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A 35-year-old male patient with long lasting HIV infection presented with confusion, haemolytic anaemia and thrombocytopenia. After a stable course over 7 days he suddenly developed coma and cardiogenic shock and died. Autopsy revealed thrombotic thrombocytopenic purpura with fibrin-rich deposits in the microvasculature of the brain, heart and pancreas. The pathogenesis and differential diagnosis of this fulminant disease are discussed.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic blood disease. The dramatic symptoms that gave the disease its name and the unique nature of the underlying cellular abnormality made the disease for many years a curiosity amongst human blood disorders. Clinical manifestations of PNH are chronic hemolytic anemia with acute exacerbations, bone marrow failure, an increased tendency to thrombosis, and episodes of severe abdominal pain. PNH has a close although not yet fully understood relationship to aplastic anemia (AA), and probably also to acute myeloid leukemia (AML). Blood cells in patients with PNH have a defect in the biosynthesis of a complex glycolipid structure which is a glycosyl phosphatidylinositol (GPI) molecule and serves as an anchor for many surface proteins. Red cells, granulocytes, monocytes, lymphocytes and platelets are therefore deficient in all proteins which are anchored to the cell membrane by such a molecule. Biochemical analysis pinpointed the metabolic block in PNH cells to an early step in the anchor biosynthesis. The block in the biosynthetic pathway is due to the deficiency of a protein called PIG-A. The PIG-A gene maps to the X-chromosome. Cloning of the gene and analysis of the gene in PNH patients lead to the identification of a number of somatic mutations which occur on the active X-chromosome in an early hematopoietic stem cell. All mutations identified thus far inactivate or impair the function of the PIG-A protein and therefore fully explain the deficiency of the missing surface proteins, which in turn explain some of the clinical features of the disease. However, the characterization of the molecular lesion does not explain how the PNH clone can expand to the extent of contributing a substantial proportion of the patient's hematopoiesis. Thus a second factor is needed to explain the pathogenesis of PNH. We hypothesize that this is most likely the coexistence of bone marrow failure that produces paradoxically a growth or survival advantage for the PNH clone. The coexistence of more than one PNH clone in many patients supports this hypothesis and suggests that bone marrow failure is the primary event. The occurrence of the PIG-A mutation causing the absence of GPI-linked proteins on blood cells allows the PNH clone to flourish and to maintain hematopoiesis; thus it seems that the PIG-A mutation is nature's own gene therapy and the price that these patients have to pay is PNH.

Complement is activated by antibodies, by necrotic cells and by the many surfaces which do not inhibit the amplification loop of the alternative pathway. Examples of such activation include hyperacute rejection in xenotransplantation models (antibody), myocardial infarction (necrotic cells) and paroxysmal nocturnal hemoglobinuria (PNH: lack of complement control on abnormal erythrocytes and platelets). Over the past decade many of the complement regulatory proteins have been described, analyzed and produced in recombinant forms. One of these proteins is complement receptor 1 (CR1, CD35), which in soluble form is capable of inhibiting complement activation in vivo. In many experimental models, soluble CR1 has been shown to reduce antibody-mediated damage, diminish inflammation at the time of cell necrosis and inhibit lysis of PNH cells. For the first time it will be possible to inhibit complement activation in humans.

Intravascular hemolysis is a rare complication following valvular replacement, particularly with bioprostheses. It is generally secondary to prosthetic malfunction and is the cause of anemia. We report a rare case of acute renal insufficiency and severe hemolysis caused by malfunction of a bioprosthesis in the mitral position.

Human proto- and metazoa, which spend a part of their life-cycle within erythrocytes or extracellularly in human blood or in monocyte-derived macrophages, are considered as blood parasites. In spite of their individually widely differing habitat, they elicit a common hematological syndrome essentially consisting in hemolytic anemia and splenomegaly. Furthermore, some basic factors of host/parasite interaction are very similar: (1) Specific cell attachment through receptor/ligand mechanisms such as the integrin/RGD-oligopeptide system, (2) competition for essential nutrients such as iron, which may be influenced therapeutically to the disadvantage of the parasite by the use of iron chelators, and (3) provocation of host defense through T-cell dependent, cytokine-mediated macrophage activation.

A patient who had undergone valvuloplasty for mitral insufficiency due to chordal rupture developed severe hemolytic anemia a few weeks after surgery. Progressive mitral regurgitation was noted at the same time. Extensive laboratory workup excluded other reasons for hemolytic anemia. In comparison with other cases in the literature it is assumed that the patient was suffering from cardiogenic mechanical hemolysis. Fourteen months later mitral valve replacement (St Jude) was performed and the hemolysis ceased promptly. A brief review of the literature is presented.

In three patients with infectious mononucleosis the disease was severely complicated by, respectively, aplastic anemia, consumptive thrombocytopenia and hemolytic anemia with acute renal failure. In contrast to the regularly recurring basic signs and symptoms of the illness, serious complications occur in less than 1% of all patients. Changes in the immunologic system seem to play an important role in hematologic and other complications, as well as in the occasionally fatal Epstein-Barr virus infection. Pathophysiological, and particularly immunologic mechanisms, and possible therapy are discussed with reference to case reports of patients with similar clinical courses and the literature on infectious mononucleosis.

Human recombinant erythropoietin (r-huEPO) is very effective in the treatment of anemia of hemodialyzed patients. We describe 4 patients who developed symptoms of central nervous dysfunction during r-huEPO therapy. Three exhibited typical hypertensive encephalopathy, whereas signs of cerebral ischemia were found in the fourth. The increase in blood viscosity with r-huEPO treatment, leading to a rise in peripheral vascular resistance and blood pressure especially in previously hypertensive patients, may be of importance in the pathogenesis of these cerebrovascular incidents; preexistent arteriosclerosis is an possible additional risk factor.

A case of chronic, lethal vitamin A intoxication is reported, the diagnosis of which was not established intra vitam. The patient presented with chronic mixed prehepatic and hepatic icterus and hypersplenism with hemolytic anemia. On post mortem histological examination, abundant deposits of neutral lipids in the reticuloendothelial cells of liver, spleen and bone marrow were found. Chemical analysis of the lipids extracted from these organs revealed esterified fatty acids. Triglycerides could be ruled out since the triglyceride content of the patient's liver was significantly lower than that of a normal control. By means of thinlayer chromatographic analysis it was possible to identify retinol, i.e. retinylester (vitamin A) in the deposits. Vitamin A was determined photometrically and found to be very elevated in the liver and, to a lesser degree, in the spleen of the patient. These findings lead to a definite diagnosis of chronic hypervitaminosis A. Unique features of the case presented are both hemolytic anemia and the lethal outcome of the chronic hypervitaminosis A.

Acute alcohol intoxication, particularly in chronic alcohol abusers, leads to qualitative and quantitative changes in all three hemopoietic systems. In addition to a hemolytic effect through various possible mechanisms, functional abnormalities of granulocytes, immunocytes and marcophages and qualitative anomalies of platelets, alcohol exerts a toxic effect on cell production which cannot, or can only partially, be prevented by correction of the frequently demonstrable folic acid deficiency.

When hemolytic anemia is diagnosed the etiology of most cases can be determined by simple methods: familial and personal history, physical examination and search for erythrocyte morphologic anomalies (spontaneous or induced). These latter are often typical of a particular mechanism of hemolysis. The antihuman globulin test and the screening test for G-6-PD deficiency and sickle cell anemia are included in the routine tests. More specialized tests should be performed only in doubtful cases. For example, the determination of erythrocyte survival by an isotopic method may confirm suspected mild hemolysis. Measurement of several enzyme activities may detect an enzymatic deficiency. Hemoglobin electrophoresis may reveal hemoglobinopathy.

Presentation of a case of disseminated intravascular coagulation with micro-angiopathic hemolytic anemia, associated with a micro-carcinoma of the prostate. In the absence of other etiology it is postulated that the carcinoma was responsible for the hematological disturbance in spite of its small size andlack of either metastases or mucin secretion. The unusual discovery in this disease of bony necroses of the vertebrae, which are attributed to ischemia following micro-thromboses, is also discussed.

The case is reported of a 19-year-old patient with gastric carcinoma, in which clinical presentation (intermittent fever, myalgia, proximal muscle weakness and diffuse nodular-trabeculated infiltration of both lungs) was very unusual. The patient developed further complications (microangiopathic hemolytic anemia with disseminated intravascular coagulation) and died of subdural hematoma. Bone-marrow biopsy showed metastatic mucin-producing adenocarcinoma, but the gastric primary site of the tumor could only be demonstrated at autopsy.

Drug induced blood dyscrasias, leukocytopenia, thrombocytopenia and hemolytic anemia were observed in 7% of 643 adverse drug reactions registered by drug monitoring in Bern, Switzerland, in the period 1970-1973. Life threatening reactions were consistently more frequent in hematological side effects (22%) than in the total of adverse drug reactions (6%). Blood dyscrasias induced by drug allergy are generally believed to belong to the allergic reactions of type II. Antigen-antibody reaction evolves in connection with cells of the blood, either by fixation of the drug itself or a metabolite on the cell surface, or by adsorption of primarily formed antigen-antibody complexes on the cell. In drug induced immune hemolytic anemia three types may be distinguished: 1. the innocent bystander type, caused by quinine, PAS, rifampicin and others, 2. the penicillin-type, caused by penicillins and cephalosporins, and 3. the autoimmune type caused by alpha-methyl-dopa etc. Agranulocytosis in Europe is most frequently due to pyrazolones, while phenothiazines play the leading role in the USA. In pyrazolone agranulocytosis an allergic pathogenesis is very probable, whereas phenothiazines probably induce agranulocytosis by a direct toxic effect on bone marrow cells. The clinical course in pyrazolone agranulocytosis is acute, whereas it is rather insidious in the phenothiazine type. The main drugs causing allergic thrombocytopenia are thiazide diuretics, quinine, quinidine and sulfonamides. Clinical aspects and therapy of drug induced blood dyscrasias are discussed.

Two weeks after leaving Nigeria for temperate zones and a few hours after giving birth to twins, a nigerian mother suffered an acute attack of malaria due to Plasmodium falciparum accompanied by cerebral, renal and hematolgical complications. Both infants were apparently healthy at birth, and no parasites were found on peripheral blood smears. Both placentas were macroscopically normal. At two months of age the second infant, a boy, developed non-febrile hemolytic anemia due to Plasmodium falciparum. The clinical picture and pathogenic mechanisms of perinatal malaria are discussed. Possible protection of the twin sister by partial glucose-6-phosphate dehydrogenase deficiency is considered.

Acute and chronic alcohol intoxication may lead to various types of corpuscular hemolytic anemias, irrespective of other coexisting organ damage such as liver cirrhosis. It also suppresses hemopoiesis in the bone marrow, leading to hyporegenerative anemia and to a pathogenetically unclear red cell macrocytosis, which in turn represents a sensitive and valuable index for occult alcoholism. Alcohol also suppresses platelet production. Acute intoxication may, furthermore, lead to reversible thrombocytopenia due to platelet sequestration. Platelet function is affected by alcohol both in vitro and in vivo, the defect being similar to that provoked by aspirin. The impaired host defense in chronic alcoholism is not yet adequately explained. It appears to be based on depression of bone marrow granulocyte reserve, granulocyte mobilization and granulocyte function, and also on impressive functional abnormalities of the lympho-plasmocellular system. The clinical relevance of alcohol-mediated hematological changes has not yet been sufficiently defined. It is certainly underestimated.

A short review is presented of the primary and the secondary types of therapy-refractory anemia. Special emphasis is placed on the newest results obtained with therapeutic plasmapheresis and with recombinant human erythropoietin.

Since 1981 an increasing number of human parvovirus infections have been reported. There is now clear evidence that parvovirus B19 is the causative agent of erythema infectiosum (fifth disease). Further clinical situations associated with this virus include aplastic crisis in patients with hemolytic anemia and acute and persistent arthropathies preferentially occurring in adult women. Transplacental infection during pregnancy may result in hydrops foetalis, intrauterine death and spontaneous abortion. Additional, thus far barely characterized parvoviruses have been isolated from individuals with enteritis or rheumatoid arthritis. The present review summarizes today's knowledge of the biological properties and relevance of human parvoviruses as pathogens. The potentialities and limitations of laboratory diagnosis in parvovirus infections are discussed.

Case reports are presented on 4 outpatients with hereditary disorders of metabolism. 1. In a 46-year-old male of Sicilian origin with haemolytic anaemia and leg ulcers, the blood contained numerous target cells, the sickling test was positive, and more than 80% of the haemoglobin was found to be HbS. Investigation of the family revealed double heterozygosity for HbS and beta-thalassaemia. 2. In a family with hereditary nonspherocytic haemolytic anaemic, the biochemical characterization of an abnormal pyruvate kinase is reported: the kinetic data were found to be normal, the electrophoretic migration rate of the abnormal enzyme was increased, and its thermostability was marked decreased. 3. Malignant hyperthermia was observed in an 18-year-old male. The limited value of all methods for identifying affected family members is discussed. 4. In 2 sisters who suffered life-threatening attacks of acute myoglobinuria, differential diagnosis comprised hereditary deficiency of phosphofructokinase, muscle phosphorylase and carnitine palmityl transferase. The activity of the former two enzymes was found to be normal. The circumstances of the myolytic crisis in the two patients provide strong evidence for the presence of a muscle carnitine palmityl transferase deficiency.

A case of angiosarcoma of the liver and the spleen following vinyl chloride exposure is described. The main symptoms in clinical diagnosis were microangiopathic hemolysis, disseminated intravascular coagulation, hepatosplenomegaly and exposure to vinyl chloride thirty years ago. It is the first case in which liver and spleen are involved in angiosarcoma due to vinyl chloride exposure. The tumor cells showed angioformative and solid histiocytoid growth with erythrophagocytosis.

Alcoholic cirrhosis is frequently accompanied by hematologic abnormalities. The most commonly observed factors responsible for combined or isolated cytopenias are alcohol, malnutrition, hypersplenism and liver dysfunction. In addition to cytopenia, functional abnormalities, particularly of the leukocytes and of the platelets, have been described. In patients with hemorrhage the severity of the hemostatic defect is influenced not only by the number and function of the platelets, but also by a decrease in several coagulation factors synthesized by the liver and by an increased level of circulating fibrinolytic activators.

Recombinant human erythropoietin (r-huEpo) was administered i.v. to eight anemic patients on hemodialysis in increasing doses 3 times a week. 7 out of 8 patients showed an increase in hemoglobin level by 2 g/dl over the baseline of 7.9 +/- 0.8 g/dl after a mean period of 8 +/- 2 weeks. During treatment a cumulative dose of 692 +/- 358 IU/kgBW erythropoietin was given. Before the rise in hemoglobin, reticulocytes increased from 1.6 +/- 0.7% initially to 5 +/- 1.6%. The serum ferritin concentration decreased from 426 (range 19-1223) to 250 (5-707) micrograms/l. No side effects were observed. Mean blood pressure before dialysis increased slightly from 125 mmHg to 137 mmHg systolic, and diastolic pressure from 75 to 80 mmHg. Maintenance doses to maintain hemoglobin values between 10 und 12 g/dl varied from 2 X 72 IU/kgBW to 3 X 168 IU/kgBW per week. Measurement of serum levels of erythropoietin by radioimmunoassay showed deficiency of the hormone in the patients with chronic renal failure: before treatment mean serum values were 4 +/- 6.4 mU/ml and during maintenance doses with r-huEpo 33.7 +/- 8.1 mU/ml, which is within normal ranges related to hematocrit. These data show erythropoietin to be effective in ameliorating anemia during hemodialysis treatment.

Two cases of microangiopathic hemolytic anemia in disseminated carcinoma are reported. Both showed the classical features of this illness, namely acute generalized hemorrhagic diathesis, severe hemolytic anemia, thrombocytopenia, fragmentation of erythrocytes in the peripheral blood smear, increased erythropoiesis and megakaryopoiesis or tumor cell invasion in the bone marrow, tumor cell emboli in venules and disseminated intravascular coagulation. In both cases the microangiopathic hemolytic anemia was the first sign of the disseminated carcinoma. Differential diagnosis, pathogenesis and therapy are discussed.

Serum samples from 41 patients who developed adverse reactions during therapy with nomifensine were screened by RAST-based immunoassay for specific IgE and IgG antibodies against nomifensine and three of its metabolites. The results were compared with those of 10 patients without side effects and with 8 non-treated controls. Nomifensine-specific IgE antibodies were found in none of the subjects. However, all patients treated with nomifensine (with and without side effects) had specific IgG antibodies. The antibody cross-reacted in all cases with the metabolites. The titers did not discriminate clearly between the different side reactions and only partially between the presence or absence of a side reaction. The finding of specific anti-drug IgG antibodies warrants more detailed investigation of immunological mechanisms, to determine the clinical relevance of these antibodies and identify patients at risk for serious side effects.

A micromethod for measurement of erythrocyte filtrability is described. The time is recorded for the spreading of drops (25 microliter) of an erythrocyte suspension in filter papers which are calibrated with the suspension solution. The spreading time for the erythrocytes in relation to a reference calibration time correlates well with the filtration time of a modified filtration technique according to TEITEL.

A patient with mitral insufficiency is described who developed severe hemolytic anemia six months after mitral valvuloplasty. Various laboratory tests suggested that the cause of the hemolysis was mechanical. A second heart operation was therefore performed which revealed intact valve function. In view of the mechanical cause of hemolysis a bioprosthesis was implanted but the patient died shortly after this operation. Since similar cases are not found in the literature the authors invite discussion of the course in this case.

To evaluate the toxic effect of ethanol on erythropoiesis in alcoholic ketoacidosis (AK), 6 male patients were studied in the acute and remittent phase of AK. Episodes of metabolic acidosis in nondiabetic chronic alcoholics were associated with protracted vomiting and prolonged intestinal symptoms. AK was associated with elevated beta-hydroxybutyrate, acetoacetate and lactate/pyruvate plasma levels. Analysis of plasma lipids showed raised HDL cholesterol, fatty acids and phospholipids resulting in a concomitant disorder of lipid metabolism in red cell ghosts. A red cell metabolic disorder with reduced ATP and glutathione levels was also observed in patients suffering from mild hemolytic anemia. On admission, miscellaneous toxic effects on erythropoiesis were detected when bone marrow was aspirated. This study lends further support to the hypothesis that there is a linkage of different factors producing serious but transient hematologic and oncologic implications of ethanol in patients with AK.

A 36-year-old patient with chronic active hepatitis developed Coombs direct positive acute hemolytic anemia 2 weeks after a second course of cyanidanol (Cy). The patient's serum agglutinated control 0 Rh- erythrocytes only in the presence of Cy. Human anti-globulin test showed that the red cells were covered with IgG as well as C3 and C4. Control erythrocytes previously treated with Cy were also agglutinated by the patient's serum (dilution 1:64). Upon addition to the serum of Cy (concentration up to 10 micrograms/ml), the agglutination was enhanced up to a serum dilution of 1:256. Further increase of the Cy concentration (greater than 10 micrograms/ml) was followed by a decreased reaction. These results indicate that red cell damage in this patient was mediated by both mechanisms, i.e. with immune complexes acting on "normal" red cells and also with antibodies acting on cyanidanol-coated red cells.

Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) have in common a microangiopathic hemolytic anemia involving disseminated platelet aggregation and endothelial damage of the microvasculature mainly of the brain (TTP) and kidney (HUS). The underlying pathomechanism still remains unclear. The disease takes an acute, dramatic and frequently fatal course. Unfortunately a broadly approved therapeutic regimen is still lacking since the rarity of TTP and HUS makes study of a large group of patients impossible. We have observed and treated 14 patients with TTP and HUS during a period of 9 years. Most of the cases have been triggered by infectious diseases and pregnancy. Diagnostic cornerstones were hemolytic anemia, schistocytes on peripheral blood smears and consumption thrombocytopenia. Renal and cerebral symptoms were observed regularly, whereas lesions of the pancreas, liver and heart were much less frequent. The treatment included plasma transfusion (47%), plasma exchange (42%), high dose corticosteroids (74%), antiplatelet agents (53%), vitamin E (32%) and vincristin (11%). The outcome of 19 episodes of TTP or HUS was as follows: in 78% complete recovery, in 11% persistence of impaired renal function, and in 11% death. From analysis of our cases it is concluded that plasma transfusions and high dose corticosteroids improve the prognosis of TTP and HUS significantly.

The findings are reported in 4 siblings in whom death was due to typical hemolytic-uremic syndrome. In one, successive treatment with heparin, dipyridamole and aspirin was unsuccessful. 125I-fibrinogen half-life was 2.1 days under aspirin and 1.9 days under combined aspirin/heparin therapy. The parents and 4 surviving sibs had normal renal function and normal platelet and fibrinogen survival. The mother and 3 sibs had an increased percentage of megathrombocytes. Two exhibited renal accumulation of 51Cr-platelet radioactivity which was suppressed by platelet inhibitors. In both, renal biopsy disclosed definite ultrastructural endothelial alterations. These changes are probably responsible for the local platelet sequestration and appear to be the primary defect in this family with hemolytic-uremic syndrome.