saline alone following embolectomy. Among 29 patients receiving saline only, 13 (44.8%) suffered persistent or recurrent limb ischaemia requiring reoperation, while three (14.3%) of 21 patients receiving reserpine had continuing ischaemia (P = 0.02). Three patients in each group required a second re-operation; all three in the reserpine group were ultimately found to have a proximal axillo-subclavian artery stenosis as the cause for their persistent or recurrent limb ischaemia. Although its underlying pathophysiology remains obscure, peripheral vasospasm appears to accompany acute embolic arterial occlusion. Manoeuvres to prevent or reverse such distal vasoconstriction may be useful in avoiding persistent or recurrent ischaemia following arterial embolectomy.

Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant

We reviewed the histopathologic findings in 28 specimens from 25 patients who had skin lesions associated with lupus anticoagulant. The clinical lesions were ulcers, gangrene, thrombophlebitis, hemorrhage, and cutaneous necrosis. Noninflammatory thrombosis of small dermal vessels was observed in all 8 biopsy specimens from gangrene lesions, 10 of 13 specimens from ulcer lesions, and 2 of 5 specimens from thrombophlebitis lesions. Necrotizing vasculitis was not significant in these biopsy specimens. Immunofluorescence findings included a positive lupus band test in lupus erythematosus—lassociated disease and nonspecific deposits in occasional cases. Focal noninflammatory intravascular coagulation is responsible for the microscopic and clinical skin lesions in these patients.

Activation of complement and coagulation in juvenile dermatomyositis.

In patients with juvenile dermatomyositis (JDM), small vessel occlusion and thrombosis result in a decrease in the capillary: muscle fiber ratio. We studied 15 patients with JDM. Six of 7 patients with clinically active JDM had elevated levels of C3d. Moreover, concentrations of fibrinopeptide A and factor VIII-related antigen were significantly increased in patients with clinically active JDM.

Photochemically induced cerebral infarction. II. Edema and blood-brain barrier disruption.

Alterations in the blood-brain barrier to proteins, and regional water and electrolyte content were documented in a rat model of photochemically induced small-vessel thrombosis leading to infarction. Horseradish peroxidase (HRP) or Evans blue was given immediately following a 2-min photochemical sensitization period. At 5 min following irradiation, multifocal sites of peroxidase extravasation were noted within the irradiated area. Ultrastructural examination revealed endothelial cells filled with HRP which in some cases extended into the basal lamina and extracellular spaces. At 15 min, protein leakage was more pronounced within the irradiated zone and reaction product was also apparent within the subarachnoid and perivascular spaces of brain regions remote from the site of irradiation. Widespread staining on the surface of the irradiated hemisphere was apparent in rats perfused 8 h following Evans blue infusion. Water content increased significantly by 15 min within the irradiated zone but not in brain regions remote from this site. Although vasogenic edema is an early event in this stroke model, increases in water content are restricted to the irreversibly damaged site. In contrast, protein tracer escaping from microvessels coursing within the irradiated zone was widely distributed. These findings implicate endothelial barrier dysfunction in the genesis of tissue injury in this model. Morphological evidence for the capability of macromolecules to escape from a site of evolving infarction and to migrate to distances remote from the area of primary microvascular damage is also discussed.

Papulonecrotic tuberculid: A neglected disease in Western countries

Papulonecrotic tuberculid was diagnosed in twelve young patients demonstrating symmetric scattered papulopustular necrotic lesions of the extremities. The diagnosis was supported by a strongly positive Mantoux reaction in all cases, evidence of preexisting or past tuberculosis in eight patients, characteristic histologic findings, and a prompt resolution with antituberculosis therapy. Recurrence of the skin lesions in three patients treated only with isoniazid or with para-aminosalicylic acid and isoniazid indicates the necessity for combination treatment with several antituberculosis drugs. A detailed study of twenty biopsies indicates that the primary lesion is a subacute lymphohistiocytic vasculitis that causes thrombosis and destruction of small dermal vessels. These changes lead to an infarctlike lesion with coagulation necrosis of dermal tissue. In eleven instances a well-marked palisaded histiocytic reaction was seen around necrotic areas, calling into question the differential diagnosis of granuloma annulare or Churg-Strauss granulomatosis.

Effects of cyclosporine on human endothelial cell cultures.

Reports of vascular changes in renal biopsies of transplant patients treated with cyclosporine prompted review of our own renal biopsies and examination of human endothelial cell cultures exposed to cyclosporine in vitro. Endothelial cells were isolated from human umbilical cords by collagenase digestion and cultured in Medium 199 with Earle's salts plus 20% pooled human serum in the absence of antibiotics. Cultures exposed to cyclosporine (0, 0.4, 1.0, 5.0, 10.0 micrograms/ml) for 0, 3, 7, 10, and 14 days were subsequently fixed in 2% glutaraldehyde in 0.1 M cacodylate buffer. Vascular thrombosis was seen in renal biopsies of cyclosporine- and azathioprine-treated patients but the incidence was the same in both groups. No change in the morphology of endothelial cell cultures was observed until 7 days when an increase in size and number of cytoplasmic inclusions became apparent in both control and cyclosporine-treated cultures. By electron microscopy, these inclusions were identified as secondary lysosomes. Their number and size increased with the length of time in culture but did not appear to correlate with the concentration of cyclosporine in the medium. No other morphologic change was identified. It is concluded that the appearance of increased numbers of secondary lysosomes in human endothelial cell cultures is a function of culture age as opposed to cyclosporine exposure. Furthermore, the data indicate that small vessel thrombosis is not specific to treatment with cyclosporine.

Intravascular fibrinolysis of small vessel thrombosis

The effect of intraarterial fibrinolysin infusion on the prevention and treatment of vascular thrombosis in arterial and venous systems of large and small dogs was studied by use of a free groin flap model. Vessel patency and clot lysis after microvascular repair of the superficial caudal epigastric artery and vein were compared in 14 dogs that received prophylactic infusion of fibrinolysin and in 10 control dogs that did not. In 22 additional dogs, after the formation of a standard fibrin clot, arterial infusion of fibrinolysin was performed to determine its therapeutic effect on fibrin clot lysis. The results demonstrate that, after blunt trauma to peripheral vessels in the dog, prophylactic infusion of fibrinolysin has no significant effect on either vessel patency or percentage of local thrombus formation at the anastomatic site. From a therapeutic standpoint, fibrinolysin was effective in fibrin clot lysis in the large vessels (internal diameter 1.8 to 3.0 mm) of 7 of 10 dogs infused within 48 hours after thrombus formation, but was not effective in the small vessels (internal diameter 0.8 to 1.5 mm) of 11 of 12 small dogs with infusion as early as 1 hour after thrombus formation. The therapeutic effectiveness of the fibrinolytic agents to lyse preformed thromboses in small vessels appears doubtful.

Induction of reproducible brain infarction by photochemically initiated thrombosis.

We have used a photochemical reaction in vivo to induce reproducible thrombosis leading to cerebral infarction in rats. After the intravenous injection of rose bengal, a potent photosensitizing dye, an ischemic lesion was formed by irradiating the left parietal convexity of the exposed skull for 20 minutes with green light (560 nm) from a filtered xenon arc lamp. Animals were allowed to survive from 30 minutes to 15 days after irradiation. Early microscopic alterations within the irradiated zone included the formation of thrombotic plugs and adjacent red blood cell stasis within pial and parenchymal vessels. Scanning electron microscopy revealed frequent platelet aggregates adhering to the vascular endothelium, often resulting in vascular occlusion. Carbon-black brain perfusion demonstrated that occlusion of vascular channels progressed after irradiation and was complete within 4 hours. Histopathological examination at 1, 5, and 15 days revealed that the associated infarct evolved reproducibly through several characteristic stages, including a phase of massive macrophage infiltration. Although cerebral infarction in this model is initiated by thrombosis of small blood vessels, the fact that the main pathological features of stroke are consistently reproduced should permit its use in assessing treatment regimens. Further, the capability of producing infarction in preselected cortical regions may facilitate the study of behavioral, functional, and structural consequences of acute and chronic stroke.

Pelvic Vein Thrombophlebitis

Pelvic vein thrombophlebitis is an unusual, but extremely serious, complication of pelvic surgery. It occurs in approximately 0.5 to 1 per cent of patients who develop operative site infections. It may present as two distinct clinical syndromes: acute ovarian vein thrombosis and diffuse thrombosis of multiple small pelvic vessels. Accurate diagnosis is hampered by the absence of a reliable, specific, and noninvasive test for the disorder. Treatment of pelvic vein thrombophlebitis requires administration of broad spectrum antibiotics, intravenous heparin, and, in selected cases, ovarian vein and vena cava ligation.

Intravascular fibrinolysis of small-vessel thrombosis

The effect of intraarterial fibrinolysin infusion on the prevention and treatment of vascular thrombosis in arterial and venous systems of large and small dogs was studied by use of a free groin flap model. Vessel patency and clot lysis after microvascular repair of the superficial caudal epigastric artery and vein were compared in 14 dogs that received prophylactic infusion of fibrinolysin and in 10 control dogs that did not. In 22 additional dogs, after the formation of a standard fibrin clot, arterial infusion of fibrinolysin was performed to determine its therapeutic effect on fibrin clot lysis. The results demonstrate that, after blunt trauma to peripheral vessels in the dog, prophylactic infusion of fibrinolysin has no significant effect on either vessel patency or percentage of local thrombus formation at the anastomatic site. From a therapeutic standpoint, fibrinolysin was effective in fibrin clot lysis in the large vessels (internal diameter 1.8 to 3.0 mm) of 7 of 10 dogs infused within 48 hours after thrombus formation, but was not effective in the small vessels (internal diameter 0.8 to 1.5 mm) of 11 of 12 small dogs with infusion as early as 1 hour after thrombus formation. The therapeutic effectiveness of the fibrinolytic agents to lyse preformed thromboses in small vessels appears doubtful.

Delayed infarction of spinal cord white matter following x-irradiation.

The thoraco-lumbar spinal cord of 4 cats were subjected to 4000 RADS of X-irradiation. Between 3 and 5 mth afterwards the animals developed weakness of the hind-legs and became uncoordinated. Small infarcts were found in the white matter of the irradiated area of spinal cord, accompanied by neuronal death and oedema of the grey matter close to the central canal. Ultrastructurally the infarcts were shown to stem from necrosis and thrombosis of small blood vessels. Comparison is made with the pathogenesis of spinal cord infarction that occurs in decompression sickness.

Hypoxic radioprotection by temporary intestinal ischemia: degradable starch microsphere embolization in the cat.

Temporary small intestinal ischemia was induced by mesenteric arteriolar embolization of degradable starch microspheres in cats. During ischemia, the small intestine received a surface dose of 7 Gy 200 kV x-ray irradiation. One group of animals also had received 7 Gy to the intact abdomen 72 hr earlier. The risk of thrombosis in small intestinal vessels during or after starch microsphere-induced ischemia combined with irradiation was evaluated by monitoring superior mesenteric arterial blood flow, by determination of blood platelets, fibrinogen, and factor VIII consumed across the mesenteric vascular bed, and by histologic examination of small intestinal vessels. Vascular integrity was inferred from intact response to isoproterenol and vasopressin after the combined trauma of ischemia and irradiation. No signs of thrombosis were detected in small intestinal vessels after temporary ischemia and irradiation. Hypoxic radioprotection of the small intestine in the cat can thus be achieved by mesenteric arterial microembolization of degradable starch spheres without evidence of thrombotic complications of significant vascular damage.

Radiographic findings in Rocky Mountain spotted fever.

Rocky Mountain spotted fever is a febrile disease caused by a tick-borne rickettsia. Diffuse small vessel vasculitis may result in thrombosis of small vessels and capillary damage and can result in radiographic abnormalities. Cardiomegaly with pulmonary edema, interstitial infiltrates, patchy alveolar infiltrates, and pleural effusions may be detected in varying combinations on the chest radiograph. Soft-tissue necrosis may also be observed.

Microsurgical techniques in free flap reconstruction

Free flap reconstruction is discussed with emphasis on microsurgical technique utilized in union of blood vessels 1 mm in external diameter. Proper microsurgical instrumentation, magnification and small vessel suture technique are all of importance in achieving a successful microvascular anastomosis. Technical maneuvers employed in identifying and avoiding small vessel thrombosis are presented. Surgical techniques, as presented here, have allowed us to successfully use free flaps to reconstruct large oral cavity defects following ablative cancer operations.

Acute Reversible Myocardial Infarction after Blood Transfusion in the Aged

Seven elderly cases with reversible electrocardiographic changes simulating acute myocardial infarction in the absence of gross myocardial infarction on postmortem examination were observed following the blood transfusion. The underlying diseases were cancer of gastrointestinal tract or gall bladder in 4, gastric ulcer in 2, and 1 of pseudomembranous enterocolitis. The electrocardiogram revealed the abnormal Q waves with monophasic ST elevation and following coronary T inversion. These findings lasted only for 2 to 7 days and returned to the previous normal tracings. The hematocrit was elevated from 28.9 to 47.7 after the blood transfusion of 800 to 1,800 ml. The disseminated intravascular coagulation was shown in 5 cases. GOT levels were within normal ranges except 1 case. Pathological findings in cases with recent electrocardiographic changes were characterized by the mural thromboses, extending into the myocardium through the Thebesian vein. The focal small necroses of the adjacent myocardium or around the thrombosis of small vessels were also observed. In the later phase the fine interstitial fibrosis took place after the resorption of the thrombi and necrotic foci. From these clinical and pathological findings we proposed a new concept of reversible myocardial infarction induced from the hypercoagulability, disseminated intravascular coagulation, and elevated hematocrit.