Dr Mere Kende, MBBS (UPNG), MMED (Path), MAACB (AUS), MACTM (AUS), MACRRM (AUS) Lecturer-SMHS UPNG

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1 Dr Mere Kende, MBBS (UPNG), MMED (Path), MAACB (AUS), MACTM (AUS), MACRRM (AUS) Lecturer-SMHS UPNG

2 Outline Hemopoiesis in Normal Pregnancy Anaemia Iron Deficiency Folate Deficiency Aplastic Anemia Hemolysis Drug-induced/G6PD Thalassaemia Sickle Cell

3 Hemopoesis in Normal Pregnancy

4 Hemopoesis in Normal Pregnancy Blood Volume Increases % (av %) Rapid 1 st tri------plateaus at 30 th wks Large women >small Singlet>multiple?Mechanism- Hormonal/aldosterone, increased fetal demand increased kidney perfusion prepare for maternal loss e.g., mls vaginal mls C/s

5 Changes in RBC/iron Red Cells Increased 33% ~450mls RBC Increase is greater with iron supplements Plasma increase>rbc until end of 2 nd trimester Iron Increase RBC...> increased requirement for iron No supplement = iron deficiency Fetus extracts iron from mother

6 Changes in WBC/PLT White Blood cells Normal /mcl Increased to 2-3x normal or even up to 5-6x?Mechanism reduced chemotaxis/adherence in 3 rd trimester prone to infection Platelets Increased production and consumption Increases in both PGI2 (aggregation inhibitor) & TXA2 (aggregation inducer),

7 Changes in coagulation factors Clotting factors Increased viz. Fibrinogen (I) and factor VIII (+++) and Factors (VII, IX, X, XII) + Factor XIII (fibrin-stabilising factor) decreased 50% towards term Depressed fibrinolysis

8 Anemia Significant problem in Pregnancy Investigate if Hb<11g/L or HCT <33% Anaemia will worsen from blood loss during birth of child (vaginal/caesarean Section).

9 Causes Nutritional iron & folate deficiency (common) Aplastic Anaemia (parvo virus B19) Drug-induced hemolysis

10 Iron Deficiency Accounts for 95% of anaemia in pregnancy Iron requirement increases in pregnancy Hb (contains 70% of body iron) Storage iron (ferritin, haemosiderin, RES) ~300mg Diet supply must meet increased demand by growing foetus Decreased BM iron (hemosiderin) is early sign of iron deficiency If severe, can endanger foetal life

11 Causes of iron deficiency. Deficient diet (children on milk) Decreased absorption Increased requirements Pregnancy Lactation Blood loss (common) Gastrointestinal (PUD/aspirin) Menstrual Blood donation Hemoglobinuria Iron sequestration Pulmonary hemosiderosis

12 Absorption: stomach, duodenum, and upper jejunum. Diet iron: heme is efficiently absorbed (10 20%), Nonheme iron less so (1 5%) Loss ---approximately 1 mg/d are normally lost through exfoliation of skin and mucosal cells.

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15 Iron requirement in Pregnancy Requirement for iron increases in 2 nd trimester Mother: 500mg (increased RBC & Hb) Baby: 300mg (growth) Total over course of pregnancy 800mg Requires 3.4mg/day or elementary iron >40mg/day

16 Clinical Findings Pallor Tachycardia/Palpiations Tiredness/Easy fatigue Low Hb (hypochromic microcytic) If severe Glossitis, stomatitis, koilonykia may endanger baby

17 Laboratory Findings Iron Studies: low iron, low ferritin, Elevated TIBC & transferrin decreased % saturation,

18 Iron Parameters

19 Red Cell indices: low MCV, low retics WbC normal Elevated soluble transferrin receptor

20 Blood Film: hypochromic Microcytic

21 Differential Diagnosis Thalassaemia Trait (normal iron studies, elevated HbA2) Chronic Inflammation (can see hypochromia, microcytosis) Sideroblastic Anaemia

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23 Complications Heart: Angina/CHF Plummer-Vinson syndrome

24 Prevention Iron supplements in pregnancy (at least 60-80mg/day elemental iron daily

25 Treatment Oral iron Ferrous Sulphate 300mg (60mg elementary iron -> 10% absorbed) tds Hb increased by 3-5g/L/week if responding Continue 3 months after Hb is normal to replenish stores

26 Iron salt Amount Contents of Ferrous iron Ferrous fumarate 200mg 65 Ferrous gluconate 300mg 35 Ferrous succinate 100mg 35 Ferrous sulphate 300mg 60 Ferrous sulphate, dried 200mg 65

27 Only marginal differences between Fe++ salts Choices depend on cost and side effects Treatment dose is t.d.s versus daily prophylaxis dose Some combined with vitamin C or folate (fefol)- cost? Fefol 150mg ferrous sulphate (47mg iron) / 500mcg folate Fefol is inadequate to treat megaloblastic anaemia

28 Parental Iron Different Forms available Iron dextran (ferric-oh + dextran) IV/IM injection Iron sorbitol (ferric- OH +sorbitol)-iv/im injection Iron sucrose (ferric OH + sucrose)-deep IM injection Reserved for unsuccessful oral iron treatment Response similar to oral dose Risk of Anaphylaxis (small test dose initially)

29 Folate in Pregnancy/Megaloblastic Anaemia Folate (+ vit B12) is required for DNA synthesis in Red cell maturation It is essential for the growth and division of all body cells for healing processes. It aids protein metabolism Helps prevent premature greying

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31 Lack of folate is associated with LBW and Neural Tube Defect.

32 Valuable sources Deep FGLV such as spinach, lettuce, brewers yeast, mushrooms, nuts, peanuts and liver.

33 Incidence on BM studies 25-60% (depends on population studied) Inadequate dietary folate in pregnancy Demand for folate increased in Pregnancy Minimum requirement: 50mcg/day Requirement increases to 800mcg in pregnancy

34 Folic Acid Deficiency Anaemia Demand is greater with multiple pregnancy and multigravid Megalobalstic picture in pregnancy always implies folate deficiency Megaloblastic picture may be concealed by iron deficiency or thalassaemia May recur in subsequent pregnancy

35 Other causes of folate deficiency Impaired absorption OCP Antibiotics (bactrim/septrin) Anticonvulsants (phenytoin/barbiturates) Malabsorption syndromes Increased requirement Hemolysis Hemoglobinopathies Malaria infection Alcohol use

36 Clinical Findings Non specific Anorexia Nausea & vomiting Diarrhoea UTI is common Purpura (occasionally) Sore mouth & tongue is rare Pallor is not marked

37 Other symptoms serious skin disorders Loss of hair impaired circulation Fatigue Mental depression.

38 Laboratory tests Blood Film hypersegmented neutrophils (5 lobes)

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40 Bone Marrow - megaloblastic change

41 High MCV >100fl Ovalo- macrocytosis Anisocytosis Poikilocytosis Low reticulocytes, +/- nucleated red cels Pancytopenia (only if severe)

42 A red blood cell folate level of less than 150 ng/ml is diagnostic Serum vitamin B 12 (deficiency extremely rare in pregnancy) Iron studies: normal.

43 Therapy Prevention: folate supplements in pregnancy Treatment: 1-5mg/day continued several weeks postpartum to replace body stores Prognosis-good with folate replacement 70% of patients with megaloblastic anaemia also need iron replacement.

44 Hemolysis Intrinsic Membrane Enzyme Hemoglobinopathies Hereditary Sperecytosis/ Ovalocytosis G6PD Deficiency PK Deficiency Thalassemia Unstable Hb Sickle Cell

45 Hemolysis Extrinsic Ab -mediated Microangiopathy Infections Coomb s +ve autoimmune, ABO/Rhrelated, Drug Induced, Cold Agglutinins, T-antigen activation HUS TTP DIC Post-heart valve Malaria Severe Sepsis

46 General Features of Hemolysis General exam: Jaundice, Pallor, dark urine Other physical findings Spleen may be enlarged; bossing of skull in severe congenital cases Hemoglobin: From normal to severely reduced MCV, MCH Usually increased

47 Reticulocytes Increased (% & absolute nos.) Bilirubin Increased (mostly unconjugated) LDH Increased (up to 10X normal with intravascular hemolysis) Haptoglobin Reduced to absent

48 Other laboratory abnormalities; increased AST Increased urine/stool urobilinogen Increased Urine Haemoglobin (Hemoglobinuria) No bilirubinuria Increased serum Hb (haemoglobinaemia) Increased Bone Marrow Activity Macrocytes (retics & sometimes nucleated RBCs) Polychromasia erythroid hyperplasia. Once a HA is suspected, specific tests will usually be required for a definitive diagnosis of the specific type of HA.

49 Autoimmune Hemolytic Disease Mechanism of antibody-mediated immune destruction of red cells

50 Coomb s antiglobulin test Used to diagnose AIHA. Coomb's reagent Is a rabbit IgM antibody raised against human IgG or human complement. Direct Coomb's test - mix the patient's red blood cells with the Coomb's reagent Positive Agglutination Presence of antibody on the red blood cell surface. Indirect Coomb's test Mixing the patient's serum with a panel of type O red blood cells. Incubate test serum and panel O red blood cells, Add Coomb's reagent Positive Agglutination Presence of free antibody in the patient's serum.

51 Drug-Induced Hemolysis Decreased G6PD activity in 1/3 of patients in 3 rd trimester Increased risk of hemolysis Over-exposure of G6PD deficiency fetus to sulphonamides commonly prescribed for UTI risk of fetal hemolysis Pregnant mother can be screened for G6PD status

52 G6PD Deficient Hemolytic Anemia Hereditary enzyme defect Decreased ability of RBC to withstand oxidative stress-----episodic hemolytic anemia Oxidized hemoglobin ----denatures -----Heinz bodies (precipitants). Heinz bodies membrane damage removal of these cells by the spleen.

53 Hexose Mono phosphate Pathway

54 Genetic Considerations G6PD gene is X-linked, Males have only one G6PD gene (i.e., they are hemizygous for this gene), Females, having two G6PD genes, can be normal, deficient (homozygous), or intermediate (heterozygous). As a result of the phenomenon of X-chromosome inactivation, heterozygous females are genetic mosaics, with a highly variable ratio of G6PD-normal to G6PDdeficient cells and an equally variable degree of clinical expression;

55 Some heterozygotes can be just as affected as hemizygous males. Gene defect: -mutations in the coding region of the G6PD gene. Almost all of the 140 different mutations known are single (missense )point mutations, entailing single amino acid replacements in the 514 amino acid G6PD protein. G6PD activity decreases with age of RBC so aging cells are more susceptible hemolysis

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57 Clinical Findings G6PD deficiency is an X-linked recessive disorder mainly affects males USA: 10 15% of American black males. Female: carriers are rarely affected only when an unusually high percentage of cells producing the normal enzyme is inactivated

58 Symptoms and Signs Asymptomatic. Hemolysis occurs as a result of oxidative stress on the red blood cells, generated either by infection or exposure to certain drugs. Common drugs initiating hemolysis include dapsone, primaquine, quinidine, quinine, sulfonamides, and nitrofurantoin.

59 Typically, a hemolytic attack starts with malaise, weakness, and abdominal or lumbar pain. After an interval of several hours to 2 3 days, patient develops jaundice often dark urine (hemoglobinuria) Most serious threat is acute renal failure (exceedingly rare in children).

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61 Laboratory Test Peripheral blood film Bite cells/immature re cells/henz bodies Reticulocyte count; increased Haptoglobulin/LDH/AST/bilirubin Low Haptoglobulin and increased LDH/AST/unconj Bil Urinalysis: urobilinogen/bilirubin/hb High urobilinogen & hemoglobin; no bilirubin G6PD assay: qualitative /quantitative test

62 Heinz Bodies: A classic test, is supravital staining with methyl violet (rarely done now) Reveals the presence of Heinz bodies, precipitates of denatured hemoglobin Regarded as a signature of oxidative damage to red cells Once the threat of acute anemia is over, and in the absence of comorbidity, full recovery from acute HA associated with G6PD deficiency is the rule.

63 Peripheral Blood Smear

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65 Treatment Treat Anemia/Infection Avoid offending drug/oxidant

66 Thalassemia/Sickle Cell Anaemia Hemoglobinopathies Genetic mutation in alpha or beta -globin chains Family history present Clinically: Anaemia/chronic hemolysis Symptomatic Trait

67 Hypochromic microcytosis film Risk of enhanced sickling of red cells during hypoventilation eg during General anaesthesia Multi-organ symptoms with SC disease Eg MSS pain and lung, CNS, renal or heart infarct or retinal vein thrombus

68 Effects on Pregnancy Effects on Mother Anaemia Iron/folate deficiency Risk of infection Heart failure Effects on Foetus Stilbirth LBW/IUGR/preterm

69 Laboratory Diagnosis Blood Film-hypochromic, microcytosis, bizzare cell FBE-Anaemia Normal/increased iron status Hb Electrophoresis DNA studies

70 Beta Thalassemia syndromes. -Globin Genes Hb A Hb A 2 Hb F Normal Homozygous 97 99% 1 3% < 1% T. Major Homozygous % 4 10% 90 96% T. Minor Heterozygous 80 95% 4 8% 1 5%

71 Hemoglobin distribution in sickle cell syndromes. Genotype Clinical DX Hb A Hb S Hb A 2 Hb F AA Normal 97 99% 0 % 1 2% < 1% AS Sickle Trait 60% 40% 1 2% < 1% SS SC Anemia 0% 86 98% 1 3% 5 15% S -T SC-Thalassemia 0-20% 70 80% 3 5% 10 20% AS, -Th Sickle trait 70 75% 25 30% 1 2% < 1%

72 Management Symptomatic Transfusion Prenatal Diagnosis (DNA studies) and counselling

73 Aplastic Anaemia Rapid Development of anaemia Bone Marrow failure (idiopathic/infection) Pancytopenia and hypocellular BM Increased risk of infection

74 Pregnancy Complications: FDIU/stillbirths Prematurity maternal death Spontaneusly resolve post-patum May recur in subsequent pregnancies

75 Pancytopenia. No abnormal cells seen. Hypocellular bone marrow

76 Causes "Idiopathic" (probably autoimmune) -MAJORITY Chemotherapy Radiotherapy Toxins: benzene, toluene, insecticides Drugs: chloramphenicol, phenylbutazone, gold salts, sulfonamides, phenytoin, carbamazepine, quinacrine, tolbutamide Posthepatitis Pregnancy Paroxysmal nocturnal hemoglobinuria Congenital (rare) Systemic lupus erythematosus (rare)

77 Clinical Findings Anemia (low RBCs) weakness and fatigue, Neutropenia (low neurtrophils) vulnerability to bacterial infections Thromtocytopenia (low platelets) mucosal and skin bleeding. Pallor, purpura, and petechiae. hepatosplenomegaly & lymphadenopathy No bone tenderness

78 Laboratory Findings Pancytopenia. one or two cell lines may be reduced. always associated with decreased reticulocytes. Anemia may be severe Normal Red blood cell morphology. Neutrophils and platelets are reduced in number, and no immature or abnormal forms are seen.

79 Bone Marrow Biopsy Hypocellular BM Only scant amounts of normal hematopoietic progenitors. No abnormal cells are seen

80 Laboratory Features Pancytopenia No abnormal cells seen Hypocellular BM

81 References 1. Emedecine.medscape.com 2. Current Obstetrics & Gynaecology, Diagnosis & Treatment, International 9 th Edition