Case 4- anaemia Flashcards

1
Q

Sickle cell anaemia (HBSS)

A

Homozygous sickle cell disease, geontype is HbSS. Most common and severe type, occurs when the child has two sickle cell genes, inheriting one from each parent. Is a haemoglobinopathy, the red blood cells become sickle shaped instead of a biconcave disk

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2
Q

Sickle Haemoglobin C disease (HBSC)

A

Has a mutation in their beta globin genes that produces both haemoglobin C and haemoglobin S which are both abnormal haemoglobin. Causes similar symptoms to sickle cell anemia but less severe anemia. When you inherit one sickle genes from one parent and a ‘C’ gene from another parent.

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3
Q

Sickle beta Thalassemia (HbSβ+ / HbSβ0)

A

Have mutations in both beta globin genes. One mutation is resulting in HbS and another is Beta Thalassemia. The severity of the disease varies according to the amount of normal beta globin produced. The sickle genes creates crescent shaped red blood cells that break down while thalassemia produces smaller RBCs. There are two types of beta thalassemias, sickle beta plus which is mild, whilst sickle beta zero is more severe

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4
Q

Sickle cell trait (HbAS)

A

Not a disease but means the person has one copy of the sickle cell gene. They are carriers and can pass it on to their children

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5
Q

Haemoglobinopathies

A

Genetic disorders affecting the structure or production of the haemoglobin molecule. Mutations in the genes encoding the globin chain. The haem portion of the molecules is normal. These Globin abnormalities can be quantitive or qualitive.

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6
Q

Quantitative Hb disorders

A

When there is a quantitive decrease in the production of alpha or beta globin chains but the chains are structurally normal. Known as Thalassemia

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7
Q

Qualitative Hb disorders

A

Causes a change in the structure of the Hb molecules. There are several hundred variants, they were originally classified by a letter in the alphabet (HbS, HbC). Majority are benign and discovered incidenty, only a few Hb variants can cause severe disease. Includes haemoglobin S which is found in sickle cell anaemia.

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8
Q

Epidemiology of sickle cell anaemia

A

Commonly affects people from African, Caribean, middle Eastern and Indian ancestory.

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9
Q

Mutation which causes sickle cell anaemia

A

It is autosomal recessive. A single base substitution of adenine to Thymine in the sixth codon of the beta-chain gene, changing from GAG to GTG. This causes coding of valine instead of glutamate which makes the body produce abnormal hemoglobin called HbS.
GAG –> GTG
Val –> Glut

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10
Q

Sickle cell crisis

A

HbS (sickle cell haemoglobin) forms polymers under deoxygenated conditions which distort the erythrocyte into a sickle shape. This can be triggered by cold, infection, dehydration, hypoxia and exercise. The sickle cells are stickier and less flexible than normal red blood cells. They can form clusters which block and damage blood vessels. Sickling can cause pain and other symptoms. When it happens suddenly it’s a sickle cell crisis.

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11
Q

Between sickling events

A

Between sickling events the RBC’s retain their normal shape. After recurrent episodes of sickling the membranes damage and RBC’s are unable to resume their biconcave disk when they reoxygenate. They are irreversibly sickled cells. The cells are also quite fragile and easily broken down or removed by the spleen leading to haemolytic anaemia. RBCs will have a shorter life span. However, haemoglobin S releases oxygen to tissues more readily than haemoglobin A (normal), and this may reduce the drive to erythropoiesis.

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12
Q

What can sickle cell anaemia lead to

A

Haematuria, blindness, and heart failure. Can lead to ischaemia (necrosis, organ dysfunction, acute pain, oxidative reperfusion stress) and Haemolysis (fatigue, anaemia, cholelithiasis, endothelial dysfunction).

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13
Q

Clinical manifestations of sickle cell anaemia

A

Evident after the first 6 months of life, variable severity. A minority have few complications and their disease is unapparent, a majority have an intermediate form and some have severe complications. Most people have a few episodes of sickle cell crisis each year. Can lead to infections, anemia and accute vaso-occlusion crisis in acute manifestations. In chronic manifestations it is mostly related to chronic organ ischaemia and infarction due to obstruction of the blood vessels by sickle cells.

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14
Q

How are most cases of sickle cell anaemia diagnosed

A

Most are diagnosed in the neonatal bloodspot screening program

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15
Q

Tests done on sickle cell anaemia

A
  • FBC and blood film: the hemoglobin level is in the range 6-8 g/dL with a high reticulocyte count (immature red blood cells); the blood films may show sickled RBCs.
  • Sickle solubility test / the sickling test: when you expose RBCs to a deoxygenated agent, they will turn cloudy because the HbS precipitates, normally it will be a clear solution. It is observed against a white background with black lines.
  • Haemoglobin analysis- by electrophoresis or high performance liquid chromatography is needed to confirm a diagnosis.
  • May use DNA analysis
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16
Q

Sickle cell anaemia management

A

Lifelong treatment and monitoring are needed. You can have treatment to prevent sickling episodes or prevent related problems such as infection. The only curative treatment is a bone marrow transplant.

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17
Q

Spherocytosis

A

Red blood cells are spherical instead of a bi-concave disk. It can be hereditary or caused be immunologically mediated haemolytic anaemia. The immunological cause can be further split into autoimmune hemolytic anaemia, the haemolytic disease of newborne and hemolytic transfusion reaction. However, hereditary spherocytes (HS) is the most common.

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18
Q

Where is HS (hereditary spherocytosis) common

A

More common in northern European ancestry, about 75% of cases are autosomal dominant, the rest are recessive

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19
Q

Pathophysiology of Spheroctosis

A

Caused by a molecular defect in some of the proteins of the red blood cell cytoskeleton. This mutation in the membrane proteins leads to separation of the lipid membrane from the cytoskeleton and weakening of the vertical connections between them. Areas of the membrane not connected to the cytoskeleton are released from the cell as microvesicles and RBCs become sphere shaped. Less surface for oxygen and CO2 to be exchanged. They are also less flexible and get caught in the microcirculation of the spleen and promote phagocytosis by the macrophages in the spleen leading to hemolysis, shortening RBC lifespan and causing anaemia.

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20
Q

Clinical features of Spherocytosis

A

Presents at any age, normally a known family history. Neonates may require an exchange transfusion. Individuals with severe hemolysis may develop additional complications such as jaundice, splenomegaly, pigment gallstones and nutrient deficiencies – such as folate, vitamin B12, or iron deficiency.

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21
Q

Tests for Spherocytosis

A
  • FBC and red cell indices: raised MCHC (an MCHC ≥36 g/dL is consistent with spherocytes), increased red cell distribution width.
  • Blood film: Spherocytes and reticulocytosis
  • Haemolysis testing: Increased reticulocytes count, increased unconjugated bilirubin and lactate dehydrogenase
  • Direct antiglobulin test/ Coombs testing- usually done to eliminate the possibility of immune-mediated haemolysis. Direct antiglobulin test is usually negative in HS but is positive in autoimmune haemolytic anaemia.
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22
Q

Whats the most important thing to look out for in Spherocytosis

A

Hemolytic anaemia and spherocytes on the peripheral blood smear.

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23
Q

How is is Thalassemia classified

A

According to what chain of the globin molecule is affected and the number of genes deleted

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24
Q

Alpha Thalessemia

A

A reduction or absence in alpha globin chain production. Its highly prevailent in Southern China, South east asia (Malaysia, Thailand), Africa and India. Associated with gene deletions on chromosome 16.

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25
Q

Alpha Thalessemia- single gene deletion (silent carrier)

A

Deletion of a single α-globin genes causes a barely detectable reduction in α-globin chain synthesis. These individuals are completely asymptomatic.

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26
Q

Alpha Thalessemia- two gene deletion (alpha thalassemia minor/trait)

A

Caused by the deletion of two α-globin genes from a single chromosome (–/αα) or the deletion of one α-globin gene from each of the two chromosomes (-α/-α). Asymptomatic but may have mild hypochromic anaemia.

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27
Q

Alpha Thalessemia- three gene deletion (haemoglobin H disease)

A

In HbH there is only one normal alpha-globin gene, so the synthesis of chains is markedly reduced. Excess beta globin chains form Hb H (beta chain tetramers - β4) which has a high affinity for oxygen and therefore is not useful for oxygen delivery, leading to tissue hypoxia. HbH is prone to oxidation which causes it to precipotate and form intracellular inclusions that promote hemolysis in the spleen leading to moderately severe anemia, marked microcytosis, splenomegaly and bone marrow erythroid hyperplasia.

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28
Q

Alpha Thalessemia- four gene deletion (Hydrops fetalis/ Hb Barts)

A

All 4 alpha-globin genes on both alleles of chromosome 16 are deleted. Leads to a lack of HbF which is the major source of haemoglobin in gestation. γ chains takes the place and form gamma chain tetramers (γ 4) known as Hb Barts which cannot deliver oxygen to the tissues because its affinity for oxygen is too high. The baby is then stillborm.

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29
Q

Alpha Thalessemia- four gene deletion (Hydrops fetalis/ Hb Barts)

A

All 4 alpha-globin genes on both alleles of chromosome 16 are deleted. Leads to a lack of HbF which is the major source of haemoglobin in gestation. γ chains takes the place and form gamma chain tetramers (γ 4) known as Hb Barts which cannot deliver oxygen to the tissues because its affinity for oxygen is too high. The baby is then stillborn. Due to severe anaemia and heart failure

30
Q

Alpha Thalassemia investigations

A
  • Complete blood count and peripheral blood smear
  • Haemoglobin analysis- determines the type and percentage of heamoglobin present. Hb Barts (gamma chain tetramers) or HbH (beta chain tetramers) are consistent with alpha thalassemia.
  • Molecular analysis of DNA- detects silent carriers
31
Q

Beta Thalassaemeia

A

Reduction or absence of beta Globin chains, resulting in anaemia. Prevailent around the Mediterranean, Middle East, Central South and Southeast Asia, and in Southern China. Associated with point mutations on chromosome 11.

32
Q

Beta Thalassaemia minor

A

Most patients are heterozygous carriers of a β+ or β0 allele. These patients are usually asymptomatic. Defective beta chain synthesis results in mildly reduced production of beta chains. Anaemia, if present, is mild.

33
Q

Beta Thalassaemia intermedia/ non-transfusion dependent Thalassemia

A

Less severe then beta thalassemia major. Tend to have anaemia but are not transfusion dependent during childhood but may as an adult. Typical age of presentation is between 2 and 4. Wide range of clinical presentations. Severity depend on percentage of HbA, the more HbA they have the less severe the anaemia is.

34
Q

Transfusion-dependent Thalassemia/ beta thalassemia major/ Cooley’s anaemia

A

Most severe form with minimal to no beta globin chain production and consequently no HbA. Symptoms develop between 6-12 months. Unpaired α chains precipitate within red cell precursors, forming insoluble inclusions. Many red cell precursors succumb to membrane damage due to these inclusions and undergo apoptosis which leads to ineffective erythropoises (destruction of RBCs) and anemia. Red blood cells with inclusions may be destroyed in the spleen leading to extravascular hemolysis. Due to anaemia more red blood cells are produced leading to erythroid hyperplasia (lots of immature red blood cells) and extramedullary erythropoiesis (production of red blood cells).

35
Q

Symptoms of transfusion dependent Thalassemia

A
  • Abdominal swelling from Hepatosplenomegaly (due to extramedullary erythropoiesis)
  • Bone deformities (frontal bossing, prominent facial bones, and dental malocclusion) due to erythroid hyperplasia. Mongoloid appearance
  • Marked pallor and slight to moderate jaundice and dark urine due to hemolysis.
  • Exercise intolerance, cardiac flow murmur or heart failure secondary to severe anaemia.
36
Q

Investigations for Beta thalassemia

A
  • Complete blood count and peripheral blood smear- tests for bypochromic microcytic anaemia, low haemoglobin levels
  • Iron studies- Iron overload
  • Hemolysis testing- increased seru bilirubin, LDH and reticulocytes
  • Hemoglobin analysis- determines types and percentage of haemoglobin present. In beta thalassemia major and intermedia, HPLC will show increased HbF and HbA2 (complete absence of HbA1 in major). Beta thalassemia trait is also characterized by an increased HbA2 level.
  • DNA analysis- detects carriers
  • Imaging- plain skull x-ray shows ‘hair on end appearance’ due to erythroid hyperplasia.
37
Q

Prognosis for beta Thalassemia

A

Thalassaemia minor has no effect on mortality or significant morbidity. In severe beta thalassameia major you wll die by 5 without treatment. With treatment the outlook is good because anaemia and complications can be controlled by transfusions and chelation treatment. Cure is possible with stem cell transplantation.

38
Q

Treatments for anaemia- Iron

A

Usually given orally (ferous fumarate, ferrous gluconate, polysaccharide iron complex). Ferrous sulphate 2-3 times per day, its absorbed best when the patient is fasting. It may take up to 6 months of treatment to replenish iron stores. Treatment for iron deficient anaemia. Parenteral preparations (e.g. iron sucorse, iron dextran) are required for very severe iron deficiency. Regularly check Hb levels

39
Q

Treatment for anaemia- Iron side effects

A

GI side effects i.e. constipation, nausea and vomiting, these are common. Unwanted side effects can be dose related, acute toxicity/poisoning is usually seen in young kids who accidently swallowed the pills. It may cause GI irritation with bleeding and green tarry stools, the antidotes is desferrioxamine (iron chelator). If side effects are worrying combine with food or reduce the dose. Can cause indigestion with pain in your upper abdomen (dyspepsia) or burning pain behind the breastbone (heartburn).

40
Q

Anaemia treatment- chronic iron toxicity

A

Due to too many Iron transfusions. Hemosiderosis is acquired iron overload

41
Q

Anaemia treatment- Vitamin B9 (folic acid)

A

Used to treat megoblastic anaemia as it increases purine and thymidine synthesis which is essential for DNA synthesis. Treatment for megaloblastic and macrocytic anaemia due to folate deficiency which can be due to poor diet, malabsorbtion syndroms and drugs. Also given in pregnancy in order to reduce neural tube defects. Can causes fever and nausea. Given in sever chronic haemolytic anaemia (sickle cell anaemia) and to premature infants so they don’t develop a folate deficiency.

42
Q

Anaemia treatment- Vitamin B12 (cobalamin)

A

Prepared as either cyanocobalamin (oral and parenteral) or Hydroxocobalamin (parenteral). A parenteral preparation is injected every three months in pernicious anaemia which is lifelong. Orally it can be used as a treatment for other forms of vitamin B12 deficiency. Side effects include flushing, dizziness, headache, hypertension and GI effects like nausea and diarrhoea.

43
Q

Anaemia treatment- Haemopietic factors

A

These are growth factors that are used in the proliferation and differentiation of pluripotent stem cells. Erythropoitenin regulates the synthesis of red blood cells and colony stimulating factors (CSFs) regulate the myeloid division of white blood cells. These drugs are administered parenterally and are used to treat bone marrow failures. GM-CSF regulates platelet production, monocytes, neutrophils and Eosinophils.

44
Q

Anaemia treatment- Erythrocyte factors

A

Epoietin and darbepoietin both promote erythropoiesis, both are forms of recumbent human erythropoietin. They are administered via IV or subcutaneous. Darbepoeietin has a longer half life and can be administered less frequently. It is used as a treatment for anaemia in patients with chronic renal failure, in cancer patients who are receiving chemotherapy and in AIDS patients as their anaemia will be exacerbated by anti-HIV drugs. Also helps to prevent anaemia in premature babies. The side effects include transient flu-like symptoms i.e. fever, arthralgia. Can also induce iron deficiency as more iron is required for enhanced erythropoiesis. Increases blood viscosity and the risk of thrombosis as well as hypertension.

45
Q

Anaemia treatment- Granulocytes factors (Sargamstim)

A

It is a recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Stimulates proliferation, differentiation and functional activity of neutrophils, eosinophils, monocytes and macrophages. Used to treat aplastic anaemia where the bone marrow is damaged so less blood can be produced. It promotes myeloid (bone marrow tissue) recovery after standard dose chemotherapy. Side effects can be fevers, chills, rash, GI effects like nausea, bone pain, myalgia and enlargement of liver and spleen.

46
Q

Anaemia treatment- Filgrastim, Pegfilgrastim and Lenograstim

A

Granulocytes colony-stimulating factor (G-CSF). Stimulates the production, maturation and activation of neutrophils. Administered by via IV or SC. Used to stimulate granulocyte production in chemotheraphy induced neutropenia, promotes myeloid recovery in patients undergoing BMT. Side effects include fever, bone pain, myalgia (muscle pain) and splenomegaly (spleen gets bigger).

47
Q

Anaemia treatment- platelet factor (Oprelvekin)

A

It is a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte (bone marrow cell responsible for platelet production) maturation resulting in increased platelet production. It is marketed under the trade name Neumega. Is a recombinant human interleukin (IL-11). Used clinically to prevent and treat chemotherapy induced thrombocytopenia. Its side effects include allergic reaction, tachycardia, fever, chills, rash, edema.

48
Q

Treatment for Haemolytic anaemia

A

In most forms of haemolytic anaemias, treatment is symptomatic ( analgesia for painful crises) and supportive (fluid balance, oxygen, blood transfusion, treatment of iron overload, provision of adequate folate to support increased red cell turnover and in some cases antibiotic and immunization). Some people with hemolytic anaemia may need surgery to remove their spleen as the diseased spleen may be removing more red blood cells then normal, causing anaemia.

49
Q

Treatment for Haemolytic anaemia- Hydroxycarbamide

A

Increases production of fetal hemoglobin that then reduces the tendency of sickle cells to sickle, as well as reducing white blood cells that contribute to the general inflammatory state in sickle cell patients. It is a cytotoxic drug that inhibits DNA to red cell precursors that produce abnormal haemoglobin S (from sickle cells). It therefore reduces the severity of sickle cell disease. Side effects include myelosuppresion, nausea and rashes.

50
Q

How is anaemia classified

A

Two standard deviations below the normal haemoglobin levels for age and sex. For men over 15 this is below 130 g/l, in non-pregnant women aged over 15 its 120g/l. In children aged 12-14 it is below 120 g/l.

51
Q

Haematopoiesis

A

Decreased production of red blood cells

52
Q

Haemolysis

A

Accelerated destruction of red blood cells

53
Q

Haemorrhage

A

Loss of RBC’s due to bleeding

54
Q

How does iron deficiency result in anaemia

A

Erythropoiesis requires Iron, as Iron regulates globin synthesis at both transcriptional and translational levels.

55
Q

Pernicious anaemia

A

An autoimmune disease which causes the destruction of factors essential for the absorption of vitamin B12. Due to the low vitamin B12 you will get macrocytic anaemia. You will get low Hb and high MCV.

56
Q

Intrinsic haemolytic factors

A

Membrane- hereditary spherocytosis
Haemoglobin- sickle cell disease
Enzymes- Pyruvate kinase deficiency

57
Q

Extrinsic haemolytic factors

A

Immune- the cold
Non-immune intravascular- infection
Non-immune extravascular- cirrhosis

58
Q

MCV- case 4

A

Mean cell volume, measures how big the cell is

59
Q

Microcytic anaemia

A

Presence of small often hypochromic red blood cells, often due to iron deficiency. Will cause low Hb and low MCV (mean circulating volume). Thalassaemia, anaemia of chronic disease

60
Q

Normocytic anaemia

A

Low number of normal red blood cells

61
Q

Macrocytic anaemia

A

Has overly large red blood cells and not enough normal red blood cells. Will result in low HB and high MCV. If its megaloblastic there will be vitamin B12 or folate deficiency, if its non-megaloblastic there will be no deficiency. Alcohol, folate deficiency, hyperthyroidism, pernicious anaemia

62
Q

Symptoms of anaemia

A

Dyspnoea (shortness of breath), fatigue and headache, cognitive dysfunction, restless leg syndrome and vertigo. Other symptoms include dizziness, weakness, dysgeusia (altered taste sensation), irritability, palpation (heart beats too fast), pica (abnormal dietary cravings i.e. ice or dirt), pruritus (itching), sore tongue, tinnitus and impairment of body temperature regulation.

63
Q

How does chronic disease lead to anaemia- small

A

Anaemia of chronic disease is anaemia with evidence of immune system activation. It affects males and females in equal proportions. Anaemia is usually mild or moderate and the exact cause may vary.

64
Q

What chronic diseases is anaemia associated with

A

Acute and chronic infection, autoimmune disorders, chronic diseases, malignancy, after major trauma, surgery, critical illness and among older adults.

65
Q

What the FBC (full blood count) shows for chronic disease anaemia

A

Normocytic or microcytic anaemia. Shows low reticulocyte count, low serum ion, low total iron-binding capacity, low to normal percent transferrin saturation elevated ferritin.

66
Q

What causes Iron deficiency

A

Excess output or reduced input. the blood loss can be obvious, such as heavy menstrual bleeding, or more occult such as a bleeding gastro/duodenal ulcer or colorectal cancer. Iron deficiency can also be the result of poor iron intake, either through dietary restrictions or through poor absorption due to coeliac disease or inflammatory bowel disease affecting the duodenum/proximal ileum.

67
Q

How drugs cause anaemia

A

• Marrow aplasia- toxic effects on the marrow may occur after large doses or long treatment courses of alkylating agents, the plant alkaloids vinblastine and vincristine, and antibiotics used in cancer chemotherapy.
• Megaloblastic anaemia due to defective metabolism of folate- METHOTREXATE
• Intestinal bleeding with anaemia as a result (NSAID/SSRI)
• Sideroblastic anaemia- rare, particularly those used in the treatment of tuberculosis. (Isonaiazid/pyridoxine).
You can have immune haemolytic anaemia where the immune system attacks its own red blood cells. The drug attaches to the red blood cell and the antibody detects this and destroys it more quickly then normal

68
Q

Hyperchromic

A

Erythrocytes that contain more haemoglobin then normal

69
Q

Hypochromic

A

Erythrocytes that contain less haemoglobin then normal

70
Q

Why do chronic diseases lead to anaemia

A

Hepcidin is released from the liver during inflammation. It blocks the release of Iron from the spleen and prevents absorption in the duodenum

71
Q

Equation for calculating MCV

A

MCV= (HCT X 1000) / RBC