Therapeutic plasmapheresis as a bridge to liver transplantation in fulminant Wilson disease

Wilson disease is an autosomal recessive disorder of copper metabolism that leads to the accumulation of copper mainly in the liver, cornea, brain, and kidney. Rarely, Wilson disease can present as fulminant hepatic failure with direct antiglobulin test-negative hemolytic anemia and renal failure. In the absence of liver transplantation, this disease is uniformly fatal because medical therapy is ineffective. This report describes the successful use of plasmapheresis for a patient with fulminant Wilson disease as a bridge to transplantation. Five daily therapeutic plasmapheresis procedures using fresh frozen plasma as a replacement fluid were performed over 6 days. Serum copper, urinary copper excretion, and hemolysis were significantly reduced and renal function improved. The patient's clinical status improved and she remained clinically stable until a liver transplant was possible. Plasmapheresis can be a successful medical treatment in fulminant Wilson disease and should be considered as a therapeutic measure to stabilize a patient by decreasing serum copper, reducing hemolysis, and helping to prevent renal tubular injury from copper and copper complexes until liver transplantation is possible.     

Cefotetan disodium-induced hemolytic anemia.

OBJECTIVE: To report a case of cefotetan disodium-induced hemolytic anemia. DATA SOURCES: Original research articles and case reports. DATA SYNTHESIS: A 46-year-old woman developed fulminant hemolytic anemia following a second exposure to intravenous cefotetan disodium for postoperative prophylaxis. She developed respiratory failure requiring intubation and acute renal failure requiring hemodialysis. The hemolysis was successfully treated with plasmapheresis, but the patient died on the 25th postoperative day. Positive Coomb's tests have been reported in less than three percent of patients receiving cefotetan. To our knowledge, this is the first case of fulminant hemolytic anemia associated with intravenous cefotetan disodium therapy. CONCLUSIONS: Cefotetan should be added to the list of drugs known to cause hemolytic anemia. Monitoring for hemolysis should be considered for patients who receive multiple courses of therapy.     

Hemolytic anemia and plasma exchange

Hemolytic anemia is a disease caused by autoantibodies and resulting in various complaints and clinical symptoms. In about half of cases, the cause of autoimmune hemolytic anemia can not be determined. Corticosteroids are the first-line treatment option for warm autoantibody-related hemolytic anemia. In patients who develop steroid side effects or do not respond adequately, other immunosuppressives may be preferred. In case a rapid response is required or fulminant hemolysis occur, human immunoglobulins (IVIGs) may be added to treatment. Finally, plasma exchange (PE) may additionally be utilised. The essence of PE is based on the removal of immune complexes, protein-bound toxins, autoantibodies and high molecular weight solutes and protein-bound solutes. The main clinical aim of the removal of solutes is usually to gain a faster response than immunosuppressive therapy. Studies related to hemolytic anemia and PE are usually based on case reports. Our case report is about a patient with severe IgG subtype hemolytic anemia. The treatment was started with 1 mg/kg methylprednisolone; to which there was no response with weekly rituximab 375 mg/m² and IVIG administered. Because of unresponsiveness to all of the immunosuppresives, a total of 5 sessions of PE were added to the treatment procedure every other day. After these sessions, the requirement for transfusions has decreased and the patient underwent splenectomy. The patient is currently being followed up only on oral cyclosporine and the last hemoglobin level was 14.7 g /dl. In severe and refractory anemia, especially in the case of cardiovascular imbalance in fulminant hemolysis, PE may be preferred as a third series option after immunosuppressive treatments and play a role as a bridge to splenectomy.     

Application of therapeutic plasma exchange in hematology

Therapeutic plasma exchange (TPE) was used in 146 patients with hematologic disorders: hyperviscosity syndrome, 74; cryoglobulinemia, 53; porphyria, 9; immune complex disease, 3; cold agglutinin disease, 1; hemolytic uremic syndrome, 1; autoimmune hemolytic anemia, 1; autoimmune thrombocytopenia, 1; autoimmune neutropenia, 1; Clq deficiency, 1; and secondary immunodeficiency, 1. It was shown that TPE applied in patients with hyperviscosity syndrome resulted in rapid reduction of paraprotein concentrations, and normalization or significant decrease of serum viscosity associated with marked clinical improvement (regression of neurologic, renal, hematologic, visual and other disturbances). Application of TPE in patients with cryoglobulinemia resulted in plasma cryoglobulin reduction and clear clinical effects (blood flow improvement, skin ulcer healing, reversal of impaired renal function and disappearance of purpura and other abnormalities). Very good results were obtained in patients with porphyria (decreased sensitivity to sunlight) and also in patients with Clq deficiency. Satisfactory clinical improvement and better laboratory findings were also seen in patients with immune complex disease, autoimmune hemolytic anemia, autoimmune thrombocytopenia and hemolytic uremic syndrome.     

Eculizumab as a bridge to immunosuppressive therapy in severe cold agglutinin disease of anti‐Pr specificity

Severe cold agglutinin disease with hemodynamic compromise requires rapid stabilization of the autoimmune hemolytic anemia as a bridge to the immunosuppressive effect of rituximab. Herein, we describe eculizumab treatment of severe complement‐mediated hemolysis in a patient whose hemodynamic status deteriorated in spite of supportive blood transfusions and therapeutic plasma exchange.     

Western blot analysis in patients with hypocaeruloplasminaemia

Inherited copper toxic disease, Wilson's disease, is an autosomal recessive disorder arising from a defect in biliary copper excretion. Although there are several pathognomonic clinical features, such a multisystem disease can be difficult to diagnose, particularly in the early stages of copper toxicity. Even measurements of serum copper and caeruloplasmin, the major copper-transporting protein typically reduced in Wilson's disease, may mimic other metabolic conditions such as Menke's disease and chronic active hepatitis. We have previously shown that the major biliary isoform of copper-transporting protein is 125 kDa caeruloplasmin, and this is always absent in the bile of Wilson's disease patients. In this paper we describe Western blot analysis of molecular species of caeruloplasmin in hypocaeruloplasminaemia, which can distinguish between the overlap which occurs in Wilson's disease homozygotes, heterozygotes and other conditions mimicking Wilson's disease. This may be useful for identifying patients with low plasma caeruloplasmin concentrations, and hepatic or neurological clinical features which may also be found in Wilson's disease.      

Erythrocyte adenylate kinase isoenzyme as a marker for hemolysis

The presence in serum of adenylate kinase isoenzyme originating from erythrocyte can be useful as a marker for detecting hemolysis. We have presented preliminary evidence for identifying hemolytic anemia patients earlier by determining erythrocyte AK isoenzyme activity in serum (or plasma) rather than using measurement of plasma hemoglobin concentration. This test being quite specific for hemolysis should find use as a quick method for estimating the extent of in vivo hemolysis in hemolytic patients earlier than heretofore possible. J. Clin. Lab. Anal. 11:351–356, 1997. © 1997 Wiley-Liss, Inc.     

Hemoglobin Catabolism Following a Hemolytic Transfusion Reaction in a Patient with Sickle Cell Anemia

A hemolytic transfusion reaction occurring in a patient with sickle cell anemia provided insight into the handling of massive amounts of hemoglobin in patients who lack haptoglobin. Despite the acute intravascular release of 33 gms of hemoglobin, the peak plasma hemochromogen was only 134 mg/100 ml and only 6 per cent of the hemoglobin load was recovered in the urine. In contrast, the serum bilirubin rose sharply to a peak of 30 mg/100 ml within three hours of hemolysis.
The minimal hemoglobinuria, the relatively low peak level of plasma hemoglobin, and the marked and rapid elevation of serum bilirubin suggest an increased hemoglobin clearing capacity of the chronically stimulated reticuloendothelial system in patients with chronic severe hemolytic disease.     

Defective biliary copper excretion in Wilson's disease: the role of caeruloplasmin

Abstract. Previous studies have failed to explain the link between copper accumulation and abnormal caeruloplasmin expression in Wilson's disease. Furthermore, despite the isolation of a candidate gene for Wilson's disease, which predicts a defective copper transport protein, the localization of this putative protein and its relationship to the pathway involved in copper excretion and to caeruloplasmin remain unknown. We now present evidence that caeruloplasmin, the major plasma copper-carrying protein, is present in the liver in Wilson's disease, and thus that reduced circulating levels of the protein result from a post-translational defect in the secretory pathway. We have also identified a novel form of caeruloplasmin, molecular weight 125 kD, which we propose may act as the carrier for excretory copper into bile, since it is normally present in both liver and bile, although largely absent from serum, and undetectable in bile from Wilson's disease patients. The presence of this form of caeruloplasmin in Wilson's disease liver suggests that a related post-translational defect may also be responsible for its absence from bile in Wilson's disease. This study thus provides the first plausible explanation of a link between the defective copper excretion and the reduced plasma caeruloplasmin, which characterize Wilson's disease.     

Chronic hemolytic anemia due to cold agglutinins: II. The role of C′ in red cell destruction

The sera of four patients with chronic hemolytic anemia due to cold agglutinins deposited C' globulins on normal red cells at 37 degrees C. The circulating cells of the patients were heavily coated with C' complex and were relatively resistant to C' hemolysis by cold agglutinin. Such red cells were removed from the patients' circulation at an exponential rate with (51)Cr t((1/2)) that varied from 7 to 19 days. Normal red cells were removed rapidly by hepatic sequestration during the first hours in the patients' circulation. Thereafter, a slower rate of abnormal destruction occurred which was associated with the accumulation of C' complexes on the red cell and the development of resistance to C' hemolysis by cold agglutinin. Normal red cells coated with sufficient C' complex by action of cold agglutinins in vitro to produce resistance to C' hemolysis by cold agglutinins demonstrated varying degrees of improved survival during the first hours in the circulation of three of the patients.The levels of serum C' were reduced in all four patients with chronic hemolytic anemia due to cold agglutinins. Transfusion of large volumes of normal red cells into two patients further reduced serum C'. (51)Cr-labeled normal red cells survived longer after red cell transfusions than before, because of less rapid destruction during the first hours in the circulation. The reduction in serum C' levels appeared responsible for the improved survival.In subjects without cold agglutinins, the presence of the spleen decreased the survival of red cells from a patient who had previously undergone splenectomy. Splenic removal also predominated in the reduced survival of autologous red cells in one patient. Neither hepatic nor splenic mechanisms predominated in removing autologous C'-coated cells in the other two patients.     

Plasma exchange in the treatment of immune disease

Plasma exchange was investigated as an alternative to the use of toxic drugs to remove unwanted antibody. Studies in rabbits immunized with bovine serum albumin demonstrate that exchange transfusion after a primary immunization results in a rebound of antibody to above preexchange levels. However, exchange transfusion seven, 11, or 18 days after secondary immunization results in permanent lowering of antibody levels. Plasma exchange with the continuous flow centrifuge was used in four patients with hematologic diseases. White cell isoantibodies were removed in a septic leukopenic patient, permitting white cell transfusions. Two patients with immune thrombocytopenia were exchanges; one showed prompt and permanent elevation of platelet count, while the other did not improve. A patient with immune hemolytic anemia had stabilization of hemoglobin levels and decreased Coombs reactivity following plasma exchange.     

Therapeutic plasma exchange for fulminant hepatic failure secondary to Wilson's disease

Wilson's disease (WD) is an autosomal‐recessive disorder of impaired copper metabolism resulting in accumulation of copper primarily in the liver but ultimately in many organs and tissues. A small number of patients with WD initially present with fulminant hepatic failure (FHF), hypercupremia, and intravascular hemolysis. The therapeutic goals for these patients include quickly removing the copper and preparing the patient for liver transplantation. Here, we report on a 6‐year‐old male with WD in FHF with anemia, renal insufficiency, and coagulopathy. The patient received a series of therapeutic plasma exchanges (TPE) as adjunctive therapy to remove copper and stabilize his coagulopathy and anemia until a transplant was possible. A total of five single plasma volume (1500 mL) TPE were performed over the course of 11 days with plasma as the replacement fluid. Laboratory results demonstrated temporary improvement after each procedure. Liver transplantation was performed 12 days after beginning TPE and 35 days after admission to the hospital. TPE was a successful adjunctive therapy to bridge this patient with WD to transplantation. J. Clin. Apheresis 27:282–286, 2012. © 2012 Wiley Periodicals, Inc.     

Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats.

Several clinical studies have suggested that excess hepatic iron accumulation is a progressive factor in some liver diseases including chronic viral hepatitis and hemochromatosis. However, it is not known whether iron-induced hepatotoxicity may be directly involved in hepatitis, cirrhosis, and liver cancer. The Long-Evans Cinnamon (LEC) rat, which accumulates excess copper in the liver as in patients with Wilson's disease, is of a mutant strain displaying spontaneous hemolysis, hepatitis, and liver cancer. We found previously that LEC rats harbored an additional abnormality: accumulation of as much iron as copper in the liver. In the present study, we compared the occurrence of hepatitis and liver cancer in LEC rats fed an iron-deficient diet (ID) with those in rats fed a regular diet (RD). The RD group showed rapid increments of hepatic iron concentrations as the result of hemolysis, characteristics of fulminant hepatitis showing apoptosis, and a 53% mortality rate. However, no rats in the ID group died of fulminant hepatitis. Hepatic iron, especially "free" iron concentration and the extent of hepatic fibrosis in the ID group were far less than those of the RD group. At week 65, all rats in the RD group developed liver cancer, whereas none did in the ID group. These results suggest that the accumulation of iron, possibly by virtue of synergistic radical formation with copper, plays an essential role in the development of fulminant hepatitis, hepatic fibrosis, and subsequent hepatocarcinogenesis in LEC rats.     

Treatment of Wilson's disease with zinc: III. Prevention of reaccumulation of hepatic copper

Twelve patients with Wilson's disease, most of whom had received intensive treatment with penicillamine, were given zinc therapy as their sole medication for copper control. Serial liver biopsies were performed during a 12- to 20-month follow-up period to determine whether hepatic copper reaccumulates during zinc therapy. Mean baseline liver copper concentration was 255 micrograms/gm dry weight, whereas the mean value after therapy was 239 micrograms. No patient demonstrated hepatic reaccumulation of copper during zinc therapy. Copper balance, 24-hour urinary copper excretion, and nonceruloplasmin plasma copper concentration all indicated good copper control during zinc therapy. Hepatic zinc concentration increased twofold to threefold over baseline values but no toxicity was seen. Hepatic zinc concentrations appeared to reach a plateau after 12 to 18 months of zinc therapy. We conclude that oral zinc as the sole maintenance therapy in patients with Wilson's disease prevents hepatic reaccumulation of copper.     

Copper distribution among serum proteins in paediatric liver disorders and malignancies

Fractionation of normal serum on Sephadex G-150, followed by determination of copper, caeruloplasmin and albumin concentrations, indicated that only approximately 71% of total serum copper was associated with caeruloplasmin; less than previously reported values. Seven per cent was associated with a high molecular weight protein, designated 'transcuprein', 19% with albumin and 2% with amino acids. Compared with adult serum the concentrations of caeruloplasmin and of copper associated with caeruloplasmin were low both in serum from neonates and in serum from patients with symptomatic Wilson's disease. However, in contrast to the neonate, Wilson's disease patients exhibited a raised total serum copper and raised non-caeruloplasmin-copper. In Indian Childhood Cirrhosis serum caeruloplasmin and caeruloplasmin-copper levels were normal, whilst the non-caeruloplasmin-copper was raised. Elevated non-caeruloplasmin-copper in Wilson's disease and Indian Childhood Cirrhosis may therefore represent an overspill into the serum from a copper-laden liver. Children with malignancy showed increased serum concentrations of copper and caeruloplasmin. Both caeruloplasmin-bound and non-caeruloplasmin-bound copper concentrations were elevated. It remains to be determined whether increased 'transcuprein'- and albumin-bound copper result from a sequestering of copper released from peripherally utilized caeruloplasmin, or are associated with increased rates of caeruloplasmin synthesis.     

Plasma exchange and rituximab treatment for lenalidomide‐associated cold agglutinin disease

BACKGROUND: Lenalidomide is an amino‐substituted analog of thalidomide with potent immunomodulatory properties. The drug has been widely used for treatment of multiple myeloma and myelodysplastic syndrome (MDS) associated with 5q‐abnormality. The most common side effects are cytopenias, infections, and deep venous thrombosis. CASE STUDY: We report a clinical observation of severe autoimmune hemolytic anemia (AIHA) due to cold agglutinin disease (CAD) that developed 11 days after initiation of lenalidomide treatment in a patient with MDS who relapsed after allogeneic bone marrow transplantation. RESULTS: CAD was diagnosed by the presence of hemolytic variables and cold agglutinin detected in patient's plasma. The antibody screen, which was performed at 37°C, was negative throughout. The direct antiglobulin test was positive only for complement (C3d). These findings supported the diagnosis of CAD associated with lenalidomide administration. Other causes of hemolysis including ABO incompatibility and infectious etiologies were ruled out. Rituximab therapy in conjunction with daily plasma exchange decreased the rate of hemolysis and transfusion requirement in our case. CONCLUSION: In addition to warm AIHA, lenalidomide use can also be associated with development of CAD. Rituximab given in conjunction with plasma exchange can be effective in treating CAD in this setting.     

Successful exchange transfusion of an infant for AIHA developing late in mother's pregnancy

A 25-year-old woman with apparently inactive Hodgkin's disease developed fulminant autoimmune hemolytic anemia in the 37th week of pregnancy. The baby required four exchange transfusions for hyperbilirubinemia. The same IgG antibody was found in mother and infant.     

Evaluation and management of patients with thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) describes syndromes with multiple etiologies, some of which are rapidly fatal without plasma exchange treatment. Although there have been advances in understanding the pathogenesis of TTP, evaluation and management remain difficult because there are no specific diagnostic criteria, as TTP can be clinically similar to other acute disorders, such as sepsis, disseminated malignancy, malignant hypertension, and preeclampsia, and because urgent treatment is required. An unexpected observation of anemia and thrombocytopenia should trigger consideration of TTP; evidence that the anemia is due to microangiopathic hemolysis, suggested by the presence of red cell fragmentation on the blood smear, supports the diagnosis. When the diagnostic criteria of microangiopathic hemolytic anemia and thrombocytopenia without an apparent alternative etiology are fulfilled, plasma exchange treatment is appropriate. However, plasma exchange has risks for severe complications and death; therefore, this management decision must be balanced against the confidence in the diagnosis. With plasma exchange treatment, approximately 80% of patients survive, in contrast to only 10% in the era prior to the availability of plasma exchange. The continuing mortality from TTP, the risks of plasma exchange treatment, and the potential for recurrent episodes of TTP are clinical challenges that remain to be solved.     

Microangiopathic hemolytic anemia as the initial manifestation of porcine valve failure

We compare the findings in a patient whose microangiopathic hemolytic anemia was the initial sign of porcine valvular dysfunction, with those of six other patients with porcine valve failure seen at Tripler Army Medical Center and with those of 12 patients with hemolytic anemia and porcine valve failure whose cases have been reported in the literature. Total bilirubin and serum lactic dehydrogenase were directly related to the degree of anemia in patients with porcine valve dysfunction. Echocardiography confirmed valve dysfunction in only four of eight patients, while cardiac catheterization confirmed valve failure in 16 of 17 patients. Laboratory evidence for hemolysis was minimal in 31 patients who had normal, functioning porcine valves. Microangiopathic hemolytic anemia in the presence of a porcine prosthetic heart valve, and in the absence of other causes, warrants a thorough evaluation to rule out valve dysfunction. Routine laboratory screening for hemolysis may aid the early diagnosis of porcine valve failure.