Presentation on theme: "Guide- Dr. Neeta Singh CO-guide- Dr. Sujata Rawat Candidate- Dr. Prerna."— Presentation transcript:
Guide- Dr. Neeta Singh CO-guide- Dr. Sujata Rawat Candidate- Dr. Prerna
Headings Disorders of RBC’S – Anemia, Hemoglobinopathies & polycythemia Disorders of WBC’s Disorders of Platlets Coagulation disorders – Inherited/Aquired Hematological malignancies
Anemia ANEMIAS OF DECREASED RBC PRODUCTION ANEMIA DUE TO RBC DESTRUTION DECREASED Hb SYNTHESIS- MICROCYTIC IRON DEFICIENCY THALASSEMIA SIDEROBLASTIC ANEMIA DECREASED DNA SYNTHESIS- Megaloblastic anemia STEM CELL FAILURE – Aplastic anemia ANEMIA OF CHRONIC DISEASE Hemolytic anemia Autoimmune Hemoglobinopathies
Hemolytic anemia Premature destruction of RBCs - inherited defects/acquired intravascular abnormalities. Hemolysis -Intravascular or extravascular General features of hemolytic anemia General examinationPallor, jaundice Other physical findingsSplenomegaly, bossing of skull HemoglobinNormal to severely reduced MCV, MCHUsually increased ReticulocytesIncreased BilirubinIncreased (mostly unconjugated) HaptoglobinReduced to absent LDHIncreased( upto 10 times with intravascular hemolysis)
schistocytes Causes - mechanical trauma, complement fixation, toxic damage to the RBC. Decreased serum haptoglobulin, hemoglobinemia hemoglobinuria, hemosiderinuria Iron loss
Extravascular destruction of RBCs
Causes - bound immunoglobulin, or physical abnormalities restricting RBC deformability that prevent egress from the spleen. Iron overload leading to secondaryhemochromatosis-damage to liver& heart
Clinical features Due to anemia Weakness, exhaustion & lassitude, indigestion, loss of appetite Palpitations, giddiness, dyspnoea Pallor, hyperdynamic circulation, flow murmur Due to hemolysis Icterus, splenomegaly in extravascular hemolysis, gall stone disease Lab investigations in hemolytic anemias Complete hemogram with reticulocyte count PBS – anemia with reticulocytosis & fragmented RBC on PBS Decreased serum haptoglobulin. LFT/KFT DCT USG abdomen- Hepatosplenomegaly HPLC, Osmotic fragility test
RBC membrane structure
Membrane disorders-Hereditary spherocytosis MC -northern European ancestry AD, chr 8p Defect- abnormality of ankyrin. Decreased surface area/vol- Spherocytes - less flexible – extravascular hemolysis-splenomegaly. Only condition with increased MCHC. Increased osmotic fragility (Pink test) TT- No tt aimed at cause. Splenectomy – Obligatory. In pregnancy (rare)- fetal loss in 1 st trimester, aplastic or hemolytic crisis, increased folic acid requirement due to chronic hemolysis Splenectomy – 2 nd trimester Affected Fetus – neonatal jaundice, need for exchange transfusion PND- by CVS, amniocentesis Normocytes, Spherocytes.
ENZYME DISORDERS- G-6-PD deficiency MC enzyme deficiency. X linked recessive Mediterranean, West African, Mid-East, and Southeast Asian populations Interaction between extracorpuscular & intracorpucular cause. Heterozygotes - resistant to P falciparum. Oxidative stress- Increased methemoglobin, aggregates of denatured hemoglobn to form heinz bodies, membrane injury Screening – NADPH mediated dye decoloration Diagnosis – spectophotometric assay of NADPH production, G6PD enzyme assays
Contd……. In pregnancy: Spontaneous abortion, still birth & low birth wt babies with neonatal jaundice Affected fetus – non immune hydrops if mother ingests oxidant drugs crossing the placenta PND- CVS or FBS Avoid agents causing hemolysis Acute hemolytic episode – adequate hydration, maintain urine output, BT if needed spherocytes, schistocytes, bite cells & blister*
Autosomal recessive Reduced ATP formation causes RBC membrane rigidity. PBS- polychromasia, anisocytosis, poikilocytosis with burr cells & acanthocytes Symptoms -usually mild (right shift of the 02-dissociation curve). Homozygote -severe anemia & usually discovered in childhood. Splenomegaly, cholelithiasis and jaundice. In pregnancy – well tolerated, supportive management during crisis & BT if needed Splenectomy – 2 nd trimester Fetus– nonimmune hydrops. FBS for diagnosis & IUT if needed Pyruvate kinase deficiency
MECHANICAL TRAUMA RBCs striking against abnormal surfaces (aortic stenosis, atherosclerosis) or artificial surfaces (prosthetic heart valves; arterial grafts). Microangiopathic hemolytic anemia - RBCs torn apart on fibrin strands strung across small vessels or on damaged endothelial surfaces of small vessels. Accompanies DIC, malignant hypertension, HUS, TTP, pre-eclampsia, and some vascular neoplasms.
HEMOGLOBINOPATHIES Abnormalities due to alteration in structure, function or production of hemoglobin inherited disorders- autosomal dominant (unstable hemoglobins) and autosomal recessive (Hgb S). The most common are thalassemia and sickle cell disease/trait. Minor disorders Sickle cell trait- Hb AS Hb SE disease Hb SD disease Hb S Memphis Major disorders Sickle cell anemia – Hb SS Hb SC disease Hb S ß thal
Sickle cell Disease Qualitative disorder Point mutation in the ß-chain at codon 6 encoding of a valine instead of normal glutamin. Hb S- poorly soluble in low oxygen tension, polymerizes into fibrilary structures/ tactoids-- causing them to become rigid and sickled. M.C inherited hematological disease worldwide Most prevalent in African descent(1 in 625). ACOG technical bullein, no. 185, Oct 1993 The term sickle-cell disease is preferred because it is more comprehensive than sickle-cell anaemia.
Diag -chances (for each pregnancy)of two carrier parents having a child with a sickle cell or thalassaemia disorder. Autosomal recessive Homozygous/Heterozygous(coinheritance with other abnormal hemoglobin ; mostcommonly HbSC or b thalassemia)
If the mother is anemic & the father is healthy carrier 50% of the off springs are carriers and 50% is anaemic
PATHOPHYSIOLOGY Hemolysis Vaso-occlusion-because of- a)sickled cells are less deformable& more fragile & also have increased tendency for cellular dehydration b) Increased adhesion of red cells to vascular endothelium(increased expression of adhesion molecules, upregulation of thrombotic pathways, proinflammatory state) Life span of sickle cells – 17 d Initially, oxygenation restores normal shape. With repeated cycles of agglutination & polymerisation, sickling becomes irreversible
Diagnosis HIGH PRESSURE LIQUID CHROMATOGRAPHY Isoelectric focussing Cellulose acetate electrophoresis at alkaline pH Capillary electrophoresis Sickle cell solubility test- Widely used screening method. Relies on the relative insolubility of Hgb S in concentrated phosphate buffers compared to Hgb A and other Hgb variants. Hgb S precipitates causing a cloudy solution.
Sickle cell trait Hgb SA % of the hemoglobin is Hgb S; remainder being Hgb A, Hgb F & Hgb A2. No anemia and normal RBC morphology is the rule. Two rare complications-hematuria and splenic infarction. No risk from anesthesia, surgery, pregnancy, or strenuous physical activity. Normal growth & development, normal life spans Increased incidence of pre-eclampsia in pregnancy
Preconceptional care General advice & care - At least annual review at specialist clinic - BP measurement, KFT testing, ophthalmological checkup, screening for red cell antibodies & iron overload*, cardilogy review for pulmonary hypertension( echo not done in last year) o Specific issues in women trying to conceive- counselling about Risk of worsening anemia, increased infections(especially UTI), pain, IUGR, PTL, Pre-eclampsia, caesarean section & perinatal mortality. Role of dehydration(Early detection & treatment of nausea &vomiting), cold, hypoxia, overexertion, &stress in frequency of sickle cell crisis
ANTENATAL SCREENING Pregnancy Offer screening Blood sent to laboratory for haemoglobinopathy Screen Positive results Information & counseling-Offer partner screening Partner screening Blood sent to laboratory for haemoglobinopathy Screen Positive results: At risk couple Information & counseling-Offer prenatal diagnosis Affected fetus- Information &counseling Parents Make- Informed Choice Termination of Pregnancy Prenatal diagnosis Fetal blood Sampling/ Chorionic Villus sampling Negative Result Information: No further action Unaffected Fetus Information- No further action Negative Result Information: No further action Continue with Pregnancy
Sickle cell disease contd…. Medications-Daily penicillin prophylaxis (250 mg BD) Folic acid 5mg once daily throughout pregnancy Hydroxycarbamide should be stopped 3 months prior to conception( termination is not indicated based on exposure to hydroxycarbamide alone). ACE inhibitors & Angiotensin 2 receptor blocker, iron chelating agents should be stopped NSAID’s are not recommended 28 weeks ; should only be taken after medical advice in 2 nd trimester. Vaccinations ( preconceptional)*-H.influenza type b, conjugated meningococcal C vaccine, Hepatitis B, Influenza & swine flu vaccine annually, pneumococcal vaccine every 5 years. Management of sickle cell Disease in pregnancy. RCOG2011
Sickle cell disease contd…. Indications of urgent transfusion therapy- 1) Acute anemia - top up transfusion, Hb <6 g/dl or a fall of over 2g/ dl or symptomatic patients. 2)Acute chest syndrome& acute stroke – exchange transfusion Role of prophylactic transfusion in pregnancy- Insufficient evidence to draw the conclusion about role of prophylactic blood transfusions in pregnancy. Mahomed K et al. prophylactic versus selective blood transfusion for sickle cell anemia The cochrane library, issue 2. Indicated for women who are on a long term transfusion regime prior to pregnancy.*
Antenatal care Multidisciplinary team Pregnancy – exacerbations of disease manifestations increased metabolic demands, hypercoagulable state, increased vascular stasis – Vaso-occlusive crisis – common in later half of pregnancy Pyelonephritis – altered immune system added to renal changes of pregnancy Symptomatic cholelithiasis – chronic hemolysis, progesterone induced changes in GIT Susceptible to infections, pre-eclampsia,thromboembolism IUGR, preterm labour, abruption, SCREENING – selective (low preevalance area) versus universal(high prevalance area) mainly to diagnose minor forms. If positive, screen partner, genetic counselling, PND
Antenatal management Early booking ANC Visits monthly upto 24weeks, 2weekly until 36weeks& weekly thereafter. Low dose aspirin (75mg daily )from early pregnancy(12weeks) till 28weeks. Routine thromboprophylaxis only if they have additional risk factors, but should receive LMW heparin during antenatal hospital admission. RCOG Reducing the risk of thrombosis in pregnancy & puerperium. Green top guideline 37. Role of iron suplementation: Iron supplementation is withheld unless there is e/o iron deficiency. Akien’ova YA et al. Ferritin & serum iron levels in adult patients with sickle cell anemia in Ibadum, Nigeria. Afr J Med Sci1997;26.
Contd………. Routine iron supplementation entails a negligible theoretical risk of iron overload for a substantial benefit. Streetly A et al, BMJ 2000; 320. BP & Urinalysis at each visit. Serial USG for GP & AFI from 24 weeks; every 4 weekly& more frequently if there is evidence of poor growth. Monthly assessment of hct, reti count, urine c/s Fetal monitoring – DFMC, weekly NST & BPP Maintain oral hydration, diagnose & treat infections early Mode of delivery- In the absence of obstetric indications allow spontaneous labour at term Role of cytotoxic agents to HbF & HbA – 5-azacytidine, hydroxyurea – investigational in pregnancy. `
Management of acute painful episodes during pregnancy Most frequent complications, incidence- 27%-50%. Mild pain –rest, fluids & simple analgesia(paracetamol& week opoids) Severe pain- low threshold for admitting to hospital. Assess for other complications precipitating factors(Dehydration) Ix-spo2, urinalysis, full blood count, reticulocyte count, KFT, Urine c/s, blood c/s, chest x-ray. Tt- strong opoids- morphine/ diamorphine(oral/parenteral) are the first line agents. Give adjuvant non-opoid analgesia: PCM, NSAIDS(12-28weeks) Monitor for pain score, sedation score, & oxygen saturation using a modified obstetric early warning chart(MEOWS), RR every minutes until pain is controlled & signs are stable, then monitor every 2 hour or hourly if receiving parenteral opiates. Give rescue dose of analgesia if required. Rees DC et al. Guidelines for the management of acute painful crisis in sickle cell disease. BJH. 2003;120.
Contd… If RR<10/min, omit maintenance analgesia; consider naloxone Oral/ iv fluids – 60 mg/kg/24 hours.(precaution – PET) Maintain I/o chart Antibiotics & Thromboprophylaxis should be used. Consider reducing analgesia after 2-3days & replacing injections with equivalent dose of oral analgesia. Discharge when -pain is controlled/ improving without analgesia or on acceptable doses of oral analgesia. Rees DC et al. Guidelines for the management of acute painful crisis in sickle cell disease. Br J Hematol 2003;120.
Intrapartum management Timing of delivery weeks. Mode of delivery- vaginal. Adequate hydration Pulse oxymetry should be used throughout labour Supplemental oxygen therapy used if necessary to maintain spo2 >94%. Antibiotic therapy should be used if there is evidence of, or high clinical suspicion of infection. Continuous fetal monitoring Epidural analgesia Regional anaesthesia preferred for caesarean section. Hourly vital signs- low threshold to start broad spectrum antibiotics Management of sickle cell Disease in pregnancy. RCOG2011
Post partum management Risk of thrombo-embolism, painful crisis Early ambulation, hydration,pain releif (NSAIDS/pcm/ opoids) Prophylactic sucutaneous LMW heparin for 7 days after vaginal delivery & 6 weeks following a caesarean section. Aggressive treatment of suspected infection Cord blood – HPLC Encourage breast feeding Antithrombotic stocking Baby affected- prophylactic penicillin from 3 months of age- ↓ incidence of pneumonia. Contraception- progesterones are effective & safe contraceptive. First line- PIC, MIRENA, Implanon, pop, barrier method. Second line- COC, Cu- IUD, Vaginal ring, Combined patch.
THALASSEMIAS Imbalance of globin chains available for hemoglobin dimer construction. ß thalassemia - defective synthesis of the ß chain. A thalassemia, defective synthesis of the a chain (quantitative). Globin chain (a, b, d, e, g & z) structural genes are located on chromosome 16 (a;z) and chromosome 11 (b;d ; e;g).
Geographic distribution ß -thalassemia is common in the Mediterranean region, Africa, Asia, the South Pacific, and India. a -thalassemia more common in Southeast Asia. Prevalance- 16% in southern European, 10% in Thiland, 3-8% in Indian, Pakistani & Bangladeshi population Leung TN et al. Thalassemia screening in pregnancy.Curr Opin Obstet Gynecol 2005; 17.
ß-Thalassemia point mutations or a partial deletions of chromosome 11 cause defective synthesis of the ß chain.( >100 mutations) Normally- a and b globin chains are roughly equal amounts. When ß-globin chains are in short supply or absent, the excess a- chains combine with other available ß-family globin chains ( d or g) to form increased amounts of Hgb A2 (a2d2) & HgbF (a2g2). Hgb Barts( g4) or tetramers of excess gamma chains may form.
The clinical severity depends on the degree to which production of the ß- chain is inadequate. ß-thalassemia major -no ß chains (ßo) or very little is made (ß+). ß-thalassemia minor - ß+ chains are made in mildly reduced amounts. ß+thalassemia intermedia ß+ chains are made in amounts intermediate to the major and minor forms. Signifcance of ß-gene Mutation type 1 ß+ - about 10% of normal ß chain production type 2 ß+ -about 50% of normal ß chain production type 3 ß+ - >50% of normal ß chain production
ß-Thalassemia major No ß chains (homozygous for ßo, Cooley's anemia), or very little ß chain (homozygous for ß+). Hgb electrophoresis- ↑ HbF, ↑ HbA2, variable amounts of Hb A. PBS - severe anisocytosis& poikilocytosis, targets, elliptocytes, teardrops Asymptomatic till 6 months of life** C/F- severe, transfusion dependent anemia. Nearly all have hepatosplenomegaly. Expansion of the marrow by erythroid hyperplasia - enlargement of bones. Iron overload, secondary to transfusion dependency, results in damage to the heart, liver and endocrine organs. Short life span, most dying before adulthood.
ß-Thalassemia minor ß-thalassemia trait/ minor- Heterozygous- mildly reduced production of ß+ chains & thus, a mild excess of a globin chains which denature, causing damage to young red cells in the marrow (ineffective erythropoiesis) or decreased survival in the peripheral blood. ß-thal intermedia mb homozygous for type 2 ß+ and type 3 ß+. Mild anemia High Hemoglobin A2 levels are classic. Hb F - mildly increased. Folic acid 1mg/d to be supplemented PBS- microcytic & hypochromic; often with associated erythrocytosis. Basophilic stippling and reticulocytosis may help to distinguish the b- thal minor & fe def anemia(more common in thalassemia ).
a -Thalassemia Classical a-thal- deletion from chromosome 16 of a-genes. Less common is point mutations. Exess ß-chains form pairs and combine to form HbH (ß4). Unpaired ß chains precipitate, damages RBC membrane. Severity vary with the number of alpha-chain genes deleted
a -Thalassemia One alpha gene deleted- silent carrier state. Two alpha genes deleted-homo/heterozygous a -thalassemia trait. a-thalassemia trait - microcytosis, hypochromia, & mild anemia. Normal HbA2 3 genes deleted:( - - /-a) hemoglobin H is produced (four ß chains) - unstable & precipitates in vivo causing hemolysis. Crystal violet/new methylene blue supravital stains- Heinz bodies (precipitated Hgb H). All 4 genes deleted- Bart's hemoglobin- tetramer of g chains - hydrops fetalis- death in utero - encountered in people of Asian and African ancestry.
Thalassemia screening Incidence- very high, with over 30 million people carrying the defective gene. Carrier frequency varies from 3 to 17% in different populations Over 9000 thalassemic children born every year & treatment is very expensive Carrier screening program offers genetic counselling, PND and selective termination of affected fetuses. Various options available are: Screening of school going children; Screening of high risk communities; Premarital screening; Extended family screening - screening of relatives if there is a thalassemic child in a faimly; and Routine antenatal screening in early pregnancy ideally between weeks(Most faesible) Menon P.S.N et al, dept of paeds, AIIMS
Methods of Antenatal screening RBC indices:MCV (<77 fl) and MCH (<27 pg) with sensitivity98% and specifity92%. NESTROFT: Positive test is due to the reduced osmotic fragility of red cells. sensitivity – 91%, specificity-95%, ppv-55% & npv-99%. Raised Hb A2 level >3.5%: Gold standard Methods- Microcolumn chromatography, HPLC and capillary isoelectrofocusing. 16% of ANC were positive by NESTROFT & RBC indices. However, only 4.5% were confirmed by HbA2 Unpublished data, ICMR project, dept of paeds, AIIMS
contd When MCH/MCV is low, check both hb pattern & iron status. HPLC- HbH inclusion bodies – diagnostic of alpha thalassemia trait.Beta thal trait – HbA2 &HbF both are elevated. False negative- carrier of both alpha & beta thalassemia, associated iron deficiency. Therefore a normal Hb pattern in presence of iron deficiency can not exclude a co-existing thalassemia trait. A repeat HPLC after correction of iron deficiency should be done.
Non-invasive prenatal diagnosis Unlike beta- thalassemia, alpha thalassemic fetuses present from early gestation with anemic signs ; detectable on USG: safe alternative in prenatal diagnosis. USG surveillance for couples with alpha thalassemia – cardiomegaly, thickened placenta, increased MCA-PSV, & Hydropic changes. CTR is the best marker in first trimester.Between weeks –using CTR 50% or greater as cut off, Sn 97.5%, Fp 9.1%. Placental thickness ≥ 18mm- Sn- 71%. Fp- 19%. 2 nd trimester- CTR is still the best marker( Sn -100%, Fp- 5.9%. Leung KY et al.Ultrasonographic prediction of homozygous alpha thalassemia using placental thickness, fetal CTR, MCA doppler: alone or in combination? Ultrasound Obstet Gynecol2010;35.
Noninvasive prenatal diagnosis for couples with beta thal USG- Not applicable Analysis of circulating fetal nucleic acid in maternal plasma- most specific absence of paternal mutation in maternal plasma excludes beta thal major & invasive testing can be avoided.presence of paternal mutation in maternal plasm- 50% risk of beta thal major; invasive testing needed.(Disadv- father & mother must carry different mutation) When dealing with other paternally inherited beta-gene defect involving point mutation, allele specific/ single allele extension reaction followed by mass spectrophotometry. Lo YM et al. Noninvasive approaches to prenatal diagnosis of hemoglobinopathies using fetal DNA in maternal plasma.Hemaatol Oncol Clin North Am 2010; 24.
Digital PCR combined with fetal DNA enrichment strategy- Allelic ratio-1:1-carrier, >1- fetus homozygous for mutation, <1- fetus has not inherited any mutation. Lun et al.Noninvasive prenatal diagnosis of prenatal monogenetic disease by digital size selection and relative mutation doses on DNA in maternal plasma. Prac Natl Acad Sci U S A 2008;105. Most recent- application of massively parallel DNA sequencing technologies in cell free fetal DNA in maternal plasma. Lo YM et al. Maternal plasma DNA sequencing reveals the genome-wide genetic & mutational profile of fetus. Sci Transl Med 2010;2. Pre-implantation genetic diagnosis- cleavage stage biopsy is better than polar body / blastocyst biopsy. Petrou et al.Preimplantation genetic diagnosis. Hemoglobin 2009; 33:s7-s13
Maternal health & Obstetric outcome Assessment &management of pre-existing complications Cardiac effects Endocrine problems Alloimmunisation Assessment & treatment of viral infections Hypercoagulable state & thrombosis Effect of hemolysis & depletion of nitric oxide Osteopaenia, osteoporosis & bone deformity Pre-pregnancy assessment & management.
Contd…….. Maternal anaemia and transfusion of red blood cells- target Hb-10gm/dl Prophylaxis for thromboemboism- no specific regime. Acetylsalicylic acid antenatally for women who have undergone splenectomy & postpartum LMW heparin. Thalassaemia trait-Screening for fetal congenital anomalies, especially neural tube defects-in alpha & beta thalassaemia carrier anencephaly was more common(OR 3.99). Tong et al. C-reactive protein & insulin resistance in subjects with thalassaemia major & family history of diabetes. Diabetes Care 2002; 25. Lam YH et al.Risk of neural tube defects in offspring of thalassaemia carriers in Hongcong Chinese. Prenat diag 2006.
Contd…… Gestational glucose intolerance-markedly increased. Mechanism- increased insuline resistance in liver & muscle, low grade hepatic inflammation, increased oxidative stress secondary to hepatic damage from the increased iron owing to low grade hemolysis. Antanatal complications- IUGR(OR 2.4) Oligohydroamnios (OR 2.1) Hydrops fetalis & mirror syndrome- can result as a result of hemoglobin Bart’s disease & non-deletional form of hemoglobin H disease. Origa R et al. Pregnancy and beta thalassaemia: an Italian multicenter experience. Hematologica 2010; 95.
Autoimmune hemolytic anemia Most common form of aquired hemolytic anemia( exept where malaria is endemic) Autoantibody directed against red cells Triad- abrupt onset, jaundice, splenomegaly. Coomb’s test- Positive- clinches diagnosis; Negative- diagnosis unlikely. Two types: a) IgG or "warm" type (optimally active at 37oC) b) IgM or "cold" type (optimally active at 4oC) Treatment- 1 st line- Glucocorticoids- prednisone- 1mg/kg/day Second line- low dose prednisone, azathioprine, cyclosporine. Severe acute AIHA- blood transfusion
Cold AIHA IgM Ab, optimally active at 4oC Causes - Iymphoma, Mycoplasma pneumonia& rarely infectious mononucleosis IgM- C3 complex fixation on the RBC surface at 28-31oC. RBC agglutination and hemolysis in acral cold exposed areas of the body. Intravascular hemolysis Detected by the DCT. PBS-agglutination of RBCs (room temperature). Antibody does NOT cross placenta, fetus is NOT affected
Warm AIHA IgG antibodies against RBC surface Ag (active at 37°C). Causes- Non-Hodgkin's Iymphomas, Hodgkin's disease, autoimmune disorders (rheumatoid arthritis; SLE)& drugs (methyl dopa) PBS - Prominent spherocytosis Positive DCT (direct Coombs' test). Treatment ( warm or cold): 1) treatment of the underlying disease, 2) discontinue offending drugs, & 3) corticosteroids (Prednisone). Antibody may cross placenta & affect fetus
Paroxysmal nocturnal hemoglobinuria Clonal disorder of gene (PIG-A) encoding GPI anchor Proteins requiring GPI anchor to attach to the RBC membrane are deficient - DAF, C8- bp, MIRL. Bone marrow - usually cellular with marked to massive erythroid hyperplasia, with mild to moderate dyserythropoietic features Iron deficiency - chronic loss of iron in urine. Blood instead of urine Most consistent- anemia.( m.b Pancytopenia). Hypercoagulable state- venous thrombosis (Budd chiari syn – MC cause of death) Gold standard- Flow cytometry( CD59-, CD55-) Rx- Allogenic BMT ; eculizumab.
Pregnancy & PNH o Fertility is low, 15 pregnancies reported in 10 patients- 5 SA, 10 reached viability- good outcome o ? Prophylactic washed RBC transfusions o Folic acid supplementation(3 mg/day) o Steroids to ↓ hemolysis in acute episode o BT may be needed o BMT, androgens – No role in pregnancy o Postpartum thrombotic events are common & complete anticoagulation with warfarin is needed
Aplastic anemia o Failure of pluripotential stem cells to produce RBC, WBC, platelet. o pancytopenia + hypocellular bone marrow& absence of underlying malignant/myeloproliferative disease. o Severe aplastic anemia- pancytopenia with two of these- ANC< 500/ dl, Platelet count< 20,000/dl& Anemia with Reticulocytes < 1%, with either bone marrow cellularity 50% with <30% hematopoietic cells. o Pure red cell aplasia- progenitor cell of BFU-E is affected. o Incidence- 2 cases per million(Europe) Choudhary vp et al. Pregnancy associated aplastic anemia –a series of 10cases with review of literature. Hematology Diagnosis & treatment of aquired aplastic anemia. Hematol oncol clin N Am 2009,
Aplastic anemia o Pregnancy- increased placental lactogen, erythropoietin & estrogen. Placental lactogen & erythropoietin stimulates erythropoiesis estrogen supresses bone marrow. Pregnancy exacerbate the bone marrow depression – if so, terminate pregnancy; else supportive treatment o Maternal mortality % o Cause of death- Hemorrhage & infection. o Women who survive pregnancy –associated aplastic anemia, 50-70% achieve spontaneous remission Choudhary vp et al. Pregnancy associated aplastic anemia –a series of 10cases with review of literature. Hematology 2002;7. Pregnancy with aplastic anemia serious condition.
Aplastic anemia & pregnancy Maternal Antenatal complications- Preterm birth- 12.1% IUD- 16.7% Stillbirth- 15.1% Spontaneous miscarriage- 16.7% Intrapartum- Risk of hemorrhage during delivery Postpartum- risk of hemorrhage & infection. Fetal- IUGR, IUD, Fetal thrombocytopenia, rarely gangrene of fetal intestine. Kown et al. Supportive management of pregnancy associated aplastic anemia. Int J Gynecol Obstet 2006.
Treatment Supportive therapy- Most important Repeated blood transfusion to maintain Hb>8 mg/dl Platelet transfusion yo maintain platelet count > 20,000/mcl. WBC transfusion can be considered in case of fulminating infection Antibiotic & barrier nursing. Early stages -First line therapy - erythropoietin &GM-CSF. If it fails - thymocyte gamma globulin & cyclosporine G-CSF & GM-CSF can be used in for neutropenia/infection BMT- Most effective. 5 year survival rate 70-80% BMT is contraindicated in pregnancy Androgen is relatively contraindicated. Deka D et al. Pregnancy associated aplastic anemia: Maternal & fetal outcome. J Obstet Gynecol Res 29, 2003.
ANEMIA OF CHRONIC DISEASES Underlying disease - inflammation, infection, or malignancy usually mild(Hct 30-40%)normochromic/normocytic, Occ mildly hypochromic/microcytic Low serum iron, normal or low transferrin, low transferrin saturation, and high serum ferritin. Bone marrow iron stores are usually increased. Ferritin(acute phase reactant)- elevated in inflammation. Primary mechanism - decreased red blood cell production.Inflammatory and infectious disorders release factors (IL-1, tumor necrosis factor) that suppress erythropoiesis.* Treatment of the underlying disease. Inappropriately low serum erythropoietin levels for the degree of anemia. Human recombinant erythropoietin (EPO) therapy can correct the anemia in such cases.
Thrombocytopenia Platelet count below 1lakh Affects 10% of all pregnancies Platelet count decreases by 10% in normal pregnancies Mostly physiologic Most common causes- Gestational thrombocytopenia(70%), preeclampsia(21%), ITP(3%)& others(6%) Mild thrombocytopenia- PC >65000/mcl: 65% have no associated pathology. Paula L et al.Thrombocytopenia in pregnancy. Hematol Oncol Clin N Am 25 (2011)
ITP Immune Thrombocytopenia Diagnosis of exclusion Incidence per 1000 pregnancies Most common cause of isolated thrombocytopenia in 1 st & early 2 nd trimester. Pathogenesis: Autoantibody platelet destruction Immune mediated decreased platelet production Nugent D. Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction &/or decreased platelet production. Br J Hematol 2009;146.
ITP H/o- easy bruisability, epitaxis, petechiae, menorrhagia before pregnancy, thrombocytopenia in prior pregnancy, PBS- Thrombocytopenia with an increased mean platelet volume & normal red cell morphology. Lab ix- CBC, Reticulocyte count, PBS, Coagulation screen, LFT, & Virology screen including Hepatitis C. Exclude spurious thrombocytopenia Others- Kft, DCT, TFT, autoimmune profile, antiphospholipid antibodies. Bone marrow biopsy-indicated in minority of cases only.*
Gestational thrombocytopenia Commonest cause of thrombocytopenia in healthy pregnant women Features- o Tendency to recur in each pregnancy(20%), o typically in 2 nd trimester, o Platelet count remains > 70,000/L, o Neonatal platelet count remains normal, & o Postpartum platelet count returns to normal within 7 days. PBS- No abn. No associated increased incidence of maternal bleeding No indication for therapy Sankaran & Robinson. ITP & Pregnancy. Obstetric medicine 2011.
Management of ITP in pregnancy Preconceptional counselling Antenatal management- Team work. Treatment to be initiated when platelet count falls < /mcl. Asymptomatic & PC>50000/mcl- No treatment required. < 50000/mcl & symptomatic- treatment to be considered. >50000 but< Consider treatment if – neuaxial anaesthesia/ analgesia or elective LSCS due to obstetric indication is to be considered. Neuraxial anaesthesia/ analgesia-contraindicated if platelet count <50000/mcl. Caesarian delivery is safe if platelet count is > 50000/mcl. Provan D et al. International consensus report on the investigation & management of primary ITP. Blood 2010; 115.
Management of ITP in pregnancy First line therapy- Corticosteroids- oral prednisolone 1mg/kg once daily ; initial response 3-7 days & maximal response in 2-3 weeks. MOA- To block antibody production& to reduce phagocytosis of antibody-coated platelets by RE system in the spleen. Fetal s/e- risk of cleft palate 3 per Maternals/e- Hyperglycemia, hypertension, immunosuppression, osteoporosis on long term use Lactating mother – low dose <30mg/day appears safe.* Baseline immunoglobulin profile to exclude a common variable immunodeficiency prior to a trial of steroid is recommended. Provan D et al. International consensus report on the investigation & management of primary ITP. Blood 2010; 115.
Contd…… Immunoglobulin- 2 g/kg iv divided over 2-5 days. Adv- rapid response, Disadv- transient response(1-4 weeks), expansive, risk of pathogen transmission, infusion reaction, aseptic meningitis, hedache. Second line options- combination therapy with high dose methylprednisolone combined with Ivig in refractory cases. Azathioprine 2mg/kg, in refractory cases(disadv- delayed response- 6-8 weeks). Splenectomy – rarely needed. Platelet transfusion is NOT indicated exept- severe hemorrhage, immediately before surgery/ delivery.* Provan D et al. International consensus report on the investigation & management of primary ITP. Blood 2010; 115.
ITP in pregnancy Mode of delivery – guided by obstetric need. Vaginal delivery preferred. kelton et al.Idiopathic thrombocytopenic purpura complicating pregnancy. Blood Rev 2002; 16. Instrumental delivery should be avoided Management of unexpected delivery, emergency intervention or hemorrhage - combination of high dose intravenous methylprednisolone 0.5-1g daily for 2-3 days & 2g/kg total dose iv ig over 2-3 days with/ without platelet support& oral/iv tranexamic acid.
Contd….. Postpartum- Maternal- NSAIDs & IM injections to be avoided. PC>50000& absence of bleeding elsewhere - thromboprophylaxis to be considered. Neonatal- cord blood platelet count ( if low, confirm it by venous sample) If PC <50000 at delivery – oral vit-k 2mg at birth, 2mg at one week, 2mg at 1 month(instead of im vit k). Transcranial USG, Alternate day platelet count. If hemorrhage is evident/neonatal platelet count is <20000, treatment is ivig 1g/kg infusion; repeated if necessary. Platelet support may be needed. Sankaran & Robinson. ITP & Pregnancy. Obstetric medicine 2011.
Prenatal diagnosis for carriers of haemophilia Prenatal testingTimings(weeks POG) Risk of miscarriage(%) Comments Non-invasive determinations of fetal gender ffDNA≥6-8Weeks-----Currently only available in certain centres USG11-14Weeks-----First- trimester USG fetal sexing available at certain centres Prenatal diagnosis of haemophilia ffDNA≥6-8Weeks-----Under research CVS Known causative mutation Amniocentesis≥15weeks1Known causative mutation Cordocentesis18-2o1-2Causative mutation unknown
Hemophilia contd…. Antenatal- PND- fetus affected; consider for MTP. assess factor level at booking, 28weeks& at 34weeks POG. Consider for planned delivery. Intrapartum- prophylactic cover is recommended for women with Vwf, FVIII, FIX levels <50iu/dl at term, & they should be maintained above this level for at least 3 days after vaginal delivery / 5 days after caesarean section. Delivery by least traumatic method; Meticulous hemostasis No invasive fetal monitoring Postpartum- risk of PPH Neonatal- Cord blood sample to assess coagulation status & clotting factor level.
Pregnancy can be a time of significantly increased morbidity & mortality in women with hematologic disease; however, with careful planning & preparation, most women can be cared for safely, resulting in “Healthy Mother& Healthy Child”