Tag Archives: Erythrocyte

Case No 1 – Severe Microcytic Anaemia

1 Nov

A 17-year-old woman from a farming community presented with the history of severe weakness, fatigue and dyspnoea on moderate exertion.

She was well till about 4 months before presentation when she complained of fatigue that gradually became worse. Though progressively symptomatic she was able to attend school till 3 days before presentation.

There was no history of fever, weight loss, abnormal bleeding or melena. There was no increase in the menstrual blood loss. The patient was living with her parents and two sisters both of whom were healthy.

Her appetite had been normal through most of the illness though off late it had diminished.

On examination the patient was comfortable but tachypnic  in bed. She had severe pallor of the skin, conjunctiva and mucous membranes.  There was platonychia and glossitis. The jugular venous pressure was elevated. There was no icterus, clubbing, lymphadenopathy. The pulse was 108/min and the blood pressure 110/60. The third heart sound was audible at the apex. She had bilateral fine crepitation in the bases of both lungs. The was no hepatomegaly. There was no splenomegaly. Examination of the neurological system revealed no abnormality.

A haemogram was performed and the results were as follows:

  • Haemoglobin: 1.7g/dL
  • RBC Count: 0.9 X 1012/L
  • Haematocrit: 5.9%
  • WBC Count: 4.1 X 109/L
  • Differential Count:
    • Neutrophils: 35%
    • Lymphocytes 49%
    • Monocytes 10%
    • Eosinophils: 6%
  • Platelet Count: 505 X 109/L
  • RBC Indices
    • MCV: 66.1 fl
    • MCH: 19.4 pg
    • MCHC: 29.3 g/L
    • RDW: 44%
  • Reticulocyte Count: 8%

What are the probable causes of anaemia in this patient?

Presence of platelet and/or leucocyte anomalies in a patients with anaemia suggests that the pathology lies in the bone marrow. Anaemia without leucocyte or platelet anomalies may be caused by increased erythrocyte loss or decreased erythrocyte production. Anaemias caused by decreased production of erythrocytes are further divided according to erythrocyte size into microcytic, normocytic and macrocytic  (see Evaluating anaemia).

This patient does not have platelet or leucocyte anomalies. The anaemia is either a result of a decreased production or increased loss of erythrocytes. Both erythrocyte loss and decreased production are difficult to quantify in clinical practice and are diagnosed by indirect methods. Increased eryrthrocyte production should increase haemoglobin unless there is an equal or greater loss. Increased erythrocyte production result in reticulocytosis. In patients with anemia the reticulocyte production index is a more accurate index of erythrocyte production. A patient with normal or low haemoglobin but an increased reticulocyte production index is presumed to be loosing erythrocytes  (see diagnosis of haemolytic anaemia).  Others are presumed to have decreased erythrocyte production.

Reticulocyte production index is calculated as follows:

RPI = [Reticulocyte count X HCTPatient] / [HCTNormal X CF]

where

RPI is the Reticulocyte Production Index. RPI values less than 2 indicate inadequate erythrocyte production

HCTPatient is the patient’s haematocrit

HCTNormal is the normal haematocrit

CF is the correction factor. The correction factor depends on the haematocrit. It’s values are as follows:

  • Haematocrit 40-45%: 1
  • Haematocrit 35-40%: 1.5
  • Haematocrit 25-35%: 2
  • Haematocrit 15-25%: 2.5

The reticulocyte production index in this patient is as follows

RPI = [8 X 5.9 ] / [45*2.5]  =  0.41

RPI of 2 indicates an adequate marrow response. This patient, despite having a high reticulocyte count, has decreased erythrocyte production.

Anaemias due to inadequate erythrocyte production are classified according to erythrocyte size as microcytic, normocytic and macrocytic (see red cell indices). This patient has microcytosis. The causes of microcytic anaemia include:

  • Iron deficiency
  • Thalassaemia
  • Sideroblastic anaemia
  • Anaemia of chronic disease

Chronic inflammation is associated with mild to moderate anaemia that is proportional to the degree of inflammation. Most of the patients have normochromic anaemia but about 30-50% of the patients may develop mild microcytosis with a normal RDW.  This patient has no evidence of chronic inflammatory process. She has severe anaemia, pronounced microcytosis and a high RDW. She is unlikely to have anaemia of chronic disease.

Iron deficiency and thalassaemia are the commonest causes of microcytic anaemia. β-Thalassaemia has three clinical forms, major, minor and intermedia. Thalassaemia minor does not cause symptoms. Symptomatic β-thalassaemia (thalassaemia major and intermedia) usually present early. The transfusion dependent patients present by 8.4±9.1months and non-transfusion dependent patients by 17± 11.8 months (Cao A Birth Defects 1988;23;219) . This patent has a late presentation making thalasaemia unlikely.

The haemogram of patients with iron deficiency shows anaemia, microcytosis, hypochromia and anisocytosis. Thrombocytois is not uncommon. The platelet counts in patients with iron deficiency are twice those without deficiency (Dan K Intern Med 2005; 10: 1025). The thrombocytosis associated with iron deficiency has an inverse relationship with serum iron but no relationship with TIBC and transferrin saturation. (Park MJ et al Platelets 2012 Jun 27. [Epub ahead of print]). This patients has anaemia, microcytosis, hypochromia and thrombocytosis. The high red cell distribution width (RDW) indicated the presence of anisocytosis. The most likely diagnosis in this patient is iron deficiency anaemia.

Is there a haemoglobin value that should trigger a blood transfusion?

It was common to use the 10/30 (haemoglobin 10g/dL or PCV 30%) trigger for transfusion. Transfusion is associated with morbidity and mortality (Marik et al. Crit Care Med 2008; 36:2667-74). Following the 10/30 rule results in overtransfusion. The case highlights poor relation between haemoglobin levels and symptoms. Anaemia is compensated by increasing cardiac output, redistributing blood from non-critical to critical circulations and increasing oxygen extraction (see Pathophysiology of anaemia). Older individuals may have one or more of these mechanisms compromised hampering their ability to withstand anaemia. Younger individuals can compensate efficiently and can withstand lower haemoglobin values. Compensation takes time and is more complete in anaemias that have a slow onset. Nutritional deficiencies develop slowly. Patients with nutritional anaemia compensate better and become symptomatic at lower haemoglobin values than anaemia with a more acute onset.

She was in cardiac failure and was transfused. But would she have been transfused if she was not in cardiac failure and had a haemoglobin of 7g/dL? The threshold for transfusion according to most current guidelines is 7-8 g/dL. Trials evaluating transfusion threshold have been performed in hospitalized, surgical or intensive care patients. Transfusion guidelines are most appropriate when used for indications the were developed. There are few trials addressing the issue of transfusion in patients with nutritional anaemia. Clinical experience shows that patients without respiratory or cardiovascular co-morbidities are able to tolerate severe nutritional anaemia. One needs to balance the risk of anaemia against risk of transfusion in patients with nutritional anaemias. The transfusion trigger for patients of nutritional is not established. Symptoms guide transfusion in patients with nutritional anaemia.

How should the patient be investigated?

As iron deficiency is the commonest cause of microcytic anaemia, patients should be evaluated for iron deficiency. The serum iron, total iron binding capacity and serum ferritin are estimated and the transferrin saturation calculated . The results of these investigation are diagnostic for iron deficiency and often allow the diagnosis of other causes of microcytic anaemia. The interpretation these tests are as follows:

Serum Iron Total Iron Binding Capacity Transferrin Saturation Serum Ferritin
Iron Deficiency Anaemia  Low  Normal/High  Low (<16%)  Low (<12ng/ml)
Thalassaemia Normal Normal Normal Normal/High
Sideroblastic
Anaemia		 High Normal High (>50%) High
Chronic Disease low/Normal Low Normal Normal/High

This patients was diagnosed as iron deficiency anaemia because of a low serum iron, high total iron binding capacity and a low transferrin saturation. Does that complete the diagnosis?

The diagnosis of iron deficiency is incomplete without finding out its cause. The following populations are prone to iron deficiency.

  1. Preterm infants: Most of the iron transfer to the foetus takes place in the third trimester. Premature infants have less time to absorb iron from the mother.
  2. Infants and Toddles: Dietary iron is not able to keep up with the requirements of rapid growth.
  3. Women in the childbearing age group: Losses due to menstruation and pregnancy cause iron deficiency.
Iron deficiency is due to inadequate iron intake or increased iron/blood loss. Blood/iron is lost because of diseases/conditions causing exacerbation of physiological blood/iron loss or diseases causing physiological loss. Multiple pregnancies cause exacerbation of physiological iron loss. The only physiological blood loss is menstrual blood loss.
This patient gave no history of increased menstrual blood loss. Hookworm (Ancyclostoma duodenale and Necator americanus) infestations infestations affect over 500 million individuals in the hot and humid areas of the world. Infestations are common in farming communities. The stool examination of this patients showed hookworm ova.
Finally, does the diagnosis of iron deficiency rule out other causes of microcytic anaemia? No. Iron deficiency is very common that it may co-exit with another cause of microcytic anaemia particularly anaemia of chronic disease and thalassaemia trait. Anaemia of chronic disease is characterized by a low iron, low total iron binding capacity and normal transferrin saturation. When such patients become iron deficient the transferrin saturation falls below 16%. Ferritin is increased in the presence of inflammation/infection. While a low ferritin is diagnostic of iron deficiency in the presence of infection/inflammation, a normal ferritin does not exclude iron deficiency. β-Thalassaemia is diagnosed by an elevated HbA2. HbA2 has been shown to fall with iron deficiency. This may not have any clinical significance (Madan N et al. Ann Hematol 1998; 77; 93-6, Passarello C et al 2012; 97:472). If the haemoglobin and/or microcytosis fail to correct after therapy the patients must be evaluated for thalassaemia.

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Red Cell Indices

13 Oct

Estimation of haemoglobin concentration, erythrocyte count, haematocrit, total and differential leucocyte count and platelet count along with examination of the peripheral smear are a part of evaluation of anaemia. Examination of the peripheral smear detects abnormalities in size (microcytosis or microcytosis, anisocytosis), shape and haemoglobnization. Reporting a peripheral smear need experience and is subjective. Red cell indices evolved to bring objectivity and increase reproducibility reporting of red cell characteristics. Red cell indices have allowed a reproducible algorithmic approach to the diagnosis of anaemia.

Normal red cell counts were described in 1852 . This measurement made on four subjects was the normal standard for the next 70 years. Wintrobe in the 1930s determined the normal red cell count described the method for calculating red cell indices (Wintrobe MM Am J Med Sci 1929;177:513–23) and classified anaemia into four groups, macrocytic, normocytic, microcytic and microcytic hypochromic (Wintrobe MM Arch Intern Med. 1934. 54:256-280). Though the methods of determining red cell indices has changed, the concept of classification of red cells by size and the classes of anaemia described by Wintrobe still hold. The three indices are

  1. Mean corpuscular volume (MCV)
  2. Mean corpuscular haemoglobin (MCH)
  3. Mean corpuscular haemoglobin concentration (MCHC)

Mean Corpuscular Volume (MCV)

MCV is the average volume of erythrocytes and is defined as follows:

MCV = [Haematocrit (in percentage) X 10]/RBC count (in millions/mm3)

The normal value is 92±9fl

At the time MCV was described it was calculated as described above. Erythrocyte counts performed manually were cumbersome, technician dependent and inaccurate limiting the value of MCV. Automated haematology counters may be based on impedance or light scatter. Sensors of counters, impedance as well as those based on light scatter, generate signals according to cell size and number. The size of each particle is calculated by the pulse it generates and the MCV reported as an average of these measurements. The standard deviation of observation of MCV is reported as red cell distribution width. When automated counters are used MCV is a measured parameter rather than a calculated parameter. These measurements are accurate and reproducible.

Mean Corpuscular Haemoglobin (MCH) and Mean Corpuscular Haemoglobin Concentration (MCHC)

Mean corpuscular haemoglobin is defined as follows.

MCV = [Haemoglobin (in g/dL) X 10]/RBC count (in millions/mm3)

The normal value for MCH is 29.5±2.5pg.

Mean corpuscular haemoglobin concentration is calculated as follows

MCHC = [Haemoglobin (in g/dL) X100]/[Haematocrit (in percentage)]

Normal 33±1.5g/dL

The MCV and MCHC are of limited value in diagnosis of anaemias. A low MCH has the same significance as a low MCV. MCHC is low in microcytic anaemias. Macrocytic anaemias may have a high MCH but the MCHC is normal in these case. Some anaemias like hereditary spherocytosis, sickle cell anaemia and haemoglobin C disease are characterized by a high MCHC indicating cellular dehydration

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Red Cell Distribution Width

1 Oct

Features of peripheral smear like erythrocyte size, haemoglobinization and variability in size have long been useful in evaluation of patients with anaemia. The definitions of these parameters before the advent of haematological counters were subjective. The haematological counters have allowed an accurate measurement of erythrocyte size and numbers allowing reliable determination of mean cell volume (MCV), mean cell haemoglobin (MCH) and mean cellular haemoglobin concentration (MCHC). Mean cellular volume is used to classify anaemias (see Evaluating Anaemias). MCV is of little value in differentiating two of the commonest causes of anemia, iron deficiency and β-thalassaemia trait as both are microcytic hypochromic.

Anisocytosis is and abnormal variation in erythrocyte size. It is a feature of nutritional deficiencies, myelofibrosis, bone marrow infiltrations, microangiopathic haemolytic anaemia and in the presence of erythrocyte aggregates. Thalassaemias do not show anisocytosis. The erythrocyte is a disc approximately the diameter of the nucleus of a small lymphocyte and the central one-third is pale. The assessment of anisocytosis is subjective. Red cell distribution width(RDW) is quantitation of aniscytosis.

Standard deviation of a parameter is a measure of its scatter from the mean. MCV is an average of erythrocyte volumes measured by the counter. RDW is the standard deviation of these observations. It is expressed as a percentage of MCV. The normal values are 11.5-14.5%. High RDW means more anisocytosis.

Despite the apparent promise RDW has a limited role in diagnosis. A normal RDW in a microcytic anaemia can suggest the presence of on thalssaemia but can not be relied on as a sole criteria for separating iron deficiency from thalassaemia. The presence of a high RDW should alert one to the presence of one of the causes of anaemia listed above but again RDW can not be relied on for making a final diagnosis of any of these conditions. Blood transfusion in an anaemic patient increases the RDW.

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Evaluating Anaemia

28 Sep

Anaemia is a manifestation of many diseases. Figure 1 gives the outline for evaluation of a patients with anaemia. The details of evaluation are given below.

Definition of Anaemia

Anaemia is defined and severity classified as per the WHO guidelines given in table 1. These definitions are for non-smokers individuals living at sea level (<1000 meters above seas level). Definitions for smokers and those living ≥1000 meters above sea level can be found at Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. World Health Organization (WHO/NMH/NHD/MNM/11.1)

Population Normal haemoglobin Mild Anaemia Moderate Anaemia Severe Anaemia
6-59 months ≥11 g/dL 10-10.9 g/dL 7-9.9 g/dL 7 g/dL
5-11 years  ≥11.5 g/dL 11-11.4 g/dL  8-10.9 g/dL  <8 g/dL
12-14 years  ≥12 g/dL 11-11.9 g/dL  8-10.9 g/dL  <8 g/dL
Pregnant Woman  ≥12 g/dL 11-11.9 g/dL 8-10.9 g/dL  <8 g/dL
Non-Pregnant Woman  ≥11 g/dL 10-10.9 g/dL 7-9.9 g/dL  <7 g/dL
Men (≥15 years)  ≥13 g/dL 10-12.9 g/dL 8.8-10.9 g/dL  <8 g/dL

Initial Evaluation of a Patient of Anaemia

  1. The diagnostic workup of a patient of anaemia should establish the type of anaemia, the cause of anaemia and complications caused by anaemia. Red cell transfusions in anaemic patients are for relieving symptoms due to a low haemoglobin. Patients without symptoms should not be transfused. Patients with symptoms because of low haemoglobin should be teated urgently with blood transfusion. A pre-transfusion serum sample should be stored to perform tests likely to be affected by blood transfusion (e.g. serum ferritin, serum B12, serum folic acid and haemoglobin electrophoresis).
  2. The history, examination, haemogram and red cell indices are available in all anaemic patients. This information gives a reasonable idea about the cause of anaemia. A diagnosis can be made with a few additional investigations. No patient should be treated without a complete diagnosis.
  3. Iron deficiency is the commonest cause of anaemia. Most patient of anaemia will respond to iron supplementation. Iron supplementation without complete investigation of anaemia is a common but dangerous practice as it may delay the diagnosis of dangerous underlying illnesses like colorectal carcinoma.

Clinical manifestations of anaemia result from manifestations of  impaired oxygen deliver, manifestations of the underlying disorder and manifestations due to compensation to anaemia.

  1. Manifestations of of anaemia: The symptoms of anaemia depend on the degree of anaemia, rate of fall of haemoglobin and conditions of the vessels. The body adapts to anaemia by increasing cardiac output, redistribution of blood from non-critical to the critical circulations and the and increased oxygen extraction (see Pathophysiology of anaemia). These adaptation occurs slowly. Patients with a gradual fall in haemoglobin can tolerate a more severe anaemia than a patient who become  anaemic rapidly because they get time to adapt to anaemia. Vascular disease results in the patient becoming symptomatic at a higher haemoglobin level. These patients manifest with ischaemic symptoms of the region supplied by the vessel. Thus a patient with a gradually developing anaemia and without coronary heart disease becomes symptomatic at a lower haemoglobin than one with a rapidly developing anaemia, one having a coronary or one with both.  Nutritional anaemias have a slow onset and thus present with a lower haemoglobin than anaemia or blood loss or acute haemolysis.
    Manifestations of anaemia are a result of impaired oxygen delivery. In patients without a significant coronary compromise the symptoms of anaemia include fatigue, lightheadedness and breathlessness. Frank cardiac failure sets in as the severity increases. Ischaemic symptoms, typically angina pectoris, may predominate in patients with significant coronary narrowing. Pallor, the most prominent sign of anaemia is of less diagnostic use than it is percieved to be. It has been reported to have a sensitivity of 19% to 70% and a specificity of 70% to 100%. There is inter-observer variation and clinical examination can not exclude mild anaemia. There have been suggestions that the tongue is the best site for diagnosing anaemia others have differed (PLoS ONE 5(1): e8545. doi:10.1371/journal.pone.0008545). Lack of pallor does not exclude mild anaemia and a haemoglobin assessment must be done is every patient with suspected anaemia.
  2. Clinical features may give a clue to the nature of the disease causing anaemia: The table below gives clinical features that may give a clue to the nature of the disease causing anaemia.
  3. Manifestations due to compensatory changes: Tachycardia, wide pulse pressure and decreased exercise tolerance result from cardiovascular compensation to anaemia. Chronic haemolytic anaemias result in marrow hyperplasia that results in a typical facies and increased risk of fracture. Facial features include bossing of the skull  hypertrophy of the maxilla resulting in exposure of upper teeth, prominent malar eminences with depression of the bridge of the nose, puffiness of the eyelids and a mongoloid slant of the eyes.
Clinical Finding <strong >Significance
Painful Crisis Sudden onset of pain is a feature of sickle cell disease. Four regions are commonly affected: bone, chest, abdominal and joint
Jaundice
  1. Achloruric Januduce: Achloruric jaundice is a result of increased haemoglobin catabolism (see haemoglobin catabolism) It is seen in patients with haemolytic anaemia, where the erythrocyte turnover is increased, and megaloblastic anaemia, where the turnover of haemoglobinized erythroid precursors in the bone marrow is increased. The presence of reticulocytosis in haemolytic anaemias (see diagnosis of haemolytic anaemia) as opposed to reticulocytopenia megaloblastic anaemia differentiates the two conditions. Every anaemia with achloruric jaundice may not be a haemolytic anaemia or megaloblastic anaemia. Gilbert’s syndrome is a common asymptomatic defect of bilirubin metabolism that may co-exist of anemia of another cause. Rarely achloruric jaundice with reticulocytosis may be seen in large occult haematomas. Haematomas of the retroperitoneal region may present in this manner.
  2. Chloruric Jaundice: Patinets with haemolytic anaemia may develop chloruric jaundice because of biliary obstruction from pigment stones.
Nail Changes Platonychia (flat nails) and koilonychia (spoon shaped nails) are features of iron deficiency. These changes may be congenital and the duration of the changes must be enquired into.
Clubbing Clubbing is seen in infectious endocarditis, chronic liver diseases, bronchiectasis, inflammatory bowel disease and lung cancer
Leg ulcers Leg ulcers are a complication typically seen in patients with sickle cell anaemia. They are not specific to sickle cell disease. They may be seen in severe α and β thalassaemia, hereditary spherocytosis and pyruvate kinase deficiency. The incidence of leg ulcers increases with age. They are more common in the tropics where no foot ware is worn. The are less common in Sβ0 and not seen in Sβ+ and SC disease. Co-inheritance of α thalassaemia with sickle cell disease decreases the incidence of ulcers. They are typically seen on the medial aspect of the tibia of behind the medial malleolus, are persistent and are a major cause of morbidity in sickle cell disease
Bleeding Manifestations Bleeding due to thrombocytopenia is characterized by petichiae and purpura. Anaemia with thrombocytopenia may be seen under three circumstances

  1. Bone marrow pathology: Aplastic anaemia, acute leukaemia, bone marrow infiltrations and myelodysplastic syndromes
  2. Increased periphreal distruction/sequestration of platelets: Thrombotic thrombocytopenic purpura/Haemolytic ureaemic syndrome, Evan’s syndrome and hypersplenism
  3. Anaemia caused by bleeding associated with thrombocytopenia
Mouth ulcers Mouth ulcers are a feature of aplastic anaemia
Lymphadenopathy Generalized lymphadenopathy is seen in patients with acute or chronic lymphoid leukaemia or rarely in autoimmune diseases
Splenomegaly Splenomegaly may be seen in patients with lymphoid neoplasia, chronic myeloid leukemia, idiopathic myelofibrosis, extra hepatic portal hypertension and hairy cell leukemia
Neurological changes
  1. Subacute Combined degeneration of the Spinal Cord: Subacute combined degeneration is a myelopathy caused by B12 deficiency. It presents with parasthesiae of the upper and lower limbs that progress to weakness and ataxia in untreated patients. Vibratory and joint position sense is lost early in disease and progresses to impaired pinprick, light touch and temperature sensations with progression. Upper motor neuron involvement results in hyperreflexia of the knees but the ankle reflexes are depressed due to a co-existing peripheral neuropathy. Plantars reflexes give a extensor response. Rarely features of autonomic involvements may be seen including orthostatic hypotension and bladder and bowel incontinence. Features that may be present include
  2. Neuropathy: Chronic lead poisoning is characterized by a peripheral neuropathy that manifests with motor disturbances with few sensory symptoms.
  3. Other Neurological Manifestations: B12 deficiency can rarely cause cognitive or psychiatric manifestations (3%) or bilateral optic neuropathy and blindness (0.5%). Exposure to lead can cause encephalopathy.

Initial Investigations in a Patient of Anaemia

The starting point in evaluation of an anaemic patient is a haemogram and a reticulocyte count. The aim of initial investigation is determine

  1. If the pathology involves only the red cells or is there involvement of the white cells and /or platelets.
  2. If the bone marrow responding to anaemia by producing erythrocytes

Alterations in more than one cell lines of blood cells occurs because blood cells share precursors, developmental microenvironment and antigens. Diseases involving more than one series of blood cell include.

  1. Diseases of haemopoietic precursors: Aplastic anaemia, Acute leukaemia, myeloproliferative diseases, Myelodysplastic syndrome
  2. Pathology of bone marrow microenviorment: Bone marrow infiltration, myelofibrosis
  3. Antibodies mediates diseases
    1. Antibody to antigen of precursors: Aplastic Anaemia
    2. Shared antigen Aplastic anaemia: Autoimmune pancytopenia, Evan’s syndrome
  4. Complement Mediated Damage: Paroxysmal nocturnal haemoglobinuria
  5. Other diseases: Thrombotic thrombocytopenia purpura/haemolytic uraemic syndrome (TTP/HUS)

All the above diseases other the TTP/HUS need a bone marrow examination for diagnosis. TTP/HUS is characterized by microangiopthic haemolytic anaemia in a patients with characteristic clinical presentation.

Anaemia induces erythropoietin production. Increased erythrocyte production manifests as reticulocytosis (see reticulocyte count). Reticulocytosis in an anaemic patient indicates that the anaemia is because of erythrocyte loss and the bone marrow is normally responding to anaemia. Patients with erythrocyte loss may fall into three catagories.

  1. Acute blood loss: These patients give history of blood loss and present with anemia with reticulocytosis without evidence of haemolysis.
  2. Chronic Blood loss: Blood loss is a alarming symptom that prompts patients to immediately seek medical advise. Patients with occult blood loss, those with altered blood loss or those with not capable of recognizing a blood loss may present with manifestations of chronic blood loss. Chronic blood loss causes iron deficiency. Unlike acute blood loss the manifestations of chronic blood loss are those of iron deficiency anaemia (microcytic anaemia with reticulocytopenia).
  3. Haemolytic anaemia: Patinets who have anaemia with reticulocytosis but have no demonstrable blood loss should be considered to have a haemolytic anaemia.

Evaluation of Microcytic Anaemia

As haemoglobin forms about 97% of the erythrocyte proteins. Disorders impairing haemoglobin synthesis cause microcytic anaemia. Haemoglobin synthesis needs an intact genetic code, normal heme synthesis, adequate supply of iron and proper incorporation of heme in haemoglobin. If any of these are defective a microcytic anaemia develops. The commonest cause of microcytic anaemia is iron deficiency. The first investigation in a patients of microcytic anaemia is assessment of serum iron, total iron binding capacity and serum ferritin. The results of iron studies microcytic anaemia are depicted in figure 3. Further evaluation of patients depends on the result of iron studies. If the irons studies are normal then an study for abnormal haemoglobin should be performed either by HPLC or cellulose acetate electrophoresis in alkaline pH. Patients with HbA2 between 3.5-8% have heterozygous β-thalassaemia. Higher HbA2 values should be considered to be due to an abnormal haemoglobin that separates with HbA2. Patients with homozygous and heterozygous HbE disease may be diagnosed in this manner. Those with a normal hemoglobin electrophoresis are likely to have α-thalassaemia trait. Unless HbH disease is prevalent in the ethenic group the patients belongs to, further investigation for patient with suspected thlassaemia is not necessary. Patients with transferrin saturation more than 50% need to have  bone marrow aspiration for diagnosis of sideroblastic anaemia.

Evaluation of Normocytic Anaemia

Patinets with normocytic anaemia need to be evaluated for liver disease, renal failure or endocrine disease. The endocrine disease associated with anaemia include hypothyroidism, hyperthyroidism, adrenal insufficiency and hypopituitarism. If these disorders are not found the iron status should be assessed. Patinets may have iron deficiency (transferrin saturation <16%), anaemia of chronic disease (transferrin saturation ≥16% with a low total iron binding capacity). A bone marrow aspiration should be performed in whom diagnosis can not be made by the above investigations.

Evaluation of Macrocytic Anaemias

Macrocytic anaemias may be megaloblastic or non-megaloblastic. Features of megaloblastic anaemia include hypersegmentation of neutrophils, macroovalocytosis, indirect hyperbilirubinaemia and markedly elevated lactate dehydrogenase levels. Macrocytosis is pronounced and almost all patients with an MCV > 110fl have nutritional megaloblastic anaemia, are of antiviral therapy or on chemotherapy. The converse is not true. Patients of megaloblastic anaemia may have a MCV <110fl in early disease or in the presence of co-existing iron deficiency. Serum iron levels are increase in nutritional megaloblastic anaemia. They  fall rapidly within 24-48 hours after therapy. Iron studies should be performed after a few days after administration of vitamins when the iron levels have stabilized. Nonmegaloblastic macrocytic anaemias are seen with alcoholism, hypothyroidism, liver disease and myelodysplastic syndromes.

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Pathophysiology of Anaemia

3 Jul Oxyhaemoglobin Dissociation Curve

Low haemoglobin decreases the oxygen carrying capacity of the blood. This is offset by the following mechanisms.

  1. Increased cardiac output: Tissue hypoxia causes peripheral vasodialatation and decreased haemoglobin decreases blood viscosity. Together these reduce peripheral resistance allowing a higher cardiac output without increasing blood pressure.  Increased cardiac output increases tissue oxygen delivery but decreases the patient’s  exercise tolerance. Increase in cardiac output is seen at haemoglobin values less than 7g/dL.
  2. Redistribution of cardiac output: Blood flow from non-critical areas like the skin is diverted to critical organs like heart and brain.
    The Figure shows three oxyhaemoglobin dissociation curves. The blue curve is the physiological curve. This may be shift to the right (red) or left (green). When the curve shifts to the right the oxygen affinity of haemoglobin falls. Haemoglobin is more desaturated ar a given P02. The opposite happens when curve shifts to the left. The three arrows show the change in oxygen saturation between arterial and venous blood at venous and arterial PO2
  3. Increased Oxygen Extraction: Anaemic patients have increased tissue oxygen extraction from the blood. This is not seen in organs like the heart and brain that already have high oxygen extraction.
  4. Changes in oxygen affinity of haemoglobin: Patients with chronic anaemia have increased of 2,3 diphosphoglycerate (2,3-DPG). 2,3-DPG shifts oxyhaemoglobin dissociation curve to the right and increases oxygen delivery. The figure above shows three curves. The blue curve is the curve of normal haemoglobin the red shows shift to left and the green shift to right. Shift to left increases the oxygen delivery.
  5. Isovoluaemic haemodilution: Patinets with anaemia have increased plasma volume. This allows maintaining a normal cardiac output.

 

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Clinical Manifestations of Polycythaemia

19 Jun Polycythaemia-20120618_100337

Figure 1. Plethora of the face Figure 2. Plathoric mucosa Figure 3. Palmar erythrma

This 50 year old male presented with an incidentally diagnosed haemoglobin of 21.2g/dL. He had no symptoms. Despite a dark complexion the malar plethora its evident. Mucosal plethora and palmar erythrma is evident.

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Normal Erythrocytes

26 May Normocyte-100X-400px

Normal erythrocytes are round disks about 7.5μm in diameter.The central one third is paler than the periphery because of the discoid shape of the erythrocyte. The picture above is a 40X image that shows the uniformity of size and staining of normal erythrocytes. Can one say that the

se cells are 7.5μm in diameter? They could all be 10μm or be 6μm. Is it possible to known about the size of erythrocytes using an unsophisticated laboratory microscope?

The small lymphocyte comes to the rescue! The size of the small lymphocyte nucleus is approximately 8.5μm and it does not vary significantly with disease. The picture above is a 100X image comparing the normal erythrocyte with a small lymphocyte. The cells are slightly smaller than a small lymphocyte. The uniformity of size and that of the pale staining area is evident. Microcytes are smaller erythrocytes and macrocytes larger erythrocytes. Hypochromia is increase in the pale staining area and indicates decreased content haemoglobin. Anisocytosis is increased variability in erythrocyte shape.

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Sickle Haemoglobin and Varients

14 May Sickle Cell 100X - IMG_0538

Substitution of the amino acid glutamic acid by valine at position 6 of the beta globin gene (HBB glu6val) results in a mutant haemoglobin that polymerizes at low oxygen pressure. This mutation results in sickle shaped cells under hypoxic conditions. The haemoglobin gets its name, sickle haemoglobin, from the phenomena. Sickling is responsible for symptoms of sickle cell anaemia. Shown above are sickle cells from the smear of a patient with sickle cell anaemia.

HbS is an autosomal co-dominant trait. Homozygous individuals suffer from sickle cell anaemia (SS). The clinical profile of compound heterozygous depends on the non-HbS allele.

  1. HbA: HbA does not participate in sickling. Patients with AS have about 35% HbS and 65% HbA there is little sickliness and symptoms. These patients said to have sickle cell trait. A patient with as with an apparent AS pattern can have see sickling (see below).
  2. β-Thalassaemia: The severity of interaction between HbS and β-thalassaemia depends on the severity of the co-thalassaemia. β0-thalassaemia is identical to SS and β+-thalassaemia is a milder disease with severity depending on the degree of impairment of the β-chain synthesis.
  3. Other Sickling haemoglobinopathies: Co-inheritnce of Hb-O Arab and Hb D Punjab produces a sickle cell anaemia like disease. Co-inheritance of Hb E produces a sickling disease milder than SS.
  4. Haemoglobinopathies than mimic AS on electrophoresis but produce sickling: There are two categories in this class. First, is a disease that resulting from co-inheritance of an abnormal haemoglobin, Hb Quebec Chori, migrates like HbA but promotes sickling. Patients compound heterozygous for Hb S and and Hb Quebec Chori show and electrophoretic pattern of AS but show sickling. Second are variants of HbS where a second mutation has resulted in an increased tendency to precipitate making a individual heterozygous for these variants symptomatic. These include Hb South End, Hb Jamican Plain Hb S Antilles and Hb S-Oman. The first three have mutations reducing the affinity of the haemoglobin increasing polymerization and sickling.

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The ABH Blood Group System

17 Apr

The risk of transfusion reactions prevented widespread use of blood transfusion till the turn of the 20th centaury. In 1900 Karl Landsteiner while mixing red cells and serum from his colleagues discovered that the serum of some individuals reacted against the red cells of other individuals. Based on reactions between sera and red cells he described three blood groups, A, B and C (which was later renamed as O). The fourth group of the ABO system, AB, was described a year later. In 1907 Ruben Ottenberg and Schultz suggested that before transfusion both the donor and the recipient be grouped and the blood mixed in the laboratory to ensure compatibility. Using this process Ottenberg virtually eliminated transfusion reaction.  Landsterner and Weiner discovered the Rh Group in 1940. The use of blood grouping (ABO and Rh) and cross-matching has made blood transfusion safe.

Figure 1. Biochemistry of ABO Groups

The ABO antigens (figure 1)
Antigens of the ABO system are polysaccharides. They are produced by the interaction of genes at two loci, 19q13.2 and 9q34.1 in two steps. The first step involves addition to a precursor of fucose in a α1-2 linkage to a precursor by the action of FUT1 a fucosyltransferase synthesized by the gene encoding for the H antigen located at 19q13.2. The second step is addition of N-acetylgalactosamine or galactose by glycosyltransferases encoded by the genes for A and B group antigens respectively. These genes are located at 9q34.1. The phenotypes resulting from the action of the two genes are listed in table 1.

A and B are codominant and O is recessive. O group is encoded by a gene carrying a mutation resulting in a product that is neither capable of adding GalNAc nor Gal. The commonest O allele has a frame shift mutation resulting in the formation of a stop codon resulting in a premature termination of translation

About 200 alleles ABO genes have been described. Qualitative and quantitative differences between glycosyltransferases encoded by these gene produces a spectrum of antigenicities on the red cell.

Figure 2. Inheritance of ABO and Bombay phenotype


  1. Quantitative Differences in ABH Genes: Quantative differences exist in both A and B group antigens. A1, A2, A3, Ax, Am, Ael are subtypes of A with progressively decreasing Aantigen sites. It has been estimates that A1, which is the commonest A subtype has 800,000 antigenic sites per erythrocyte, A2 has 250,000 sites and Am has only 800 sites. B1 is the most common type of B antigen. Weaker B antigens include B3, Bx, Bel. Individuals with a weak type of antigen can produce antibodies against a strong subtype of the same antigen. Patients with A2 can produce antibody against A1.
  2. Qualitative Differences in ABH Genes
    1. The Cis-AB Group: A rare and interesting type of blood group is cis–AB. Usually individuals with AB have a gene for glycosyltransferase for A group on one chromosome and that for B on the other chromosome. They inherit one gene from each parent. Cases of AB children born to AB group mothers and O group fathers can only be explained if both the A glycsyltransferase and B glucosyltrasnferase activity is carried by the samegene. This is known as cis-AB. Apart from raising paternity disputes cis-AB can also complicate transfusion. The common types of cis-AB express a weak B (B3) and can have anti-B antibodies making only washed O or A cells suitable for transfusion to these patients (Br J Anaesthe 1999; 83:491-2).
    2. The Bombay Phenotype (figure 1 and 2): Blood grouping involves mixing patients cells with anti-A and anti-B sera. Group A cells agglutinate with anti-A, group B with anti-B and group AB with both. If no agglutination is seen the blood group is designated as O. The H antigen is a precursor to A and B antigens.  Patients who have blood group O have inactive glycoryltransferases and nothing is added to H. H is the group O antigen.  Rarely the gene for FUT1 mutated (h) resulting in an inactive product. These individuals do not synthesize H antigen and will not synthesize A or B antigens even if they have genes for the respective glycoryltransferases on chromosome 9q34.1. Their red cells will neither agglutinate with anti-A nor with anti-B sera and will be grouped blood group O. As they lack H they have agglutinating naturally occurring anti-H antibodies. When serum from these patients is mixed with cells from O group individuals the anti-H antibodies in their serum agglutinate O group cells. These individuals are group O on forward matching but not on cross-matching. This is known as the Bombay phenotype. Such individuals can only be transfused red cells from individuals of Bombay phenotype.

Synthesis of Universal Blood Group
Groups A and B are synthesized from H antigen. Bacterial glycosidases can be used to lyse GalNAc and Gal convert A and B group antigens to group O. O blood cells can be given to any individual (except Bombay phenotype). This technology when available for clinical use has the potential to eliminate blood shortages.

Table 1 ABO antigens and antibodies

Antibodies to ABO Antigens (table 1)
The ABO antigens are polysaccharide antigens capable of stimulating T independent B cell responses. Unlike other blood group antigens like the Rh, the serum contains naturally occurring antibodies to the antigens of the ABO and other polysaccharide (Le, Ii and P) blood group systems that are believed to be produced following exposure to environmental antigens like bacteria (J Clin Invest. 1969 July; 48(7): 1280–1291). The antibodies belong to the IgM class and are agglutinating, bind C3. They can cause haemolytic disease of the newborn but the presentations are uncommon and mild.

Physiological Role, Variations and Disease AssociationsThe physiological role of ABO antigens in not known. A relationship between falciparum malaria and ABO antigens has been proposed. Malaria infected cells express a protein PfEMP-1 a protein that can bind to A (and B) on the endothelium. Plasmodium infected cells are less likely to adhere to endothelium of group O individuals reducing the severity of malaria in these individuals (Blood 2007; 110:2250-2258).

The levels of von Willebrand Factor and factor VIII vary with blood group. They are highest in blood group AB and lowest in blood group O. Group O individuals are at risk of bleeding and AB at the risk of thrombosis. About 30% of the variation in vWF can be explained by ABO blood groups. vWF expresses A and/or B antigens and these may be responsible for conferring vWF resistance to degradation by ADAMTS13 resulting in higher vWF levels.

Group O individuals have a lower risk of squamous and basal cell cancer of the skin, pancreatic cancer and gastric cancer. Individuals expressing B antigen are at a higher risk of ovarian cancer and group A individuals are at a higher risk of gastric cancer. Peptic ulcer is more common in O group individuals.

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Diagnosis of Haemolytic Anaemia

23 Nov

Haemolysis is decreased erythrocytes lifespan (normal about 100-120 days). The bone marrow responds to haemolysis by increasing erythrocyte production. Anaemia occurs only when the erythrocyte life span is reduced to about 15-20 days. A compensated haemolytic state is when a patient has a shorted erythrocyte lifespan that is adequately compensated by increased erythrocyte production. These patients may have features of haemolysis except anaemia.


Figure 1. Manifestations of Haemolysis

Clinical Manifestations of Haemolysis

The site of haemolysis, intravascular or extravascular, determines the clinical manifestations of haemolysis (figure 1). Extravascular haemolysis is an exacerbation of a physiological catabolic process. The end product of extravascular haemolysis, like that of normal erythrocyte breakdown, is unconjugated bilirubin. Unconjugated bilirubin can cause brain damage in the forms of kernicterus. The conjugation of bilirubin is so efficient that the serum bilirubin rarely increase to more than 5mg/dL only due to bilirubin overproduction. The blood brain barrier prevents entry of bilirubin in the brain. Both the mechanisms are compromised in a neonate making them prone to kernicterus in case of haemolysis as is seen in haemolytic disease of the newborn. The only consequences of extravascular haemolysis occurring in patients beyond the neonatal period are anaemia, unconjugated hyperbilirubinaemia, mild to moderate splenomegaly and pigment gallstones.

Intravascular haemolysis is lysis of cells within the blood vessels. Cell free haemoglobin is oxidizing and pro-inflammatory. Haptoglobin binds and detoxifies cell free haemoglobin but it has a limited capacity. Haemoglobinaemia resulting from intravascular haemolysis causes serious clinical manifestations including renal failure, hypertension, smooth muscle spasm and a prothrombotic state. Many of these result from the nitric oxide scavenging capacity of haemoglobin (Rother et al JAMA 293:1653;2005). Persistent haemoglobinuria is a feature of chronic intravascular haemolysis, e.g. those with haemolysis due to prosthetic valves and paroxysmal nocturnal haemoglobinuria. Iron deficiency may accompany chronic intravascular haemolysis because of haemoglobinuria. Extravascular haemolysis is not associated with haemoglobin loss and does not cause iron deficiency.

Intravascular haemolysis often presents with acute severe haemolysis as may be seen with drug induced immune haemolysis, haemolysis in G6PD deficient patients, severe malaria and mismatched transfusion reactions. The diseases causing extravascular haemolysis have a less acute presentation.

The Diagnosis of Haemolytic Anaemia

Estimation of erythrocyte lifespan is too cumbersome to be used routinely in clinical practice. The diagnosis of haemolytic anaemia instead relies on indirect evidence of increased erythrocyte destruction. This includes:

  1. Increased production of erythrocytes in an anaemic patient with no evidence of blood loss
  2. Increase in products of erythrocyte destruction – Lactate dehydrogenase (LDH) and haemoglobin
  3. Consequences of haemoglobinaemia – low haptoglobin, haemoglobinuria, renal failure and hemosiderinuria

Increased erythrocyte production manifests as reticulocytosis (see The Reticulocyte Count for performing and interpreting reticulocyte count). If polycythaemia is not seen despite reticulocytosis, an equivalent erythrocyte loss is presumed to be occurring. Erythrocytes loss may internal, e.g., haemolysis, or external, e.g., bleeding. Reticulocytosis is seen when a large amount of blood is lost over a short period. Such losses are rarely occult. If there is no obvious blood loss, reticulocytosis in a patient whose haemoglobin is not increasing indicates haemolysis. Large occult haematomas, typically occurring retroperitoneally, may mimic haemolysis.

Lactate dehydrogenase (LDH) is abundant in brain, erythrocyte, liver and lung. Injury to any of these organs increases LDH. LDH is also increased in diseases characterized by increased cell proliferation e.g. acute leukaemia, lymphomas (particularly high grade non-Hodgkin lymphoma), myeloproliferative diseases and myelodysplastic syndrome. The clinical picture, radiology and laboratory investigations can exclude non-erythrocyte sources of LDH.

Haemolytic anaemias are characterized by an increase in LDH. The increase in LDH is more pronounced in patients with intravascular haemolysis and is matched by that seen in patients with nutritional megaloblastic anaemia. Unlike megaloblastic anaemia, intravascular haemolysis is characterized by reticulocytosis, haemoglobinaemia and haemoglobinuria.

The alterations caused by catabolism of haemoglobin released during haemolysis depend on the site of haemolysis (see haemoglobin catabolism). Haemoglobin released during extravascular haemolysis is metabolized to unconjugated bilirubin. The liver responds by increasing conjugation and excretion of bilirubin which increases urinary urobilinogen. Unconjugated hyperbilirubinaemia (unconjugated bilirubin >85% of total bilirubin) with increased urobilinogen is a characteristic of haemolytic anaemia. It differentiates haemolytic anaemia from Gilbert’s Syndrome, a common disorder of bilirubin conjugation that is seen in 3-7% of population. The urobilinogen levels in Gilbert’s syndrome are low. Crigler-Najjar syndrome type I and II are present with a more pronounced increase in bilirubin (>5mg/dL and >20mg/dL respectively) and are rarely considered as a differential diagnosis of an uncomplicated haemolytic anaemia. Bilirubin congugation defects do not show reticulocytosis. The bilirubin levels in patients with haemolytic anaemia rarely exceed 5mg/dL. Higher levels indicate a co-existing illness. If the bilirubin is unconjugated then an incidental co-inheritance of Gilbert’s syndrome should be suspected. Haemolytic anaemia increases the risk of pigment stones. These may cause obstructive jaundice. These patients, unlike those with haemolysis have a higher proportion of conjugated bilirubin with an elevated alkaline phosphatase. Donor screening for hepatitis B and C have made transfusion induced hepatitis a thing of the past.

Haemolysis releases haemoglobin. Cell free haemoglobin has oxidizing and pro-inflammatory properties. Haptoglobin is a haemoglobin scavenger that protects the body from the toxic effects of cell free haemoglobin. Haemolysis decreases serum haptoglobin (see haemoglobin catabolism). Extravascular haemolysis does not cause haemoglobinaemia, but contrary to what may be expected, it does cause low haptoglobin levels.  Low haptoglobin is of no value in differentiating intravascular and extravascular haemolysis. It appears that there is some haemoglobinaemia during extravascular haemolysis. It is possible that there is some intravascular component to extravascular haemolysis or there is regurgitation of haemoglobin from the macrophage during phagocytosis. Haptoglobin is synthesized by the liver. Decrease synthesis limits the usefulness of haptoglobin in the diagnosis of haemolysis in the presence eof chronic liver disease. Haptoglobin is an acute phase reactant that in increased by corticosteroid administration. Patients with acute inflammation and those on corticosteroid therapy may have a normal haptoglobin despite haemolysis.

Haemoglobin filtered into the glomerular fluid results in haemoglobinuria when the absorptive capacity of renal tubules (5g/day, Turgeon, ML. Clinical Hematology: Theory and procedures 4th ed. Lippincott Williams and Wilkins, 2005:89) is exceeded. Haemoglobin can precipitate in the tubules and causes renal failure. The haemoglobin absorbed by the renal tubules in metabolized by haemoglobin oxygenase to iron, bilirubin and amino acids. The iron is stored in the renal tubular cells as hemosiderin. These cells desquamate and cause hemosiderinuria. Hemosiderinuria appears a few days after hemolysis and may persist for a week or more after hemolysis has abated. Iron deficiency anaemia caused by hemosiderinuria may complicate chronic low grade intravascular haemolysis as is seen in prosthetic valve haemolysis, paroxysmal nocturnal haemoglobinuria or march haemoglobinuria.

Diagnosis of haemolysis by transfusion requirements

Even with complete cessation of erythropoiesis only about one unit of blood is needed every week in an adult to maintain haemoglobin of about 10g/dL. A greater requirement in the absence of evidence of blood loss suggests haemolysis. Transfused blood will only be lysed if there is an extrinsic defect e.g. autoimmune haemolytic anaemia. Cells transfused to patients with an intrinsic defect e.g. hereditary spherocytosis will have a normal life span. A patient who needs more than one unit of blood per week to maintain haemoglobin of about 10g/dL is likely to have a haemolytic anaemia if blood loss can be excluded. This haemolysis is likely to be due to an extrinsic cause.

Differential Diagnosis of Haemolysis

Haemolysis may be confused with conditions associated with unconjugated hyperbilirubinaemia, anaemia and reticulocytosis. These include bilirubin conjugation defects, acute blood loss and megaloblastic anaemia.

Bilirubin Conjugation Defects Bilirubin conjugation defects include Gilbert’s syndrome and Crigler-Najjar syndrome types I and II. The bilirubin levels in Crigler-Najjar syndrome type I and II are more than 5mg/dL so these entities are rarely confused with haemolysis. Gilbert’s syndrome is characterized by bilirubin levels which can be seen in haemolysis but there is no associated reticulocytosis. Bilirubin conjugation defects are characterized by low urobilinogen levels.

Acute blood loss: Acute blood loss, like haemolysis, causes anaemia and reticulocytosis but these are not the presenting complains. Blood loss needed to cause reticulocytosis is rarely ignored by the patient and is in fact the reason for seeing the doctor. When severe, it may be accompanied by signs of hypovolemia. The presenting complains of patients with haemolytic anaemia are related to anaemia and hyperbilirubinaemia. Chronic occult blood loss has a different presentation that acute blood loss or haemolysis. The gradual fall in haemoglobin associated with occult blood loss makes the patients tolerant to anaemia unless a cardiovascular or respiratory co-morbidity exist. These patients present with a clinical picture of iron deficiency namely, fatigue, malaise and hypochromic microcytic anaemia with anisocytosis. There is no jaundice and there is reticulocytopenia. Large occult haematomas cause anaemia and reticulocytosis. As the haematoma resolves jaundice may be seen.

Megaloblastic anaemia Megaloblastic anaemia, like haemolytic anaemia, presents with macrocytic anaemia, indirect hyperbilirubinaemia, and a low serum haptoglobin. These patients have reticulocytopenia. The macrocytosis is more pronounced. An MCV of >110 fl usually indicates a megaloblastic anaemia. Patients with nutritional megaloblastic anaemia respond to treatment with pronounced reticulocytosis, usually seen by 5-7 days after initiating therapy and lasting for up to 2 weeks.  Reticulocyte counts may be as high as 20-25%. A history of treatment with vitamin B12 and/or folic acid must be sought in every patient of haemolytic anaemia to avoid confusion with megaloblastic anaemia.

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