Several clinical studies have shown decreased erythrocyte filterability during cerebral ischemia. Concomitantly, leukocytes may become activated, and may release chemical mediators such as leukotrienes and platelet-activating factor (PAF), which act to increase chemotaxis and their adhesiveness, and thus leukocytes may be associated with the pathogenesis of microcirculatory impairment, particularly in the area of ischemic penumbra.
In this study, to examine the rheologic behavior of leukocytes in cerebral vascular disease, we measured the leukocyte filterability through a Milipore membrane of leukocyte subpopulations in 34 patients with various subtypes of cerebral infarction (12 atherothrombotic, 17 lacunar, and 5 cardioembolic), who were compared with 13 normal controls, using the St. George's filtrometer. In addition, formyl-methionyl-leucyl-phenylalanine (FMLP) and PAF were added to the leukocyte suspensions, that were separated from heparinized whole blood obtained from healthy volunteers, and the effects on leukocyte filterability were studied. The effect of TCV 309 (PAF antagonist) on leukocyte filtreability was also determined after stimulation of leukocytes with PAF.
Leukocyte filterability was reduced in patients with atherothrombotic stroke and lacunar stroke but not in those with cardioembolic stroke compared with controls (p<0.05). There was no significant difference in leukocyte filterability between patients treated with and without antiplatelet agents (aspirin and/or ticlopidine). In vitro study, FMLP and PAF decreased leukocyte filterability, and TCV 309 improved the filterability of leukocytes activated with PAF.
Decreased leukocyte filterability in patients with atherothrombotic and lacunar stroke may play a role in the pathophysiology of microcirculatory impairment. An pharmacological improvement of leukocyte filterability may be a new strategy for treating microcirculatory impairment in the penumbra area associated with cerebral ischemia. Further ex vivo studies on this class of compounds appear necessary for clinical application in future.

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This paper evaluates the effect of iodinated X-ray contrast media on plasma clotting time, plasma thrombin generation and thrombin activity. Investigated materials consisted of diatrizoate, iothalamate and ioxaglate as ionic contrast media (ICM), and iopamidol, iohexol, ioversol and iotrolan as nonionic contrast media (NICM). Both the prothrombin time and the activated partial thromboplastin time of normal pooled plasma were markedly prolonged in the presence of contrast media in a dose-dependent manner. All the contrast media also inhibited thrombin generation in plasma, as assessed in the def ibrinated plasma with a chromogenic substrate, S-2238. Although these contrast media did not affect the thrombin amidolytic activity, they interfered with thrombin-clotting of fibrinogen by affecting either thrombin-fibrinogen interaction or fibrin polymerization, or both. The anticoagulant activities of the contrast media were more evident in 3 ICM than in 4 NICM used in this study. These results suggested that NICM could not sufficiently suppress the thrombin generation in the catheter-syringe system because of this lesser degree of anticoagulant activity than that of ICM. In a separate set of experiment, heparin cofactor activity of antithrombin III was not impaired in the presence of these contrast media, suggesting that heparin would be an effective agent to prevent the thromboembolic complications during angiography using NICM.

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The anticoagulant and antithrombotic effects of a glycosaminoglycan-modified urinary thrombomodulin (GAG-UTM) expressed in C-127 cells were investigated.
Among several species of blood tested, GAG-UTM induced a 2-fold prolongation at 0.24μg/ml in human whole blood clotting time.
Following the injection of ¹²⁵I-fibrinogen, the rat was infused with Tissue factor (TF) 30mg/kg/hr intravenously (i.v.), and the macro-autoradiogram was conducted. Marked accumulations of ¹²⁵I-fibrin comprising microthrombi were observed in major organs such as kidney, spleen, liver and lung. The tissue/blood (T/B) ratio of the radioactivity was used to indicate the distribution of thrombi. TF infusion gave rise to 1.1 through 4.7 in the T/B values.
In the above treatment, i.v. infusion of GAG-UTM (10 to 300μg/kg/hr) dose-dependently decreased the T/B values. Moreover, significant improvement of the platelet counts and plasma fibrinogen levels were induced by GAG-UTM administration (more than 30μg/kg/hr).
Those results indicate that GAG-UTM shows an excellent inhibitory effect on TF-induced thrombus formation, and it markedly normalizes the bleeding tendency caused by TF-infusion.
It seems that GAG-UTM may be a potent antithrombotic agent without affecting bleeding tendency in clinical use.

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