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.     

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.     

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 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.     

Microangiopathic Haemolytic Anaemia and Experimental Tumour-Cell Emboli

S ummary . The mechanism by which disseminated carcinoma may induce microangiopathic haemolytic anaemia has been studied in rats using intravenous injections of Walker carcinosarcoma-256 cells. Following the injection of tumour cells there was sequestration of radio-labelled fibrinogen and platelets in the lungs and a simultaneous fall in peripheral platelet count and rise in free plasma haemoglobin. Anti-fibrinolytic treatment (EACA) and triamcinolone accentuated the changes whereas heparin abolished the effect. Electron microscopy demonstrated fibrin and platelet deposition around tumour cells. It is concluded that intravascular coagulation around tumour cell emboli is an important mechanism in the production of microangiopathic haemolytic anaemia in disseminated carcinoma.     

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.     

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.     

Novel uses for recombinant erythropoietin therapy in unlicensed indications

Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.     

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.     

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.      

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)     

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.     

Microangiopathic haemolytic anaemia secondary to lupus nephritis: an important differential diagnosis of thrombotic thrombocytopenic purpura

Systemic lupus erythematosus (SLE) has been described as a cause of microangiopathic haemolytic anaemia (MAHA), however there is little literature to support this assertion. We report on three patients presenting with SLE and MAHA with a clinical picture indistinguishable from thrombotic thrombocytopenic purpura (TTP), who had underlying lupus nephritis. They all had significant proteinuria and normal Von Willebrand Factor cleaving protease (vWF-CP) levels. Their MAHA fitted better for haemolytic syndrome (HUS) and their cerebral signs were explained either by malignant hypertension or cerebral lupus. Their MAHA only improved when the appropriate treatment for lupus nephritis was given.We propose that the previously described association between SLE and MAHA, in actuality relates to the underlying presence of lupus nephritis causing haemolytic uraemic syndrome, not TTP. Significant proteinuria was present in all cases of MAHA due to lupus nephritis, so may be a useful discriminatory sign. Furthermore the demonstration of a normal vWF-CP assay aided in the distinction between TTP and MAHA due to lupus nephritis. All our patients responded to mycophenolate mofetil suggesting this may be useful in other cases of lupus nephritis causing HUS.     

Anti-CD20 antibody in thrombotic thrombocytopenic purpura refractory to plasma exchange

Thrombotic thrombocytopenic purpura is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, altered neurology, renal impairment and fever. While plasma exchange has reduced mortality from more than 90% to between 10 and 30%, a proportion of cases fail to respond. Rituximab may be efficacious in the management of refractory cases of thrombotic thrombocytopenic purpura. We present two cases in which rituximab was used with successful outcomes. Treatment resulted in resolution of severe clinical and haematological abnormalities in both patients. There has been no relapse after 16 months follow up. Our experience supports the use of rituximab in difficult cases of TTP. Ongoing evaluation of its use is in progress at our institution.     

Two types of nomifensine-induced immune haemolytic anaemias: drug-dependent sensitization and/or autoimmunization

Thirty-one patients who developed immune haemolytic anaemia while receiving nomifensine were studied. We provide evidence that nomifensine can cause two forms of immune haemolytic anaemia: one that is associated with an abrupt haemolytic episode due to drug-dependent antibodies, and a less acute form associated with IgG autoantibodies. The majority of patients' serum samples (23 cases) contained IgG and/or IgM antibodies reacting to a highly variable extent with red blood cells (RBC) only in the presence of the drug and/or its metabolites. Sera of six patients contained IgG autoantibodies which reacted, like those in warm autoimmune haemolytic anaemia, with RBC in the absence of drugs. Three patients had developed both types of antibodies. From a diagnostic viewpoint, nine of the drug-dependent antibodies could not be identified by using the drug itself, but by its known (three cases) or unknown urine-born metabolites (ex vivo antigens). We conclude that nomifensine can induce in vivo the production of RBC drug- and/or metabolite-dependent antibodies, autoantibodies, or both in the same patient.     

Chronic haemolytic anaemia in hypertrophic cardiomyopathy.

A patient with hypertrophic cardiomyopathy was found to have a chronic intravascular haemolytic anaemia. After investigation this was attributed to the abnormal haemodynamics of the cardiac disease. Treatment with propranolol was associated with an improvement in the anaemia. No further cases of haemolytic anaemia were found in 37 other patients with hypertrophic cardiomyopathy. It is concluded that haemolytic anaemia is a very rare feature of the condition.     

Thrombotic Thrombocytopenic Purpura as an Initial Presentation of Primary Sjo¨gren’s Syndrome

A healthy woman presented with ecchymoses due to thrombocytopenia, with numerous bone marrow megakaryocytes, microangiopathic haemolytic anaemia, disorientation, irritability, and normal renal function. Thrombotic thrombocytopenic purpura (TTP) was diagnosed and treated successfully by plasma exchange therapy, both on presentation and during a further three relapses. The TTP was considered idiopathic until, 4 months later, definite primary Sjo¨gren’s syndrome (1°SS) was diagnosed following the appearance of sicca symptoms. Only four similar cases have been cited in the literature. TTP should be added to the varied haematological manifestations that may occur in patients with 1°SS. The possible presentation of 1°SS not with classic sicca symptoms but rather with haematological abnormalities, including TTP, should be recognised. Received: 26 January 2001 / Accepted: 23 July 2001     

Congenital haemolytic anaemia associated with adenylate kinase deficiency

SUMMARY. Chronic haemolytic anaemia associated with adenylate kinase (AK) deficiency is very rare and only seven cases in five families have been described. We present six children of one family who are deficient of this enzyme and in three of them a combined G6PD deficiency was found. AK deficiency was transmitted by an autosomal recessive gene and heterozygous state was not accompanied by disease, whereas homozygously affected individuals present a congenital chronic non-spherocytic haemolytic anaemia with haemoglobin levels of 8-9 g/dl. Patients also deficient in G6PD suffer from a more severe haemolytic anaemia with haemoglobin levels around 6 g/dl. The AK-deficient children are also mentally retarded. Splenectomy performed in five of the six patients resulted in complete remission of the haemolytic process.     

Diclofenac-induced immune haemolytic anaemia: simultaneous occurrence of red blood cell autoantibodies and drug-dependent antibodies

During the last 5 years we have identified a total of 17 patients (nine females and eight males aged between 53 and 85 years) with immune haemolytic anaemia related to diclofenac (a nonsteroidal anti-inflammatory drug). All patients developed acute intravascular haemolysis. Two patients died, and eight patients developed temporary renal failure that required haemodialysis. The direct antiglobulin test was positive with anti-IgG and anti-C3d in all cases, with anti-IgA in 4/10 cases tested, and negative with anti-IgM. The indirect antiglobulin test was moderately or weakly positive in 11 cases, and IgG autoantibodies could be eluted from the red blood cells (RBCs) of all patients. Initially, the diagnosis of autoimmune haemolytic anaemia of warm type was suggested in all cases. All patients had simultaneously developed autoantibodies and drug-dependent antibodies. The majority of drug-dependent antibodies ( n =13) reacted with urine containing the drug and its metabolites ( ex vivo antigen), the native drug, and diclofenac-treated RBCs. The antibodies in the remaining four cases were detectable only in the presence of ex vivo antigen. Diclofenac appears to bind only weakly to RBCs in the absence of the drug-dependent antibodies.
We conclude that diclofenac forms neoantigens with RBCs that may stimulate the production of autoantibodies and drug-dependent antibodies. The resulting haemolytic syndrome is very similar to autoimmune haemolytic anaemia of warm type.