Sickle cell vaso-occlusion: multistep and multicellular paradigm.

Sickle cell disease is characterized by recurrent, painful episodes and organ damage resulting from microvascular occlusion. Seminal studies performed 20 years ago revealed increased adherence of sickle erythrocytes to vascular endothelial cells. Subsequent work showed that these interactions were mediated by multiple adhesion pathways, but the relevance of these interactions has not been evaluated in vivo. Clinical data suggest that leukocytes may play a role, because leukocytosis correlates with clinical severity and early death, and administration of myeloid growth factors to patients can precipitate sickle cell crises. In addition, recent experimental data using intravital microscopy indicate that sickle erythrocytes can interact with adherent leukocytes in inflamed postcapillary and collecting venules. A novel multistep model for sickle cell vaso-occlusion is proposed in which endothelial activation is induced by sickle cells or secondary inflammatory stimuli and leads to the recruitment of adherent leukocytes. The resulting adherent leukocytes interact with circulating sickle erythrocytes, and this interaction impedes microvascular blood flow. Finally, irregularly shaped sickle cells become nonspecifically trapped, resulting in vaso-occlusion. The molecular mechanisms and requirements for the heterotypic interactions between erythrocytes and leukocytes are currently unknown and may involve further activation of adherent leukocytes or circulating erythrocytes. This model offers exciting new opportunities for therapeutic intervention and suggests a critical participation of adherent leukocytes in sickle cell vaso-occlusion.

Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin.

The adhesive protein thrombospondin (TSP) potentially mediates sickle (SS) red blood cell (RBC) adhesion to the blood vessel wall, thereby contributing to vaso-occlusive crises in sickle cell disease. We previously reported that SS RBCs bind to immobilized TSP under flow conditions, whereas normal (AA) red cells do not. However, the SS RBC receptors that mediate this interaction are largely unknown. Here it is reported that integrin-associated protein (IAP), or CD47, mediates the adhesion of these cells to immobilized TSP under both flow and static conditions. A peptide derived from the C-terminal IAP binding site of TSP also supports sickle cell adhesion; adhesion to this peptide or to TSP is inhibited specifically by the anti-IAP monoclonal antibody, 1F7. Furthermore, these data suggest that IAP on SS RBCs is structurally different from that expressed on AA RBCs but that IAP expression levels do not vary between AA and SS RBCs. This structural difference may contribute to the enhanced adhesion of SS RBCs to immobilized TSP. These results identify IAP as a TSP receptor on SS RBCs and suggest that this receptor and its binding site within TSP represent potential therapeutic targets to decrease vaso-occlusion. (Blood. 2001;97:2159-2164)

[A rare cause of intra-alveolar hemorrhage: a transfusion-related incident with leukoagglutination due to antigranulocyte antibodies (Trali syndrome)]. / Une cause rare d'hémorragie intra-alvéolaire: l'accident transfusionnel avec leucoagglutination par anticorps antigranuleux (syndrome Trali).

INTRODUCTION: Transfusion-related acute lung injury (TRALI) is an infrequent but life-threatening complication of hemotherapy, usually secondary to passive transfer of antibody from the donor's plasma to the recipient. TRALI is a diagnosis of exclusion often masked by underlying factors. EXEGESIS: We report a new case of TRALI in a patient with severe multinevritis associated with Sjögren's syndrome and cryoglobulinemia, who had received intravenous immunoglobulins. CONCLUSION: This case report underlines the difficulty to establish a diagnosis in both acute respiratory failure and intra-alveolar hemorrhage in patients with auto-immune disorders. This case report also emphasizes the necessity of taking precautions in these immunocompromised patients in whom hemoglobin transfusion is required.

Nephron function in the early phase of ischemic renal failure. Significance of erythrocyte trapping.

Trapping of red blood cells (RBCs) in renal medulla vasculature in postischemic acute renal failure (ARF) was found to depend upon the length of the ischemic period. Thus trapping occurred after 45 minutes but not 25 minutes of ischemia. By prior hemodilution to a hematocrit (hct) of 30%, RBC trapping after 45 minutes of ischemia could be completely prevented. Likewise hemo-concentration (hct = 60%) before 25 minutes of ischemia resulted in extensive RBC trapping. By increasing or decreasing the hct, the contribution of RBC trapping to the functional defects and decrease in renal blood flow that follows minor (25 min) and more substantial (45 min) ischemia was investigated. Renal blood flow (RBF) was measured by microspheres, and vascular and tubular pressure by the micropuncture technique. Glomerular filtration rate (GFR) was estimated from inulin clearance, and tubular function from urine osmolality and sodium and potassium excretion. It was found that postischemic RBF was not correlated to RBC trapping but depended on the length of ischemia. After both 25 and 45 minutes of ischemia tubular obstructions occurred in the proximal tubules and/or loops of Henle, causing an increase in proximal tubular pressure. These obstructions were dependent on the length of ischemia but not on RBC trapping. After hemoconcentration and 25 minutes of ischemia there was an increment in distal tubular pressure, indicating that abundant RBC trapping may contribute to an increase in tubular pressure by compression of medullary tubules and thereby reduce GFR. When the damage was more severe other factors came into play and the contribution of RBC trapping to the decrease in GFR was minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

[Relation between disorders of the rheological properties of the blood and the system of hemostasis in patients with ischemic heart disease]. / Vzaimosvia'z narushenii reologicheskikh svoistv krovi i sistemy gemostaza u bo'lnykh ishemicheskoi bolez'niu serdtsa.

The paper gives evidence for relationship between blood rheologic parameters (erythrocyte aggregation, plasma and whole blood viscosity, hematocrit) and the hemostatic system. A correlation was found between the presence of high molecular fibrinogen and fibrin derivatives and the function of erythrocytes and platelets in patients with coronary heart disease.

[Ultrasonic study of gallbladder motility during exclusive continuous enteral feeding]. / Etude échographique de la motricité vésiculaire au cours de l'alimentation entérale continue exclusive.

Total parenteral nutrition may be responsible for gallbladder sludge and lithiasis which might possibly be related to gallbladder bile stasis. Gallbladder motility has not yet been studied during constant-rate enteral nutrition. We performed serial ultrasonographic studies of gallbladder volume and contents in ten patients receiving constant-rate enteral nutrition during 35 +/- 17 days. Each patient had two weekly examinations at 9 AM and 2 PM on the same day. None of the patients developed gallbladder sludge or lithiasis. The gallbladder was frequently seen to be contracted. Mean gallbladder volume during constant-rate enteral nutrition was not significantly different from mean gallbladder volume after Bladex. Individual gallbladder volume changed significantly from one measurement to another. This study showed that gallbladder motility is preserved during constant-rate enteral nutrition. The persistence of gallbladder contractions may prevent the development of biliary sludge ad lithiasis.

Renal capillary permeability and intravascular red cell aggregation after ischaemia. I. Effects of xanthine oxidase activity.

The macromolecular permeability of renal capillaries and the intravascular red cell aggregation resulting from 45 min of warm ischaemia were investigated. The effects of the xanthine oxidase inhibitor Allopurinol on these factors and also on the post-ischaemic nephron function were also studied. Following ischaemia there was a more than 10-fold increase in the transport from plasma to renal hilar lymph both of plasma proteins and of two isomers of lactate dehydrogenase (LDH)-the nearly neutral LDH-M4 and the negatively charged LDH-H4. The ischaemia also resulted in massive intravascular red cell aggregation, especially in the renal medulla. Through reduction of plasma xanthine oxidase activity from 13.1 +/- 1.1 microU microliter-1 (mean +/- SEM) to essentially zero by Allopurinol, the capillary leakiness was substantially diminished with almost complete normalization after 120 min. At the same time the relative volume of trapped red cells was reduced; in the inner stripe of the outer medulla, for example, it decreased from 11.3 +/- 1.7% in untreated animals to 4.0 +/- 1.1% after treatment with 20 mg of Allopurinol given intravenously 3 h before the ischaemia. Oral feeding with 4 mg of Allopurinol day-1 for one week gave essentially the same result. The net driving force for filtration after treatment with this drug was thus 19 mmHg, as against 26 mmHg in the normal kidney and the resulting SNGFR was half the normal. The total filtration rate was proportionally more reduced to less than 1/3 of the normal. Tubular obstruction was still present but was not as severe as in untreated kidneys (Karlberg et al., 1982b) where the tubular fluid flow and thereby the filtration are essentially zero. It is suggested that oxygen free radicals increased the macromolecular permeability and the adhesiveness of white blood cells and that these two factors combined underlie the aggregation of red blood cells in the medullary vasa recta with consequent persistence of medullary ischaemia.

Polyagglutination in hospitalized patients: a prospective study.

A hospital population at high risk for red cell polyagglutination was studied prospectively in search for cryptantigen exposure. The patients included in this study suffered from: malignancies, sepsis, direct antiglobulin test (DAT) negative anemias and various combinations of these three. 238 patients were examined, and 18 of these (7.6%) were found to have exposed cryptantigens on their erythrocytes. This is an unexpectedly high percentage. Our findings suggest that cryptantigen exposure on the red cells is a more common phenomenon than previously described, especially when looked for in a carefully chosen population. The red cells of these patients are potentially polyagglutinable, and screening with lectins will ensure their pretransfusion identification and evaluation.

Fatal warm antibody autoimmune hemolysis with marked erythrocyte autoagglutination and liver necrosis.

We have described a fatal case of autoimmune hemolysis associated with marked organ ischemia and lactic acidosis. Serologically the case was unusual because of the marked autoagglutination due to a warm antibody. Red cell agglutination at normal body temperature may have contributed to massive liver necrosis, lactic acidosis, and death.

Intravascular hemolytic transfusion reaction without detectable antibodies: A case report and review of literature.

A case of intravascular hemolytic transfusion reaction without detectable antibodies occurring in a 55-year-old male is reported. Specificity for the C antigen in the Rh system was demonstrated by technetium-99m red cell survival studies. A cell-mediated mechanism of hemolysis was suspected and investigated. Previously reported cases are reviewed and discussed. The entity of intravascular hemolytic transfusion reaction associated with minimal symptoms and no detectable antibodies deserves further investigation.

Dextran as a modulator of immune and coagulation activities in trauma patients.

Low Mr dextran has been utilized as a prophylactic therapy in treatment of coagulopathy. There is evidence that monocyte dysfunctions are important contributors to hypercoagulability episodes, as well as to immunoincompetence post-trauma. Dextran is a known monocyte modulator. Consequently, we evaluated the efficacy of dextran infusion in moderating immune dysfunction, monocyte aberrations, and hypercoagulability episodes. Twenty-eight trauma patients were randomly divided into two groups. One group of 15 received dextran at 1 g/kg wt/24 hr for 5 days in addition to standard resuscitation and treatment. The control or nontreated patient group received only standard treatment. Trauma patients in the two groups were retrospectively matched by injury severity score (ISS) to ensure comparability. Blood samples were collected daily for some studies and at 3-day intervals for other assays. In vivo coagulation status was evaluated by assessing the changes in intravascular fibrinopeptide A (FPA). Immune reactivity to the mitogen phytohemagglutinin (PHA) was also evaluated. Both monocyte production of plasminogen activator (PA) and monocyte production of procoagulant activity (PCA) have been shown to correspond to and be augmented by monocyte-T lymphocyte interactions. Consequently, monocyte production of plasminogen activator and procoagulant activity were assessed as measures of monocyte immune activity as well as indicators of monocyte function in controlling the balance between fibrinolysis and coagulation. Only patients with ISS of greater than 25 experienced significant immune, coagulation, or monocyte aberrations. Of those having an injury severity score (ISS) score of 25-35, all of the control and two of the dextran patients had significant perturbations in their immune and monocyte functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Microcirculatory disorders in congenital heart diseases with insufficient or relatively excess blood supply to the greater circulation.

On the material of 25 children, who died in the first year of life of congenital heart disease, pathomorphological changes in the vessels of the microcirculatory bed of the greater omentum were studied. In 14 patients, the heart disease was characterized by reduced blood inflow to the greater circulation, in 11 children by increased inflow. A dependence of morphological changes in vessels of the microcirculatory bed on the character of disorders in central haemodynamics was documented. Adaptive and pathological changes in the microvessels are distinguished, and their clinical functional significance is assessed. The progressive development of pathological structural changes in the microcirculatory bed is considered a consequence of functional depletion not only of central (cardiac) but also of peripheral (microcirculatory system) adaptive mechanisms.

[Microcirculatory disorders in patients with abdominal typhoid]. / Narusheniia mikrotsirkuliatsii u bol'nykh briushnym tifom.

The microcirculatory disorders in 85 patients with typhoid fever are described according to biomicroscopy of the bulbar conjunctiva performed at different periods of the disease and depending on the disease gravity. The greatest microcirculatory disorders were detected in patients with severe and medium-severe disease patterns. In those patients, the clinical recovery was not always marked by normalization of the microcirculation.

Intravascular aggregation after acute intracranial hypertension by epidural balloon compression in cats.

The authors have studied the effect of acute intracranial hypertension produced by placement of an epidural balloon (control group) in cats, on cerebral perfusion, evoked responses, and hematological parameters. These elements were measured in similarly injured animals which underwent isovolemic hemodilution with dextran 75, after relief of intracranial hypertension. Four hours after balloon deflation, perfusion was markedly impaired in 30% of the control group, and was reduced to 11% in the dextran-infused group. The suppressed N1 amplitude of somatosensory evoked responses on the compression side, the reduced platelet aggregability, and the erythrocyte-deformability by intracranial hypertension were all significantly more restored in the dextran-infused group after decompression. The percentage of platelets with volumes between 21.75 and 48.75 cu mu (normal 9.75 to 12.75 cu mu) significantly increased after decompression. Activation of platelets during intracranial hypertension leads to an increase in platelet volume from platelet aggregation, and correlates with a decrease in platelet aggregability. It was also suggested that reduction of erythrocyte deformability was not caused by erythrocyte aggregation. The authors emphasize the role of intravascular factors such as vascular obstruction by platelet aggregates, and difficulty in passage of erythrocytes through capillaries due to reduced deformability, in the disturbance of the microcirculation following acute intracranial hypertension. The protective effect of dextran 75 by inhibition of platelets as well as hemodilution is stressed.