Microangiopathic hemolytic anemia

It is reported on a more infrequent or too little regarded clinical picture within the form circle of the disseminated intravasal coagulation disturbances, the microangiopathic haemolytic anaemia (MHA). Diagnostically heuristic is the clinical triad haemolytic anaemia, thrombocytopenia and haemorrhagic diathesis. The microangiopathic haemolytic anaemia is described on the basis of a casuistics, the present knowledge about pathogenesis and therapy are discussed.     

Fibrinogen Catabolism in Microangiopathic Haemolytic Anaemia

S ummary . Fibrinogen catabolism has been studied in six patients with microangiopathic haemolytic anaemia, three patients with fragmentary haemolytic anaemia following the insertion of valve prostheses into the heart and ten control patients. Increased rates of catabolism of ¹³¹ I-fibrinogen were found in the patients with microangiopathic haemolytic anaemia. Evidence of enhanced fibrinolysis was not present.
This finding suggests that intravascular coagulation is a feature of some cases of microangiopathic haemolytic anaemia and supports the hypothesis that the interaction of red cells with fibrin may result in the characteristic morphological appearances in these cases.     

Disseminated prostatic carcinoma presenting with acute interstitial nephritis and microangiopathic haemolytic anaemia

Abstract A 74-year-old man with metastatic prostatic carcinoma developed acute oliguric renal failure, a microangiopathic haemolytic anaemia and thrombocytopaenia. A renal biopsy showed an acute interstitial nephritis but no changes suggestive of the haemolytic uraemic syndrome. He recovered normal renal function after treatment with haemodialysis and prednisone 20 mg daily for five days. Previous assumptions about the renal lesion in patients with malignancy-associated microangiopathic haemolytic anaemia may need review.     

Microangiopathic Haemolytic Anaemia and Mucin-forming Adenocarcinoma

S ummary . Twelve patients are described who developed well-marked micro-angiopathic haemolytic anaemia in association with metastatic carcinoma. The tumours originated in the stomach in six cases, in the breast in two cases, in the lung in one case and the origin was uncertain in three cases. All 11 tumours studied were found to be mucin-secreting adenocarcinomas.
Ten out of the 12 patients were thrombocytopenic. Fibrinogen metabolism was studied in four patients and in each patient the catabolism of fibrinogen was found to be greatly increased despite normal or near normal plasma fibrinogen levels and an absence of overt fibrinolysis. Fibrin degradation products were demonstrated in the serum of five out of six patients. Hyaline thrombi were seen in the small blood vessels in the kidneys and suprarenals in one patient and in the myocardium in two patients, while changes suggestive of organized thrombi were present in the interlobular arteries of the kidneys in three patients.
It is thought likely that the microangiopathic haemolytic anaemia develops secondarily to intravascular coagulation brought about by thromboplastins derived from mucin-forming tumour cells which have entered blood vessels, and that contact between circulating red cells and tumour emboli within blood vessels may be an additional cause of red-cell damage.     

Microangiopathic Haemolytic Anaemia Associated with Hypercakaemia in an Experimental Rat Tumour

A severe microangiopathic haemolytic anaemia develops during the course of tumour growth in rats bearing the solid Walker carcinosarcoma 256. Early changes of blood coagulation are the prolongation of the clotting and clot-forming time in the thrombelastogram, a reduction of factor-VIII activity and impaired platelet aggregation. Subsequent decrease of plasma fibrinogen and blood platelets indicate intravascular coagulation as the cause of the haematological changes. Fibrinogen turnover studies with homologous ¹³¹I-fibrinogen showed a significantly shortened half time. Concomitant with the alterations of the clotting mechanism a decrease of plasminogen level as well as an increasingly prolonged euglobulin lysis time were found; these may be interpreted as the result of the fibrinolytic response to intravascular fibrin deposition. Histological examination of the animals' organs demonstrated fibrin strands and large fibrin thrombi exclusively in the capillaries of the tumour. Simultaneously with the intravascular coagulation syndrome the animals develop a hypercalcaemia caused by a parathyroid hormone-like substance elaborated by the tumour tissue. Since clinical reports point to an interrelation between thrombotic disorders and hyperpara-thyroidism, the possible role of hypercalcaemia in triggering intravascular coagulation is briefly reviewed.     

Treatment of Patients with Microangiopathic Haemolytic Anaemia with Heparin

The response of three children and four adult women with microangiopathic haemolytic anaemia to treatment with heparin is described. The one child and three adults treated within 10 days of the onset of the illness recovered rapidly and completely from their anaemia, thrombocytopenia and uraemia. The two children and one adult treated between 18 and 31 days after the onset of the illness responded less well. The two children who were given small doses of heparin died from complications of the renal microangiopathy despite improvement in the haemolysis and thrombocytopenia. The adult woman made a slow and partial recovery; the haemolysis and thrombocytopenia improved, but renal function did not return to normal.
The importance of recognizing and treating the low grade intravascular coagulation which may accompany microangiopathic haemolytic anaemia is stressed. It is suggested that the variable response to treatment with heparin of patients with microangiopathic haemolytic anaemia observed by ourselves and others may be due to relative roles of intravascular coagulation and primary vascular disease in the pathogenesis of the microangiopathy, and to the development of irreversible vascular damage if treatment is delayed.     

Microangiopathic haemolysis associated with occult carcinoma

Summary Microangiopathic haemolytic anaemia (MAHA) is a well recognized complication of disseminated carcinoma and its treatment. It is however, rarely seen with localized carcinoma. The case presented here is a previously unreported association of a patient, who having been successfully treated for MAHA, was found to have occult breast carcinoma on a routine screening mammogram six months after the haemolytic episode.     

Microangiopathic haemolysis associated with occult carcinoma.

Microangiopathic haemolytic anaemia (MAHA) is a well recognized complication of disseminated carcinoma and its treatment. It is however, rarely seen with localized carcinoma. The case presented here is a previously unreported association of a patient, who having been successfully treated for MAHA, was found to have occult breast carcinoma on a routine screening mammogram six months after the haemolytic episode.     

Haematology of the haemolytic uraemic syndrome

The Haemolytic Uraemic Syndrome (HUS), characterised by a microangiopathic haemolytic anaemia, thrombocytopenic purpura and renal failure, is the commonest cause of acute renal failure in children. Most cases of HUS are associated with enteropathogenic Escherichia coli which elaborate an exotoxin called verotoxin. Verotoxin has been shown to produce red cell abnormalities and induce a platelet aggregating activity. It also exerts a cytopathic effect on cultured endothelial cells. These findings are discussed in relation to the pathogenesis of HUS. Recent studies demonstrating homology between the verotoxin glycolipid receptor and the red cell P group antigens have led to the hypothesis that variability in the expression of these red cell antigens may account for the marked individual variations in the degree of organ damage in children with HUS. This hypothesis could provide a criterion for rational immunisation of at risk children.     

von Willebrand factor-cleaving protease inhibitor in a patient with human immunodeficiency syndrome-associated thrombotic thrombocytopenic purpura

Antibodies that inhibit von Willebrand Factor (VWF)-cleaving protease activity occur in patients with acute thrombotic thrombocytopenic purpura (TTP) and often persist in the chronic phase. A deficiency of this protease is likely to be responsible for the generation of ultrahigh VWF multimers and influence the formation of intra-arterial platelet aggregates that result in microangiopathic haemolytic anaemia, thrombocytopenia and end in organ failure. This report demonstrates complete deficiency of VWF-cleaving protease and the presence of a concentration-dependent IgG1 inhibitor in the plasma of a patient with acquired immunodeficiency syndrome (AIDS). These data may contribute to understanding the pathophysiology of human immunodeficiency syndrome (HIV)-related TTP.     

Plasma from patients with thrombotic thrombocytopenic purpura induces activation of human monocytes and polymorphonuclear neutrophils

Thrombotic thrombocytopenic purpura (TTP) is a rare but severe disorder characterized by microangiopathic haemolytic anaemia, consumptive thrombocytopenia, neurological involvement and formation of platelet thrombi in the small vessels. The aetiopathology of TTP and the mechanism behind the beneficial effect of plasma exchange with plasma infusion have not yet been fully elucidated. We have studied the effect of plasma from four patients with TTP on human blood phagocyte activation, as measured by reactive oxygen species (ROS) production and CD11b expression. TTP plasma obtained in the acute phase of the disease induced ROS production by human monocytes and enhanced CD11b expression on neutrophils. This activation effect remained in the cryosupernatant but not in the cryoprecipitate made from TTP plasma, and disappeared when a complete response was achieved by plasma exchange. These findings suggest that activated blood phagocytes may be involved in the pathophysiology of TTP.     

Microangiopathic haemolytic anaemia in cancer patients with bone marrow infiltration.

Eight patients suffering from wide-spread malignancies presented with a severe microangiopathic haemolytic anaemia (MHA) without gross evidence for coagulation abnormalities. The common feature in these patients was bone marrow infiltration with malignant cells, suggesting a pathogenic link between bone marrow carcinosis and red cell destruction. Furthermore, it is concluded that MHA is a rare complication of malignancy and a terminal syndrome rather than an early manifestation of the disease.     

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.     

Systemic lupus erythematosus, thrombocytopenia, microangiopathic haemolytic anaemia and anti-CD36 antibodies [clinical conference]

Thrombocytopenia in patients with acute systemic lupus erythematosus (SLE) frequently presents the clinician with considerable diagnostic and therapeutic difficulties. In this Grand Round, we present a 48-yr- old woman with a 7 yr history of lupus, who presented with acute proliferative glomerulonephritis and nephrotic syndrome, pneumonia, profound hypocomplementaemia and a severe microangiopathic haemolytic anaemia with associated thrombocytopenia. Her thrombocytopenia proved initially refractory to conventional immunosuppressive therapy, and corticosteroids, and resolved only with plasma exchange and repeated fresh frozen plasma infusions. Serological testing revealed high-titre antinuclear antibodies (ANA) and markedly raised antibodies to double- stranded (ds) DNA, but no significant elevation in anticardiolipin antibodies. Platelet-associated IgG and IgM and antibodies to the CD36 glycoprotein antigen, expressed on platelets and endothelium, were detected in the serum. We address some of the difficult diagnostic and management issues raised by this complex patient and the possible immunopathological links between antibodies to CD36, immune-mediated red cell destruction, thrombocytopenia and thrombotic microangiopathic haemolytic anaemia.      

How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome

Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS) are acute, rare life‐threatening thrombotic microangiopathies that require rapid diagnosis and treatment. They are defined by microangiopathic haemolytic anaemia and thrombocytopenia, with renal involvement primarily in aHUS and neurological and cardiological sequelae in TTP. Prompt treatment for most cases of both conditions is with plasma exchange initially and monoclonal therapy (rituximab in TTP and eculizumab in aHUS) as the mainstay of therapy. Here we discuss the diagnosis and therapy for both disorders.     

Microangiopathic haemolytic anaemia in cancer patients with bone marrow infiltration

Summary Eight patients suffering from wide-spread malignancies presented with a severe microangiopathic haemolytic anaemia (MHA) without gross evidence for coagulation abnormalities. The common feature in these patients was bone marrow infiltration with malignant cells, suggesting a pathogenic link between bone marrow carcinosis and red cell destruction. Furthermore, it is concluded that MHA is a rare complication of malignancy and a terminal syndrome rather than an early manifestation of the disease.P. H. was supported by a grant from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, F.R.G. (Hi 213/4)     

Electrophoresis of Blood Platelets and Erythrocytes: A Study in Healthy Persons and Patients with Haematological Diseases,Prosthetic Heart Valves,Virus Infections and Hyperlipaemia

The mean electrophoretic mobility of normal human blood platelets in 301 samples from 260 healthy individuals was 1.08 μm/s/V/cm in citrated plasma and 0.84 and 1.05 μm/s/V/cm in 0.145 M saline (pH 7.3) and in sucrose/phosphate/saline buffer (pH 6.4), respectively. Normal red cell mobility in citrated plasma in 229 samples from 195 persons was 1.41 μm/s/V/cm, in 0.145 M saline and 0.0667 M phosphate buffer (pH 7.3) 1.09 and 1.28 μm/s/V/cm, respectively. The results of blood platelet and red cell electrophoresis in 90 patients with various diseases are reported. Severe abnormalities in platelet mobility were not found in any of the patients. In patients with von Willebrand's disease a slight increase in platelet mobility was observed. In 4 patients with haemolytic-uraemic syndrome and 2 patients with microangiopathic haemolytic anaemia a reduced red cell mobility in citrated plasma and buffers was found. In a case of red cell polyagglutinability, two populations of erythrocytes were observed electrophoretically. About half of the red cells had a mobility of about 43 % of normal in citrated plasma.     

Thrombotic thrombocytopenic purpura mimicking an acute meningoencephalitis

Thrombotic thrombocytopenic purpura is a rare, threatening disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and organ dysfunction, e.g., neurological impairment and renal insufficiency. We describe a patient with neurological impairment mimicking a meningoencephalitis in whom a thorough clinical evaluation along with appropriate laboratory tests led us to identify an underlying thrombotic thrombocytopenic purpura. The successful outcome of this patient was based on plasma exchange and immunosuppressive treatment. Thrombotic thrombocytopenic purpura should be considered in the differential diagnosis of patients presenting with any neurological abnormalities, anaemia and unexplained thrombocytopenia.     

The Significance of Microangiopathic Haemolytic Anaemia in Accelerated Hypertension

S ummary . Twenty-two patients with accelerated hypertension and varying degrees of renal involvement have been studied in order to assess the significance of microangiopathic haemolytic anaemia (MAHA) and the possible pathogenic role of intravascular fibrin deposition in this condition. Vascular damage was assessed by retinal photography including fluorescein angiography. Haematological investigations including examination of peripheral films and assessment of red cell fragmentation were carried out. Fibrinogen catabolism was measured using radio-iodine labelled fibrinogen.
No correlation between the degree of vascular damage in the retinal vessels and the blood pressure, degree of red cell fragmentation or evidence of renal damage was found. There was a significant increase in red cell fragmentation when the creatinine clearance was 20 ml/min or less. Fibrinogen derivatives were demonstrated in the serum in the minority and in the urine of the majority of those patients with MAHA. Fibrinogen catabolism was normal in all cases.
The significance of microangiopathic haemolytic anaemia in accelerated hypertension is discussed. It is suggested from these data that the red cell fragmentation occurs predominantly within the kidney and that there is no evidence that fibrinogen deposition plays an important role in red cell damage, or that it is an important pathogenic factor in producing accelerated hypertension.     

Sequential development of platelet,neutrophil and red cell autoantibodies associated with measles infection

Summary. This study describes the development of autoimmune thrombocytopenia followed by autoimmune haemolytic anaemia in a Negro woman with measles. An IgM platelet autoantibody was detected using a fluorescent labelled antiglobulin technique. The thrombocytopenia resolved spontaneously, although the platelet autoantibody persisted and platelet survival remained shortened, suggesting a compensated thrombocytolytic state. An IgG granulocyte autoantibody was present transiently although the patient was never neutropenic. The haemolytic anaemia was due to an IgM cold autoantibody (anti-I), which was active up to 30°C, and an IgG warm autoantibody, which was detectable only when she was severely anaemic. After an initial blood transfusion, the anaemia resolved and the red cell autoantibodies disappeared. The platelet, granulocyte and red cell autoantibodies were cell-specific and not a single cross-reacting antibody.