OBJECTIVES

General Instructional Objectives

After completing this module, students are expected to choose and interpret laboratory test especially at hematology, clinic-chemist, and immunoassay which is needed to help standing the diagnosis, observing, and definiting the prognosis of diseases.CHAPTER 1

BRAIN STORMING

1.1. SCENARIO

A woman, Ms. H, 19 years old, a student candidate in a university, came up with complain: rather pale, weak, and felt enlargement of abdomen in recent years. She was afraid if she suffered a chronic disease.1.2. MAIN PROBLEM

Ms. H, 19 years old, complaining of rather pale, weak, and feels enlargement of abdomen in recent years.1.3. KEYWORDS

Woman, 19 years old Rather pale Weak Feels enlargement of abdomen

In recent years1.4. HYPOTHESIS

Ms. H suffered a myeloproliferatif disease.

Ms. H suffered a chronic diseases, such as: anemia, lack of nutrition, or obstruction of GI tract1.5. ADDITIONAL INFORMATION

Identity: Ms. H, 19 y.o, a candidate of a college student

She comes from Tulungagung

She lives in a dormitory at Kalikepiting 2, Surabaya

The main complain: rather pale, weak, feels enlargement of abdomen; she forgot since when.

There are no pain, no fever, easy masuk angin, nggliyeng, seems like seeing bright stars She have not been treated There is no same complain at her family

Theres is no nausea,

She had normal menstruation

Physical examination:

TB/BB: 162 cm/48 kg

Tension: 110/70 mmHg

Temperature of body: 36,5 C

RR: 16x/minute

Pulse rate: 76x/minute, normal

Icterus (-)

Anemic (+)

Sianosis (-)

Retraction of costae while breathing (-)

Simmetrical thorax

Liver is on 2 finger under the arcus costae

Spleen is on Schuffner 4

Normal bowel sounds Laboratory test:

Hb: 9.8 mg/dLWBC: 9.9x103 per microlitre

Platelet: 280.000 per microlitre

MCH: 19 pg

MCV: 59 fl

MCHC: 289/dl

1.6. EARLY MIND MAP1.7. LEARNING ISSUES 11. Explain all about anemia, include its prosses and its tests! 2. Explain about organomegaly, hepatomegaly, and spleenomegaly! 3. What are the differential diagnosis of myeloproliferatif diseases?

4. Explain about the laboratory tests for myeloproliferatif diseases!

CHAPTER 2LEARNING ISSUES

2.1 ANSWER OF LEARNING ISSUES 12.1.1 Explain all about anemia, include its prosses and its tests!

Anemia is present in adults if the hematocrit is less than 41% (hemoglobin < 13.5 g/dl) in males or less than 37% (hemoglobin < 12 g/dl) in females. Physical examination includes attention to signs of primary hematologic diseases, there are: lymphadenopathy, hepatosplenomegaly, or bone tenderness.[1]

Possible symptoms include chest pain, dizziness or light-headedness (especially when standing up or with activity), Fatigue or lack of energy, Headaches, Problems concentrating, Shortness of breath (especially during exercise). Blood tests used to diagnose some common types of anemia may include: Blood levels of vitamin B12, folic acid, and other vitamins and minerals, Red blood count and hemoglobin level, Reticulocyte count, Ferritin level, Iron level. Anemia are classified according to their pathophysiologic basis, which related to diminished production or accelerated loss of red blood cell, or according to cell size.

Classification of anemias by pathophsiology

Decreased prodution

Hemoglobin synthesis: iron deficiency, thalassemia, anemia of chronic disesase

DNA synthesis: megaloblastic anemia

Stem cell: aplastic anemia, myeloproliferative leukemia

Bone marrow infiltration: carcinoma, lymphoma

Pure red aplasia

Increased destruction

Blood loss

Hemolysis (intrinsic)

Membrane: hereditary spherocytosis, ellyptocytosis

Hemoglobin: sickle cell, unstable hemoglobin

Glycolisis: piruvat kinase deficiency, etc

Oxidation: glucose 6 phosphate dehidrogenase deficiency

Hemolysis (extrinsic)

immune warm antibody, cold antibody

microanyopathic: thrombotic thrombopenic purpura, hemolytic-uremic syndrome, mechanical cardiac valve, paravalvular leak

Infection: clostridial

Hypersplenism

Classification of anemias by Mean Cell Volume

Microcytic (MCV< 70 fl)

Iron deficiency

Thalassemia

Anemia of chronic disease

Sideroblastic anemia

Macrocytic (MCV > 125 fl)

Megaloblastic

Vitamin B12 deficiency

Folate deficiency

Nonmegaloblastic

Myelodysplasia, chemotherapy

Liver disease

Increased reticulocytosis

Myxedema

Normocytic

Many causes [1]

In our cases, in additional information, we know that the MCV and MCHC are low. Therefore, we discuss the anemia more focusing on microcytic.

IRON DEFICIENCY

Iron deficiency is the most common cause of anemia worldwide. Iron is necessary for the formation of heme and other enzymes. Total body iron ranges between 2 and 4 g: approximately 50 mg/kg in men and 35 mg/kg in women. Most (70-95%) of the iron is present in hemoglobin in circulating red blood cells. Iron absorption occurs in the stomach, duodenum, and upper jejunum.

Menstrual blood loss in women plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL, or about 0.7 mg/d.

Iron loss can be due to bleeding. Common causes of bleeding are:

Heavy, long, or frequent menstrual periods

Cancer in the esophagus, stomach, or colon

Esophageal varices

The use of aspirin, ibuprofen, or arthritis medicines for a long time

Peptic ulcer disease[2]

Symptoms and Signs

As a rule, the only symptomps of iron deficiency anemia are those of anemia itelf (easy fatigability, tachycardia, palpitations and tachypnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, and cheilosis. Dysphagia because of the formation of eosophageal webs (plummer-vinson syndrome) also occurs.

An upper esophageal web (arrow) in a patient with Plummer-Vinson syndrome

Laboratory findings

Iron deficiency develops in stages. The first is depletion of iron stores. At this point, there is anemia and no changes in RBC size. The MCV remains normal. The serum ferritin will become abnormally low. Ferritin value less than 30 g/L is highly reliable indicator of iron deficiency. The serum total iron binding capacity (TIBC) rises.

After the depletion of iron stores, red blood cell formation will continue with deficient supplies of iron. Serum iron values decline to less than 30 g/dL and transferrin saturation less than 15%. For the MCV, it subsequently falls and the blood smear shows hypochromic microcytic cells. With further progression, anisocytosis and poikilocytosis develop. Severe iron deficiency will produce a bizarre pheripheral blood smear, with severely hypochromic cells, target cells, hypochromic pencil-shaped cells, and occasionally small numbers of nucleated red blood cells. The platelet count is commonly increased. [1]

ANEMIA OF CHRONIC DISEASE

Anemia of chronic disease is a blood disorder that refers to anemia that is found in people with certain long-term (chronic) medical conditions. [2] Many chronic systemic diseases are associated with mild and moderate anemia. Common causes include Autoimmune disorders; such as crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, chronic infection or inflammation; such as bacterial endocarditis, osteomyelitis (bone infection), HIV/AIDS, hepatitis B or hepatitis C, cancer (particularly lymphoma and Hodgkin's disease) [2], chronic renal disease and liver disease. Red blood cell survival is modestly reduced, and the bone marrow fails to compensate adequately by increasing red blood cell production. Failure to increase RBC is largely due to sequestration of iron within the reticuloendothelial system. Decrease in erythropoietin is rarely important cause of underproduction of RBC except in renal failure. [1]

Symptoms and signs

The clinical features are those of the causative condition.

Laboratory findings

The diagnosis should be suspected in patients with known chronic diseases which is confirmed by the findings of low serum iron, low TIBC, and normal or increased serum ferritin. If the serum ferritin value of less than 30 g/dL, should suggest coexistent iron deficiency. The transferrin saturation may be extremely low, leading to an erroneous diagnosis of iron deficiency. The hematocrit rarely falls below 60% of baseline (except in renal failure). The MCV is usually normal or slightly reduced. Red blood cell morphology is non-diagnostic, and the reticulocyte count is neither strikingly reduced nor increased.

THALASSEMIAS

ESSENTIALS OF DIAGNOSIS

Microcytosis out of proportion to the degree of anemia.

Positive family history of lifelong personal history of microcytic anemia.

Abnormal red blood cell morphology with microcytes, acanthocytes, and target cells

In -thalassemia, elevated level of hemaglobin A2 or F

General Considerations

The thalassemia are hereditary disorders characterized by reduction in the synthesis of globin chains ( or ). Reduced golobin chain synthesis causes reduced hemoglobin synthesis and eventually produces a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. Thalassemias can be considered among the hypoproliferative anemias, the hemolytic anemias, and the anemias related to abnormal hemoglobin, since all of these factors play a role in pathogenesis.

Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer two chains and two chains- and can be designate 22. Two copies of the -globin gene are located on chromosome 16, and there is no substitute for -globin in the formation of hemoglobin. The -globin gene resides on chromosome 11 adjacent to genes encoding the -like chains, and . The tetramer of 2 2 forms hemoglobin A2, which normally comprises 1-2% of adult hemoglobin., the terramer 2 2 forms hemoglobin F, which is the major hemoglobin of fetal life but which comprises less than 1% of normal adult hemoglobin.

-thalassemia is due primarily to gene deletion causing reduced -globin chain synthesis (Table 13-4). Since all adult hemoglobins are containing, -thalassemia produces no change in the percentage distribution of hemoglobins A, A2, and F. in severe forms of -thalassemia, excess chains may form a 4 tetramer called hemoglobin H.

- Thalassemias are usually caused by point mutations rather than deletions ( Table 13-5). These mutations result in premature chain termination or in problems with transcription of RNA and ultimately result in reduced or absent -globin chain synthesis. The molecular defects leading to -thalassemia are numerous and heterogeneous. Defects that result in absent globin chain expression are termed 0, whereas those causing reduced synthesis are termed +. The reduced -globin chain synthesis in -thalassemia results in a relative increase in the percentages of hemoglobins A2 and F compared to hemoglobin A, as the -like globin ( and ) substitute for the missing chains. In the presence of reduced chains, the excess chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to intra medullary and peripheral hemolysis . the bone marrow becomes hyperplastic under the drive of anemia.

Table 13-4. -Thalassemia syndromes.

Globin GenesSyndromeHematocritMCV

4

3

2

1

0Normal

Silent carrier

Thalassemia minor

Hemoglobin H disease

Hydrops fetalisNormal

Normal

28-40%

22-32%60-75 fl

60-70 fl

T

MCV = mean cell volume

Table 13-4. -Thalassemia syndromes.

-Globin GenesHb1AHb A2Hb F

Normal

Thalassemia major

Thalassemia major

Thalassemia intermedia

Thalassemia minorHomozygous

Homozygous 0

Homozygous +

Homozygous +(mild)

Heterozygous 0

Heterozygous +97-99%

0%

0-10%

0-30%

80-95%

80-95%1-3%

4-10%

4-10%

0-10%

4-8%

4-8%90% of cases. Infiltrates appear in the sinusoids, which are partly dilated and display fibrosis and deposits of haemosiderin. This results in portal hypertension ; ascites and oesophageal varices are rare (about 7% of cases). Further potential complications include cholelithiasis (its relationship has not been clarified so far), Budd-Chiari syndrome and portal vein thrombosis. The diagnosis is established by liver histology. Imaging procedures are of no significance here.Polycythaemia Vera

Liver involvement in Osler-Vaquez disease is rare or not detectable at all. There is, however, evidence of hepatosplenomegaly due to extramedullary haemopoiesis. Of importance here is the association with Budd-Chiari syndrome and veno-occlusive disease. Polycythaemia vera should be considered in cases of aetiologically unclarified portal vein thrombosis.Essential thrombocytosis

With the exception of occasional hepatosplenomegaly, liver involvement is rare. There is again an association with Budd-Chiari syndrome and veno-occlusive disease.Haemolytic Syndrome

Numerous congenital or acquired diseases lead to haemolysis. They are subsumed under the term haemolytic syndrome. Particularly, sickle-cell anaemia, thalassaemia and paroxysmal nocturnal haemoglobinuria are worthy of mention in this context.Sickle-Cell Anaemia

This form of genetic haemoglobinopathy is characterized by chronic haemolysis and haemolytic crises. Acute haemolysis is associated with acute right upper quadrant pain, leucocytosis, jaundice and elevated transaminases, AP and LDH. This hepatic crisis can mimic acute cholecystitis. It lasts 23 weeks. The condition is caused by a slowing down of the sinusoidal blood flow, which contains sickle cells, and, in addition, by a multiplication of the Kupffer cells. The liver is enlarged, rich in blood and violet-red. The sinusoids are dilated and contain agglutinates of sickle cells. The Kupffer cells contain ceroid and siderin as well as phagocytosed erythrocytes. (s. fig.a) Single-cell necroses of hepatocytes with Councilman bodies are detectable. Acute liver failure, usually with cholestasis and deep jaundice, is a rare event. Chronic haemolysis can lead to mostly asymptomatic gallstones (approx. 25% in children, 5070% in adults). Furthermore, portal hypertension and portal fibrosis may develop. Therapy: Exchange transfusion is indicated. Surgery must be avoided in cases where acute cholecystitis is only mimicked. Successful liver transplantation has been reported.

Fig A. Erythrophagocytosis in Kupffer cells (arrows) in haemolytic anaemiaThalassaemia

As a result of the crises entailing destruction of the red blood cells and the frequently required blood transfusions, liver siderosis develops. This may subsequently lead to fibrosis in some cases. Episodic cholestasis can be witnessed. In progressive siderosis, treatment with deferoxamine is indicated. Pigment gallstones can appear in the course of chronic haemolysis.

Paroxysmal Haemoglobinuria

Paroxysmal nocturnal haemoglobinuria may also give rise to chronic haemolysis. This membrane defect of the erythrocytes is due to mutation of the PIG-A gene on chromosome X resulting in deficient biosynthesis of the glycosylphosphatidlinositol anchor. The erythrocytes are sensitive to lysis when the pH of the blood becomes more acidic during sleep. This clinical picture can lead to hepatomegaly, a rise in transaminases, iron deficiency and siderosis as well as centrizonal necrosis. Thrombosis of the portal and splenic veins as well as Budd-Chiari syndrome are possible complications. Sclerosing cholangitis is likely to develop due to ischaemia.Spleenomegaly

A normal spleen is 11 (1014) cm in length, 7 (68) cm in width and 4 (34) cm in depth. The weight of the spleen varies considerably (< 100 g to >250 g); a mean value of 150170 (180) g can be accepted. The normal diameter of the splenic artery is 45 mm, while that of the splenic vein is 814 mm with a normal mean value of about 10 mm. With a flow rate of 500700 ml per minute, the blood flow through the spleen exceeds the arterial blood supply of the liver by a factor of almost 3. The longitudinal axis of the spleen runs parallel to ribs 911 from the upper dorsal to the lower ventral (Kuntz, 2006).The symptom of splenomegaly is defined as an enlargement of the spleen in which the normal values (4 7 11 cm) are clearly exceeded by >23 cm in at least two dimensions with a corresponding rise in the normal CT index (160440). Sonographic reliability depends largely on spleen thickness: >5cm 67%, >6 cm 85%, and >7 cm 100%. The thickness of the spleen is therefore regarded as the parameter which correlates best with clinical findings. An increase in the longitudinal diameter to well over 11 cm is also considered to be splenomegaly. A diameter of the splenic vein of >10 mm is deemed pathological.Enlargement of the spleen can have numerous causes. It is important to rule out any possibility that the method of investigation itself could lead to splenomegaly being simulated, such as upside-down spleen, accessory spleen(s) or wandering spleen. The involvement of the spleen in disorders of the lymphatic and reticuloendothelial system as well as of the portal and systemic circulation explains why splenomegaly is frequently found in connection with widely differing diseases.Splenomegaly is very closely related to a number of liver diseases and, in particular, to the clinically recognizable involvement of the liver in a variety of pathological processes. Inclusion of the differential diagnosis of splenomegaly can, therefore, provide valuable information for the clarification of hepatological findings.Drainage Disorders In The Portal and Systemic Circulation

Liver Cirrhosis, Liver Tumours, Liver Echinococcosis, Portal Vein Thrombosis, Thrombosis of The Splenic Vein, Right Heart Failure, Budd-Chiari Syndrome, Peliosis Hepatis, etc.

Hepatolienal Storage Diseases

Amyloidosis, Fatty Liver, Glycogenoses, Wolmans Syndrome, Hyperchylomicronaemia, Wilsons Disease, Zellwegers Cerebrohepatorenal Syndrome, Niemann-Pick Disease, Mucopolysaccharidoses, etc.

Infectious Diseases

Acute Viral Hepatitis, Acute Salmonellosis, Measles, Bacterial Sepsis, Histoplasmosis, Leptospirosis, Malaria, Mononucleosis, Bangs Disease, Visceral Leishmaniasis (22), Rickettsioses, Toxoplasmosis, Tularaemia, Schistosomiasis, etc.

Chronic Infections

Cholangitis, Endocarditis Lenta, Malaria, Eosinophilic Granuloma, Tuberculosis, Chronic Hepatitis, etc.

Collagenoses and Rheumatic Diseases

Feltys Syndrome, Lupus Erythematosus, Reiters Disease, Stills Disease, Wegeners Disease, Histiocytosis, etc.

Diseases of The Haematopoietic System

Acute Leucosis, Chronic Lymphadenosis, Chronic Myelosis, Erythroblastosis, Haemolytic Anaemias, Werlhofs Disease, Osteomyelosclerosis, Polycythaemia Vera, Thalassaemia, Shunt Hyperbilirubinaemia, etc.

Diseases of The Lymphoreticulohistiocytic System

Lipogranulomatosis, Lymphosarcoma, Hodgkins Disease (36), Brill-Symmers Disease, Waldenstrms Disease, etc.

Chronic Exposure To ArsenicIsolated (Primary) Splenomegaly

Echinococcus, Splenic Abscess, Splenic Tumours, Splenic Cysts, etc.

Non-Tropical Idiopathic Splenomegaly

Dacies syndrome

Tropical Idiopathic Splenomegaly SyndromeMassive spleen is a condition in which spleen may extend into one or both lower quadrants of the abdomen. It could be caused by Chronic Myeloid Leukemia, Gaucher disease, Hairy Cell Leukemia, Idiopathic and Secondary Myelofibrosis, Leishmaniasis (kala azar), Lymphoma, Malaria, and Thalassemia major.

Splenectomy for hypersplenism in patients with a massive spleen size (>1500 g), especially in idiopathic myelofibrosis, is accompanied by higher morbidity and mortality than is removal of spleens for immune cytopenias. Possible postoperative complications include extensive adhesions with collateral blood vessels, concomitant hemostatic disturbances, a tendency to hepatic or portal vein thrombosis, injury to the tail of the pancreas, operative site infections, and subdiaphragmatic abscesses (Kuntz, 2006).

The differential diagnostic possibilities are much fewer when the spleen is "massively enlarged," palpable more than 8 cm below the left costal margin or its drained weight is 1000 g. The vast majority of such patients will have non-Hodgkin's lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, chronic myelogenous leukemia, Autoimmune hemolytic anemia, myelofibrosis with myeloid metaplasia, or polycythemia vera (Fauci, 2008).2.1.3 What are the differential diagnosis of myeloproliferatif diseases?

Myeloproliferative disorders is the name for a group of conditions that cause blood cells -- platelets, white blood cells, and red blood cells -- to grow abnormally in the bone marrow. Though myeloproliferative disorders are serious, and may pose certain health risks, people with these conditions often live for many years after diagnosis. The prognosis largely depends on the type of disorder.

Myeloproliferative disorders include:

Polycythemia vera -- occurs when the bone marrow produces too many blood cells, especially red blood cells. More than 95% of people with polycythemia vera carry the blood mutation JAK2V617F.

Essential thrombocytosis -- occurs when the body produces too many platelet cells, which help blood to clot. Clots can block blood vessels leading to heart attack or stroke.

Primary or idiopathic myelofibrosis, also known as myelosclerosis -- occurs when the bone marrow produces too much collagen or fibrous tissue in the bone marrow. This reduces bone marrow's ability to produce blood cells.

Chronic myelogenous leukemia (CML) -- cancer of the bone marrow that produces abnormal granulocytes, a type of white blood cell, in the bone marrow.

Signs and Symptoms:

Many people with myeloproliferative disorders have no symptoms when their doctors first make the diagnosis. One symptom shared by all myeloproliferative disorders, with the exception of essential thrombocytosis, is an enlarged spleen. An enlarged spleen can cause abdominal pain and a feeling of fullness.

Some signs and symptoms of the different types of myeloproliferative disorders include:

Polycythemia vera

Fatigue, general malaise

Trouble breathing

Intense itching after bathing in warm water

Stomachaches

Purple spots or patches on the skin

Nosebleeds, gum or stomach bleeding, or blood in the urine

Throbbing and burning pain in the skin, often with darkened, blotchy areas

Headache and problems with vision

High blood pressure

Blockage of blood vessels. This may cause heart disease, stroke, or gangrene (tissue death) of the arms and legs.

Essential thrombocytosis

Heart attack or stoke

Headache

Burning or throbbing pain, redness, and swelling of the hands and feet

Bruising

Gastrointestinal bleeding or blood in the urine

Primary myelofibrosis

Fatigue, general malaise

Trouble breathing

Anemia

Weight loss

Fever and night sweats

Abnormal bleeding

Chronic myelogenous leukemia (CML)

Fatigue, general malaise

Weight loss or loss of appetite

Fever and night sweats

Bone or joint pain

Heart attack or stroke

Trouble breathing

Gastrointestinal bleeding

Infection

Causes:

All myeloproliferative disorders are caused by overproduction of one or more types of cells. No one knows what triggers the overproduction of cells, but theories include:

Genetics -- Some people with CML have an abnormally shortened chromosome known as the Philadelphia chromosome.

Environment -- Some studies suggest that myeloproliferative disorders may result from an overexposure to radiation, electrical wiring, or chemicals.

Risk Factors:

These factors may increase your risk for developing a myeloproliferative disorder:

Polycythemia vera

Gender -- Men are 2 times more likely than women to develop the condition.

Age -- People older than 60 are most likely to develop the condition, though it may happen at any age.

Environment -- Exposure to intense radiation may increase the risk for the condition.

Essential thrombocytosis

Gender -- Women are 1.5 times more likely than men to develop the condition.

Age -- People older than 60 are most likely to develop the condition, though 20% of those with this condition are under 40.

Environment -- Some researchers suggest that exposure to chemicals or to electrical wiring may increase a person's risk for the condition.

Primary myelofibrosis

Gender -- Men are slightly more likely than women to develop the condition.

Age -- People ages 60 - 70 are most likely to develop the condition.

Environment -- Exposure to petrochemicals, such as benzene and toluene, and intense radiation may increase the risk of developing the condition.

Chronic myelogenous leukemia (CML)

Gender -- Men are more likely than women to develop the condition.

Age -- People ages 45 - 50 are the most likely to develop the condition.

Environment -- Exposure to intense radiation may increase the risk of developing the condition.

Diagnosis:

A sign shared by all myeloproliferative disorders, with the exception of essential thrombocytosis, is an enlarged spleen. Your doctor may detect an enlarged spleen during a routine physical examination. In addition to doing a physical exam, the doctor may also conduct the following tests:

Blood tests -- to find abnormal types or numbers of red or white blood cells. They can also detect anemia and leukemia.

Bone marrow biopsy -- sample of bone marrow may be taken after blood tests. It can show the presence of abnormal types or numbers of red or white blood cells and may detect certain types of anemia and cancer in the marrow.

Cytogenetic analysis -- views blood or bone marrow are viewed under a microscope to look for changes in the chromosomes.

Treatment:

There is no cure for most myeloproliferative disorders. There are, however, several treatments that help improve symptoms and prevent complications associated with the conditions.

The treatment for each type of myeloproliferative disorder is slightly different:

Polycythemia vera -- lower red blood cell count by removing blood, called phlebotomy. Treatment with medication, called myelosuppressive therapy, is also available.

Essential thrombocytosis -- treat symptoms, when present, with medications

Primary myelofibrosis -- treat symptoms, when present, with medications and blood transfusion

CML -- Treatment options for CML have expanded greatly and may include: targeted therapy, chemotherapy, biologic therapy, high-dose chemotherapy with stem cell transplant, donor lymphocyte infusion (DLI), surgery.

Medications

A person's diagnosis and symptoms will determine the type of medication prescribed. Some possible medications include:

Polycythemia vera

Hydroxyurea (Droxia, Hydrea) or anagrelide (Agrylin) -- reduces number of blood cells.

Low-dose aspirin -- reduces skin redness and burning, and lowers increased temperature that may occur with the condition.

Antihistamines -- decreases itching.

Allopurinol -- reduces symptoms of gout, a potential complication of polycythemia vera.

Essential Thrombocytosis

Low-dose aspirin -- may treat headache and burning pain in the skin.

Hydroxyurea (Droxia, Hydrea) or anagrelide (Agrylin) -- reduces number of blood cells.

Aminocaproic acid -- reduces bleeding. This treatment may be used before surgery to prevent bleeding as well.

Primary myelofibrosis

Hydroxyurea -- may control complications, such as enlargement of the liver and spleen, reduce the number of white cells and platelets in the blood, and improve anemia.

Thalidomide and lenalidomide -- to reduce symptoms and treat anemia.

Chronic myelogenous leukemia (CML)

Targeted drugs -- affect a specific protein that lets cancer cells multiply. These drugs include Dasatinib (Sprycel), Imatinib (Gleevec), and Nilotinib (Tasigna).

Interferon -- helps the immune system combat cancer cells. Used only if bone marrow transplant is not an option.

Chemotherapy -- drugs such as cyclophosamide and cytarabine are often combined with other treatments to kill cancer cells.

Surgery and Other Procedures

With primary myelofibrosis, CML, and late stage polycythemia vera, blood cells are produced in sites other than the bone marrow, such as the liver and spleen. That causes these organs to get bigger. When enlargement of the spleen becomes painful, the person may have surgery to remove it.

In very serious cases of primary myelofibrosis, the person may undergo a stem cell transplant. In this procedure, abnormal stem cells (cells that manufacture blood cells) in the bone marrow are replaced with healthy stem cells. A stem cell transplant has life-threatening risks, however. In one study, 5-year survival was 62% in patients younger than 45 years and 14% in those that were older.

For people with CML, a bone marrow transplant may be an option. After either a stem cell or bone marrow transplant, the healthy bone marrow cells begin to grow and produce healthy blood cells.

Phlebotomy -- removing some blood from the body -- may lower the risk of stroke in people with polycythemia vera. It is the primary therapy in polycythemia vera, and it's the only treatment that has improved survival. People with anemia may need blood transfusions. In one study, researchers suggest that low dose aspirin (81-325 mg/day) may lower the risk of blood clots in people with polycythemia vera.

Nutrition and Dietary Supplements

A treatment plan for myeloproliferative disorders may include a range of complementary and alternative therapies. Ask your team of health care providers about the best ways to incorporate these therapies into your overall treatment plan. Always tell your doctor about the herbs and supplements you are using or considering using, as some supplements may interfere with conventional cancer treatments.

Myeloproliferative disorders need conventional medical treatment. There aren't any supplements that can specifically help with these conditions. However, following a healthy diet and getting regular exercise may help to keep your body strong while coping with a myeloproliferative disorder. Try these tips:

Eat antioxidant foods, including fruits (such as blueberries, cherries, and tomatoes), and vegetables (such as squash and bell peppers).

Avoid refined foods, such as white breads, pastas, and especially sugar.

Eat fewer red meats and more lean meats, cold-water fish, tofu (soy, if no allergy), or beans for protein.

Use healthy oils, such as olive oil or vegetable oil.

Reduce or eliminate trans-fatty acids, found in commercially baked goods such as cookies, crackers, cakes, French fries, onion rings, donuts, processed foods, and margarine.

Avoid caffeine, alcohol, and tobacco.

Drink 6 - 8 glasses of filtered water daily.

Exercise at least 30 minutes daily, 5 days a week.

Ask your doctor if you would benefit from the following supplements:

A daily multivitamin, containing the antioxidant vitamins A, C, E, the B-complex vitamins, and trace minerals such as magnesium, calcium, zinc, and selenium.

Omega-3 fatty acids, such as fish oil, 1 - 2 capsules or 1 - 3 tablespoonfuls oil, 1 - 3 times daily, to help decrease inflammation and help with immunity. Cold-water fish, such as salmon or halibut, are good sources, but you may need to take supplements to get enough omega-3 fatty acids. If you are taking aspirin or other blood thinners such as warfarin (Coumadin) or clopidogrel (Plavix), talk to your doctor. Omega-3 fatty acids may increase bleeding.

Probiotic supplement (containing Lactobacillus acidophilus), 5 - 10 billion CFUs (colony forming units) a day, when needed for maintenance of gastrointestinal and immune health. You should refrigerate your probiotic supplements for best results. People with weakened immune systems or those who take drugs to suppress the immune system should ask their doctor before taking probiotics.

Herbs

Herbs are generally a safe way to strengthen and tone the body's systems. As with any therapy, you should work with your health care provider to diagnose your problem before starting any treatment. You may use herbs as dried extracts (capsules, powders, teas), glycerites (glycerine extracts), or tinctures (alcohol extracts). Unless otherwise indicated, make teas with 1 tsp. herb per cup of hot water. Steep covered 5 - 10 minutes for leaf or flowers, and 10 - 20 minutes for roots. Drink 2 - 4 cups per day. You may use tinctures alone or in combination as noted.

If you are undergoing treatment for cancer, you should always ask your doctor before taking any herbs or supplements. No herbs have been studied specifically for myeloproliferative disorders, but the following herbs may help your general health:

Green tea (Camellia sinensis) standardized extract, 250 - 500 mg daily, for inflammation, and for antioxidant and immune effects. Use caffeine-free products. You may also prepare teas from the leaf of this herb.

Indirubin (Indigofera tinctoria) -- In case reports, indirubin showed positive results in treating CML long-term. However, no scientific studies have been done on using indirubin for CML. Indirubin is from the indigo plant and is included in a traditional Chinese herb formula that has been used historically to treat CML. Not much is known about the safety of indirubin. Ask your doctor before taking it and only use under the guidance of a knowledgeable prescriber.

Olive leaf (Olea europaea) -- for anticancer and immune effects. People with diabetes and high blood pressure should ask their doctor before taking olive leaf.

Turmeric (Curcuma longa) -- for pain and inflammation. Do not use turmeric if you have gallbladder problems. Turmeric may increase the risk of bleeding, especially if you take blood-thinners such as warfarin (Coumadin), clopidogrel (Plavix), or aspirin.

Other Considerations:

Pregnancy

Pregnant women should avoid the drug hydroxyurea because it may pose a risk to the baby.

Prognosis and Complications

Myeloproliferative disorders are slow acting, and don't always cause life-threatening symptoms. The complications of these conditions, however, may be serious. Some complications include:

Enlargement of the spleen and liver

Gout

Anemia

Bleeding

Kidney or liver failure

Heart attacks or stroke

Infection

CML can transform into acute leukemia, a more dangerous condition.

The survival rate for myeloproliferative disorders varies, depending on both the type of disorder and the kind of symptoms each person experiences.

Ehrlich, S. D., 2011, Myeloproliferative disorders, available at http://www.umm.edu/altmed/articles/myeloproliferative-disorders-000114.htm accessed at June 5 20122.1.4 Explain about the laboratory tests for myeloproliferatif diseases!

A. Polycythemia vera

Signs and symptoms are usually caused by an increase in hematocrit (plethora symptoms), hyperviscosity (causing symptoms of headache, dizziness, vertigo, tinnitus, visual disturbances, stroke, angina pectoris, myocardial infarction, and claudication), splenomegaly, hepatomegaly, pruritus, urticaria and gout. Manifestations of thrombotic and bleeding into the cause of death which is common in patients with this disease.

PV diagnosis is confirmed by the following criteria:

Criteria for Category A:

A1 Increased hematocrit> 25%

A2 There were no causes of secondary polycythemia

A3 There is splenomegaly? Palpable?

Clonality A4 marker

Criteria for category B

B1 Thrombocytosis: platelet numbers> 400.000/ul

B2 Granulositosis: neutrophils> 10.000/ul

B3 Splenomegaly skening obtained through examination of the isotope / Ultrason

B4 eritropoitin reduction and increased levels of BFU-E

To note the use of these criteria is that:

- Levels of hematocrit checked by inspection using the 51Cr erythrocyte labeling, unless the levels of hematocrit> 60%

- No examination of clonal applicable clinically for evidence of PV

- Item B4 can not be applied widely and is not specific for PV2

Definitive diagnosis is made when the PV obtained:

- Category A1 and A2 and either A3 or A4 or

- Category A1 and A2 and one of the criteria B

2. Trombositemia essential

Criteria for the diagnosis of TE include:

A. Platelet count> 1 million / EUR which are persistent.

2. No other causes of thrombocytosis (eg: a history of splenectomy, the signs of Fe deficiency, malignancy, gastrointestinal bleeding).

3. Bone marrow examination showed an increase in the number megakaryosit hiperselularitas and the results of the cytogenetic examination showed Philadelphia chromosome gene rearrangement without BCR / ABL and signs of myelodysplasia

3. Chronic idiopathic myelofibrosis with myeloid metaplasia (MMM)

Criteria for the diagnosis of this disease include:

- Splenomegaly.

- The leukoeritroblastik (erythrocyte nucleus and granulositosis), anisositosis and poikilositosis on examination of peripheral blood smear.

- The number of normal hematocrit (by examination of 51Cr)

- Examination of bone marrow aspiration: fibrosis in> 1/3 cross sectional area. Fibrosis is not secondary due to other causes.

- No PH1 chromosomes and no diseritropoisis

MMM patients with laboratory test results usually show:

A. Anemia was (on 2/3 of cases) is probably caused by an ineffective eritropoisis,

autoimmune hemolysis, hemoglobin H disease or paroxysmal hemoglobinuria like syndrome. Examination of peripheral blood smear shows erythrocyte shape dakrosit / teardrop cells, ovalosit, anisositosis, polikromasia and erythrocyte nucleus is patognomonis to MMM

2. The number of granulocytes ranged between 10 thousand - 30 thousand / MMK by the blast and promielosit 50% of cases), polyclonal hiperglobulinemia, rheumatoid factor and antinuclear antibody, and provide the results of (+) on direct examination Coomb?? S test (20% of cases )

Signs and symptoms that occur is the manifestation of anemia and splenomegaly

Other signs and symptoms that can be found include fever, weight loss and bone pain. Some of the syndrome, which can be found in this disease is acute myelofibrosis (known as the LMA type M7), portal hypertension, tumors and dermatoses netrofilik hematopoitik ekstrameduler

4. Hipereosinofilik syndrome (SHE)

The criteria used for diagnosis of this disease are:

A. Persistent increase in absolute eosinophil count (> 1500/mmk) for> 6 months.

2. There were no parasites, allergies or other causes of eosinophilic.

3. There are signs of organ system involvement.

4. There were no chromosomal abnormalities

5. Chronic Leukemia netrofilik

The disease is similar to the CML and is one of the differential diagnosis of CML. LMK is a difference with a normal cytogenetic examination results in these patients.

This diagnosis should be considered when patients with suspicion of CML found that showed non-clonal mature picture netrofilia and found no other cause of netrofilianya. If the disease is found in patients with other malignancies (eg myeloma), the diagnosis should be confirmed by cytogenetic examination results illustrating myeloid malignancies

6. Mielogenous chronic leukemia / CML

Approximately 30% of patients are asymptomatic at the time was diagnosed while the rest showed the symptoms are not specific such as feeling tired, fatigue, malaise, anorexia, weight loss, abdominal discomfort and a sense of early satiety due to hepatosplenomegaly. Small fraction of patients experience mild symptoms such as fever and hypermetabolic hyperhidrosis.

On physical examination found anemia, splenomegaly and sternal tenderness.

Symptoms and signs of hyperviscosity lekostasis and disruption of the microcirculation in the lungs, brain, eyes, ears or penis may occur in 15% of patients by the number of leukocytes> 300 ribu/mm3 where the symptoms can be takipneu, dyspnoea, cyanosis, dizziness, speech pelo, impairment of consciousness, visual disturbances (blurred vision and double, v distension. retinalis, retinal hemorrhages and edema papil) and hearing (tinnitus or deafness)

Made Putra Sedana, T. Ivone Wulansari, http://ejournal.unud.ac.id/abstrak/6% 282% 29.pdf2.2 ADDITIONAL INFORMATION She drinks no alcohol, no smoking, rather of doing some sports She slept normally Review of System:

Normal defecation Physical examination:

Ascites (-) Laboratory test:

PCV: hitung!Serum iron: 108 microgram/dL

HbA: 76,6%

HbA2: 2.5%

HbF: 0.9%

Hb4: 20%

2.3 LEARNING ISSUES 21. What is Thalassemia? 2. Explain about chronic diseases! 3. Mention kind of Hbs!CHAPTER 3ANALYSIS AND CONCLUSION3.1 ANSWER OF LEARNING ISSUES 23.1.1 What is Thalassemia?Disorders of Globin Synthesis: The Thalassemias

The thalassemias are the most common monogenic diseases in man. They are seen commonly in countries to which these high-frequency populations immigrate.

Thalassemia consists of two main classes, and , in which the - and -globin genes are involved. Rarer forms of thalassemia result from abnormalities of other globin genes. The conditions have in common an imbalanced rate of production of the globin chains of adult hemoglobin: excessive chains in -thalassemia and chains in -thalassemia. Several hundred different mutations at the - and -globin loci have been defined as the cause of the reduced or absent output of or chains. The high frequency and genetic diversity of the thalassemias are related to past or present heterozygote resistance to malaria.

The pathophysiology of the thalassemias can be traced to the deleterious effects of the excessively produced globin-chain subunits. In -thalassemia, excess chains damage the red cell precursors and red cells, leading to profound anemia. The result is extensive expansion of erythropoietic marrow, which is ineffective in producing mature red cells but impinges on developing bones, severely affecting development, bone formation, and growth. The major cause of morbidity and mortality is the effect of iron deposition on the endocrine organs, liver, and heart, which results from increased intestinal absorption and the effects of blood transfusion. The pathophysiology of the -thalassemias is different because the excess chains resulting from defective -chain production form 4 molecules, or hemoglobin H, which is soluble. However, hemoglobin H is unstable and precipitates in older red cells. Hence, the anemia of -thalassemia is hemolytic rather than dyserythropoietic.Definitions

Cooley and Lee first described a form of severe anemia that occurred early in life and was associated with splenomegaly and bone changes. George H. Whipple and William L. Bradford published a comprehensive account of the pathologic findings in this disease. Whipple coined the phrase thalassic anemia and condensed it to thalassemia. The disease described by Cooley and Lee is the homozygous state of an autosomal gene for which the heterozygous state is associated with much milder hematologic changes. The severe homozygous condition became known as thalassemia major. The heterozygous states, thalassemia trait, were designated according to their severity as thalassemia minor or minima. Later, the term thalassemia intermedia was used to describe disorders that were milder than the major form but more severe than the traits.

Thalassemia is not a single disease but a group of disorders, each resulting from an inherited abnormality of globin production. The conditions form part of the spectrum of diseases known collectively as the hemoglobinopathies, which can be classified broadly into two types. The first subdivision consists of conditions, such as sickle cell anemia, that result from an inherited structural alteration in one of the globin chains. Although such abnormal hemoglobins may be synthesized less efficiently or broken down more rapidly than normal adult hemoglobin, the associated clinical abnormalities result from the physical properties of the abnormal hemoglobin. The second major subdivision of the hemoglobinopathies, the thalassemias, consists of inherited defects in the rate of synthesis of one or more of the globin chains. The result is imbalanced globin chain production, ineffective erythropoiesis, hemolysis, and a variable degree of anemia

Different Forms of Thalassemia

Thalassemia can be defined as a condition in which a reduced rate of synthesis of one or more of the globin chains leads to imbalanced globin-chain synthesis, defective hemoglobin production, and damage to the red cells or their precursors from the effects of the globin subunits that are produced in relative excess.

The -thalassemias are divided into two main varieties. In one form, 0-thalassemia, there is no -chain production. In the other form, +-thalassemia, there is a partial deficiency of -chain production. The hallmark of the common forms of -thalassemia is an elevated level of hemoglobin A2 in heterozygotes. In a less common class of -thalassemias, heterozygotes have normal hemoglobin A2 levels. Other rare forms include varieties of -thalassemia intermedia that are inherited in a dominant fashion, that is, heterozygotes are severely affected, and there is a variety in which the genetic determinants are not linked to the -globin gene cluster.

The -thalassemias are characterized by reduced output chains and hence reduced hemoglobin A2 levels in heterozygotes and an absence of hemoglobin A2 in homozygotes. They are of no clinical significance except that, when inherited with -thalassemia trait, the level of hemoglobin A2 is reduced to the normal range.

Because chains are present in both fetal and adult hemoglobins, a deficiency of -chain production affects hemoglobin synthesis in fetal and in adult life. A reduced rate of -chain synthesis in fetal life results in an excess of chains, which form 4 tetramers, or hemoglobin Bart's. In adult life, a deficiency of chains results in an excess of chains, which form 4 tetramers, or hemoglobin H. Because there are two -globin genes per haploid genome, the genetics of -thalassemia is more complicated than that of -thalassemia. There are two main groups of -thalassemia determinants. First, in the 0-thalassemias (formerly called -thalassemia 1), no chains are produced from an affected chromosome, that is, both linked -globin genes are inactivated. Second, in the +-thalassemias (formerly called -thalassemia 2), the output of one of the linked pair of -globin genes is defective. The +-thalassemias are subdivided into deletion and nondeletion types. Both the 0-thalassemias and deletion and nondeletion forms of +-thalassemia are extremely heterogeneous at the molecular level. There are two major clinical phenotypes of -thalassemia: the hemoglobin Bart's hydrops syndrome, which usually reflects the homozygous state for 0-thalassemia, and hemoglobin H disease, which usually results from the compound heterozygous state for 0- and +-thalassemia.

Because the structural hemoglobin variants and the thalassemias occur at a high frequency in some populations, the two types of genetic defect can be found in the same individual. The different genetic varieties of thalassemia and their combinations with the genes for abnormal hemoglobins produce a series of disorders known collectively as the thalassemia syndromes.

Pathophysiology

Almost all the pathophysiologic features of the thalassemias can be related to a primary imbalance of globin-chain synthesis. This phenomenon makes the thalassemias fundamentally different from all the other genetic and acquired disorders of hemoglobin production and, to a large extent, explains their extreme severity in the homozygous and compound heterozygous states.

Mechanisms of Erythroid Precursor and Red Cell Damage

Damage to the red cell membrane by the globin-chain precipitation process occurs by two major routes: generation of hemichromes from excess alpha chains with subsequent structural damage to the red cell membrane, and similar damage mediated through the degradation products of excess alpha chains. The degradation products of free alphachainsglobin, heme, hemin (oxidized heme), and free ironalso play a role in damaging red cell membranes. Excess globin chains bind to different membrane proteins and alter their structure and function. Excess iron, by generating oxygen free radicals, damages several red cell membrane components (including lipids and protein) and intracellular organelles. Heme and its products can catalyze the formation of a variety of reactive oxygen species that can damage the red cell membrane. These changes are reflected in an increased rate of apoptosis of red cell precursors. The red cells are rigid and underhydrated, leak potassium, and have increased levels of calcium and low, unstable levels of ATP. Damage to the red cells can be mediated by the presence of rigid inclusion bodies during passage of the red cells through the spleen.

The anemia of beta-thalassemia has three major components. First and most important is ineffective erythropoiesis with intramedullary destruction of a variable proportion of the developing red cell precursors. Second is hemolysis resulting from destruction of mature red cells containing alpha-chain inclusions. Third are hypochromic and microcytic red cells resulting from the overall reduction in hemoglobin synthesis.

Because the primary defect in beta-thalassemia involves beta-chain production, synthesis of hemoglobins F and A2 should be unaffected. Fetal hemoglobin production in utero is normal. The clinical manifestations of thalassemia appear only when the neonatal switch from gama- to beta-chain production occurs. However, fetal hemoglobin synthesis persists beyond the neonatal period in nearly all forms of beta-thalassemia. beta-Thalassemia heterozygotes have an elevated level of hemoglobin A2. The elevated level appears to reflect not only a relative decrease in hemoglobin A as a result of defective beta-chain synthesis but also an absolute increase in the output of deltachains both cis and trans to the mutant beta-globin gene.

The consequences of excess nonalpha-chain production in the alpha-thalassemias are quite different. Because alphachains are shared by both fetal and adult hemoglobin, defective alpha-chain production is manifest in both fetal and adult life. In the fetus, it leads to excess gama-chain production; in the adult, to an excess of betachains. Excess gamachains form gama4 homotetramers or hemoglobin Bart's; excess betachains form beta4 homotetramers or hemoglobin H. The fact that betaand gamachains form homotetramers is the reason for the fundamental difference in the pathophysiology of alpha- and beta-thalassemia. Because gama4 and beta4 tetramers are soluble, they do not precipitate to any significant degree in the marrow, and therefore the alpha-thalassemias are not characterized by severe ineffective erythropoiesis. However, beta4 tetramers precipitate as red cells age, with the formation of inclusion bodies. Thus, the anemia of the more severe forms of alpha-thalassemia in the adult results from a shortened survival of red cells consequent to their damage in the microvasculature of the spleen as a result of the presence of the inclusions. In addition, because of the defect in hemoglobin synthesis, the cells are hypochromic and microcytic. Hemoglobin Bart's is more stable than hemoglobin H and does not form large inclusions.

Another factor exacerbates the tissue hypoxia of the anemia of the alpha-thalassemias. Both hemoglobin Bart's and hemoglobin H show no hemeheme interaction and have almost hyperbolic oxygen dissociation curves with very high oxygen affinities. Thus, they are not able to liberate oxygen at physiologic tissue tensions; in effect, they are useless as oxygen carriers.

Consequences of Compensatory Mechanisms for the Anemia of Thalassemia

The profound anemia of homozygous beta-thalassemia and the high oxygen affinity of the blood produced combine to cause severe tissue hypoxia. Because of the high oxygen affinity of hemoglobins Bart's and H, a similar defect in tissue oxygenation occurs in the more severe forms of alpha-thalassemia. The major response is erythropoietin production and expansion of the dyserythropoietic marrow. The results are deformities of the skull and face and porosity of the long bones. Extramedullary hematopoietic tumors may develop in extreme cases. Apart from the production of severe skeletal deformities, marrow expansion may cause pathologic fractures and sinus and middle ear infection as a result of ineffective drainage.

Another important effect of the enormous expansion of the marrow mass is the diversion of calories required for normal development to the ineffective red cell precursors. Thus, patients severely affected by thalassemia show poor development and wasting. The massive turnover of erythroid precursors may result in secondary hyperuricemia and gout and severe folate deficiency.

The effects of gross intrauterine hypoxia in homozygous alpha0-thalassemia have been described. In the symptomatic forms of alpha-thalassemia (e.g., hemoglobin H disease) that are compatible with survival into adult life, bone changes and other consequences of erythroid expansion are seen, although less commonly than in beta-thalassemia.

Splenomegaly: Dilutional Anemia

Constant exposure of the spleen to red cells with inclusions consisting of precipitated globin chains gives rise to the phenomenon of "work hypertrophy." Progressive splenomegaly occurs in both alpha- and beta-thalassemia and may worsen the anemia. A large spleen acts as a sump for red cells, sequestering a considerable proportion of the red cell mass. Furthermore, splenomegaly may cause plasma volume expansion, a complication that can be exacerbated by massive expansion of the erythroid marrow. The combination of pooling of the red cells in the spleen and plasma volume expansion can exacerbate the anemia in both alpha- and beta-thalassemia. The same process can occur in an enlarged liver, particularly after splenectomy.-Thalassemia Major

Hemoglobin levels at presentation may range from 2 to 3 g/dl or even lower. The red cells show marked anisopoikilocytosis, with hypochromia, target cell formation, and a variable degree of basophilic stippling. The appearance of the blood film varies, depending on whether the spleen is intact. In nonsplenectomized patients, large poikilocytes are common. After splenectomy, large, flat macrocytes and small, deformed microcytes are frequently seen. The reticulocyte count is moderately elevated, and nucleated red cells nearly always are present in the blood. These red cell forms may reach very high levels after splenectomy. The white cell and platelet counts are slightly elevated unless secondary hypersplenism occurs. Staining of the blood with methyl violet, particularly in splenectomized subjects, reveals stippling or ragged inclusion bodies in the red cells. These inclusions can nearly always be found in the red cell precursors in the marrow. The marrow usually shows erythroid hyperplasia with morphologic abnormalities of the erythroblasts, such as striking basophilic stippling and increased iron deposition. Iron kinetic studies indicate markedly ineffective erythropoiesis, and red cell survival usually is shortened. Populations of cells with very short survival and longer-lived populations of cells are seen. The latter contain relatively more fetal hemoglobin. An increased level of fetal hemoglobin, ranging from less than 10 percent to greater than 90 percent, is characteristic of homozygous -thalassemia. No hemoglobin A is produced in 0-thalassemia. The acid elution test shows that fetal hemoglobin is heterogeneously distributed among the red cells. Hemoglobin A2 levels in homozygous -thalassemia may be low, normal, or high. However, expressed as a proportion of hemoglobin A, the hemoglobin A2 level almost invariably is elevated. Differential centrifugation studies indicate some heterogeneity of hemoglobin F and A2 distribution among thalassemic red cells, but their level in whole blood gives little indication of their total rates of synthesis.

-Thalassemia Minor

Hemoglobin values of patients with -thalassemia minor usually range from 9 to 11 g/dl. The most consistent finding is small, poorly hemoglobinized red cells, resulting in MCH values of 20 to 22 pg and MCV values of 50 to 70 fl. The red cell indices are particularly useful in screening for heterozygous carriers of thalassemia in population surveys. The marrow in heterozygous -thalassemia shows slight erythroid hyperplasia with rare red cell inclusions. Megaloblastic transformation as a result of folic acid deficiency occurs occasionally, particularly during pregnancy. A mild degree of ineffective erythropoiesis is noted, but red cell survival is normal or nearly normal. The hemoglobin A2 level is increased to 3.5 to 7 percent. The level of fetal hemoglobin is elevated in approximately 50 percent of cases, usually to 1 to 3 percent and rarely to greater than 5 percent.

-Thalassemias

Hemoglobin Bart's Hydrops Fetalis Syndrome

In infants with the hydrops fetalis syndrome, the blood film shows severe thalassemic changes with many nucleated red cells. The hemoglobin consists mainly of hemoglobin Bart's, with approximately 10 to 20 percent hemoglobin Portland. Usually no hemoglobin A or F is present, although rare cases that seem to result from interaction of 0-thalassemia with a severe nondeletion form of +-thalassemia show small amounts of hemoglobin A.

Hemoglobin H Disease

The blood film shows hypochromia and anisopoikilocytosis. The reticulocyte count usually is approximately 5 percent. Incubation of the red cells with brilliant cresyl blue results in ragged inclusion bodies in almost all cells. These bodies form because of precipitation of hemoglobin H in vitro as a result of redox action of the dye. After splenectomy, large, single Heinz bodies are observed in some cells. These bodies are formed by in vitro precipitation of the unstable hemoglobin H molecule and are seen only after splenectomy. Hemoglobin H constitutes between 5 and 40 percent of the total hemoglobin. Traces of hemoglobin Bart's may be present, and the hemoglobin A2 level usually is slightly subnormal.

0-Thalassemia and +-Thalassemia Traits

The 0-thalassemia trait is characterized by the presence of 5 to 15 percent hemoglobin Bart's at birth.7 This hemoglobin disappears during maturation and is not replaced by a similar amount of hemoglobin H. An occasional cell with hemoglobin H inclusion bodies may appear after incubation with brilliant cresyl blue. This phenomenon is often used as a diagnostic test for the -thalassemia trait. However, the test is difficult to standardize and requires much experience to be useful. In adult life, the red cells of heterozygotes have morphologic changes of heterozygous thalassemia with low MCH and MCV values. The electrophoretic pattern is normal. Globin-synthesis studies show a deficit of -chain production, with an -/-chain production ratio of approximately 0.7.

The +-thalassemia trait ( / ) is characterized by no or minimal hematologic changes, 1 to 2 percent of hemoglobin Bart's at birth in some but not all cases, and a slightly reduced -/-chain production ratio of approximately 0.8; thus, this genotype often is referred to as silent carrier. Approximately 30 percent of African Americans carry one or two chromosomes with 3.7 deletion, so hematologists should be aware of the range of hematologic values associated with this genotype. Unfortunately, few firm data are available. However, in one study of African-American neonates, a large number of newborns with the 3.7 deletion had nondetectable hemoglobin Bart's. Globin-gene synthetic ratios can be distinguished from normal only by studying relatively large numbers of samples and comparing the mean / ratio with that of normal control subjects. This approach is not reliable for diagnosing individual cases of the +-thalassemia trait, and unfortunately no truly reliable method of diagnosis in adults is available except for DNA analysis.

Studies using DNA analysis indicate a marked overlap between the different -thalassemia carrier states with regard to the hematologic and globin-synthesis findings. In addition, the studies show that many +-thalassemia carriers do not have elevated levels of hemoglobin Bart's at birth. These studies confirm that, short of gene-mapping analysis, no method identifies specific -thalassemia carrier states with certainty.3.1.2 Explain about chronic diseases!a. What is chronic infection?

A chronic infection is an infection that develops slowly and lasts a long time. (Stephen T. 2009)

http://www.mansfield.ohio-state.edu/~sabedon/biol2040.htm#chronic_infectionStephen T. Abedon. 2009. Principles of disease.b. What is the link between anemia and chronic infection?

Anemia of Chronic Disease

Anemia of chronic disease (ACD) is also referred to as anemia of inflammatory response. Although ACD can accompany life-threatening illness, anemia of inflammatory response is in fact a protective and natural mechanism that the human body uses to limit the amount of iron available when potentially harmful things get into our body. All living things, including bacteria and cancer cells, which are living things, depend upon iron to sustain life just like humans and plants do. This system was described by Eugene Weinberg, Ph.D., Indiana University in the early 1980s.

When the body senses a potential threat, iron gets shuttled to ferritin to be contained so that the harmful invader cannot get to the iron. Just enough iron is made available to make red blood cells but no surplus is left to nourish harmful pathogens. Depending on the underlying cause of disease, a person with ACD will experience a modest decline in hemoglobin. This will take place over time following the onset of inflammation due to the presence of the infection or disease. Hemoglobin values will generally reach a low normal range of 9.510.5 g/dL and remain there within this moderately low range until the underlying condition is cured. If disease that results in blood loss is present, the person will develop iron deficiency anemia (IDA). ACD and IDA can be distinguished with a serum ferritin test. Taking iron pills for anemia of chronic disease could be harmful, even fatal.

The exact mechanism of ACD is not fully understood. Dr. Eugene Weinberg, Professor of Microbiology Indiana University and Iron Disorders Institute Medical & Scientific Advisory Board Member, is an expert in anemia of chronic disease. Since the mid 1950s Weinberg has been aware of the bodys alteration of iron metabolism during disease. He first defined the Iron Withholding Defense System in the early 1980s where he described how the human body recognizes iron as a potential hazard to health. Iron is one metal that cannot be excreted by the body effeciently; so, extra precautions are taken by humans to avoid absorbing too much iron. When a harmful germ invades the body, the immune system team of white blood cells charge to the site to destroy the pathogen before it has time to multiply. Inflammation results as a part of this natural immune response. Inflammation triggers the release of chemicals that signal the iron regulation mechanism to adopt a defense mode. What physicians see when the iron withholding defense system is activated is a mild drop in hemoglobin. However, what many physicians miss is that less iron is being absorbed and extra free iron is being collected by macrophages and stored in liver cells (hepatocytes). As a result serum ferritin rises. Anemia of chronic disease is not progressive. Hemoglobin values may remain in a slightly low range, but the levels can drop to as low as 7.0 g/dL depending on the severity of the inflammation and the length of time present. Other tests such as serum ferritin or C-reactive protein (CRP) can be performed to help differentiate between iron-deficiency anemia, where oral iron can be beneficial and anemia of chronic disease, where oral iron should not be given.

In adults, anemia of chronic disease is likely due to some common ailment such as urinary tract infection, a head or chest cold, mononucleosis, tonsillitis or strep, stomach or intestinal flu, and bacterial infections such as H. pylori. ACD can also occur when an autoimmune disease is present. Most of these conditions are treatable and when the patient is cured, the anemia will be corrected. If the anemia persists once an illness is cured, the doctor will want to investigate further for a secondary underlying cause of anemia that may be more serious such as kidney disease, tumor, or cancer.Anemia of chronic disease can be an indicator that a serious life-threatening condition is in the initial stages of development. However, when disease advances beyond this mild form of anemia, where treatment of the underlying condition cannot affect a cure, levels such as serum ferritin and transferrin iron saturation percentage change. For this reason, persons who have experienced anemia of chronic disease, where suspected underlying conditions have been addressed but the anemia persists, further investigation is needed. Blood loss, kidney function, bone marrow function, cancer, abnormal absorption or chronic hemolysis could be pursued as causes. Anemia of chronic disease can also be present even when tissues have excessive levels of iron. Tissue iron is different from functional iron in hemoglobin. Persons with hereditary hemochromatosis can have excessively high tissue iron but develop anemia because of iron damage to the kidney, anterior pituitary, or bone marrow. The damaged kidney produces less erythropoietin, a hormone vital to red blood cell production (erythropoiesis). An inflamed or damaged anterior pituitary can result in hypothyroidism, which causes diminished erythropoiesis and mild anemia. The bone marrow is the site of red blood cell formation.

Differentiating between anemia of chronic disease and iron-deficiency anemia. Patients with anemia of chronic disease do not generally have hemoglobin values below 9.5 g/dL, although levels can go much lower. Iron-deficiency anemia is often suspected in patients with anemia of chronic disease because the two conditions have many similarities. In both conditions, the serum iron level is low. Small or microcytic cells can be present in either disorder, though this type of cell is more indicative of true iron deficiency. Transferrin, a protein that transports iron, is elevated in iron-deficiency anemia, indicating that the body needs more iron. The total iron-binding capacity (TIBC), an indirect measurement of transferrin, is low in anemia of chronic disease because there is ample iron, but it is not easily available. TIBC tends to be increased when iron stores are diminished and decreased when they are elevated. In iron-deficiency anemia, the TIBC is higher than 400450 mcg/dL because stores are low. In anemia of chronic disease, the TIBC is usually below normal because the iron stores are elevated. In nearly two-thirds of the patients, the serum ferritin is one test that can be used to distinguish between anemia of chronic disease and iron-deficiency anemia. Ferritin is an acute-phase reactant, which means that it can be elevated in the presence of inflammation and this factor must be taken into consideration when examining the findings. Serum ferritin can be raised to normal levels even in the presence of iron deficiency. For this reason, difficulties arise in distinguishing iron deficiency in a patient with inflammation or infection from the anemia of chronic disease. Tests for inflammation like CRP are not helpful in this case. For some cases in which both iron deficiency and anemia of chronic disease are possible, bone marrow aspiration with iron staining is the traditional means of determining that a person is iron deficient. However the serum transferrin receptor test can be used to help differentiate between iron-deficiency anemia and anemia of chronic disease. The serum transferrin receptor is much less affected by inflammation than serum ferritin; results will be high in iron-deficiency anemia and usually low to low-normal in anemia of chronic disease. The ratio of the serum transferrin receptor to the logarithim of the serum ferritin concentration is better able to distinguish anemia of chronic disease from iron deficiency than is either test alone.

The greatest risk for harm is mistaking anemia of chronic disease for iron-deficiency anemia and allowing the patient to take iron pills. This risk can be reduced or eliminated by differenetiating between to the two iron disorders with serum ferrtin test and by informing the patient about the differences in these two iron disorders.

TreatmentThere is no treatment for anemia of chronic disease except to address the underlying condition. Iron supplementation is inappropriate in these patients because the added iron can become free to nourish bacteria and cancer cells. (IDI. 2012)

http://www.irondisorders.org/anemia-of-chronic-disease

Iron Disorders Institute. 2012. Anemia of Chronic Disease.c. How is the pathophysiology and the diagnosis oh anemia of chronic disease?

Pathophysiology

In response to inflammatory cytokines, increasingly IL-6 (Nemeth E. 2004),hepcidinHYPERLINK "http://en.wikipedia.org/wiki/Anemia_of_chronic_disease" \l "cite_note-2"

the liver produces increased amounts of . Hepcidin in turn stops ferroportin from releasing iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing ferroportin expression, and probably directly blunting erythropoiesis by decreasing the ability of the bone marrow to respond to erythropoietin.

Before the recent discovery of hepcidin and its function in iron metabolism, anemia of chronic disease was seen as the result of a complex web of inflammatory changes. Over the last few years, however, many investigators have come to feel that hepcidin is the central actor in producing anemia of chronic inflammation. Hepcidin offers an attractive Occam's Razor (parsimonious) explanation for the condition, and more recent descriptions of human iron metabolism and hepcidin function reflect this view. (Nermeth E.2006)

Nonetheless, in addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow produces both white blood cells and red blood cells from the same precursor stem cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This effect may be an important additional cause for the decreased erythropoiesis and red blood cell production seen in anemia of inflammation, even when erythropoietin levels are normal, and even aside from the effects of hepcidin. Nonetheless, there are other mechanisms that also contribute to the lowering of hemoglobin levels during inflammation: (i) Inflammatory cytokines suppress the proliferation of erythroid precursors in the bone marrow; (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival of circulating red cells is shortened.

In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacterial pathogens in the body, while producing more immune cells to fight off infection. Bacteria, like most life forms, depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow to produce red blood cells. These cells require iron for their massive amounts of hemoglobin which allow them to transport oxygen.

Because anemia of chronic disease can be the result of non-bacterial causes of inflammation, future research is likely to investigate whether hepcidin antagonists might be able to treat this problem.

Anemia of chronic disease may also be due to the neoplastic disorder and non infectious inflammmatory diseases. (Weng, CH, et al. 2011) Neoplastic disorder include Hodgkins disease lung and breast carcinoma and non infectious inflammmatory diseases include Rheumatoid arthritis and systemic lupus erythematosus.

Anemia of chronic disease as it is now understood is to at least some degree separate from the anemia seen in renal failure in which anemia results from poor production of erythropoietin, or the anemia caused by some drugs (like AZT, used to treat HIV infection) that have the side effect of inhibiting erythropoiesis. In other words, not all anemia seen in people with chronic disease should be diagnosed as anemia of chronic disease. On the other hand, both of these examples show the complexity of this diagnosis: HIV infection itself can produce anemia of chronic disease, and renal failure can lead to inflammatory changes that also can produce anemia of chronic disease.

Diagnosis

Anemia of chronic disease is often a mild normalcy anemia, but can sometimes be more severe, and can sometimes be a microcytic anemia; (Weng, CH, et al. 2011). thus, it often closely resembles iron-deficiency anemia. Indeed, many people with chronic disease can also be genuinely iron deficient, and the combination of the two causes of anemia can produce a more severe anemia. As with iron deficiency, anemia of chronic disease is a problem of red cell production. Therefore, both conditions show a low reticulocyte production index, suggesting that reticulocyte production is impaired and not enough to compensate for the decreased red blood cell count.

While no single test is always reliable to distinguish the two causes of disease, there are sometimes some suggestive data:

In anemia of chronic disease without iron deficiency, ferritin levels should be normal or high, reflecting the fact that iron is stored within cells, and ferritin is being produced as an acute phase reactant but the cells are not releasing their iron. In iron deficiency anemia ferritin should be low. (Weng, CH, et al. 2011)

TIBC should be high in genuine iron deficiency, reflecting efforts by the body to produce more transferrin and bind up as much iron as possible; TIBC should be low or normal in anemia of chronic disease.

If the importance of pethidine in this condition is borne out, tests to measure heparin or cellular expression of proportionate may one day be useful, but neither are available as validated clinical assays.

Examination of the bone marrow to look for the absence or presence of iron, or a trial of iron supplementation (pure iron deficiency anemia should improve markedly in response to iron, while anemia of chronic disease will not) can provide more definitive diagnoses.

1. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. (2004). "IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.". J Clinical Invest. 113 (9): 12513. DOI:10.1172/JCI20945. PMC398432. PMID15124018.

2. Nemeth E, Ganz T. (2006). "Regulation of iron metabolism by hepcidin.". Annu. Rev. Nutr. 26 (1): 32342. DOI:10.1146/annurev.nutr.26.061505.111303. PMID16848710.

3. Weng, CH; Chen JB, Wang J, Wu CC, Yu Y, Lin TH (2011). "Surgically Curable Non-Iron Deficiency Microcytic Anemia: Castleman's Disease.". Onkologie 34 (8-9): 4568. DOI:10.1159/000331283. PMID21934347.

d. What is the association between malnutrition and anemia?

anemia was high in children, particularly those aged 6--11 months. Anemia is a common clinical manifestation of micronutrient deficiency, particularly iron deficiency. The prevalence of anemia was much higher in the children than in their mothers, despite access to similar foods. Potential reasons for this include 1) inadequate numbers of iron-rich foods, 2) poor feeding practices, and 3) frequent episodes of common diseases, such as those causing diarrhea and respiratory infections, which can increase loss of micronutrients.

CDC. 2008. Malnutrition and Micronutrient Deficiencies Among Bhutanese Refugee Children --- Nepal, 2007. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5714a3.htm. access on : May 30,2012

3.1.3 Mention kind of Hbs!Hemoglobin (abbreviated Hb or Hgb) is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates (with the exception of the fish family Channichthyidae) as well as the tissues of some invertebrates. Hemoglobin in the blood carries oxygen from the respiratory organs (lungs or gills) to the rest of the body (i.e. the tissues) where it releases the oxygen to burn nutrients to provide energy to power the functions of the organism, and collects the resultant carbon dioxide to bring it back to the respiratory organs to be dispensed from the organism. (1-2 di daftar pustaka)

Hemoglobin has an oxygen binding capacity of 1.34 ml O2 per gram of hemoglobin,which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. The mammalian hemoglobin molecule can bind (carry) up to four oxygen molecules. (3-4 di daftar pustaka)Hemoglobin is involved in the transport of other gases: it carries some of the body's respiratory carbon dioxide (about 10% of the total) as carbaminohemoglobin, in which CO2 is bound to the globin protein. The molecule also carries the important regulatory molecule nitric oxide bound to a globin protein thiol group, releasing it at the same time as oxygen. Hemoglobin is also found outside red blood cells and their progenitor lines. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism.Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi, and plants. In these organisms, hemoglobins may carry oxygen, or they may act to transport and regulate other things such as carbon dioxide, nitric oxide, hydrogen sulfide and sulfide. (5 6 di daftar pustaka)

Heme Biosynthesis

Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol.The first step in heme synthesis takes place in the mitochondrion, with the condensation of succinyl CoA and glycine by ALA synthase to form 5-aminolevulic acid (ALA). This molecule is transported to the cytosol where a series of reactions produce a ring structure called coproporphyrinogen III. This molecule returns to the mitochondrion where an addition reaction produces protoporhyrin IX

The enzyme ferrochelatase inserts iron into the ring structure of protoporphyrin IX to produce heme. Deranged production of heme produces a variety of anemias. Iron deficiency, the world's most common cause of anemia, impairs heme synthesis thereby producing anemia. A number of drugs and toxins directly inhibit heme production by interfering with enzymes involved in heme biosynthesis. Lead commonly produces substantial anemia by inhibiting heme synthesis, particularly in children.

Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).

Figure 1 Heme Biosynthesis. The sythesis of heme is a complex process that involves multiple enzymatic steps. The process begins in the mitochondrion with the condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid. A series of steps in the cytoplasm produce coproporphrynogen III, which re-enters the mitochondrion. The final enzymatic steps produce heme.

Globin Synthesis

Two distinct globin chains (each with its individual heme molecule) combine to form hemoglobin. One of the chains is designated alpha. The second chain is called "non-alpha". With the exception of the very first weeks of embryogenesis, one of the globin chains is always alpha. A number of variables influence the nature of the non-alpha chain in the hemoglobin molecule. The fetus has a distinct non-alpha chain called gamma. After birth, a different non-alpha globin chain, called beta, pairs with the alpha chain. The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule (a total of four chains per molecule).

The combination of two alpha chains and two gamma chains form "fetal" hemoglobin, termed "hemoglobin F". With the exception of the first 10 to 12 weeks after conception, fetal hemoglobin is the primary hemoglobin in the developing fetus. The combination of two alpha chains and two beta chains form "adult" hemoglobin, also called "hemoglobin A". Although hemoglobin A is called "adult", it becomes the predominate hemoglobin within about 18 to 24 weeks of birth.

The pairing of one alpha chain and one non-alpha chain produces a hemoglobin dimer (two chains). The hemoglobin dimer does not efficiently deliver oxygen, however. Two dimers combine to form a hemoglobin tetramer, which is the functional form of hemoglobin. Complex biophysical characteristics of the hemoglobin tetramer permit the exquisite control of oxygen uptake in the lungs and release in the tissues that is necessary to sustain life.

The genes that encode the alpha globin chains are on chromosome 16 (Figure 2). Those that encode the non-alpha globin chains are on chromosome 11. Multiple individual genes are expressed at each site. Pseudogenes are also present at each location. The alpha complex is called the "alpha globin locus", while the non-alpha complex is called the "beta globin locus". The expression of the alpha and non-alpha genes is closely balanced by an unknown mechanism. Balanced gene expression is required for normal red cell function. Disruption of the balance produces a disorder called thalassemia.Alpha Globin Locus

Each chromosome 16 has two alpha globin genes that are aligned one after the other on the chromosome. For practical purposes, the two alph globin genes (termed alpha1 and alpha2) are identical. Since each cell has two chromosomes 16, a total of four alpha globin genes exist in each cell. Each of the four genes produces about one-quarter of the alpha globin chains needed for hemoglobin synthesis. The mechanism of this coordination is unknown. Promoter elements exist 5' to each alpha globin gene. In addition, a powerful enhancer region called the locus control region (LCR) is required for optimal gene expression. The LCR is many kilobases upstream of the alpha globin locus. The mechanism by which DNA elements so distant from the genes control their expression is the source of intense investigation. The transiently expressed embryonic genes that substitute for alpha very early in development, designated zeta, are also in the alpha globin locus.

Beta Globin Locus

The genes in the beta globin locus are arranged sequentially from 5' to 3' beginning with the gene expressed in embryonic development (the first 12 weeks after conception; called episolon). The beta globin locus ends with the adult beta globin gene. The sequence of the genes is: epsilon, gamma, delta, and beta. There are two copies of the gamma gene on each chromosome 11. The others are present in single copies. Therefore, each cell has two beta globin genes, one on each of the two chromosomes 11 in the cell. These two beta globin genes express their globin protein in a quantity that precisely matches that of the four alpha globin genes. The mechanism of this balanced expression is unknown.

The globin genes are activated in sequence during development, moving from 5' to 3' on the chromosome. The zeta gene of the alpha globin gene cluster is expressed only during the first few weeks of embryogensis. Thereafter, the alpha globin genes take over. For the beta globin gene cluster, the epsilon gene is expressed initially during embryogensis. The gamma gene is expressed during fetal development. The combination of two alpha genes and two gamma genes forms fetal hemoglobin, or hemoglobin F. Around the time of birth, the production of gamma globin declines in concert with a rise in beta globin synthesis. A significant amount of fetal hemoglobin persists for seven or eight months after birth. Most people have only trace amounts, if any, of fetal hemoglobin after infancy. The combination of two alpha genes and two beta genes comprises the normal adult hemoglobin, hemoglobin A. The delta gene, which is located between the gamma and beta genes on chromosome 11 produces a small amount of delta globin in children and adults. The product of the delta globin gene is called hemoglobin A2, and normally comprises less than 3% of hemoglobin in adults, is composed of two alpha chains and two delta chains.

Figure 2. Schematic representation of the globin gene loci. The lower panel shows the alpha globin locus that resides on chromosome 16. Each of the four alpha globin genes contribute to the synthesis of the alpha globin protein. The upper panel shows the beta globin locus. The two gamma globin genes are active during fetal growth and produce hemoglobin F. The "adult" gene, beta, takes over after birth.

(no 9 di daftar pustaka dari heme synthesis sampe beta globin locus)Human Hemoglobins

Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants such as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.

In the embryo:

Gower 1 (22)

Gower 2 (22)

Hemoglobin Portland (22)

In the fetus:

Hemoglobin F (22)

In adults:

Hemoglobin A (22) (PDB 1BZ0) - The most common with a normal amount over 95%

Hemoglobin A2 (22) - chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5%

Hemoglobin F (22) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

Variant forms that cause disease:

Hemoglobin H (4) - A variant form of hemoglobin, formed by a tetramer of chains, which may be present in variants of thalassemia.

Hemoglobin Barts (4) - A variant form of hemoglobin, formed by a tetramer of chains, which may be present in variants of thalassemia.

Hemoglobin S (2S2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the -chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.

Hemoglobin C (2C2) - Another variant due to a variation in the -chain gene. This variant causes a mild chronic hemolytic anemia.

Hemoglobin E (2E2) - Another variant due to a variation in the -chain gene. This variant causes a mild chronic hemolytic anemia.

Hemoglobin AS - A heterozygous form causing Sickle cell trait with one adult gene and one sickle cell disease gene

Hemoglobin SC