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Hematology FBC Hb 13-15 WBC 4-10 Platelets 150-400 MCV 85-95 Case 2

60yo female: Hb 7.2, WBC 12, Platelets 470, MCV 71 What are the causes of hypochromic, microcytic red cells? - Iron deficiency 98% - Thalassemia intermedia coz of age - Lead poisoning, sideroblastic anemia, anemia of chronic dz (rare) Blood film - pale centre in the middle - Pale area should not exceed >1/3 area of RBC Causes of Fe deficiency (a) Females Young menorrhagia GI bleed Tests used for Ix of Fe deficiency - Colonoscopy + OGD to find blding source esp in post menopausal - dont waste time on fobt

low MCV, MCH w anemia Case: Thalassemia PBF: poikilocytosis and anisocytosis , target cell circle w dot in middle Tests used for Ix of Thal Intermedia - Thalassemia screen - electrophoresis - Fe panel (to ensure GI pathology not missed out) check serum ferritin lvls. should be high in thalassemia

60yo female, pale and jaundiced: Hb 5.0, WBC 12, platelets 480, MCV 99 MCV and MCH raised DDx: haemolytic anemia, liver pathology MCV and MCH raised bcoz of reticulocytes, larger cell size Haemolytic anemia bcoz of jaundice n significant anemia PBF: loss of central pallor (spherocytes) no longer biconcave Spherocytes indicate loss of membrane (reduced diameter, decreased surface area but normal volume)

Spherocytosis - Hereditary (1%) coombs test negative, born with spherocytes - Acquired (99%) Develop antibodies against the RBC membrane (autoimmune haemolytic anemia)

What are the necessary lab tests: direct coombs test! dist acquired fm non acquired Positive direct Coombs test for acquired form Coombs test looks for antibodies direct looks for presence of antibodies on surface of RBCs; indirect looks for freely floating antibodies in patients plasma E.g. direct coombs test of babys blood, indirect of mothers blood Causes of acquired autoimmune haemolytic anemia Infective Mycoplasma Inflammatory SLE Sjogrens disease Neoplastic Lymphoma leukemia Drugs PENICILLIN Methyldopa Mefenamic acid Idiopathic (50%)

AIHA is most often caused in great part due to the inability of corrupted IgM produced by CLL cells to control the IgG produced by normal B-cells. IgG can and does attack "self antigens", if it is not controlled by proper functioning of IgM. One way of handling this is to use intravenous injections of Ig obtained from healthy blood donors, which contain the good and effective variety of Ig. Viral or bacterial infections that cause danger signals to be sent out can get the immune system go into over-drive. Lactate dehydrogenase is one of these danger signals, and any viral infection that causes increase in LDH will activate macrophages, which may exacerbate AIHA

AIHA treatment

A tried-and-true approach to treating AIHA is corticosteroid drugs such as prednisone. These drugs control AIHA by immune suppression, reducing the level of inflammation, reducing the level of T-cell and macrophage activation. But steroid drugs by their very nature also expose patients to increased risk of infections and even secondary cancers. Since the bulk of the red blood cells are killed by activated macrophages from the spleen, one drastic way of controlling AIHA is to remove the spleen surgically. Or, one can look to recent studies where low-toxicity liposomal drugs such as clodronate have been effective in targeting splenic macrophages (in mice studies). the viral or bacterial infection may well do the job of reducing the LDH, reduce macrophage activation, reduce the killing of red blood cells.

case 5; Chronic haemolytic anaemia: Hereditary spherocytosis Epidemiology

Most common cause of hereditary haemolytic anaemia in people of Northern European heritage Rare locally Pathogenesis AD inheritance in 75% Affects membrane protein spectrin RBC loses part of membrane as it passes through the spleen spherocytes (SA:V ratio) Clinical Features Asymptomatic Cardinal features of o Anaemia (mild: 9-11g/dL) o Jaundice o Splenomegaly (mild to moderate) Aplastic crisis o Clinical course may be punctuated by aplastic crises: transient cessation of RBC production o Triggered by parvovirus infections o Because of the shortened lifespan of the RBCs, even a short period of failure of erythropoiesis results in rapid worsening of anaemia o Self-limited in most cases o May require blood transfusions Gallstone disease Investigations FBC: anaemia PBF: spherocytes + Pseudohyperkalaemia: K leakage as blood is cooled osmotic fragility Management No treatment available When they present, we need to prevent complications of haemoglobinuria by hydrating patient and encouraging diuresis. Give folate supplements. Cholecystectomy may be needed in patients with gallstone disease. If patient requires cholecystectomy, perform splenectomy at same sitting for convenience. Splenectomy is beneficial because the major site of destruction is removed. Administer vaccination against meningococcus, pneumococcus and Hib and possible

case 6 post Splenectomy changes PBF: Cell membrane abnormalities target cells seen morphology on film Howell-jolly bodies (purplish blue inclusion seen in RBC) Remnants of DNA in circular erythrocytes Basophilic stippling (RNA)

basophilic stripping

HJ body

Causes - Surgical splenectomy - Splenic atrophy Sickle cell disease (autosplenectomy) IBD (celiac disease, ulcerative colitis) can p/w hyposplenism

Case 60yo female with SOB, diarrhea: Hb 3, WBC 3.2, platelets 70, MCV 110 DDx for pancytopenia and raised MCV - Bone marrow failure e.g. primary (aplastic anemia, myelodysplastic syndrome), secondary: replaced by malignant cells (leukemia) - SLE and other autoimmune dz. Abx against BM cells - Hypersplenism fm liver dz - Vit B12/folate deficiency Vit B12 is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. cells cant divide hence larger PBF of megaloblastic anemia - Hypersegmented neutrophils. oval n huge rbc

More often seen in renal failure hence its a d/d B12 def in vegan. folate def in those who nvr eat veg more impt in those w gastrectomy ( parietal cells that produces IF removed) or ileum ( IC of absorption of b12) removed! Malaria PBF - Vivax usu BENIGN: ring forms (early trophozoites), amoeboid forms (growing trophozoites, diving forms (schizonts), gametocytes all types of cells seen

Falciparum: ring forms (early trophozoites), gametocytes

Determine severity of parasitemia - 20% medical emergency - 40% fatal Determine resistance to medication
complications Manifestation 1. Cerebral malaria: Features Unarousable coma not attributable to any other cause, with a Glasgow Coma Scale score 9; Coma should persist for at least 30 min after a generalized convulsion Hematocrit <15% or hemoglobin < 50 g/l in the presence of parasite count >10000/l Urine output <400 ml/24 hours in adults (<12 ml/kg/24 hours in children) and a serum creatinine >265 mol/l (> 3.0 mg/dl) despite adequate volume repletion

Initial World Health Organization criteria from 1990 [3]

2. Severe anemia 3. Renal failure

4. Metabolic (Lactic) Metabolic acidosis is defined by an arterial blood pH of <7.35 with Acidosis/acidosis a plasma bicarbonate concentration of <22 mmol/L; hyperlactatemia is defined as a plasma lactate concentration of 25 mmol/L and lactic acidosis is characterized by a pH <7.25 and a plasma lactate >5 mmol/L. 5. Pulmonary edema or acute respiratory distress syndrome (ARDS) 6. Hypoglycemia Breathlessness, bilateral crackles, and other features of pulmonary oedema. The acute lung injury score is calculated on the basis of radiographic densities, severity of hypoxemia, and positive endexpiratory pressure Whole blood glucose concentration of less than 2.2 mmol/l (less than 40 mg/dl).

7. Hypotension and Systolic blood pressure <50 mmHg in children 1-5 years or <70 shock (algid malaria) mm Hg in patients 5 years; cold and clammy skin or a core-skin temperature difference >100C 8. Abnormal bleeding Spontaneous bleeding from the gums, nose, gastrointestinal tract, and/or disseminated retinal haemorrhages and/or laboratory evidence of disseminated intavascular intravascular coagulation.

coagulation 9. Repeated 3 generalized seizures within 24 hours generalised convulsions 10. Haemoglobinuria Macroscopic black, brown or red urine; not associated with effects of oxidant drugs or enzyme defects (like G6PD deficiency) Added World Health Organization criteria from 2000 [4] 11. Impaired Various levels of impairment may indicate severe infection consciousness although not falling into the definition of cerebral malaria. These patients are generally arousable 12. Prostration Extreme weakness, needs support 13. Hyperparasitemia 5% parasitized erythrocytes or > 250 000 parasites/l (in nonimmune individuals) 14. Hyperpyrexia Core body temperature above 400C 15. Jaundice Serum bilirubin of more than 43m mol/l (2.5 mg/dl). (Hyperbilirubinemia) Other 16. Fluid and Dehydration, electrolyte hypovolemia disturbances [5] postural hypotension, clinical evidence of

17. Vomiting of oral Patients with persistent vomiting may have to be admitted for drugs parenteral therapy. 18. Complicating or Aspiration bronchopneumonia, septicemia, urinary tract infection associated infections etc. 19. Other indicators Leukocyte count >12,000/cumm; high CSF lactate (>6 of poor prognosis [5] mmol/l)and low CSF glucose; more than 3-fold elevation of serum enzymes (aminotransferases); increased plasma 5'-nucleotidase; low antithrombin III levels; peripheral schizontemia; papilloedema/retinal oedema 20. Retinopathy Malarial A large, prospective autopsy study of children dying with cerebral malaria in Malawi found malarial retinopathy to be a better indicator of malarial coma. Similar retinopathy in an adult has also been reported.


Acute: short hx, higher % of blast cells If the cells do not mature past the blast stage Early cells nucleus takes up whole cell. nucleus size decreases as it matures. To differentiate AML vs ALL flow cytometry Use antibodies against myeloid and lymphoid antigens, see which is taken up

Chronic: longer hx

myeloproliferative ( abnormal quantity) vs myelodysplastic dz ( abnormal quality/ morphology hence undergoes apoptosis)

ALL most common in childn ALL is most common in childhood with a peak incidence at 25 years of age, and another peak in old age. See that compared to AML there is RAISED WBC level bcoz lymphocytes = wbc form

The FAB classification

Subtyping of the various forms of ALL used to be done according to the French-AmericanBritish (FAB) classification,[18] which was used for all acute leukemias (including acute myelogenous leukemia, AML).

ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features)

Each subtype is then further classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. There are 2 main immunologic types: pre-B cell and pre-T cell. The mature B-cell ALL (L3) is now classified as Burkitt's lymphoma/leukemia. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.

Case Hb WBC Platelets Cause

21 17 500 Polycythemia

10 240 500 CML

15 18 1800 Essential thrombocytosis Thrombocytes platelets

9 17 680 Myelofibrosis

Essential primary and not due to causes ie surgery 60yo female headache, CVA: Hb 21, WBC 17, Platelet 600 Myeloproliferative disease, predominantly high Hb (polycythemia) Ix - O2 saturation - Erythropoietin levels - Jak2 mx - hydrate - venesection - aspirin cox worried about stroke - myelosupprsssion Hb 10, WBC 240, platelets 600 Check Differential count increased nos of most mature cells and blasts hence chronic CML - increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is the main finding. - a/w characteristic chromosomal translocation (Philadelphia chromosome) 60yo female TIA: Hb 15, WBC 18, platelet 1800 MPD - Essential thrombocytosis - Vs reactive thrombocytosis or secondary form; here, essentially a bone marrow problem - Overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause - Platelets derived from the abnormal megakaryocytes do not function properly, which contributes to the clinical features of bleeding and thrombosis Physical signs: TIA, stroke related stuff, decreased cerebral bld flow, ischemia symptoms : erythromelalgia - a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities (or hands), are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. There is severe burning pain (in the small fiber sensory nerves) and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia may occur either as a primary or secondary disorder (i.e. a disorder in and of itself or a symptom of another condition). Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, essential thrombocytosis, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders

60yo female splenomegaly: Hb 9, WBC 6.8, platelet 364

MPD - Myelofibrosis

Myelofibrosis (MF) is a chronic bone marrow disorder in which excessive scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. MF is thought to be caused by abnormal blood stem cells in the bone marrow. The abnormal stem cells produce more mature cells that grow quickly and take over the bone marrow, causing both fibrosis (scar tissue formation) and chronic inflammation. As a result, the bone marrow becomes less able to create normal blood cells and blood cell production may move to the spleen, causing enlargement, or to other areas of the body.

Production of cytokines which causes fibrosis of marrow Proliferation of an abnormal type of bone marrow stem cell results in fibrosis, or replacement of the marrow with collagenous connective tissue fibers PBF: tear-drop cells

Case: 60yo female, backache: Hb 9, WBC 7, platelets 150, MCV 99 Bone scan normal (looks for osteoblast activity; MM has increased osteoclast activity) PBF:

Rouleaux formation of RBCs due to clumping together like stack of coins Occur when the plasma protein (globulins) concentration is high positively charged proteins link negatively charged rbc tgt The presence of acute phase proteins, particularly fibrinogen, interacts with sialic acid on the surface of RBC and allows the formation of rouleau. Anemia, by altering the ratio of RBC to plasma, increases rouleaux formation and accelerates sedimentation. Rouleaux formation is retarded by albumin proteins. Causes an increased ESR Causes: Infx, multiple myeloma, inflammatory and connective tissue disorders, cancers to diff cause - Check protein electrophoresis Polyclonal band many types of proteins inflammation/ chronic infx/autoimmune disease . maybe TB

Monoclonal pattern (all from 1 type, 1 malignant cell producing protein) multiple myeloma Check bone marrow for evidence of multiple myeloma many plasma cells (basophilic stained v blue bcoz of RNA, eccentric- peripheral and round nucleus) plasma cells produce a lot of proteins, RNA, ribosome hence v blue

Multiple myeloma - Cancer of plasma cells (WBC responsible for pdtion of antibodies). Collections of abn cells accumulation in bones where they cause bone lesions (abnormal areas of tissue), and in the bone marrow where they interfere with the production of normal blood cells. - Most cases of myeloma also feature the production of a paraprotein, an abnormal antibody that can cause kidney problems and interferes with the production of normal antibodies leading to immunodeficiency. Hypercalcemia (high calcium levels) is often encountered.

DIFFERENTIALS for Very HUGE SPLEEN myelofibrosis which is essentially a myeloproliferative dz. fibrosis in marrow due to cytokine production CML lymphoma hypersplenism

Elliptocytes, also known as ovalocytes are abnormally shaped red blood cells that appear oval or elongated. These abnormal red blood cells are seen in blood films of patients with:

Hereditary elliptocytosis Thalassemia Iron deficiency Myelophthisic anemias Megaloblastic anemias