Case Report: Severe Anemia with Anemic Heart Disease

By: Rohmantuah Trada Purba Advicer: dr. I Nyoman Suarjana, Sp.PD-KR Department of Internist, Ulin Hospital/Unlam School of Medicine Banjarmasin, Indonesia Mei 2012

Abstract A 36-year-old woman was admitted to Ulin Hospital on 1 Mei 2012. She complained of limp, pale and skin that turn to yellow from 15 day before. She also complained nausea and urin color like color of tea. She is married and not have child yet. The patients blood pressure was 80/40 mmHg; heart rate, 100 beats per minute; body temperature, 36,5 oC; and respiratory rate, 28 breaths per minute. On physical examination, the patient was somnolen, has decreased of conscious and babbling. She also has anemic konjunctiva, icteric sclera and pale skin. In the Blood Test, she has very low value of Hemoglobin that is 1,9 g/dL. On 4 th day of admission in Ulin Hospital, Chest X-ray was have an appreance of cardiomegaly. In this phase patient was diagnosed with Severe Anemia with Anemic Heart Disease Introduction In order to make a generalized approach to the diagnosis of anemia, the World Health Organization (WHO) has established a reference range for normal blood hemoglobin concentration, depending on age and sex.(1)According to this criterion, anemia is present if the blood concentration of hemoglobin falls below 130 g/L in men or 120 g/L in women. This rule does not apply to infants, children and pregnant women, who have their own tables of lower limits of hemoglobin concentration. The WHO criteria has Age/Sex Adult male Adult female Adult female pregnant Children 6 months to 6 years Children 6 to 14 years

been accepted widely for diagnosis and publication, but its universal application has been questioned mainly because of racial differences. Beutler has proposed a lower limit of hemoglobin (1-2 g less) in African Americans than in Caucasians. The reference range of hemoglobin concentration in blood may vary depending on the population analyzed, age, sex, environmental conditions and food habits. (2,3)

Hb Gram/dL (venous blood) 13 12 11 11 12

Anemia is one of the most frequent causes of medical visits because of the high incidence in children, young women and elderly people, especially if malnutrition is present. Moreover, anemia is one of the leading sings in many diseases or is the first evidence of disease observed in routine blood cell enumeration. Anemia is unusually prevalent in developing countries because of malnutrition, and genetic, parasitic or infectious diseases. The prevalence of anemia varies greatly, from 2.9% to 61%, depending on population, age, sex, and normal limits of hemoglobin used by the author. (1) Severe anemia dened as Hb < 6.0 g/dL. It has been observed that in malaria-endemic areas, the incidence of severe anemia and agespecic rates of anemia strongly correlate with the intensity of Plasmodium falciparum transmission .Beside that severe anemia is common in patients with myelodysplastic syndromes and Leukimia (6,7). Chronic severe anemia is known to cause high-cardiac-output heart failure (HF). Moreover, anemia is common in patients with HF, and many recent observations have shown that reduced hemoglobin indicates an independent risk of hospitalization and all-cause mortality in patients with HF. Anemia is frequently seen in patients with systolic, as well as diastolic, HF. Several factors, such as hemo dilution, impaired erythropoietin (Epo) secretion, chronic inammation, and disturbed iron metabolism, are supposed to cause

anemia in patients with HF; however, the mechanism by which anemia causes or facilitates HF remains largely unknown. (4) There are several potential reasons anemia may be a riskfactor for CVD outcomes. First, the presence of anemia, if extended for a long period, may result in ventricular remodeling and cardiac dysfunction. Chronic anemia with hemoglobin 10 g/dl is known to result in increased cardiac output that may lead to LVH. The latter is well appreciated in patients who are anemic secondary to their kidney disease, as well as in patients with sickle cell disease. Second the presence of anemia may in theory be a risk factor for myocardial ischemia. Third, reduced hemoglobin may be associated with other risk factors for CVD that were not ascertained in this study, such as decreased nutritional status, additional measures of lower socioeconomic status, or increased inammatory status. (8) There are physiologic reasons, however, to suspect that the presence of chronic anemia may result in adverse long-term cardiovascular consequences. Chronic anemia may result in an increased cardiac output secondary to decreased afterload, increased preload and increased chronotropic and inotropic effects. Over time this may lead to ventricular dilation and LVH. The chronic increase in cardiac output may also lead to arterial remodeling of central elastic arteries such as the aorta or the carotids. This remodeling in turn results in arterial enlargement and compensatory arterial intima media

thickening, or arteriosclerosis. The presence of either LVH or arteriosclerosis may be more directly associated with future CVD risk. (5) The increased myocardial workload due to hemodynamic and neurohormonal alterations observed in chronic anemia could cause adverse LV remodeling. LV hypertrophy and dilation are observed in animal models of severe anemia and they may contribute to poor outcomes. Whereas LV hypertrophy is consistently found in anemic patients with CKD, it is unclear whether it is related to anemia or hypertension. Although there are no data directly linking LV hypertrophy and anemia in HF, a 1g/dl increase in Hgb over the course of 24 weeks was associated with a 4.1-g/m2 decrease in LV mass in the RENAISSANCE (Randomized Etanercept North American Strategy to Study Antagonism of Cytokines) trial. (9) When faced with hemodynamic load burden, heart compensated with Frank-Starling mechanisms to increase cross-bridge formation, increase muscle mass to face the additional burden, and use of neurohormonal mechanisms to increase contractility. In accordance with the law of LaPlace that the load on all parts of the heart muscle = (pressure x radius) / (2 x wall thickness), then persistent pressure load on the heart muscle that settled in a long time, such as hypertension and aortic stenosis, will causes muscle fibers to grow thicker and increases muscle mass. Parallel arranged sarcomeres causes dilation of myocyte and result in the form of concentric hypertrophy remodeling

(increase ratio of wall thickness / size of the room). Because systolic stress (load end) is a major determinant of the pumping performance, so normalization of systolic stress to maintain a normal ejection fraction is required.(10) Increased wall stress and strain is generate stimulation signal causing transcription of mRNA to increase muscle protein. These nuclear reactions produce protection to cardiac muscle against excessive pressure wall to minimize oxygen consumption.(10) Biomechanical stress such as hypertension and chronic pressure load enable signal hypertrophy and apoptosis in parallel. At the same time, also led to induction of biomechanical stress-related ligands on gp130 as kardiotropin 1. This cytokine bound to receptors that contain gp130-LIF (leukemia inhibitory factor) heterodimer, resulting in activation of gp130 pathway that inhibits the action of the apoptosis pathway. Without gp130, cardiac myocytes respond to biomechanical stress shifted toward apoptosis, resulting in loss of functional myocytes and the incidence of heart failure.The result of biomechanical stress depends on the balance between these two opposing signaling transduction pathways. (10) The regulation of cell growth mediators that including cytokines, growth hormone (GH) and insulinlike growth factor 1 (IGF-1), also plays an important role in influence growth and composition of the heart muscle. These mediators are also involved in a regression that caused the transition from compensated left

ventricular hypertrophy types of structural changes towards severe heart muscle leading to heart failure. mRNA IGF-1 is increased by angiotensin II heart through hemodynamic and non hemodynamic mechanisms and regulate cardiac structural changes that occur in hypertension. There has been evidence of a direct effect of GH in Case Report A 36-year-old woman was admitted to Ulin Hospital on 1 Mei 2012. She complained of limp, pale and skin that turn to yellow from 15 day before. She also complained nausea and urin color like color of tea. She is married and not have child yet. According to her family, she was have complain like this 10 years ago and diagnosed with Hepatitis. Her blood pressure was 80/40 mmHg; heart rate, 100 beats per minute; body temperature, 36,5 oC; and respiratory rate, 28 breaths per minute. On physical examination, the patient was somnolen, has decreased of conscious and babbling. She also has anemic konjunctiva, icteric sclera and pale skin. She was diagnosed then with Anemia Gravis e.c Hemolitic Anemia and differential diagnose Hepatitis B. On 1st day admission on Ulin Hospital, laboratotium finding for this patient is : Hb = 1.9 g/dL, Leukosit=6500/uL, Eritrosit : 670.000/uL, Hematokrit 5 vol%. She has very low value of Hemoglobin. On day 1st day of hospitalization, she still had mental status changes, which included somnolen and hard to talk with others. She sent to the ward after get

the ventricular response to a number of physiological and pathological stimuli that increase cardiac load. GH / IGF-1 pathway may also help explain the relationship between obesity, increased blood pressure, the development of hypertrophy of the left ventricle, and the metabolic syndrome.(1)

2 kolf PRC transfusion and she is getting better at respiration and her consciousness. In the ward physical examination has found an anemic konjunctiva and pale skin especially in palmar. This clinical findings suggested that patient still has anemia even after treated in emergency care. 1st day of admission she was given IVFD NaCl 20 dpm, Lameson injection 12 gr vial/12 hour, Ranitidin injection 50 mg/12hour, 2 kolf PRC transfusion/day and O2 3 lpm. On day 4rd Bone marrow Aspiration has been do to patient and the result is MDS. On day 4th, Coombs test, Thorax rontgen and EKG have been do to patient and the result is Coomb test:negative, Thorax rontgen and EKG suggested that there are left ventricular hyperthropy so in day 4th patient diagnosed with Anemia Gravis with Anemic Heart Disease. On day 2nd until day 9th of adminission her blood pressure, heart rate, respiratory and body temperature rate were in normal level. Her complain of limp and hard move is decrease. She was discharged 9 days after admission with skin still pale, limp body and other anemic sign .

The doctor planned to give IVFD NaCl 20 dpm, Lameson injection 12 gr vial/12 hour, Ranitidin injection Discussion On admission at the Ulin Hospital, the patient come with some severe anemic sign such as pale and icteric skin, limp, somnolen and anemic conjunctiva. Her Hemoglobin value is 1,9 gr/dL indicated that this patient has a anemia gravis (Hb < 6 gr/dL) resulting a decrease in the oxygencarrying capacity of the blood. As the oxygen content is diminished in anemia, the anemic patient can maintain the overall supply of oxygen to the tissues only by increasing cardiac output and that compensation reducing the cardiac reserve. If the coronary blood flow fails to deliver sufficient oxygen the heart muscle becomes relatively hypoxic, and there will be a fall in cardiac output and a reduction in systemic blood flow. Hyperanemia is a severe form of anemia, in which the hematocrit is below 10%. Critical condition of patient reported in this case, required aggressive treatment in order to avoid fatal consequences of anemia and hypovolemia. In this case, management is aimed at preventing tissue hypoxia by maintaining an adequate circulating volume of red cells. this requires a multidisciplinary approach including control of the relevant physiological parameters, maintenance of tissue perfusion, temperature control and blood component or pharmacological treatment to support coagulation. (11) The effects of anemia must be separated from hypovolemia,

50 mg/12hour, PRC transfusion until patient Hb > 10 and Kemotherapy for her MDS. although both can impede tissue oxygen delivery. Oxygen delivery in healthy adults is maintained even with hemoglobin levels as low as 6-7 g/dl. But with Hb value 1,9 this patient will need an O2 treatment to increase tissue perfusion. So this patient get O2 treatment 3 lpm in emergency care. (11) Transfusion is necessary to minimize symptoms and risks associated with symptomatic chronic anemia when hemoglobin is below 6 g/dl. This patient get repeatedly PRC transfusions 2 kolf/ day to increase physiological parameters that caused by this severe anemia, maintenance of tissue perfusion and blood component. This patient get given IVFD NaCl 20 dpm. The purpose of fluid resuscitation is to delay or prevent the chain of events that leads to irreversible shock caused by severe anemia. (11) This patient has sign of hemolytic anemia that she complain her skin turn to yellow and in physical examination we get an icteric sclera so patient get a methylprednisolon therapy in Lameson injection 12 gr vial/ 12 hour. Immunosuppressive therapy with corticosteroids is the first line therapy of warm type AIHA (Auto Immune Hemolytic Anemia) and a response is seen in approximately 80% of cases. But in day 4th Coomb test is done and the result is negative so in purpose to get a cause of anemia BMA is done in 4th day and the result of BMA is Myelodisplasia

Syndrome. Because this BMA result, planning for this patient is kemotherapy but patient was discharge before she get kemotherapy. (12) In the Antero-Posterior thorax rontgen on 4th day, there are a cardiomegaly in this patient. Without any history of etiology or risk factor of cardiomegaly such as hypertension, heart disease or thyroid disorders, the cause of this cardiomegaly is expected from severe anemia. The lack or the insufficient presence of Red Blood Cells (RBCs) in the blood may be highly responsible for causing cardiomegaly. This exerts pressure on the heart to beat at a fast pace so as to compensate for the loss of adequate oxygen to the tissues. But this has the unfortunate consequence of enlarging the heart and this is causing cardiomegaly. (13) Severe anemia dened as Hb < 6.0 g/dL and this patient Hb value

in 1st day of admission is 1,9g/dL. With this low value of Hb, oxygen will not delivered normally. The result is tissue and end organ will have a hipoperfusionand will give a feedback to increase perfusion. In severe anemia, low Hgb reduces systemic vascular resistance (SVR) as the result of decreases in blood viscosity and enhanced nitric oxidemediated vasodilation. Low SVR reduces blood pressure (BP) and causes baroreceptor-mediated neurohormonal activation , identical to that seen in low output HF . The increased sympathetic and rennin angiotensin activity decreases RBF and glomerular ltration rate, resulting in salt and water retention by the kidneys and expansion of the extracellular and plasma volumes. The combined effect of volume expansion and vasodilation increases the cardiac output which may help to increase oxygen transport. (9)

When faced with hemodynamic load burden, heart compensated with Frank-Starling mechanisms to increase cross-bridge formation, increase muscle mass to face the additional burden, and use of neurohormonal mechanisms to increase contractility. In accordance with the law of LaPlace that the load on all parts of the heart muscle = (pressure x radius) / (2 x wall thickness), then persistent pressure load on the heart muscle that settled in a long time, such as hypertension and aortic stenosis, will causes muscle fibers to grow thicker and increases muscle mass. Parallel arranged sarcomeres causes dilation of myocyte and result in the form of concentric hypertrophy remodeling (increase ratio of wall thickness / size of the room). Because systolic stress (load end) is a major determinant of the pumping performance, so normalization of systolic stress to maintain a normal ejection fraction is required.(10) Increased wall stress and strain is generate stimulation signal

causing transcription of mRNA to increase muscle protein. These nuclear reactions produce protection to cardiac muscle against excessive pressure wall to minimize oxygen consumption.(10) Biomechanical stress such as hypertension and chronic pressure load enable signal hypertrophy and apoptosis in parallel. At the same time, also led to induction of biomechanical stress-related ligands on gp130 as kardiotropin 1. This cytokine bound to receptors that contain gp130-LIF (leukemia inhibitory factor) heterodimer, resulting in activation of gp130 pathway that inhibits the action of the apoptosis pathway. Without gp130, cardiac myocytes respond to biomechanical stress shifted toward apoptosis, resulting in loss of functional myocytes and the incidence of heart failure.The result of biomechanical stress depends on the balance between these two opposing signaling transduction pathways.(10)

The regulation of cell growth mediators that including cytokines, growth hormone (GH) and insulinlike growth factor 1 (IGF-1), also plays an important role in influence growth and composition of the heart muscle. These mediators are also involved in a regression that caused the transition from compensated left ventricular hypertrophy types of structural changes towards severe heart muscle leading to heart failure. mRNA IGF-1 is increased by angiotensin II heart through hemodynamic and non hemodynamic mechanisms and regulate cardiac structural changes that occur in hypertension. There has been evidence of a direct effect of GH in the ventricular response to a number of physiological and pathological stimuli that increase cardiac load. GH / IGF-1 pathway may also help explain the relationship between obesity, increased blood pressure, the development of hypertrophy of the left ventricle, and the metabolic syndrome.(10) The treatment of patients with anemic heart disease conditions including causative therapy and symptomatic therapy. In this patient clinician has planning to give a kemotherapy as a causative therapy for her MDS because that MDS that make a conditions of severe anemia in this patient. Until the recent past, treatment for MDS was limited to best supportive care (growth factors and transfusion support) for the majority of patients and allogeneic stem cell transplant for the small minority of patients eligible for the procedure. Of these treatments, only transplant offered an approach that changed the

natural history of the disease and offered a cure. More recently, newer agents, such as azacitidine and decitabine, have been FDA approved to treat MDS based on their impact on the natural history of disease through decreasing the rate of transformation from MDS to AML.
(14)

Cyclosporine and ATG were among the first immunomodulatory agents used in the treatment of MDS and showed partial success in producing transfusion independence. Early studies of thalidomides effectiveness in patients with MDS reported 31% hematologic responses after twelve weeks of therapy. Subsequent studies revealed response rates from minimal to nearly 50% with partial success inducing transfusion independence seen in a subset of patients . Unfortunately, the side effect profile of hypotension, neuropathy, constipation, and drowsiness makes the drug poorly tolerated, especially in elderly patients . Consequently, based on the clinical activity of thalidomide, newer analogues have been developed to try to minimize side effects. Lenalidomide is the only currently clinically available thalidomide analogue for treatment of patients with MDS. It is reported to share many of the same mechanisms of action with thalidomide; however, lenalidomide has not shown the same effect on endothelial cell proliferation. (14) Anemia in cancer patients is frequent but often underestimated. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Treatment

options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with cancer. Presently, trials investigate whether treatment of anemic cancer patients Conclusion A 36-year-old woman was admitted to Ulin Hospital on 1 Mei 2012. She complained of limp, pale and skin that turn to yellow from 15 day before. She also complained nausea and urin color like color of tea. Her Hb value is 1,9 g/dL. In Chest X-ray there are an appreance of cardiomegaly. This patient was diagnosed as Severe Anemia with References 1. Jose A, Maria S, Martn G. Classifcation of anemia for gastroenterologists. World J Gastroenterol 2009 October 7; 15(37): 4627-4637. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration . Blood. 2006;107:17471750. Patel KV, Harris TB, Faulhaber M, Angleman SB, Connelly S, Bauer DC, Kuller LH, Newman AB, Guralnik JM. Racial variation in the relationship of anemia with mortality and mobility disability among older

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