Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation.

Coagulation proteases may act as cell signaling molecules via protease-activated receptor (PAR) cleavage, subsequently affecting cellular and inflammatory responses. Activation of PARs in the setting of systemic inflammation and disseminated intravascular coagulation (DIC) might thus exacerbate the inflammatory response contributing to tissue and organ damage. To investigate the role of PAR-4 in these processes, we subjected mice to a model of systemic inflammation and DIC (Shwartzman reaction) in the absence or presence of a cell-penetrating pepducin antagonist of PAR-4 (P4pal-10). P4pal-10 dose-dependently diminished the severity of endotoxemia and preserved liver, kidney, as well as lung function. Moreover, systemic inflammation and local (neutrophilic) inflammatory responses were attenuated. In vitro migration assays and P4pal-10 treatment in neutropenic mice suggest an essential role for neutrophils in PAR-4-mediated pathology. P4pal-10 treatment of thrombocytopenic mice excluded the involvement of platelets in this phenomenon. These results uncover an important role for PAR-4 in the Shwartzman reaction and suggest that inhibition of PAR-4 signaling in neutrophils could be protective in systemic inflammation and DIC.

Congenital neutropenia: advances in diagnosis and treatment.

PURPOSE OF REVIEW: A decade after the availability of hematopoietic growth factors, the long-term outcome of severe congenital neutropenia has dramatically changed. The prolonged survival of neutropenic patients receiving hematopoietic growth factors has drawn attention to the heterogeneity of this disease and to the complications of treatment. The dose of granulocyte colony stimulating factor that is required to obtain normal levels of circulating neutrophils and to prevent fever and infections is quite variable among patients, but is higher in children with severe congenital neutropenia than in those with other conditions of neutropenia. Moreover, leukemic transformation during treatment is not observed in all patients, but is more typical of severe congenital neutropenia and Shwachman-Diamond patients. RECENT FINDINGS: In recent years, the converging efforts of hematologists, immunologists and geneticists have led to the discovery of the genetic and biochemical basis of severe congenital neutropenia; cyclic neutropenia; warts, hypogammaglobulinemia, immunodeficiency, myelokathexis or WHIM syndrome and other rarer conditions associated to neutropenia. SUMMARY: Although the diagnosis of congenital neutropenia includes many disorders of distinct origin and variable prognosis, their treatment is still based on granulocyte colony stimulating factor administration. Understanding the pathogenesis of these forms of neutropenia and their evolution will focus future studies on the mechanisms of normal and pathological myelopoiesis and on the development of the most appropriate treatment for each type of neutropenia.

Shwartzman phenomenon in a patient with active systemic lupus erythematosus preceding fatal disseminated intravascular coagulation.

The recurrence of widespread and diverse vascular lesions is a hallmark of systemic lupus erythematosus (SLE). Inflammatory and thrombotic mechanisms almost invariably associated with circulating antiphospholipid antibodies play a role in the pathogenesis of SLE-related vascular disease. Both mechanisms can coexist in the same patient. Vasculitis is most commonly induced by the local deposition of immune complexes. However, some SLE patients have an inflammatory complement-mediated vascular injury in the absence of immune complex deposition. We report on a fatal case of disseminated intravascular coagulation (DIC) in a young woman with active SLE. Hemorrhagic lesions due to localized intravascular coagulation (Shwartzman phenomenon) preceded disseminated intravascular coagulation accompanied by disseminated cardiac necrosis. Immune complex 'independent' and other mechanisms of vascular injury and states of hypercoagulability will be discussed.

[The disseminated intravascular coagulation syndrome in endotoxin shock]. / Sindrom disseminirovannogo vnutrisosudistogo svertyvaniia krovi pri éndotoksinovom shoke.

Dynamics of blood coagulation and morphological changes after the intravenous administration of Salmonella typhimurium endotoxin is studied experimentally in Chinchilla rabbits. The stages of blood coagulation are established characteristic for the above syndrome. The signs of the developing blood stasiopathy with the domination of vascular wall damage and thrombocyte aggregation are observed. No considerable consumption of the blood coagulation factors is found. It is concluded that a leading role in the pathogenesis of the endotoxin shock microcirculatory disturbances belongs to the vascular damage and aggregation thrombocytopenia and not to the coagulopathy consumption.

Acute, massive, haemorrhagic adrenal necrosis experimentally produced by the Shwartzman mechanism in rabbits.

Acute and severe haemorrhagic necrosis of the adrenal was produced experimentally in rabbits by means of intravenous injection of endotoxin after pretreatment by adrenocorticotropic hormone (ACTH) administration. The change occurred mainly in the zona fasciculata of the adrenal cortex, and its pathology was quite similar to that of the Shwartzman reaction. Numerous microthrombi were found in and around the lesion, but no marked changes were seen in other parts of the body. Heparin administration was very effective in preventing the necrosis. The pathogenesis of this lesion was postulated to be a univisceral Shwartzman mechanism in the adrenal. This seems to be a good experimental model for massive haemorrhagic necrosis of the adrenal in man, for example in the Waterhouse-Friderichsen syndrome, the pathogenesis of which has been assumed to involve intravascular clotting. It is suggested that hyperfunction of the adrenal cortex caused by ACTH administration could be a preparative condition for the Shwartzman reaction.

Protracted histopathological change of the liver necrosis induced by Shwartzman reaction. An experimental animal model of liver cirrhosis?

Severe pathological fibrotic change of rabbits treated with endotoxin was produced. The liver of the rabbits that died within 14 days showed severe architectural distortion through wide fibrotic band which could be called morphologically post necrotic liver cirrhosis. On the other hand, in the liver of the rabbits that remained alive more than 14 days thin septal nodular structures were observed. This experimental model is proposed as a tool for the further study of the pathogenesis of human liver cirrhosis.

Shwartzman reaction in streptozotocin-induced diabetic rats.

The possibility that experimental diabetes could prepare for the generalized Shwartzman reaction was investigated in female Sprague-Dawley streptozotocin-induced diabetic rats. After 48 hours, 1 week, and 9 weeks of diabetes, the rats were injected with 2 mg/kg of endotoxin, and the animals were sacrificed 2, 4, 8, and 24 hours after endotoxin. Ninety percent of the diabetic animals given endotoxin developed massive glomerular capillary fibrin deposition accompanied by marked decrease in platelet count. The age- and sex-matched nondiabetic control rats had no such changes. This marked susceptibility to endotoxin, previously only reported in pregnant rats, was present as early as 1 week of diabetes. The degree of glycemic control greatly influenced the susceptibility of diabetic rats to the generalized Shwartzman reaction. Only 28% of the diabetic animals given insulin once daily (4.6 +/- 0.3 units, mean +/- SEM) and maintaining a blood glucose level of 269 +/- 19 mg/dl developed glomerular thrombi. In contrast, the diabetic animals that did not receive insulin and had a blood glucose level of 617 +/- 21 mg/dl all developed fibrin thrombi. We conclude that the diabetic state in rats induces a unique susceptibility to the generalized Shwartzman reaction following a single injection of endotoxin, which varies with the severity of the diabetic state. Although the pathogenesis is unclear, this phenomenon may reflect abnormalities in the glomerular capillary wall and/or the coagulation system that may be important in the development of microvascular complications. Furthermore, this phenomenon may, in the animal model, mirror the increased risk of the diabetic patient to intravascular coagulation with bacterial sepsis.

Rare complications in a case of generalized meningococcal disease: immunologic reaction versus bacterial metastasis.

A 14-year-old girl was suffering from meningococcal sepsis with initial endophthalmitis. During a secondary and prolonged fever attack including aseptic meningitis, temporary complications such as pericarditis, arthralgic pains, headache and localized phlebitis were observed. There were three relapses of pericarditis within nine months. Their course was benign. The discussion deals with the pathogenesis of these complications as metastatic and immunologic reactions. The possibility of these complications should be considered during diagnostic investigation and therapeutic treatment.

Acute hepatic cell necrosis experimentally produced by viral agents in rabbits.

Acute and extensive hepatic cell necrosis was produced experimentally in rabbits by means of the Shwartzman mechanism using adeno- and hepatitis B viruses. The change that occurred in the liver was quite severe, namely, areas of hemorrhagic necrosis of various sizes in gross appearance and lytic-coagulative necrosis with hemorrhage and leukocyte-mononuclear cell infiltration histologically. Thrombi formation was noted in and around the necrotic areas, and it was not unusual to see necrosis of an entire lobe. This seems to be a model, to some extent, for human fulminant hepatitis caused by hepatitis virus infection, and suggested that some nonspecific reaction such as intravascular clotting may also play an important role in causing or complicating acute, severe, and extensive necrosis of the liver in human cases. Heparin administration very effectively prevented such hepatic necrosis, which supports the view that the change we observed in the liver was really the Schwartzman reaction; further, it is reminiscent of the fact that heparin administration is sometimes effective in fulminant hepatitis treatment if given at te appropriate stage of the disease.

Extensive hepatic cell necrosis produced by the Shwartzman mechanism.

Acute, severe, and extensive necrosis of the liver was produced in pregnant and non-pregnant female adult rabbits by the Shwartzman mechanism. Shwartzman reagent (E. coli endotoxin) was administered in various combinations by three routes of injection, the portal vein (mesenteric vein), the bile duct, and the ear vein. Morphologic changes of the extrahepatic organs were minimal. The similarity to massive necrosis in human liver and the effect of pregnancy on hepatic necrosis in rabbit and man were discussed. The lesion is presented as a new animal model for acute massive hepatic necrosis and is proposed as a third category of Shwartzman reaction, designated the univisceral type.

Acute diffuse interstitial fibrosing pneumonitis and bilateral renal cortical necrosis.

An autopsy case of a 69-year-old male with acute diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis was presented. Autopsy revealed acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis, non-bacterial thrombotic endocarditis, involving the aortic and mitral valves, and some interesting vascular lesions, dissemination of fibrinoid change of arterioles and fibrin thrombus of small vessels in various organs; accumulation of polymorphonuclear leukocytes in the lumen of the smaller interlobular arteries and arterioles of the kidney with cellular infiltration and disintegration of the wall; severe disorganization of the wall with intraluminar and intramural fibrinous exudation in smaller branches of the hepatic artery; diminution and disarrangment of muscle fibers and patchy hyalinization in the media of the renal and interlobar arteries. The inter-relationship between acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis which may be regarded as a 'hallmark' of the generalized Shwartzman reaction, and disseminated intravascular coagulation was discussed.

Brain damage complicating septic shock: acute haemorrhagic leucoencephalitis as a complication of the generalised Shwartzman reaction.

The neuropathological findings in six patients who developed neurological signs after the onset of "septic shock" caused by Gram-negative septicaemia are described. The changes in the brains were characteristic of acute haemorrhagic leucoencephalitis, and there was evidence, particularly in the kidneys, of disseminated intravascular coagulation with tubular necrosis and, in some, appearances indistinguishable from membrano-proliferative glomerulonephritis. It is agreed that acute haemorrhagic leucoencephalitis is another manifestation of a generalised Shwartzman reaction, and it is suggested that activation of complement is the final common pathway that produces tissue damage in the brain and kidney.

Unilateral Shwartzman reaction: cortical necrosis in one kidney following in vivo perfusion with endotoxin.

Unilateral renal cortical necrosis was selectively induced by in situ perfusion of the rabbit kidney with a perfusate containing 50 microgram of endotoxin followed by the i.v. administration of 250 microgram of endotoxin 24 hr later. The results strongly support the idea that the initial event in the genesis of renal cortical necrosis during the Shwartzman reaction is a specific local effect of endotoxin on the vascular endothelium.