SummaryDisseminated intravascular coagulation (DIC) may lead to severe thrombotic or hemorrhagic complications. The present work was undertaken to study the effect of interleukin 6 (IL-6) on variations of key coagulation and fibrinolytic parameters in plasma in a baboon model of experimental DIC induced by injection of factor Xa and phospholipids at dosages leading to partial (48%) or complete fibrinogen depletion. Transient increases of D-dimer, fibrinopeptide A, thrombin-antithrombin and the activated partial thromboplastin time were observed. Each parameter had a particular (time and Xa/phospho- lipid dose dependent) pattern of changes. The principal effect of IL-6 was a more rapid restoration of fibrinogen concentrations and of overall coagulation tests. Injection of factor Xa/phospholipids led also to a rapid increase of tissue-type plasminogen activator (t-PA) the extent of which was dependent on Xa/phospholipid dose. Pretreatment with IL-6 induced a threefold increase of basal t-PA and a corresponding increase of the t-PA response. Plasminogen activator inhibitor type 1 (PAI-1) concentrations did not change after low dose Xa/phospholipids, but increased eightfold after high dose Xa/phospholipids. IL-6 pretreatment induced within 8 h a twentyfold increase of PAI-1 but no further increase was observed after injection of factor Xa/phospholipids.Thus, in vivo thrombin generation leads to dynamic modifications of the coagulation and fibrinolytic systems. The principal effect of IL-6 is a more rapid normalization of overall coagulation tests, due to normalization of fibrinogen, and an increased t-PA release response which is partially counteracted by increased PAI-1 concentrations.
Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.
Ex vivo expanded CD34+ progenitor cells from fresh or cryopreserved primate bone marrow, induced to granulocytic differentiation with growth factors, were investigated to determine whether myeloid cells produced in liquid cultures have the normal biologic functions needed for the treatment of patients with neutropenia following high-dose chemotherapy or therapeutic or accidental radiation exposure. Human and simian (baboons or macaques) CD34+ cells were cultured with granulocyte-colony stimulating factor (G-CSF), stem cell factor (SCF), interleukin-1 (IL-1), IL-3, and IL-6, and assessed at 14 days of culture for their capacity to respond to different functional tests. Immunostaining revealed that human ex vivo expanded cells contained myeloperoxydase (MPO, 82% +/- 8%) and lactoferrin (LF, 30% +/- 6%) in their granules. Maturation of cultured cells was associated with stimulated chemotactic responsiveness and respiratory burst activity (superoxide anion and hydrogen peroxide production) in expansions from human, baboon, and macaque CD34+ progenitor cells. Mature cells obtained from ex vivo expansion of selected cryopreserved human bone marrow CD34+ cells presented reduced but significant functional activities (chemotactic responsiveness and hydrogen peroxide production) when compared with human peripheral blood neutrophils. The validation of nonhuman primate ex vivo expansion systems may permit their use as models of irradiation. The feasibility of ex vivo expansion from cryopreserved bone marrow cell samples may offer considerable opportunity for banking bone marrow for autologous transfusion.
SummaryDisseminated intravascular coagulation (DIC) is a frequent complication of septicemia or tissue injury and may be accompanied by elevations of interleukin-6, a mediator of the acute phase response. It is not known whether thrombin or fibrin deposition may directly induce an acute phase response. To study this, we employed a baboon model of in vivo thrombin generation, induced by the administration of purified bovine Factor Xa and phospholipid vesicles. Two Xa/phospholipid dosages were used, a low dosage (2 animals) leading to a rapid 49% decrease in fibrinogen and a high dosage (two injections at 5h interval; 3 animals) leading to complete fibrinogen depletion. Thereafter, fibrinogen levels increased in both treatment groups, reached a maximum of 2.52 ± 0.23 g/1 (mean ± SE, n = 5; p <0.01 with respect to basal levels) at day 2, and returned to normal by day seven. In five control (injection of 0.15% NaCl) baboons no significant changes of fibrinogen were observed (maximal values: 1.88 ± 0.12 g/1). Serum concentrations of C-reactive protein, an acute phase protein, increased from 3.7 ± 0.4 mg/1 to a maximum of 33.0 ± 7.3 at day one, which was five-fold higher (p <0.01) than in control animals at day one (6.2 ± 0.5 mg/1). Transient increases were observed within 6 h for interleukin-6 from basal values of 6.2 ± 1.7 ng/1 to peak plasma levels of 42.9 ±21.4 ng/1, a value threefold higher (p = 0.07) than in control animals (14.8 ± 4.0 ng/1).The preliminary results of this observational study suggest that factor Xa/phospholipid infusion is followed by an acute phase response, leading after one day to significant increases of fibrinogen and of C-reactive protein.
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