Prevención de enfermedad hemolítica perinatal severa con inmunoglobulina intravenosa en paciente altamente sensibilizada / Prevention of severe perinatal hemolytic disease with intravenous immunoglobulin in a highly sensitized patient

RESUMEN La enfermedad hemolítica perinatal es infrecuente hoy por la prevención que de ella se hace. Sin embargo, existen casos de madres altamente sensibilizadas que desean tener un hijo, lo que obliga a que ese embarazo deseado sea controlado de manera especial y sometido a procedimientos invasivos no exentos de morbimortalidad fetal. El uso prenatal de inmunoglobulina humana en la madre puede representar una alternativa terapéutica. Se presenta un caso en que su uso impidió el desarrollo de enfermedad intrauterina y favoreció la buena evolución neonatal a pesar de que el pronóstico inicial era muy adverso.

ABSTRACT Perinatal Hemolytic Disease is uncommon today due to its prevention. However, there are cases of highly sensitized mothers who wish to have a child, that forces this desired pregnancy to be controlled in a special way and be subjected to invasive procedures not exempt from fetal morbidity and mortality. Prenatal use of human inmunoglobulin in the mother may represent a therapeutic alternative. We present a case in which its use prevented the development of intrauterine disease and favored a good neonatal evolution despite the fact that the initial prognosis was very adverse.

Eculizumab therapy in paroxysmal nocturnal haemoglobinuria patient undergoing aortic valve surgery.

Paroxysmal nocturnal haemoglobinuria is a rare disorder characterized by haemolytic anaemia and pancytopaenia. The use of cardiopulmonary bypass can lead to a haemolytic crisis in patients with paroxysmal nocturnal haemoglobinuria due to activation of complement-mediated haemolysis. We report the successful management of a 69-year-old man undergoing aortic valve replacement with standard heparin-protamine protocol by using eculizumab, a monoclonal antibody of complement factor C5. The surgery was performed without triggering a haemolytic crisis, and the patient was discharged from the hospital without major complications.

Treatment of Congenital Thrombotic Thrombocytopenia Purpura: A New Paradigm.

Congenital thrombotic thrombocytopenia purpura (cTTP) is a very rare disorder worldwide. Standard treatment of recognized cases has been to administer fresh frozen plasma as the source of ADAMTS13, to replenish the absent ADAMTS13 enzyme. An alternative source, a plasma-derived factor VIII concentrate used for hemophilia A, and found to contain this enzyme, was reported to be effective in 1 patient in the United States. We now report details on a US cohort of 8 cTTP patients who have been successfully treated for varying periods with a marketed antihemophilic factor concentrate Koate-DVI. This biological product has been used successfully on demand in varying doses to treat acute exacerbations, as well as prophylactically (3 to 6 U ADAMTS13 every 3 to 21 d). Self-infused at home, in lieu of fresh frozen plasma therapy in the hospital setting, this product has effectively prevented episodes of thrombocytopenia, microangiopathic hemolytic anemia, and the concomitant organ damage in these patients. This specific virus inactivated product can be used to prevent further manifestations of this congenital enzyme deficiency.

Congenital CD59 Deficiency.

The severe clinical symptoms of inherited CD59 deficiency confirm the importance of CD59 as essential complement regulatory protein for protection of cells against complement attack, in particular protection of hematopoietic cells and human neuronal tissue. Targeted complement inhibition might become a treatment option as suggested by a case report. The easy diagnostic approach by flow cytometry and the advent of a new treatment option should increase the awareness of this rare differential diagnosis and lead to further studies on their pathophysiology.

Mass primaquine treatment to eliminate vivax malaria: lessons from the past.

Recent successes in malaria control have put malaria eradication back on the public health agenda. A significant obstacle to malaria elimination in Asia is the large burden of Plasmodium vivax, which is more difficult to eliminate than Plasmodium falciparum. Persistent P. vivax liver stages can be eliminated only by radical treatment with a ≥ seven-day course of an 8-aminoquinoline, with the attendant risk of acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Primaquine is the only generally available 8-aminoquinoline. Testing for G6PD deficiency is not widely available, and so whilst it is widely recommended, primaquine is often not prescribed. In the past, some countries aiming for vivax malaria eradication deployed mass treatments with primaquine on a massive scale, without G6PD testing. In Azerbaijan, Tajikistan (formerly USSR), North Afghanistan and DPR Korea 8,270,185 people received either a 14-day "standard" or a 17-day "interrupted" primaquine treatment to control post-eradication malaria epidemics. These mass primaquine preventive treatment campaigns were conducted by dedicated teams who administered the drugs under supervision and then monitored the population for adverse events. Despite estimated G6PD prevalences up to 38.7%, the reported frequency of severe adverse events related to primaquine was very low. This experience shows that with careful planning and implementation of mass treatment strategies using primaquine and adequate medical support to manage haemolytic toxicity, it is possible to achieve high population coverage, substantially reduce malaria transmission, and manage the risk of severe acute haemolytic anaemia in communities with a relatively high prevalence of G6PD deficiency safely.

Impact of thyroid dysfunction on erythropoietin dosage in hemodialysis patients.

BACKGROUND: Although thyroid diseases exist in patients with renal failure, thyroid function tests are not routine tests in patients on chronic hemodialysis (HD). Therefore, the impact of thyroid diseases on erythropoietin (EPO) dosage in HD patients is not well defined. This study evaluated the relationship between the dose of EPO and the presence or absence of thyroid dysfunction in HD patients. METHODS: This study included 1013 adult patients on HD who did not have a malignancy, liver cirrhosis, thalassemia, iron deficiency, gastrointestinal bleeding, or a major operation within 6 months. Patients were characterized as being euthyroid, or having the sick euthyroid syndrome, primary hypothyroidism, subclinical hypothyroidism, hyperthyroidism, or subclinical hyperthyroidism based on thyroid function tests. Routine biochemistry profiles including an index of the efficiency of HD, along with clinical data over the previous 6-month period, were collected and analyzed. Multiple regression models were employed to assess the relationship between the dose of EPO and the presence or absence of thyroid status. RESULTS: The mean monthly EPO dosages were 77.7±37.0, 70.2±40.6, 90.8±68.4, 78.5±46.7, and 82.3±41.2 µg, respectively, in the sick euthyroid syndrome, euthyroid patients, hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism groups (p<0.05). After adjustment of all other variables in multiple regression, the mean monthly EPO dosage was 19.00±8.59 µg more in hypothyroid patients compared with euthyroid patients (p=0.027). Further, considering an interaction with the presence of diabetes, the mean monthly EPO dosage in patients with either hypothyroidism or subclinical hypothyroidism and diabetes was 54.66±17.12 µg (p=0.001) and 31.51±10.38 µg more than that of euthyroid patients, respectively (p=0.002). CONCLUSIONS: In HD patients, the EPO dosage required to maintain the target hemoglobin level is significantly higher in patients having both hypothyroidism or subclinical hypothyroidism and diabetes than in euthyroid patients.

ROCK1 functions as a critical regulator of stress erythropoiesis and survival by regulating p53.

Erythropoiesis is a dynamic, multistep process whereby hematopoietic stem cells differentiate toward a progressively committed erythroid lineage through intermediate progenitors. Although several downstream signaling molecules have been identified that regulate steady-state erythropoiesis, the major regulators under conditions of stress remain poorly defined. Rho kinases (ROCKs) belong to a family of serine/threonine kinases. Using gene-targeted ROCK1-deficient mice, we show that lack of ROCK1 in phenylhydrazine-induced oxidative stress model results in enhanced recovery from hemolytic anemia as well as enhanced splenic stress erythropoiesis compared with control mice. Deficiency of ROCK1 also results in enhanced survival, whereas wild-type mice die rapidly in response to stress. Enhanced survivability of ROCK1-deficient mice is associated with reduced level of reactive oxygen species. BM transplantation studies revealed that enhanced stress erythropoiesis in ROCK1-deficient mice is stem cell autonomous. We show that ROCK1 binds to p53 and regulates its stability and expression. In the absence of ROCK1, p53 phosphorylation and expression is significantly reduced. Our findings reveal that ROCK1 functions as a physiologic regulator of p53 under conditions of erythroid stress. These findings are expected to offer new perspectives on stress erythropoiesis and may provide a potential therapeutic target in human disease characterized by anemia.

An unusual presentation of hemolytic anemia in a patient with prosthetic mitral valve.

Although rare, periprosthetic valvular regurgitation can cause hemolytic anemia. We present the case of a 63-year-old man who had an unusual presentation of hemolytic anemia due to periprosthetic mitral valve regurgitation (PMVR) in the presence of cold agglutinins. Due to high surgical risk, PMVR was percutaneously closed with three Amplatzer devices under the guidance of three-dimensional transesophageal echocardiography.

Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C.

Chronic hepatitis C affects one-third of HIV(+) patients worldwide. High ribavirin (RBV) exposure is crucial to maximize the response to hepatitis C therapy in this population, although it may increase the risk for hemolytic anemia. PERICO is a prospective multicenter trial in which HIV/HCV-coinfected patients are randomized to receive peginterferon (pegIFN) alfa-2a 180 microg/week plus either weight-based RBV (1000-1200 mg/day) or RBV 2000 mg/day, the latest along with erythropoietin alfa (EPO) 30,000 IU/week from the first day until week 4. A total of 149 patients were assessed in a planned interim analysis at week 4. In both arms, 22% of patients achieved negative HCV-RNA (rapid virological response, RVR). Multivariate analysis [OR (IC 95%), p] showed that factors associated with RVR were HCV genotypes 2/3 vs. 1/4 [20 (5-100), <0.01] and baseline HCV-RNA [0.16 (0.07-0.37) per log IU/ml, <0.01]. The occurrence of severe anemia (hemoglobin <10 g/dl) did not differ when comparing RBV vs. high RBV + EPO (7% vs. 3%; p = 0.4). Moreover, RBV plasma trough levels were comparable at week 4 (1.9 vs. 2.4 microg/ml; p = 0.2). Use of high RBV doses with preemptive EPO during the first 4 weeks of hepatitis C therapy is safe, but fails to enhance significantly RBV plasma exposure and RVR rates. Extensive intraerythrocyte accumulation of RBV following boosted production of red blood cells by EPO could explain these findings.

Hemolysis associated with prosthetic heart valves: a review.

Hemolysis is one of the potentially serious complications of prosthetic heart valves. It is usually associated with either structural deterioration or paravalvular leak. Mild, compensated hemolysis associated with mechanical heart valves is not uncommon even in the current era. Severe hemolysis is rare, however, and usually reflects paravalvular leak. The use of transesophageal echocardiography-guided operative techniques may help prevent or minimize early postoperative paravalvular leakage. There is a gamut of available therapeutic approaches-medical, transcatheter, and surgical-to this complication and therapy should be tailored to the individual patient. Novel pharmacological agents include erythropoietin and pentoxifylline. Several reports described the feasibility of transcatheter closure of paravalvular leak with coils or devices, but their effect on hemolysis is unpredictable. Surgery remains the treatment of choice in severe cases.

Management of A2B blood group in a patient for hypothermic cardiopulmonary bypass surgery--a case report.

A2 is one of the rare subgroups in the ABO blood group system. Because of the weak antigenic power of A2 subgroup, the hemolytic reaction is not severe under normothermic situations. Under hypothermic conditions, however, such as in cardiac surgery under hypothermic cardiopulmonary bypass (CPB), lethal hemolytic reaction may occur. Autologous blood transfusion helps the anesthesiologist to avoid banked blood and thus avoid unwanted transfusion reactions. The following case report is a 59 yrs old man with an "A2B" negative blood group who underwent CABG under hypothermic CPB (28C, using cold cardioplegia 4C). Following induction, the anesthesiologist drew three units of patient's own blood (1200 cc) and replaced it with the same volume of colloid solution (Acute Normovolemic Hemodilution-ANH). The collected autologous blood was then re-transfused at the end of surgery. With the use of the ANH technique, the patient was successfully managed during hypothermic CPB without the risk of a hemolytic reaction.

The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia.

Autoimmune hemolytic anemia (AHA) is a common complication in chronic lymphocytic leukemia (CLL). The UK LRF CLL4 trial is the largest prospective trial in CLL to examine the prognostic impact of both a positive direct antiglobulin test (DAT) and AHA. Seven-hundred seventy-seven patients were randomized to receive chlorambucil or fludarabine, alone or with cyclophosphamide (FC). The incidence pretreatment of a positive DAT was 14%. Ten percent developed AHA. The DAT correctly predicted the development, or not, of AHA after therapy in 83% of cases, however only 28% of DAT-positive patients developed AHA. Of 299 patients tested both before and after treatment, those treated with single-agent fludarabine were most likely to remain DAT positive and to change from negative to positive. Patients treated with chlorambucil or fludarabine were more than twice as likely to develop AHA as those receiving FC. In a multivariate analysis, stage C disease and high beta2 microglobulin were independent predictors of a positive DAT result. AHA, or a positive DAT, with or without AHA, independently predicted for reduced overall survival (OS). Four deaths, all on fludarabine monotherapy, were attributed to AHA. In conclusion, DAT status at the time of initiation of therapy provides a new prognostic indicator, although FC may protect against AHA. This trial was registered at http://isrctn.org as no. 58585610.