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.     

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.     

Coagulation defects in cyclosporine a treated allogeneic bone marrow transplant patients

CSA toxicity includes renal impairment, microangiopathic hemolytic anemia (MAHA), thrombocytopenia and consumptive coagulopathy (CC). We report five BMT patients who developed CSA-associated hematological toxicity. All were conditioned with Ara-C, Cyclophosphamide, Methylprednisolone, TBI, and in two cases busulfan. IV CSA was started the day after marrow infusion and, when practicable, changed to the enteral route. Five patients developed MAHA and T resulting in significantly increased transfusion requirements. All patients had renal impairment and red cell fragmentation. In all patients fragmentation was noted before renal impairment. All developed disproportionate increases in BUN relative to serum creatinine consistent with decreased renal perfusion. Hypertension followed renal impairment in four cases and occurred at the same time as the renal impairment in one case. Two developed CC, prolongation in APTT, and marked decreases in plasma fibrinogen. All patients improved on reduction of the CSA dose. BMT recipients receiving CSA at variable doses may develop evidence of a TTP-like syndrome and/or CC.     

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.     

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.     

Microangiopathic haemolytic anaemia and thrombocytopenia following lung volume reduction surgery in a single lung transplant recipient on maintenance tacrolimus (FK506) therapy

Microangiopathic haemolytic anaemia (MAHA) describes intravascular haemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. It is well recognized as a complication of cyclosporin A therapy in solid organ transplantation but has been uncommonly reported in association with tacrolimus therapy and never before in the setting of lung transplantation. Discussed is a 54-year-old female recipient of a left single lung transplant who developed anaemia, thrombocytopenia and red blood cell fragmentation consistent with MAHA following lung volume reduction surgery (VRS) of the native right lung in the setting of high serum tacrolimus levels. Treatment with fresh frozen plasma and plasmapharesis plus supportive therapy with blood and platelet transfusions resulted in successful resolution of the haemolytic process. Cyclosporin A was substituted for tacrolimus and 18 months later there has been no evidence of recurrence. Tacrolimus therapy is a rare cause of MAHA in solid organ transplants but the diagnosis should be considered if there is an unexplained fall in haemoglobin and/or platelet count in the context of high serum tacrolimus levels.     

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.     

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.     

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.     

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 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.     

Observations on the Mechanism of the Haematological Changes in the Haemolytic Uraemic Syndrome of Infancy

S ummary . The haemolytic uraemic syndrome of infancy (HUSI) is one of a group of diseases described by Brain, Dacie and Hourihane under the generic name 'microangiopathic haemolytic anaemia' (MHA). Survival studies using labelled red cells support the concept that increased haemolysis results from damage to the red cells sustained in small blood vessels. Studies with labelled platelets and fibrinogen fail to provide evidence for continuing intrarenal coagulation once the classic triad of haemolytic anaemia, thrombocytopenia and renal failure has been established.     

Thrombotic microangiopathy from Australian brown snake (Pseudonaja) envenoming

Background: Australian brown snake (genus Pseudonaja) envenoming causes a venom‐induced consumptive coagulopathy (VICC). A proportion of cases go on to develop thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and acute renal failure (ARF). Aim: The aim of the study was to define better the natural history and empirical treatments for thrombotic microangiopathy in brown snake envenoming. Methods: A review of brown snake bites recruited to the Australian Snakebite Project (ASP), a national multicentre study of snake envenoming was undertaken. Serial data are recorded on clinical effects and laboratory results, including measurement of venom concentrations. We describe cases of thrombotic microangiopathy and compare these to cases without thrombotic microangiopathy. Results: From 32 cases of brown snake envenoming with severe VICC, four (13%) developed thrombotic microangiopathy, we also included two cases of thrombotic microangiopathy from prior to ASP. All six developed severe thrombocytopenia (<20 × 10⁻⁹/L), worst 3 days after the bite and resolving over a week, MAHA with fragmented red blood cells on the blood film and five developed anuric ARF requiring dialysis and lasting 2–8 weeks. All six received antivenom, which was delayed compared with other brown snake‐envenoming cases. Four were treated with plasmapheresis. The severity and recovery of the thrombocytopenia, anaemia and renal function were similar with and without plasmapheresis. The median length of stay for MAHA cases was 14 days (interquartile range (IQR) 12–14) compared to 1.8 days (IQR 1.3–2) for all other cases. Conclusion: Thrombotic microangiopathy resulting from brown snake bite appears to have a good prognosis and management should focus on early antivenom therapy and supportive care including dialysis. The role of plasmapheresis is yet to be defined.     

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)     

Treatment of mitomycin-associated microangiopathic hemolytic anemia with vincristine

A syndrome, including microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal insufficiency, has been recognized to occur as a complication of antineoplastic therapy with mitomycin. The clinical presentation can vary from a chronic course with mild anemia and slowly progressive renal dysfunction to a fulminant course with severe anemia, rapid deterioration of renal function, and death. The optimal treatment of the mitomycin-associated MAHA syndrome is unknown. Therapy with steroids, antiplatelet agents, and heparin sodium has failed to reverse the MAHA. Plasmapheresis has improved the MAHA in a few patients without reversing the renal failure. We treated two patients who had MAHA and renal dysfunction during chemotherapy that included mitomycin; the MAHA and hypertension both objectively improved after treatment that included vincristine sulfate.     

Intravascular coagulation in gestational hypertension and pre-eclampsia: the value of haematological screening tests

Summary. Routine investigations designed to detect excessive intravascular coagulation in patients with gestational hypertension and pre-eclampsia have been analysed in 936 cases. Reticulocyte counts did not differ significantly from those in normal controls and abnormal red cell morphology was detected in only two patients. Fibrinogen degradation products and thrombocytopenia were found in about 10% of all hypertensive women and macrothrombocytosis in 32%. Neither reticulocyte counts nor the scanning of stained blood films for evidence of microangiopathic haemolysis have a place in the routine investigation of preeclampsia and it is doubtful whether any of the other screening tests can influence the management of patients with uncomplicated gestational hypertension. In fully developed pre-eclampsia, macrothrombocytosis is found in about 50% of patients, fibrinogen degradation products and thrombocytopenia in about 15%. All three parameters reflect the degree of clinical severity of the disease.     

Portal and pulmonary hypertension with microangiopathic hemolytic anemia

Marked pulmonary hypertension developed in a 40-year-old man with known cirrhosis and a previous portosystemic shunt. Terminally, he also showed signs of microangiopathic hemolytic anemia. At postmortem examination, he had severe plexiform dilatation lesions in the pulmonary vasculature, with deposition of fibrin in the vasculature channels. It is suggested that the site of microangiopathic red cell damage was the pulmonary microvasculature.     

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.     

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.     

A proposed treatment algorithm for adults with Haemoglobin SC disease

Sickle cell disease is one of the commonest serious inherited diseases in the world, and red cell transfusion is still one of the few effective treatments for acute and chronic complications. Transfusion corrects anaemia and dilutes out the number of red cells able to cause vaso‐occlusion and vascular damage. Urgent red cell transfusions are used to correct acute anaemia, treat acute chest syndrome and patients with acute neurological symptoms. We use elective transfusions preoperatively for moderate risk surgery, and in some pregnant women. There is good evidence for the use of long‐term regular transfusions in primary stroke prevention, with the aim of keeping the percentage of sickle haemoglobin below 30%. Long‐term transfusions are also used in secondary stroke prevention, and the management of progressive organ damage, including renal impairment and pulmonary hypertension. Blood needs to be matched for ABO, RH and Kell, although alloantibodies may still develop and require more careful, extended cross‐matching. Delayed haemolytic transfusion reactions are relatively common, difficult to diagnose and manage, and potentially fatal.