Anaemia

Anaemia :definition • Hb < 14 g/dl in adult ♂ or .♀ g/dl in adult 12 < HCV < 42% in adult ♂ or .♀ in adult % 37 < a limitation of this definition is that alternation of Hb • → & HCV may result from changes in plasma volume plasma volume ( e.g. pregnancy )→ spurious ↑ .anaemia . plasma volume → spuriously high Hb & HCV ↓ after major bleeding , anaemia may be not apparent • .for several days until plasma volume returns to normal

C/P anaemia may be asymptomatic ;particularly when • slowly developing when haemodynamic compensation → & rise of erythrocyte 2,3 DPG occur. This 2,3 DPG Shift O2 dissociation curve to Rt.→ O2 to be liberated .readily to tissues rapidly developing anaemia→ more symptoms (esp.in • ( old people Symptoms fatigue headache palpitation & dyspnea angina .intermittent claudication Signs A- general : pallor, tachycardia,high pulse volume .systolic flow murmur,HF,edema 1

.rarely;papilloedema& retinal He ( B- specific ( of different types of anaemia . koilonychias ( spoon shaped nail ) → in iron ↓ anemia .jaundice → in haemolytic anaemia .bone deformities→ thalassaemia major .leg ulcers → in sickle cell disease -

:Classification → .According to appearance of red cells Red cell appearance microcytic-1 (hypochromic)

MCV

MCH

diagnosis

Low microcytic) (

Low hypochromic) (

iron↓ • anaemia

normocytic-2 (normochromic)

normal

normal

.macrocytic-3

high

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-

thalassaemia sideroblastic anaemia an.of • .chronic dis acute blood.loss haemolytic.anaemia aplastic.anaemia .An.of ch.dis ↓B12/folate.liver disalcoholismmyxaedemareticulocytosis.myelodysplasia

:dimorphic anaemia • When there are both small & large red cells→ denotes mixed deficiency ( e.g. Fe & folate ) or following .treatment with appropriate haematenic

2

:Investigations blood count & film:→ red cell indeces -1 ( MCV = HCV/ red cell count ( n= 80 – 96 fl • (MCH = Hb / red cell count × 10 ( n=27-33 pg • ( %MCHC = Hb / HCV × 100 ( n= 32-35 g • → : automated counters • numerical index of the distribution of red cell (volumes called the red cell distribution width(RDW this is measured at 2 points on the red cell → distribution curve RDW-CV→ is the ratio of the width of the -1 distribution curve ( at one standard deviation ) divided ( % by MCV ( n= 12-14 RDW-SD→ is the width of the distribution curve (at-2 ( 20% frequency level ) ( n= 37 – 47 fl : BM : aspiration & biopsy → in order to -2 .determine BM cellularity the type of erythropoiesis → e.g. normoblastic . or megaloblastic .determine the proportion of various cell lines .confirm the diagnosis .determine the size of Fe stores . look for BM infiltration -

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3

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Iron deficiency anaemia ( causes: ( ankylostoma is the commonest cause in ARE • .poor intake : a contributing factor only -1 .absorption : in gastrectomy & celiac dis ↓-2 :NB: factors affecting Fe absorption .haem-Fe is absorbed better than nonhaem-Fe .ferrous-Fe is absorbed better than ferric-Fe gastric acidity → helps to keep Fe in the ferrous state ( & soluble in the upper gut .(↓acidity →↓ absorption formation of insoluble complexes with phytate or .phosphate→↓ Fe absorption .low Fe stores →↑ Fe absorption erythropoeitic activity ( e.g bleeding,haemolysis,high ↑ .altitude ) →↑ absorption ( Fe over load ( except hereditary haemochromatosis .Fe absorption ↓→ Fe absorption Fe absorption

↑

Fe absorption↓

haem-Fe -

nonhaem-Fe -

ferrous state gastric acidity -

ferric state no gastric acidity -

soluble complexes -

insoluble coplexes -

low Fe stores erythropoietic activity↑ -

high Fe stores Fe over load(except .heridetary haemochromatosis

.demands : growth & child bearing ↑-3 blood loss : GIT, parasitic infestation& genitourinary -4 .disorders

4

C/P the usual clinical manifestations of anaemia in -1 (↓ general + the following ( d.t. Fe brittle & spoon shaped nails .atrophy of the papillae of the tongue .angular stomatitis .brittle hair syndrome of dysphagia & glossitis( Plummer- .( Vinson=Peterson-Brownkelly in severe cases : parotid enlargement, splenomegaly& .failure to grow .… History taking : should include -2 .dietary intake .aspirin ingetion .rectal bleeding ( ♀ details of menses ( in Rectal exam & proctoscopy : in suspected cases -3 .should be done

Investigations : blood count & film -1 red cells are microcytic ( MCV < 80fl ) & ( hypochromic ( MCH < 27 pg . anisocytosis : variation in size .poikilocytosis : variation in shape target cells & hyperpigmented polymorphs may .appear ↓..…: S. Fe -2 ↑ → ( Total Fe binding capacity ( TIBC transferring saturation ( S.Fe / TIBC ) → < 19% → ( S. ferretin ( = reflects the amount of stored Fe -3 (♀It's < normal values (n=30-300ug/l ♂ &15-200ug/l 5

BM : →↓ of Fe granules.( not needed for diagnosis -4 ( except in complicated cases .↓ investigations for the cause of Fe -5 Treatment .treatment of the underlying cause -1 ferrous sulphate 200 mg tid PO -2 is the best preparation , provides 120 mg ferrous Fe/d if the Pt.develops S.Es ( e.g. nausea,diarrhea or constipation ) → the dose may be ↓ or another preparation with less Fe content is given ( eg ferrous gluconate 200 mg .( tid PO ; provides only 70 mg ferrous Fe /d : parenteral Fe -3 .Fe dextran 50 – 250 mg/d by deep IM inj .for Pt totally intolerant to oral therapy → NB: •• enough therapy should be given & restore Hb .replase body's Fe stores → therapy is monitored by •• .follow-up of reticulocytic count ( Hb level ( w' expected to ↑ 1g/w -

Sideroblastic anaemia 6

there is failure to form protoporphyrine ( w' normally • ( combines with Fe in the erythroblasts to form haem so , Fe taken up by erythroblasts is deposited in the • mitochondria ( around the nucleus ) to form ring .siderblasts

:Causes conginetal :X-linked ( transmitted by ♀s ) , it's one -1 .of myelodysplastic syndromes → acquired : may be -2 a- 1ry : idiopathic : b- 2ry . drugs : INH, phenacetin .alcohol .lead .myeloproliferative dis .leukaemia ( carcinomas & CT diseases ( e.g SLE →:Blood film Dimorphic picture ( with normal & microcytic cells d.t. ( defective Hb synthesis

:Treatment .withdrawal of the causative agents .folic acid .pyridoxine ( B6 ) → may improve some cases -

.Anaemia of chronic dis 7

:Causes chronic inflammatory diseases : rheumatoid arthritis, -1 .SLE, Crohn's dis .hepatic dis -2 .CRF-3 .malignant disorders -4

:Pathogenesis → Inflammatory cytokines release of Fe from BM to the developing ↓.erythroblasts . inadequate erythropoietin response to the anaemia ( red cell survival ( haemolysis ↓ -

Investigations ↓→ both S.Fe & TIBC • .Fe stores → normal •

: Treatment .Is that of the cause

:D.D of microcytic anaemia 8

Fe ↓ anaemia

An. Of ch.dis

Thalassaemia (Trait (α,β

Sideroblastic anaemia

MCV •

reduced

/Low normal normal

Very low for Degree of .Anaemia

in →↓ Inherited type in →↑ .Acquired type

S. Fe •

↓

↓

normal

↑

S.TIBC •

↑

↓

normal

normal

S.ferritin• (stores )

↓

↑/Normal

normal

↑

Fe in BM•

absent

present

present

present

Fe in• -Erythrobl ast

absent

/Absent reduced

present

.Ring forms

Macrocytic anaemia 9

:Causes .megaloblastic anaemia-1 → normoblastic anaemia : in -2 .liver dis .alcohol .myxaedema .reticulocytosis .aplastic anaemia .pregnancy -

Megaloblastic anaemia characterized by presense of erythroblasts ( in BM ) • with delayed nuclear maturation d.t. defective DNA ( synthesis ( → big cells = megaloblasts

:Causes ↓ Vit.B12 -1 ↓ folic acid -2 :other defects in DNA synthesis -3 .congenital : orotic aciduria acquired : hydroxyurea, azathioprine, zidovudine ((=chemotherapy .myelodysplasia -4

Vit.B12 ↓ anaemia 10

:Causes .low dietary intake : strict vegetarians -1 ,absorption : pernicious anaemia,gastrectomy ↓ -2 ( .malabsorption syndromes (terminal ileal dis & ,miscellaneous : diphylobothrium latum,nitrous oxid -3 Congenital ↓ of intrinsic factor or transcobalamin ΙΙ

:Pathogenesis .Vit.B12 is found in : meat,fish,egg&milk • it takes up to 5y ( after absorption failure ) to develop • .↓ Vit.B12 : absorption • in the small gut; Vit.B12 binds e' the intrinsic factor in gastric juice ) → carry it to specific receptors on ) .the mucosa of the ileum → Vit.B12 is liberated there to bind e' their receptors →.Absorption of Vit.B12 then transported by ( transcobalamin ΙΙ ) to BM where it acts as Co-enzyme for transformation of methyltetrahydrofolate to tetrahydrofolate ( that is ( essential for the formation of DNA in the absence of Vit.B12 → DNA production is thus .impaired

(.Pernicious anaemia: ( P.A an autoimmune disease characterized by atrophy of the • gastric mucosa → failure of the intrinsic factor production .failure of Vit.B12 absorption → there's an association with other autoimmune diseases e.g. • .thyroid dis.,Adisson's dis.&vitiligo 11

C/P of Vit.B12 ↓ anaemia the disease is particularly common in fair haired & blue- • .eyed people :Symptoms .that of anaemia in general -1 neurological changes : occur only with very low level of -2 → S.Vit.B12 ( peripheral neuropathy ( P.N progressive involvement of the posterior & lateral columns : of the spinal cord → the Pt. present with .symmetrical parathesia of fingers & toes • .early loss of vibration sense& proprioception • .progressive weakness & ataxia • .paraplegia may result • .mental changes : → irritability, psychosis & dementia may occur • : Signs general signs of anaemia , skin occasionally has a lemon-yellow -1 .tint d.t. hyperbilirubinaemia .low grade fever may occur -2 .glossitis & angular stomatitis -3 . hepatosplenomegaly -4 .purpura & bleeding tendency d.t. thrombocytopenia -5 neurological exam. → signs of peripheral neuropathy ( PN ) & -6 .( less often subacute combined degeneration of the cord ( SCD : Investigations CBC & film : anaemia with macrocytosis ( MCV < 96 fl ), -1 hypersegmented polymorphs.& in sever cases → neutropenia & .thrombocytopenia ( S.Vit.B12 →↓ ( usually < 50 ng /L -2 ( S.bilirubin → usually ↑ ( d.t. haemolysis -3 → S.autoantibodies -4 % to parietal cells → in 90 % to intrinsic factor → in 50 12

: Schilling test : consists of 2 parts -5 → Part Ι : 2 forms of Vit.B12 are given & radioactive : CO-58B12, 1 ug PO nonradioactive : Vit.B12 1000 ug IM ( to saturate B12 binding →.… ( protein .urine is collected for 24h normally < 10 % of the radioactive dose is excreted, if less, .proceed to part ΙΙ : Part ΙΙ ( repeat part Ι ( after giving intrinsic factor capsules PO : the result .if excretion is normalized → diagnosis is PA if still abnormal → there is terminal ileal disease or bacterial over .growth : GIT investigations -6 .marked gastric atrophy with achlorhydria .endoscopy is necessary to exclude gastric carcinoma .BM : → hypercellular e' megaloblastic changes -7 : Treatment Hydroxylcobalamine 1 mg twice weekly for 3Ws, then every 3 Ms → for the Pts' life .reticulocytosis → occurs after 5 – 7 days • neurological improvement may take 6 – 12 M • .long-standing lesions → irreversible •

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↓ Folate : Causes poor intake ( major cause ) in : old age, starvation, GIT disease -1 ( ( e.g. gastrectomy .absorption : → small bowel disease ↓ -2 utilization : pregnancy, haemolysis, malignant disease & ↑ -3 .dialysis .antifolate drugs : anticonvulsants, methotrexate & trimethoprim -4 : Pathogenesis .folic acid is widely distributed in plants folic acid is the parent of a large group of compounds called the .folates in the upper GIT & during absorption, folates are broken down to → monoglutamates → methyltetrahydrofolate ( essential for DNA ( synthesis unlike Vit.B12, body reservoirs of folates are low, so on ↓ diet, ( folate ↓ rapidely develops ( over about 4 Ms : C/P .folate ↓ may be asymptomatic .symptoms ( if present ) → those of anaemia .neuropathy → rare : Investigations ( CBC & film →↑ MCV ( with / without anaemia -1 .BM examination → megaloblastic erythropoeisis -2 ( red cell folate →↓… S.folate is also ↓ ( but is less accurate -3 GIT investigations : to confirm a suspected cause of ↓ intake / -4 .absorption : Treatment .folic acid : 5 mg /d PO -1 ( prophylactic folate : indicated in pregnancy ( with Fe -2

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folic acid should not be given alone in megaloblastic anaemia -3 until B12↓ excluded, as folate may → neurological changes in .B12↓ cases

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Anaemia d.t. BM failure ( Aplastic anaemia ( .denotes aplasia of BM e' peripheral blood pancytopenia • : Causes congenital : Fanconi anaemia ( autosomal recessive, associated -1 ( e' skeletal, renal & nervous abnormalities : acquired -2 a- idiopathic → usually d.t. ↓ of BM stem cells by cytotoxic .T-cells .b- chemicals → benzene → c- drugs .antineoplastic : mercaptopurine, methotrexate, doxorubicin .anti-inflammatory : phenylbutazone, gold, NSAIDs .antidiabetic : chlorpropamide, tolbutamide .antithyroid : carbimazole, propylthiouracil .antibiotics : chloramphenicol, sulfonamides .tranquilizers : chlorpromazine .d- insecticides .e- ionizing radiation f- infection : viral hepatitis, measles, TB g- pregnancy & thymoma , both → alternation of immunological .& hormonal states →↓ BM ( h- paroxysmal nocturnal haemoglobinuria ( PNH : C/P acute / insidious onset of symptoms & signs resulting from -1 .anaemia, neutropenia & thrombocytopenia ( mouth infections → particularly fungal ( common -2 .lymphadenopathy, splenomegaly & hepatomegaly → rare -3 : Investigations : diagnosis is made on the basis of .pancytopenia -1 .virtual absence of reticulocytes -2 .hypocellular or aplastic BM, with large fat spaces -3 16

: bad prognostic features include -4 .peripheral blood neutrophil count < 500/cmm .platelet count < 20,000/cmm " " " " .reticulocytic count < 10,000/cmm .sever hypocellularity of BM : D.D : from other causes of pancytopenia ( megaloblastic anaemia ( in sever cases -1 BM infiltiration : lymphoma, acute leukaemia, myeloma, -2 .myelofibrosis, 2ry carcinoma .myelodysplasia -3 .hypersplenism -4 .SLE -5 .disseminated TB -6 .sepsis -7 .drugs -8 : Treatment ( removal of the cause ( if possible -1 supportive care : with blood transfusion, platelets concentrates -2 .& ttt.of infection : BM transplantation -3 .ttt.of choice for Pts < 20 y who have HLA identical sibling donor ( this also can be used in Pts < 45 y ) Pts < 45 y are not suitable for BM transplantation because of .high risk of graft-versus-host disease immunosuppressive therapy : for Pts < 45 y -4 : by combination of .antithymocyte globulin ( ATG ) 40 mg /kg/d → for 4 days .cyclosporine : 6 mg/kg PO twice daily .prednisolone : 1 – 2 mg /kg/d initially, followed by a rapid taper for Pts with marked neutropenia : → granulocyte-colony -5 stimulating factor ( G-CSF ) & granulocyte-macrophage colony ( stimulating factor ( GM-CSF

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androgens : ( e.g. oxymetholone ) 2 – 3 mg/kg PO daily → may -6 .be helpful in few cases .steroids : helpful in ttt.of congenital pure red cell aplasia -7 :NB • adults with pure red cell aplasia may have thymoma ( w' is hyperplasia & hyperfunction of thymus gland → cytotoxic T-cells →↓ BM → BM aplasia ) → removal of thymoma may → .remission

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Haemolytic anaemias . Def. : short red cell survival • : Causes : A- inherited : red cell membrane defect -1 . hereditary spherocytosis .elliptocytosis " ": Hb abnormalities -2 .thalassaemia .sickle cell disease : metabolic defects -3 .↓ G6PD .↓ pyruvate kinase : B- acquired : immune -1 .autoimmune . alloimmune : nonimmune -2 : membrane defects • paroxysmal nocturnal haemoglobinuria .liver diseases . renal diseases : mechanical • .damaged vessels .valve prosthesis : miscellaneous -3 ( infections ( malaria .drugs .chemicals .hypersplenism .burns -

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: Pathophysiology short red cell survival : → anaemia when the compensatory -1 .power of BM is exceeded expanding the volume of active BM →↑ erythropoisis → release of reticulocytes in the peripheral blood ( w' are immature red cells ( larger than mature RBCs . haemolysis : → may be intravascular / extravascular -2 intravascular haemolysis : destroyed red cells → Hb → removed • . by haptoglobin → liver .remaining Hb → oxidized to met-Hb → ferrihaem + globin → : … ferrihaem .attached to albumin → methaemalbumin .binds to haemopexin → liver extravascular haemolysis : red cells are removed by macrophages • .→ spleen → : red cells haemolysis -3 .S.bilirubin ↑ urine urobilinogen ( urobilinogen results from bilirubin ↑ ( breakdown in the intestine .S.haptoglobin ↓ : Lab.evidence of haemolysis -4 → red cells breakdown ↑ • ( s.bilirubin ( unconjugated ↑ .urine urobilinogen ↑ .plasma haptoglobin ↓ .abnormal cells ( large cells ) in the peripheral blood : red cells production ↑ • .reticulocytosis .erythroid hyperplasia of BM NB: ↑ plasma Hb, low or absent haptoglobin & presence of •• .methaemalbumin → suggest intravascular haemolysis → severity of haemolysis : is determined by -5 .frequency of transfusion 20

( measuring red cells survival time, using Chromium-51 ( C-51 -

( Hereditary spherocytosis ( HS Pathogenesis : red cell memb.is ↓ in structural proteins → red cell memb.more rigid → rapid destruction in spleen & abnormal ↑ +permeability to Na : C/P .jaundice -1 manifestations of anaemia , the course may be interrupted by -2 aplastic ( esp.after infection ) or megaloblastic crises ( d.t. folate ↓ ( by hyperactive BM . splenomegaly -3 ( leg ulcers ( esp.in adults -4 . hypertrophy of bone of the skull & of maxillary sinus -5 ( growth ↓ ( in sever cases -6 ( pigm.gall stones ( d.t. haemolysis -7 : Investigations .CBC & film : anaemia , film → spherocytes & reticulocytosis -1 .other Lab.evidences of haemolysis -2 osmotic fragility : ↑ if placed in hypotonic solution but direct -3 Coomb's test is –ve ( to differenciate from autoimmune haemolytic .( anaemia w' also have spherocytosis : Treatment splenectomy ( but may be postponed after childhood to ↓ risk of ( pneumococcal infection splenectomy is preceded by pneumococcal & H.influenza .( immunization & followed by penicillin prophylaxis ( life-long

21

Thalassaemia characterized by : ↓ in synthesis of the globin chains of Hb with • accumulation of abnormal chains in the red cells → ineffective .erythropoeisis & haemolysis : Pathogenesis : in β-thalassaemia -1 no β chains are produced ( β˚ ) or β chain production is ↓ ( β + ) • . ( i.e. unstable ) → d.t. mutations α-chain production is normal & may combine with γ or ∂ chains • ( → formation of ↑ quantities of HbA2 ( α2, δ ) & HbF ( α2, γ2 both β˚ & β + thalassaemia may be in homozygous / • .heterozygous states : in α-thalassaemia -2 no α chain production ( α˚ ) or ↓ α chain production ( α+ ) → d.t. • → ( deletions ( = absence genes deletions → Hb barts ( γ4 ) w' can't carry O2 →-4 .incompatible with life genes deletions → moderate anaemia & splenomegaly-3 ( ( HbH dis : β4 or 2 genes deletions → α-thalassaemia trait → microcytosis e' / 1 .e'out mild anaemia

Β-thalassaemia : clinically, the disease is divided into • T-major ( Mediterranean / Cooley's anaemia ) : d.t. -1 .homozygous inheritance → sever anaemia T-intermedia : d.t. combination of homozygous mild β- & α- -2 ( thalassaemia → moderate anaemia ( rarely requiring transfusion T-minor ( β-thalassaemia trait ) : d.t. heterozygous inheritance -3 ( asymptomatic carrier ) , present with microcytic hypochromic . ( blood picture ( but no / mild anaemia 22

: β-thalassaemia major in childhood, presents with • .failure to thrive sever anaemia ( starts at 3 – 6 Ms; time of normal switch from γ ( to β chain production .recurrent infections extramedullary haemopoeisis : → hepatosplenomegaly & bone . expansion → classical facies skull X-ray → hair- on- end appearance ( as a result of expansion ( of BM into cortical bone : Investigations : CBC & film -1 .moderate / sever anaemia with ↓ MCV & MCH reticulocytic count , peripheral blood → target cells & ↑ .poikilocytosis : Hb electrophoresis -2 ,HbF ↑ .HbA2 is normal .˚HbA is absent in β : Treatment .regular blood transfusion : to keep Hb < 10 gm/dl -1 .febrile reactions prevented by → use of leucocyte-depleted blood .Fe-over load prevented by → desferrioxamine & ascorbic acid .splenectomy : indicated if transfusion is required < every 7 Ws -2 .folic acid : d.t. over active BM. 4- BM transplantation -3

α-thalassaemia : clinically, present in 2 forms • genes deleted : → all Hb produced is physiologically useless 4 -1 ( ( Hb barts genes deleted : → HbH ppt-ed in red cells → haemolysed in 3 -2 .the spleen → splenomegaly . & anaemia is variable NB: for defenetive diagnosis of α-thalassaemia traits → Globin • .chain studies → detection of reduced ratio of α to β chains 23

antenatal diagnosis : fetus with β-thalassaemia major is • identified by DNA analysis of chrionic villous → in 1st trimester or test the umbilical cord blood → in 2nd trimester. If the fetus is .affected → abortion

24

: Thalassaemia findings findings in homoz

Type +Β ˚B δβ

thalassaemia major ( Hb ( A + F + A2 .thalassaemia major ( Hb ( F + A2 thalassaemia intermed .- HbF only

( δβ ( lepore

.T-major / intermedia .HbF & Lepore -

γδβ

not viable -

.Findings in heteroz .thalassaemia minor .↑ HbA2 .thalassaemia minor .↑ HbA2 .thalassaemia minor HbF = 5-15% HbA2 : normal .thalassaemia minor . Hb Lepore = 5-15% .HbA2 : normal .neonatal haemolysis T-minor in adults e' .normal HbF & A2

: The α-thalassaemia Gene genes 4 genes 3

Deletion Hb type --/ -- ˚α ( Barts ( γ 4 α˚ --/-α ( H ( B4

genes 2

α˚ --/αα or α /-α-

gene 1

α+ - α/ αα

some HbH HbA normal -

C/P hydropdfaetalis moderate anaem .splenomegaly .mild anaemia .α-T trait -

.α-T trait -

Sickling disorders

25

formation of ( HbS ) by change happen in globin B chain ( valine • ( for glutamine in the 6th position .it may be : - homozygous → sickle cell disease • .heterozygous → sickle cell trait Sickle cell anaemia : Pathogenesis of red cell Hb is HbS w' in deoxygenated state → the 80% .molecules link → chains → sickling & ↑ rigidity of red cells .sickling →↓ red cell survival & obstruction of microcirculation .Ppt-factors : infection, dehydration, cold & hypoxia the Pt feels well despite being anaemic ( because HbS releases its O2 to tissues more readily than does normal Hb ) except during . crises or complications : C/P : painful crisis -1 . d.t. infarctions in various organs hand & foot syndrome : → in children , painful swelling of digits .of hands & feet d.t. infarcts of small bones .ppt- by infection, dehydration & hypoxia : aplastic crisis -2 .sudden ↓ in Hb with ↓ reticulocytic count .usually follow infection with parovirus .haemolytic crisis -3 sequestration crisis : rapid ↓ in Hb d.t. red cells traping in liver -4 .& spleen … ( Complications : ( too dangerous ( osteomyelitis ( bone . papillary necrosis of the kidney spleen → recurrent infarctions → autosplenectomy →↑ infection ( with encapsulated organisms ( e.g. pneumococci .cardiac enlargement , myocardial necrosis .pulmonary infarction & pulm-HTN 26

.cerebral damage .painful priapism ( blindness ( eyes : Investigations .Lab.findings of haemolytic anaemia -1 sickling : → seen in blood film or induced by Na-metabisulphite -2 ..…rapid screening test : sickle solubility test -3 .HbS + Na-dithrionite → turbid .normal Hb + Na-dithrionite → clear solution →Hb electrophoresis : → cell Hb -4 .HbSS 80% ( HbS ( no HbA 20% .parents of the Pt : → features of sickle cell trait -5 : Treatment . ppt factors : → avoided or treated quickly -1 regular blood transfusion : →↓ production of HbS →↓ sickling -2 ( ( used for sever anaemia & frequent crisis . haemolytic crisis : → blood transfusion -3 : painful crisis -4 .analgesics, IV fluids & O2 hydroxyurea : →↑ erythropoeisis →↑ HbF ( indicated for ( frequent painful crisis ( aplastic crisis : antibiotics for infection ( if present -5 .vascular occlusion : → exchange transfusion -6 .gene therapy : may be possible in the future -7 Sickle cell trait .HbS is < 40% (no symptoms unless subjected to anoxia ( e.g. during anaesthesia .sickle cell trait protects against malaria . diagnosis : by +ve sickle test / Hb electrophoresis -

↓ G6PD 27

: Pathogenesis the red cell derives energy from glucose metabolism via 2 • : pathways .Embden-Myerhof glycolytic → 90 % of glucose -1 .hexose monophosphate shunt → 10 % of glucose -2 mature red cell doesn't have a neucleus, mitochondria or any • ( .intracellular apparatus needed for production of proteins ( enz So, it receives a package of enzs.at its birth & when these .enzs.used up → the cell dies G6PD enz. : is the 1st enz.in the hexose monophosphate shunt w' • helps maintaining glutathione in a reduced state, once reduced form of glutathione becomes unavailable → oxidation of haem → .meta-Hb the gene for G6PD is sex liked, carried on X-chromosome, ↓ • .♀ affects ♂ & carried by → variants of the enz. : 2 variants •• : G6PD GdA • .found in 10% of Africans .young cells → moderate enz.activity .↓ older cells → sever in this variant, haemolysis is selflimiting as BM compensates by .↑ its output of young cells : G6PD Gd med • .found in mediterranian people .both young & old cells → very poor enz .haemolysis is sever → death : Factors that ppt haemolysis .infections • .acute illness e.g. DKA • ( fava beans ( not seen e' G6PD GdA • : drugs • ,analgesics → aspirin, phenacetin 28

.antimalarial → quinine, chloroquine, primaquine antibiotics → sulfonamides, dapson, nitrofurazone, .chloramphenicol, ciprofloxacin .miscellaneous → Vit.K, quinidine, nalidixic acid : C/P .haemolysis : develops within a day or so after exposure -1 chronic haemolysis : ( in G6PD GdA ) persist for sometime after -2 .exposure : Investigations : CBC & film -1 .count is normal between the attacks • → blood film during the attack • .bite cells : cells with indentation of membrane blister cells : Hb appears to be partially detached from cell .membrane .Heinz bodies : oxidized denaturated Hb .Lab.findings of haemolytic anaemia -2 enz. ↓ → reduce dyes ( screening test ). also level of the enz. -3 .may be directly assayed : Treatment .offending drugs → must be stopped .underlying infections → must be treated .blood transfusion -

Immune haemolytic anaemia

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.autoimmune or alloimmune • in autoimmune haemolytic anaemia, the body produces • .antibodies against its own cells : antibodies attached to red cells at • .C˚ → warm autoimmune HA 37 .lower temperature → cold autoimmune HA Warm autoimmune HA : Causes .idiopathic .autoimmune disease e.g. SLE .lymphomas .carcinomas .chronic lymphatic leukaemia .drugs : e.g. methyl dopa .C/P : varies from mild haemolysis to life-threatining anaemia : Investigations .Lab.findings of HA .microspherocytosis d.t. ↓ red cell surface membrane direct Coomb's test +ve e' IgG alone Coomb's = antiglobulin, IgG found on the surface of the red cells • .˚→ antibodies are best detected at 37C ( NB: Coomb's test ( = antiglobulin test • Indirect Pt serum+ normal RBCs -

Direct Pt's cells ( Igs found on ( surface of the RBCs

Antiglobulin Agglutination

30

So, the normal cells are So, the Pt's cells are sensitized .Sensitized in vitro .In vivo, e.g .autoimmune HA .haemolytic transf.reaction .HDN .drug-induced immune HA : Treatment . blood transfusion : → may be required .prednisolone : 40 – 60 mg/d . splenectomy : if no response to steroid immunosupressive drugs : azathioprine & cyclophosphamide → . if no response to steroids & splenectomy

.Cold autoimmune HA : Causes .idiopathic .infection e.g. IMN, mycoplasma, pneumonia .lymphoma ( paroxysmal cold haemoglobinuria ( PCH ( chronic cold haemoagglutinin disease ( CHD : C/P .features of HA ppt-ed by cold exposure .Raynaud's phenomenon in these conditions → haemolysis is d.t. IgM w' can attach to • .RBCs at low temperature.→ agglutination in the cold peripheries when the cells return to high temperature in the core of the body • .→ activation of the complement → intravascular haemolysis : Investigations .red cells agglutinate in the cold or at room temperature .˚S.antibodies → IgM type & best react at 4C .direct Coomb's test → shows only C3 complement on red cells -

: PCH .rare condition 31

IgG complement fixing antibodies → biphasic reaction , → ( ( haemolysis .in cold peripheries → react e' red cells in central circulation → complement activation → intravascular .haemolysis this biphasic reaction is demonstrated by incubating the Pt's red cells & serum at 4C˚ & then warming the mixture to 37C˚ → .haemolytic reaction .ttt. : → transfusion of warmed blood CHD : haemolytic anaemia d.t. IgM → red cell agglutination after ( .exposure to cold → acrocyanosis ( similar to Raynaud's phenom

: Treatment of cold autoimmune HA .avoid cold exposure .chlorambucil : occasionally helpful .high dose IV immunoglobulins & interferon -

: Causes & major features of autoimmune HAs •

32

temp.at w' Abs attach Best to red cells : type of Ab : direct Coomb's test :cause of 1ry condition .causes of 2ry condit.s -

Warm ˚37C IgG Strongly +ve Idiopathic autoimmune dis.,e.g. SLE .chronic lymph.leuk .Hodgkin's disease .carcinomas .drugs e.g. M.dopa -

Cold ˚lower than 37C IgM ve+ Idiopathic ,infections e.g. IMN Mycoplasma,pneumon ( viral inf.( rare & .lymphomas .parox.cold haemogl ( IgG )

( Haemolytic disease of the newborn ( HDN : Pathogenesis it's alloimmune HA d.t. passage of IgG antibodies from maternal . circulation → fetus → destroy the fetal red cells sensitization of RhD –ve mother occurs at a previous delivery by .fetal Rh+ve cells entering the maternal circulation : C/P .mild → anaemia with /without jaundice moderate → sever anaemia, jaundice, hepatosplenomegaly, edema & cardiac failure. If Conj.bilirubin < 12mg% → deposited in the basal ganglia → Kernicterus ( mental ↓, deafness, epilepsy ( & spasticity sever → intrauterine fetal death ( IUFD ) d.t. hydrops fetalis ( ( = hepatosplenomegaly, edema & HF : Investigations : antenatal serology • .ABO & RhD groups determination for all mothers serum → for atypical Abs w' rising titre → amniocentesis → .level of bilirubin in the fetus 33

→ at birth of an affected baby : → sample of the cord blood • .anaemia with ↑ reticulocytic count .ve direct Coomb's test+ .S.bilirubin ↑ : Treatment : A- management of the baby mild cases : phototherapy → convert bilirubin → harmless • .biliverdin → excreted by the kidney →↓ Kernicterus : sever cases : exchange transfusion….. indicated if • .cord Hb < 14g/dl .cord bilirubin < 3.5 mg/dl .rapidly rising bilirubin level the exchanged blood should be : fresh, ABO compatible, lack of •• .Ag to w' maternal Ad is directed & - ve of CMV : B- prevention of Rh disease by immunization of the mother by Anti-D after delivery when all • : the following are present .mother is Rh –ve .fetus is Rh +ve .no maternal Anti-D in the mother's serum immunization must be within 48h of delivery by 500IU of IgG • . anti-D IM

( Paroxysmal nocturnal haemoglobinuria ( PNH

34

: Pathogenesis : there is a stem cell disorder .the affected clone → abnormal red cells, leucocytes & platelets the red cells have a membrane defect → lysis by complement → .chronic intravascular haemolysis .low white cells & platelets count the condition may be transforms to : aplastic anaemia or acute .leukaemia : C/P : haemolysis • .esp.at night ( urine → dark in colour ( at night or 1st in the morning .may be ppt-ed by infection, Fe therapy or surgery • recurrent thrombotic episodes ( platelets ) → MI, acute abd.pain / • .stroke : Investigations .Lab.findings of HA Ham's test : red cells lyse more readily in acidified serum than .normal cells, they also lyse in sucrose solutions .blood film : → leucopenia & thrombocytopenia : Treatment .blood transfusion → in sever anaemia .steroids → effective .anticoagulants → in thrombotic episodes .BM transplantation -

Drug-induced haemolysis

35

: by one of 3 mechanisms • immune complex formation : drug-Ab-complex → attaches to -1 (red cells → activate complement → red cells destruction( quinine membrane adsorption : drug-red cell-complex → formation & -2 ( adsorption of Abs → red cell destruction ( penicillin autoantibodies formation : drug → red cell autoantibody -3 ( (M.dopa

Mechanical HA : physical damage to red cells when pass through • .prothetic valves / arterial grafts -1 fibrin strands deposited in small vessels e.g. in → DIC, -2 malignant HTN, haemolytic uraemic syndrome, thrombotic .thrombocytopenic purpura small bones of feet : during prolonged marching or running → -3 .march haemoglobinuria

Hypersplenism Def. - peripheral blood cytopenia w' can be cured by • .splenectomy . spleen → enlarged .BM → hypercellular : pathogenesis : hypersplenism resulting from • .pooling of blood into spleen -1 .rapid destruction of cells in it -2 .in plasma volume ↑ -3 : Treatment . that of the cause of splenomegaly .splenectomy : in sever anaemia or thrombocytopenia -

: Causes of splenomegaly

36

: A- 1ry haematological disease .HAs • .lymphoproliferative disorders • . myeloproliferative disorders • : B- non-haematological disease : congestive splenomegaly • .portal HTN .splenic / portal vein thrombosis .congestive HF : infections • .bacterial → typhoid, TB, septicaemia .viral → hepatitis, IMN .parasitic → bilharziasis, malaria, Kala-azar .collagen disease : SLE, RA • .metabolic storage disease : amyloidosis • .sarcoidosis •

Polycythaemia 37

: this denotes ↑ of • .%Hb% < 18 gm .red cell count < 6,000,000/cmm haematocrite ( PCV ) < 55% .red cell volume : ♂ < 36ml/kg & ♀ < 32ml/kg true polycythaemia is differentiated from relative polycythaemia • .( haemoconcentration ) by → measuring red cell volume : Classification ( A- 1ry : polycythaemia vera ( is stem cell disease ( B- 2ry : ( ↑ erythropoietin : .appropriate ↑ ( i.e. compensatory )…. d.t -1 .high altitude .lung disease .heavy smoking .cardiovascular disease .affinity of Hb for O2 → in familial polycythaemia ↑ .inappropriate ↑ : ….. d.t -2 .renal disease e.g. hydronephrosis, carcinoma, cysts .liver carcinoma .adrenal tumours .cerebellar haemangioblastoma .massive uterine fibroma ( C- relative ( = haemoconcetration = ↓ plasma volume .stress ( spurious ) polycythaemia .dehydration .burns -

( Polycythaemia vera ( PV

38

'Pathogenesis : PV is stem cell disorder in w there is alternation in the pluripotent generator cell →↑ proliferation of erythroid, myeloid, megakaryocytic progenitor .cells this is d.t. failure of apoptosis ( programmed cell death ) as a result of deregulation of gene ( Bcl – XL ) w' is known to oppose .that process .C/P : usually present in Pt < 60 y symptoms : headache, dizziness, tinnitus, blurring of vision, .angina, intermittent claudication, V.thrombosis : ( signs ( & complications .plethoric appearance, retinal venous engorgement -1 splenomegaly : in 2/3 of the Pts d.t. extramedullary -2 haemopoeisis → this is helpful in distinguishing PV from 2ry cases .hepatomegaly : in 1/2 of cases -3 .HTN : in 1/3 of cases -4 vascular : → Hge ( in GIT, cerebral, genitourinary ) or -5 ( Thrombosis ( of arteries & veins .gout : d.t. ↑ uric acid production -6 .PUD : 5 – 10 % of cases -7 : Investigations : CBC -1 % Hb < 18 gm PCV < 55% .WBCs & platelets →↑ in 1/2 of cases : blood volume -2 red cell volume ( measured by Chromium-51 ) → 36ml/kg ( ♂ ) ( ♀ ) or 32ml/kg .↑ / plasma volume → normal .BM : → erythroid hyperplasia & ↑ megakaryocytes-3 .↑ LAP ( leucocyte alkaline phosphatase ) : → usually -4 S.erythropoeitin level : not diagnostic , but may be helpful in -5 → distinguishing PV from 2ry polycythaemia 39

S.erythropoeitin → •↓→ PV .2ry p. but its levels may be normal →↑• .Treatment : aims at keeping PCV < 45% : venesection -1 .will relieve many of the symptoms of the disease .the resulting Fe ↓→↓ erythropoeisis it's used as the sole ttt ( other therapeutic measures are reserved to ( control thrombocytosis .chemotherapy : hydroxyurea →↓ platelete count -2 : radioactive phosphorous-32 -3 .used for Pts < 70 y with sever disease one dose is effective for up to 18 Ms ( but →↑ rate of ( transformation to acute leukaemia : allopurinol -4 .to block uric acid synthesis H2-receptor antagonist ( not H1 ) → effective in relieving .pruritus → Prognosis : may transition to ( myelofibrosis ( in 30% ( AML ( in 5% 2ry polycythaemia .Causes : given before Complications : similar to those of PV ( but other ( myeloproliferative disorders not developed .… Differentiation from PV : is helped by .WBCs & platelet counts → normal .spleen → not enlarged .↑ → erythropoietin level .LAP score → normal arterial O2 saturation → low ( in Pts with cardiac & pulmonary (.dis .Treatment : - that of the cause. – venesection : helpful

40

: Differentiation between 1ry & 2ry polycythaemia 1ry polycythaemia WBCs & platelet count spleen erythropoietin LAP O2 saturation -

2ry polycythaemia

↑ Normal Enlarged Not enlarged Normal ↑ ↑ Normal ↑ (d.t. lung /heart dis ) ↓

Stress polycythaemia ( Gaisbock's syndrome ( commonly occur in middle aged men, who are : hypertensive, .( obese & smoker ( HOS red cell volume is normal but there is relative polycythaemia d.t. .↓ plasma volume this condition is often presents as a cardiovascular problem e.g. .myocardial or cerebral ischaemia smoking : → produces up to 10% carboxyHb →↓ O2 carrying capacity of the blood → consequent polycythaemia →↑ PCV → .ischaemia .treatment : - stop smoking • .venesection → until PCV is normalized -

( Myelofibrosis ( myelosclerosis

41

there is proliferation of the stem cells & fibrosis of BM with • ( extramedullary haemopoeisis ( in liver & spleen pathophysiology : abnormal proliferation → release of growth factors ( platelet derived growth factor = PDGF ) →↑ fibroblasts in .BM → fibrosis : C/P : Symptoms .weakness & Wt loss massive splenomegaly : → fullness of upper abdomen, abdominal .pain may occur d.t. perisplenitis 2ry to splenic infarction .bony pains & gout .bleeding → occur in thrombocytopaenic Pts : Signs ( fever ( infection . anaemia massive splenomegaly …. ( other causes of massive splenomegaly that must be differentiated include : bilharziasis, ( CML, malaria, Kala-azar & Gaucher's disease : Investigations : CBC & film -1 there is anaemia with leucoerythroblastic features ( = appearance ( of erythroblasts & primitive WBCs in peripheral blood . characteristic red cells seen → tear drop red cells WBCs & platelet counts → initially high but later on → .leucopenia & thrombocytopenia the differential WBCs count → may be very similar to that of .CML : BM aspiration -2 ( not usually successful ( d.t. fibrosis trephine biopsy is necessary to show → ↑ fibrosis & ↑ № of .megakaryocytes the Philadelphia chromosome ( Ph' ) : → is absent ( unlike most -3 ( case of CML 42

.↑ / leucocyte alkaline phosphatase ( LAP ) score : normal -4 : Treatment .supportive : blood transfusion & folic acid -1 alkylating agents ( e.g. hydroxyurea ) : → in cases with gross -2 . myeloproliferation .allopurinol : is needed to prevent gross hyperuricaemia -3 .splenic irradiation : → to ↓ its size -4 : splenectomy : is indicated if -5 .spleen becomes very large & painful .transfusion requirements are high .sever thrombocytopenia occur : Prognosis .median survival → is 3 y .transformation to AML → may occur -

** NB ** myeloproliferative disease : e.g. in • .PV .chronic granulocytic leukaemia leukaemoid reaction : e.g. in • .sever infection .TB .malignant BM infiltration -

leucoerythroblastic anaemia : e.g. in • .sever Hge .haemolysis .BM infiltration .myeloid leukaemia -

The white cells 43

: types of leucocytes are found in the peripheral blood 5 • .neutrophil ( polymorphnuclear ) granulocytes -1 .esinophil granulocytes -2 .basophil granulocytes -3 .lymphocytes -4 .monocytes -5 ( Neutrophil leucocytosis ( neutrophilia , = < 10,000/cmm : Causes .pregnancy & exercise .bacterial infections .corticosteroid therapy .myeloproliferative disease .leukaemoid reaction . leucoerythroblastic anaemia ( Neutropenia ( < 1500/cmm : Causes ( racial ( common in black races ( viral infection ( commonest ( sever bacterial infection ( e.g. typhoid Felty's syndrome ( rheumatoid arthritis, splenomegaly, ( neutropenia ( megaloblastic anaemia ( ↓ formation of cells .drugs → causing BM aplasia .pancytopenia : from any cause .autoimmune neutropenia . NB: agranulocytosis = absence of neutrophils : C/P of neutropenia ( recurrent infections ( esp.in mouth & throat .septicemia : may occur 44

.mouth : → characteristic glazed mucositis with ulceration Investigations : BM examination is essential to differentiat : between granulocyte formation ( there is ↓ in immature precursors ) or ↓ removal of neutrophil from the circulation ( no ↓ immature ↑ ( precursors : Treatment ( stop the causative drug ( that →↓ BM .infections : use antibiotic therapy myeloid growth factors : G-CSF or GM-CSF → usefull in .shortening the duration of neutropenia associated e' chemotherapy .in autoimmune neutropenia : → use steroids & high doses IV Igs ( Esinophelia ( < 400/cmm : Causes . parasitic disorders allergic disorders : allergic rhinitis, drug reactions & other .hypersensitivity reactions .skin disorders : urticaria, eczema .pulmonary disorders : BA, bronchopulmonary aspergillosis malignant disorders : lymphoma, esinophilic leukaemia, .carcinoma & melanoma .miscellaneous : sarcoidosis & hypoadrenalism ( Basophilia ( < 100/cmm : Causes .myeloproliferative disorders .myxaedema .ulcerative colitis .small pox & chicken pox -

45

( Lymphocytosis ( < 5000/cmm : Causes → infections .acute : IMN, rubella, pertusis, infective hepatitis, CMV infection • .chronic : TB, toxoplasmosis, brucellosis • .thyrotoxicosis .↓ adrenal .chronic lymphatic leukaemia( CLL ) & some lymphomas ( Monocytosis ( < 800/cmm : Causes chronic bacterial infections : TB, typhoid, brucellosis, .bact.endocarditis .protozoal disease .Hodgkin's disease .( myelodysplasia ( particularly myelomonocytic leukaemias -

The leukaemias .malignant neoplasms of the stem cells • 46

characterized by diffuse replacement of BM by neoplastic cells • .→ leukaemic cells into the blood → infiltrates various tissues : Classification : A- acute ( acute lymphoblastic leukaemia ( ALL -1 ( acute myeloid leukaemia ( AML -2 : B- chronic ( chronic lymphocytic leukaemia ( CLL -1 ( chronic myeloid leukaemia ( CML -2 : A/E of leukaemia : unknown , but several factors interact : Ι- genetic factors .incidence of leukaemia in chromosomal abnormalities e.g ↑ • .Down's syndrome → .Ph' chromosome : is found in 95% of Pts with CML • In Ph', the long arm of chromosome 22 is shortened by reciprocal .translocation to the long arm of chromosome 9 the oncogene ( C-ABL ) normaly present on chromosome 9 is thus translocated to come near the break point cluster region (BCR) → hybrid transcription unit → transcripted as chimeric mRNA → translated into a fusion protein e' tyrosine kinase & .enhanced phosphorylation activities a new gene is created on Ph' chromosome → encode a fusion • .protein likely to be important in pathogenesis of CML : ΙΙ- environmental factors .chemicals : e.g. benzene .drugs : e.g. cytotoxic drugs .radiation exposure .viruses : human leukaemia virus discovered in T-cell leukaemia -

Acute leukaemia : Classification 47

A- acute lymphoblastic leukaemia ( ALL ) → subdivide according : to different markers on the surface of lymphocytes into ( common ( nonB, nonT ) ALL = ( C-ALL .null cell ALL .B cell ALL .T cell ALL B- acute myeloid leukaemia ( AML ) → differentiated according to morphology & cell cytochemistry of blast cells ( more useful than : cell surface phenotypes ) → clinical forms .M0 → undifferentiated blast cells predominate .M1 → myeloblast predominate .M2 → myeloblast & promyelocyte predominate .M3 → promyelocyte predominate .M4 → myelocyte & monocyte evident . M5 → poorly differentiated monoblasts .M6 → multinucleated megablastic erythroblasts M7 → megakaryoblastic leukaemia : presents as myelofibrosis ( ( with few megakaryoblasts in BM : C/P → A- BM failure .anaemia : pallor, dyspnea, tachycardia • leucopenia : fever, malaise, infections ( mouth, throat, skin, • ( respiratory, perianal thrombocytopenia : purpura, spontannous bruising, bleeding • .gums & may be internal Hge → ( B- organ infiltration ( esp.in ALL ( bone pain & tenderness ( particularly in ALL in children • ( painful lymphadenopathy ( in ALL • ( moderate hepatosplenomegaly ( in ALL • .gum hypertrophy & infiltration • skin infiltration & rectal ulceration ( particularly in • ( myelomonocytic & monoblastic : meningeal manifestations • 48

.headache, nausea, vomiting blurring of vision, diplopia, papillaedema & retinal Hge ( with ( characteristic central white deposit .( testicular swelling ( in ALL • : Investigations : CBC & film -1 .anaemia → normocytic normochromic .WBCs count → ↑ or ↓ or normal ( blast cells → variable number ( but occasionally none at all in AML → blasts may contain ( auer rods ) w' are rod like .cytoplasmic inclusions ( platelet count →↓ ( esp.in AML ( BM examination : → hypercellular ( e' characteristic blasts -2 : blood tests -3 .++renal function tests. - S.uric acid. - S.Ca ( S.electrolytes. – blood cultures ( necessary .chest X-ray : → may show mediastinal mass -4

: Differentiation of ALL & AML Differ.item

Lymphoblasts

Myeloblasts

49

: morphology -

: cell size : cytoplasm :cyt.granules : auer rods : nucleoli -

.small .scanty .rare .absent . 2- 1 -

.large .abundant .often .may be found .2 < -

: cytochemistry -

:PAS peroxidaes/sudanblack

ve+

ve-

ve -

ve+

ve+

Usually –ve

: immunology -

genetics -

-terminal deoxynucleo (Tidyl transferase ( Tdt immunological markers ( CD )

T cell marker : CD2 - .Myeloid cell markerse.g B cell marker : CD 19 .CD 13 or CD33

:IgG light chain gene - ve ( in C-ALL& null+ ( ALL : T cell receptor gene ( ve ( in T ALL+

veve-

We can differentiate by using : morphological criteria, • .cytochemical, immunological & genetic studies

: Treatment : A- supportive care .ttt.of anaemia → red cell transfusion -1 ttt.& prophylaxis of Hge → clotting factors, fresh frozen plasma -2 .,platelet concentrate / fresh blood .ttt.& prevention of infection -3 .correction of dehydration -4 .ttt.of hyperuricaemia by IV fluids & allopurinol -5 : prevention of acute tumour lysis syndrome -6 chemotherapy → tumour cell death → release of its products → hyperkalaemia, hyperuricaemia, hyperphosphataemia, .hypercalcaemia .this is corrected by : - adequate hydration & allopurinol ( haemodialysis ( to correct the metabolic disturbances : leucopharesis -7

50

blood is collected from a vein → centrifuged → remove the leukaemic cells → both red cells & plasma returned to the Pt by .another vein done if blast cell count in peripheral blood is very high ( to ( prevent infiltration of the brai & the lungs : B- specific therapy : a- for ALL : 5 phases of therapy induction of remission : by a combination of → vincristine, -1 ( prednisolone, daunorubicin & L-asparaginase ( DPL-V .consolidation : using drugs not given in induction -2 .craniospinal prophylaxis : → to prevent relapse -3 .repeated inj.of intrathecal methotrexate .cranial irradiation : maintenance : by cyclic combination of -4 .methotrexate, 6-mercaptopurine, vincristine & prednisone .with ttt-free intervals → to allow BM recovery .duration of the therapy : 2 – 3 y : late intensification therapy -5 .after 6Ms of start of maitenence .BM transplantation : b- for AML : 3 phases of therapy induction of remission : by very intensive chemotherapy → -1 ( ( sufficient to induce hypoplastic BM consolidation : by giving several further courses of induction -2 . therapy : postremission therapy : by one of 3 options -3 .a- repeated intensive chemotherapy .b- high dose chemotherapy + BM transplantation .c- " " " " + autologous BM transplantation : C- types of acute leukaemia that require special management : promyelocytic leukaemia -1 51

breakdown of promyelocytes → DIC , this needs ttt.e' platelets, fresh frozen plasma transfusion & heparin before specific . chemotherapy is started : hairy cell leukaemia -2 : characterized by • .pancytpenia blast cells ( with cytoplasmic projections → hairy cells ) in blood .& BM . giant splenomegaly responds dramatically to ( CdA ) = chlorodeoxyadenosine → • .complete remission in 80% of cases

: Prognosis : ALL -1 .children → ttt.success upto 80% cure rate .Pts ( 20 – 70 y old ) → 30% cure rate wores prognosis : in males, blacks, ↑ leucocytic count, CNS .involvement, T & B cell types .BM transplantation : curative in 40% of Pts : AML -2 Pts < 60 y → complete remission in 80% of cases , but relapse .occur within 1 – 3 y worse prognosis in : → older age, presence of nuclear Tdt & . associated chromosomal abnormalities .BM transplantation → curative in 60% of cases -

( Chronic myeloid leukaemia ( CML

52

.seen most frequently between ages of 50 – 60 y • Ph' chromosome : present in all dividing granulocytic, erythroid • .( & megakaryocytic cells in BM ( & also in B-lymphocytes in 70% of cases → there is terminal metamorphosis to an acute • .form of leukaemia : C/P .manifestations of anaemia : → pallor, dyspnea, tachycardia -1 of hypermetabolism ( d.t. ↑ total body " " " -2 granulocyte mass ) → fever, Wt loss, lassitude, anorexia & night .sweats slpenomegaly ( frequently massive ) but lymphadenopathy is -3 .not common ………,bruising, epistaxis, menorrhagia -4 .less common features include : visual disturbances & gout -5 : Investigations : CBC & film -1 Hb → initially normal, then anaemia ( normocytic .normochromic) develop .WBCs : → < 100,000 /cm myeloid cells : → complete spectrum is seen but, neutrophils & .myelocytes exceed blast cells & promyelocytes .platelet count : → variable .↑ BM : hypercellular & granulocyte precursors markedly -2 ( cytogenic analysis of blood or BM : → Ph' ( in < 90% of cases -3 .leucocyte alkaline phosphatase score ( LAP ) → very low -4 : Treatment hydroxyurea: 2 – 4 g/d PO at the beginning, followed by → -1 ( 0.5 – 2 g/d maintainance ( to keep WBCs 5000 – 10,000 /cmm .α-interferon : 5 – 10 million U/d -2 .is now the ttt of choice .it can ↓ the Ph' & allow normal cells to appear .BM transplantation : within 1y of diagnosis -3

53

myelofibrotic transformation : is treated by blood transfusion & -4 .splenectomy .blast crisis : treated as acute leukaemia -5 : Prognosis .median survival is → 3 y • death : usually occurs from terminal acute transformation, Hge / • .infection : acute transformation : takes the form of • .increasing myelofibrosis transition to acute leukaemia ( blast crisis ) → where blast cells predominate in the blood, these blast cells are : myeloblasts ( in ( 80% of cases ) or pre-B-lymphoblasts ( in remaining 20% .BM transplantation : within 1 y of diagnosis → 75% success rate •

Chronic lymphocytic leukaemia . occur mainly in the elderly • ( it's a disorder of B-cells ( T-cells in few cases • accumulation of mature lymphocytes in the tissues & → • .peripheral blood : with advanced disease, there is • .BM failure ( lymphadenopathy ( generalized, discrete .softe tissue lymphoid masses immunological failure : results from reduced humoral & cellular • .immune processes

: C/P enlargement of LNs ( in the neck, axilla & groin ), → usually -1 .discrete, moderate size & not tender .manifestations of anaemia : pallor, dyspnoea, tachycardia -2 splenic & hepatic enlargement : not massive, pruritus occurs in -3 .many Pts but skin infiltration occurs rarely

54

tonsillar enlargement : may occur, but salivary & lacrimal -4 .glands involvement → rare about 20% of cases diagnosed only when routine blood test is -5 .done

: Investigations : CBC & film -1 .mild anaemia, but may be sever d.t. autoimmune haemolysis WBCs count : usually < 15,000/ cmm. ( of w' 40% are ( lymphocytes .thrombocytopenia : in advanced cases BM examination : → lymphocytic replacement of normal BM -2 .→ BM failure S.immunoglobulins : ↓ ( esp.in advanced cases ) because → -3 B-cell malignancy suppress normal Igs production → .immunological failure ( Staging ( classification : A- Rai staging ( stage 0 : → lymphocytosis ( < 15,000/cmm .stage Ι : → lymphocytosis + enlarged LNs stage ΙΙ : → lymphocytosis + enlarged LNs + splenomegaly or . hepatomegaly .% stage ΙΙΙ : → 0 + Ι / ΙΙ & Hb < 11gm stage ΙV : → 0 + Ι + ΙΙ / ΙΙΙ & platelets < 100,000 NB: Hb & platelets ↓ in stages ΙΙΙ & ΙV → not made by .autoimmune haemolytic anaemia / autoimmune thrombocytopenia : B- Binet staging stage A : no anaemia ( Hb < 10 g/dl ), no thrombocytopenia…. .( platelets < 100,000 /cmm ), involved lymphoid areas : < 3 stage B : no anaemia, no thrombocytopenia, involved lymphoid .areas : 3 or more stage C : anaemia & / thrombocytopenia present, involved .lymphoid areas : any number

55

: Binet staging • anaemia thrombocytopenia lymphoid areas -

A No

B No 3<

No No 3 =/<

C Yes Yes № Any

Treatment : there is no need to treat stage 0, but other stages need .ttt .A- supportive : as with acute leukaemia Pt.with hypogammaglobulinaemia → take potent IV γ-globulin .B- specific therapy : indicated only for symptomatic disease chlorambucil : 0.6 – 1 mg PO every 3 Ws → is the ttt of choice -1 .for initial ttt corticosteroids : indicated for autoimmune haemolytic anaemia / -2 ( thrombocytopenia ( but often these require splenectomy fludarabine : used for refractory cases ( but → prolonged -3 ( immunosuppression : Prognosis : median survival • ( 8y → in stage 0 ( Rai ) / A ( Binet ( 2y → in stage ΙΙΙ or ΙV ( Rai ) / C ( Binet .↓ death is d.t. infection ( 2ry to BM failure or immune • .prognosis is much worse in BM failure • transformation to aggressive large cell lymphoma : → rare but • .( may occur ( Richter's syndrome

56

Myelodysplastic syndrome ( MDS ( a group of acquired BM disorders that are d.t. defect in stem cells • they are characterized by increasing BM failure with • abnormalities in all 3 myeloid cell lines ( i.e. red cells, .granulocytes/ monocytes & platelets ) → pancytopenia : A/E . idiopathic ( 1ry ) → usually • 2ry : → after cytotoxic chemotherapy ( esp.with procarpazine & • ( melphalan : Classification .refractory anaemia -1 .refractory anaemia with ringed sideroblasts -2 ( % refractory anaemia with excess blasts ( blasts 5 – 20 -3 refractory anaemia with excess blasts in transformation ( blasts -4 ( % 20- 30 .chronic myelomonocytic leukaemia -5 : C/P MDS occur in elderly Pts who present with symptoms of • . anaemia, infection or bleeding d.t. pancytopenia .bone pains & splenomegaly may occur • : Investigations CBC : serial counts → evidence of increasing BM failure ; with -1 .anaemia, neutropenia, thrombocytopenia & monocytosis → in chronic myelomonocytic leukaemia • .monocytes < 1000 / cmm .WBCs count < 100,000 / cmm → : BM -2 .reveals ↑ cellularity despite the pancytopenia .dyserythropoiesis → is present granulocyte precursors & megacaryocytes → abnormal .morphology .ringed sideroblasts → present in all types 57

in conditions of excess blasts → there is excess blasts in BM → the prognosis is worse than in types with normal number of blast ( % cells ( i.e. < 5 : Prognosis refractory anaemia with ringed sideroblasts & normal white & -1 .platelets counts → stable for years refractory anaemia with excess blasts → progress rapidly & -2 transforms to acute myeloblastic leukaemia. ( this may be called preleukaemia but this name is better to be avoided because death usually arises from ↑ cytopenia rather than transformation to acute (.leukaemia : Treatment → : Pts with < 5% blasts in BM -1 . red cell & platelet transfusion .antibiotic for infection haemopoeitic growth factors ( e.g. erythropoietin & granulocyte ( CSF → : Pts with < 5% blasts in BM -2 supportive measures : for elderly Pts with other medical .problems .single agent chemotherapy : for Pts with ↑ WBCs count . intensive chemotherapy : ( as AML ) → in Pts < 60 y .BM transplantation -

58

Malignant lymphomas : main types 2 • ( Hodgkin's disease ( HD -1 ( non-Hodgkin's lymphomas ( NHL -2 ( Hodgkin's disease ( HD characterized by : enlargement of LNs with hyperplasia & • infiltration with histiocytes & lymphocytes & presence of .( characteristic ( Reed-sternberg cells after a period → the disease is disseminated to involve non- • .lymphatic tissues .C/P : age distribution → early peak : 20 y & later peak : 50 y enlargement of superficial LNs : → painless, not tender, -1 asymmetrical, firm, discrete & rubbery ( the cervical LNs are ( involved in 60 – 70 % of Pts .splenomegaly & hepatomegaly -2 mediastinal involvement : → is a feature of nodular sclerosis -3 .type late in the disease : → involvement of skin, bones, lungs & CNS -4 constitutional manifestations : prominent with widespread -5 : disease fever → continuous / cyclic ,( Pel-Ebstein's fever w' consists of (.few days of high fever followed by few days of apyrexia is rare .pruritus .Wt loss, profuse sweating & cachexia ( alcohol-induced pain ( at the site of enlarged nodes : Investigations : CBC & film -1 ( normocytic normochromic anaemia ( late in the disease .with BM infiltration → leucoerythroblastic anaemia ↑ : ESR 59

chest X-ray & CT : → mediastinal lymphadenopathy / -2 .pulmonary infiltration .liver function tests : → abnormal in hepatic involvement -3 → : LN biopsy -4 Reed-sternberg cells : w' are large binucleated cells ( with • vesicular nuclei & prominent nucleoli ), they are associated with .a mixture of lymphocytes & histeocytes …( Histological classification : ( 4 types • lymphocytes predominant : there is heavy lymphocytes -1 .infiltration → the best prognosis nodular sclerosis : there is much fibrous tissue, may be -2 .associated with any type .mixed cellularity : both lymphocytes & histeocytes are present -3 lymphocyte depleted : there is few lymphocytes → poor -4 .prognosis ( Staging : ( Ann Arbor system .determines both the prognosis & the appropriate ttt it requires : → a thorough history & physical examination, X-ray chest, liver function tests, abdominal imaging ( U/S, CT or MRI ) .& BM biopsy lymphangiography, laparotomy & splenectomy → now done less . frequently ……… - A Stage Ι : → involvement of a single LN region or a single ( extralymphatic organ site ( ΙE Stage ΙΙ : → involvement of 2 or more LN region on the same side of the diaphragm or localized involvement of an extralymphatic or site & 1 or more LN regions on the same side of the diaphragm → ( ( ΙΙE Stage ΙΙΙ : involvement of LNs in both sides of the diaphragm, it may be accompanied e' spleen ( ΙΙΙS ) or extralymphatic ( ΙΙΙE ) or ( both ( ΙΙΙSE 60

Stage ΙV : diffuse / disseminated involvement of 1 or more ( extralymphatic ( with /without associated LN involvement B- ……. In all stages, A or B → indicates absence ( A ) or → presence ( B ) of 1 or more of the following .˚unexplained fever < 38 C .night sweats .loss of < 10% of body Wt.within 6 Ms C- …… bulky disease : → denoted by X NB : bulky = LN mass < 10cm in diameter, mediastinal mass < .1/3 intrathoracic diameter at T 10 level

: Ann Arbor system of staging of Hodgkin's disease Stage

Ι ΙΙ ΙΙΙ ΙV

LN region Single

Diaphragm .…………

Extra-L- site ( Single ( ΙE

more / 2

same side

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/ -extra / spleen .both / Diffuse Dissiminated

: Treatment : radiotherapy -1 irradiate all nodes areas ( above & below the diaphragm ) .according to the site of the disease .the relapse rate following supradiaphragmatic disease is ↑; 40% when there is a large mediastinal mass → give chemotherapy + .radiotherapy : chemotherapy -2 the standard ttt is 6 – 8 month cycles of mustin, vincrestine, .procarbazine, prednisolone … combination therapy

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other drugs : such as adriamycin, bleomycin, vinblastine & decarbasine → added to the standard course as alternative courses ( ( alternating regimen ) or combination drugs ( hybrid regimen → : NB: the choice of ttt depends on the stage • .radiotherapy : → ΙA, ΙB, ΙΙA .chemotherapy : → ΙΙB, ΙΙΙA, ΙΙΙB, ΙVA, ΙVB .…… -3 .Pts recur after initial radiotherapy → give chemotherapy Pts relapse after initial chemotherapy → are treated with .myeloablative therapy & BM transplantation : Prognosis long term survival depends on : stage & histological grade of the • .disease : the 5 y survival rates are as follow • .stage Ι & ΙΙ→ 85% .stage ΙΙΙA → 70% .stage ΙΙΙB & ΙV → 60% -

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Non-Hodgkin's lymphomas ( NHL ( these are tumours of lymphoreticular tissue derived from • .malignant clones of B / T cells : C/P .the mean age at presentation is 50 y LN enlargement : is the dominant feature , the involved sites -1 . may be non-contageous .LN is painless .mediastinal LN → less common, except in T-cell type .abdominal LN → common .splenomegaly & hepatomegaly → occur early -2 oropharyngeal lymphatic structures ( = Waldeyer's ring ) → -3 .involved → sore throat / obstructed breathing .diffuse BM infiltration : → anaemia, infection & purpura -4 → : extranodal sites involvement -5 .BM → GIT , then .skin, brain, testes & thyroid gland .pruritus → is uncommon constitutional manifestations : such as fever, night sweats & Wt -6 .loss → less frequent than in HD : Investigations → : CBC & film -1 .anaemia advanced cases → leucoerythroblastic picture d.t. BM infiltration .lymphoma cells → may seen in the peripheral blood .liver function tests : → abnormal in hepatic involvement -2 .imaging : → chest X-ray, chest CT, CT abdomen → LNs -3 .BM biopsy : → infiltration by lymphoid tissue -4

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S.immunoglobulins : since the majority of cases are B-cell -5 tumours → there may be an associated monoclonal paraprotein → .IgM or IgG biopsy : of LN or involved extranodal tissue → is the most -6 .important investigation ( Histological classification : ( still controversial : A- low grade .small lymphocytic -1 .small lymphocytic & plasmacytoid -2 .follicular small-cleaved cell -3 .follicular mixed cell -4 .follicular large cell -5 .diffuse small-cleaved cell -6 .diffuse mixed cell -7 .diffuse large cell -8 ( B- high grade : …..( the most aggressive .diffuse large cell -1 .immunoblastic -2 ( small non-cleaved ( Burkitt's & non-Burkitt's -3 .lymphoblastic -4 .true histiocytic -5 Staging : → the same as HD ( i.e. Ann Arbor system ) but less .clearly related to prognosis than the histological grading : Treatment radiotherapy : → restricted to cases of localized low grade -1 .lymphoma if symptomatic : chemotherapy -2 used for Pts with disseminated low grade lymphoma & all high • .grade lymphomas → : in disseminated low grade • single agent therapy is sufficient to induce response e.g. → .chlorambucil 5 – 10 mg /d PO 64

.stopped once a good response is achieved ( re-used if relapse occurs ( relapse is frequent → : in high grade lymphoma • .may be curable, & treated by high dose combimation regimens .ttt is usually continued for about 3Ms after complete remission in Pts with lymphoblastic / small non-cleaved cell lymphoma → • cranial irradiation & intrathecal methotrexate is necessary to avoid .CNS relapse BM transplantation : considered for high grade lymphomas Pts -3 .who relapse after combination therapy :.choice of ttt •• : low grade lymphoma -1 ( stage Ι & ΙΙ → radiotherapy ( if symptomatic ( stage ΙΙΙ & ΙV → single agent chemotherapy ( if symptomatic : high grade lymphoma -2 .combination chemotherapy .if relapse → BM transplantation : Prognosis low grade lymphoma → relapse & continuing risk of death are .the rule high grade lymphoma → 2/3 of Pts who obtain a complete .remission are probably cured .by 10 y, the over all survival of low & high grade → the same -

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: D.D. of lymphadenopathy : A- localized → infections -1 .pyogenic : pharyngitis, dental abscess .viral : cat scratch fever, lymphogranuloma venereum .TB .fungal : actinomycosis .lymphomas → HD & NHL -2

: B- generalized → infections -1 .viral : infectious mononucleosis, measles, rubella & HIV .bacterial : brucellosis, syphilis, TB, salmonella .fungal : histoplasmosis .protozoal : toxoplasmosis → inflammatory, noninfective -2 .sarcoidosis .rheumatoid arthritis .SLE ( leukaemia : esp.( CLL & ALL -3 .lymphomas : HD & NHL -4 .carcinoma → 2rys -5 .drug reaction : hydantoin -6 .hyperthyroidism -7 .Kawasaki's syndrome -8

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Paraproteinaemias a group of disorders characterized by monoclonal proliferation of • ( B-cells accompanied by secretion of monoclonal Ig ( paraprotein → A/E : they include .multiple myeloma -1 .Waldenstorm's macroglobulinaemia -2 MGUS ( monoclonal gammopathy of undetermined significance -3 .plasma cell leukaemia -4 paraproteins are demonistrated by a single band ( dark staining ) • on serum electrophoresis → referred to as M or ( monoclonal band

Multiple myeloma Pathogenesis : there is malignant proliferation of plasma cells in : the BM → leads to skeletal destruction : 2ry to release of osteoclast activating -1 factor ( OAF ) → osteoporosis, bone lytic lesions, fractures & .hypercalcaemia replacement of BM : → anaemia, leucopenia & -2 .thrombocytopenia .recurrent infections d.t. ↓ of normal Ig production -3 production of abnormal protein ( paraprotein ) → hyperviscosity -4 ., renal damage, bleeding tendency & amyloid deposition .C/P :→ occurs predominantly in the elderly .bone pains ( backache ) & pathological fractures -1 .manifestations of anaemia -2 repeated infections : d.t. ↓ antibody ( Ig ) production & later on -3 .neutropenia bleeding tendency : d.t. interference with the platelet function, -4 .coagulation factors , later on → thrombocytopenia

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manifestations of hypercalcaemia : → polyuria, polydepsia, -5 anorexia, vomiting, abdominal pain, constipation & mental .disturbances → renal failure : d.t. precipitation of -6 .Ig light chain .amyloid deposition .hypercalcaemia .hyperuricaemia .myeloma infiltration amyloid disease → macroglossia, carpal tunnel syndrome, -7 .diarrhea hyperviscosity syndrome : → lethargy, confusion, loss of vision -8 .& coma some paraproteins are also cryoglobulin ( = act on low -9 .temperature i.e. at tissue periphery ) → Raynaud's phenomenon : Investigations : CBC & film -1 normocytic normochromic anaemia with rouleaux formation ( d.t. ( hyperviscosity .neutropenia & thrombocytopenia → in advanced cases .↑ ESR : always .abnormal plasma cells → rarly appear in blood film : BM -2 .plasma cells : №↑ & abnormal shape ( plasmacytosis ( < 10% .plasma cells are often abnormal with centrally placed nucleus plasma protein electrophoresis : → narrow monoclonal band ( in -3 .75% of cases ) : 1/2 cases → IgG & 1/4 cases → IgA urine : → Bence-Jones' proteiuria w' consists of free light chains -4 .↑ S.B2-microglobulin → usually -5 S.Ca++ : →↑ in 1/3 of Pts but, S.alkaline phosphatase → normal -6 ( ( except following pathological fractures .lab.manifestations of RF : encountered in 20% of cases -7 68

→ skeletal survey : may show -8 osteolytic areas ( without evidence of surrounding osteoblastic ( reaction .sclerosis .generalized osteoporosis .pathological fractures → very common Diagnosis : is established by the presense of at least 2 of the : following criteria BM plasmacytosis ( < 20% but lower level is acceptable if -1 ( monoclonal lytic lesions on X-ray ( sever osteoporosis is acceptable if BM -2 ( plasmacytosis < 30% .paraproteins in blood / urine -3 : Treatment → A- supportive : …..for .pain → local radiotherapy hypercalcaemia → rehydration, loop diuretics, steroids & .bisphosphonates .infections → antibiotics .anaemia & thrombocytopenia → blood & platelet transfusion .hyperviscosity → plasmapharasis .lytic bone lesions → orthopedic surgery : B- specific .…… combination of -1 melphalan 7mg /m² daily is given for 4 days every 3Ws …. (providing that the renal function is normal ) + prednisone .60 mg/m² /d. over the ttt days .courses can be gradually extended until → ↓ WBCs count in resistance to melphalan → combination regimen containing -2 doxorubicin, nitrosouria, vika alkaloid & very high dose steroid are . tried

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α-interferon : → used to prolong remission induced by other -3 .drugs in Pts < 40 y → intensive use of high dose of melphalan & BM -4 .transplantation used : Prognosis presense of sever anaemia & RF at presentation → poor .prognostic factors .if they present → 2 y survival is 10% .if they absent → this rises to 75% -

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Amyloidosis tissue infiltration with amorphous hyaline substance that stain • .pink with H & E and red with congo red stain with congo red stain + polarized light → it shows green • .florescence characteristically, the amyloid protein consists of β-pleated sheets • .that are responsible for its insolubility & resistance to proteolysis classification : amyloidosis is classified according to the nature : of protein deposited into 4 groups : A- amyloidosis associated with Ig-producing tumours the amyloid deposits ( AL ) consists of Ig light chains/ fragments • .of them substitution of a particular amino acid into their regions → • .deposition of ( AL ) in tissues : this condition may be • .1ry : → no cause is found 2ry : → associated with myeloma / Waldenstorm's .macroglobulinaemia C/P : d.t. involvement of the heart, tongue, peripheral nerves & • → the kidney .HF .macroglossia .peripheral neuropathy .carpal tunnel syndrome .nephrotic syndrome : B- reactive systemic amyloidosis the amyloid deposit ( AA ) consists of an acute phase protein → • ( ( amyloid A protein ( it occurs 2ry to ( i.e. A/E of reactive systemic • .chronic infection : TB & bronchiectasis .chronic inflammation : RA .malignancy : e.g. Hodgkin's disease 71

( familial mediterranian fever ( FMF C/P : it's d.t. involvement of the liver, spleen & the kidney → • .- hepatosplenomegaly .nephrotic syndrome & RF .renal vein thrombosis NB: renal amyloid is more prominent in reactive amyloidosis, but • cardiac & gut involvement predominate in Ig-producing tumours, .however the overlape is wide : C- familial amyloidosis .a group of autosomal dominant diseases • .start usually in middle age • in the most common form, amyloid deposits consists of a mutant • variant of transthyretin ( transport protein for thyroxin ) → destabilization of the protein → PPt in peripheral & autonomic → nerves, heart & the kidney : C/P • ( neuropathy ( peripheral sensory & autonomic .cardiomyopathy & conduction defects ( renal affection ( less common than AL amyloidosis : D- localized ( organ-limited ( amyloidosis d.t. deposition of other types of amyloid protein in specific • .organs : include • : cerebral amyloidosis -1 intracerebral / cerebrovascular amyloid deposits are seen in Alzheimer's disease, hereditary spongiform encephalopathy & .Down's syndrome in these conditions : → apoprotein E interacts with B-A4 protein ( ( in the senile plaques & neurofibrillary angles found in the brain the gene of apoprotein E is found on chromosome 19 & may be .an important factor in the pathogenesis of Alzheimer's disease haemodialysis : → released amyloidosis d.t. deposition of B2- -2 .microglobulin 72

.senile amyloidosis : → d.t. cerebral deposition of A4 protein -3 : Investigations histological examination of the infiltrated tissues → diagnosis -1 NB: when tissues aren't readily available → rectal / gum biopsy • .or abdominal fat aspiration → the characteristic amyloid deposits electrophoresis & immunoelectrophoresis of serum & urine → -2 .detecting paraproteins scintigraphy : → using I-123-labeled serum amyloid protein -3 component → useful in assessment of various types of amyloidosis : Treatment ( ttt.of the underlying A/E ( if present -1 1ry amyloidosis : → regimens incorporating prednisone & -2 ( alkylating agents ( e.g. hydroxy urea transthyretin associated amyloidosis : → is treated by liver -3 ( transplantation ( as the liver is the source of this abnormal protein renal transplantation : → effective in some Pts with renal -4 .disease

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Bleeding disorders : diagnosis of bleeding disorders •• : A- history & examination ? is bleeding a local / generalized problem • : type of bleeding • .purpura & mucosal bleeding → platelet disorder skin bruising, MS haematoma, haemarthrosis → co-agulation .disorder .F.H : → of bleeding tendency • .drug history : → in details • : B- screening tests CBC & film :→ to detect thrombocytopenia, abnormal platelet morphology . the cause of bleeding may be revealed e.g. DIC or .acute leukaemia bleeding time : prolonged in vascular wall & platelet defects and .in Von-Willebrand's disease prothrombin time ( PT ) : prolonged in defects of extrinsic & .common coagulation pathways activated partial thromboplastin time ( APTT ) : prolonged in .defects of intrinsic & common coagulation pathways thrombin time ( TT ) : prolonged in fibrinogen ↓, ( dysfibrinogenaemia & coagulation inhibitors ( e.g. heparin PT : →↑ in abnormalities in factors VΙΙ, X, V or ΙΙ , liver • . disease or if the Pt is on warfarin .( aPTT : →↑ in ↓ of VΙΙΙ, ΙX, X, XΙ, XΙΙ, Ι, ΙΙ & V ( but not VΙΙ • .BT : →↑ vascular wall defects, platelet defects & Von-Will.dis • TT : →↑ in ↓ fibrinogen, dysfibrinogenaemia or coagulation • .inhibitors

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: C- further tests if an abnormality is detected in the coagulation cascade, the test is repeated using 50/50 mixture of Pt's plasma & normal plasma. → if full correction does't occur, this means the presence of a .coagulation inhibitor specific factors can be measured functionally by the use of mixtures of Pt's serum & serum known to be deficient in a single specific factor. → thus, if a prolonged aPTT is obtained w' is corrected by normal plasma but not corrected by plasma with .factor ΙX deficiency → SO, the Pt is deficient in factor ΙX . some factors can be measured immunologicaly → platelet aggregation studies : to detect .Von-Wellibrand's factor activity • .congenital platelet abnormalities • → other tests : include ( estimation of fibrinogen & fibrin degradation products ( FDPs • .assays of coagulation factors • .tests of fibrinolytic pathway •

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The purpuras Def. : a group of disorders associated with superficial capillary • bleeding mainly in skin & mucous membranes d.t. thrombocytopenia, platelet functional disorders or ↑ capillary ( permeability ( vascular purpura purpuric rash : consists of small spots ( purple red ) that does • .not blanch on pressure, …… when confluent → ecchymosis

Thrombocytopenic purpura : Causes . №↓ & platelet function : →↓ survival ↓ -1 .BM infiltration : leukaemia, tumours, myelofibrosis, myeloma BM damage : chemotherapy, chemicals, alcohol, drugs, aplastic .anaemia .↓ B12 / folate : platelet destruction ↑ -2 .autoimmune : SLE coagulation : DIC, thrombotic thrombocytopenic purpura, .( haemolytic uraemic syndrome ( HUS . massive transfusion : abnormal platelet sequestration -3 . hypersplenism .haemangiomas -

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Autoimmune thrombocytopenic purpura the platelets are sensitized with an autoantibody ( IgG ) → • ( removal by liver & spleen ( RES : C/P : acute form -1 .seen in children .following a viral infection / vaccination . remits spontaneously : chronic form -2 . seen in adults presents with → purpuric rash, superficial bruising, epistaxis & .menorrhagia .splenomegaly is rare : Investigations .platelet count : < 20,000 / cmm -1 .BM examination : →↑№ of megakaryocytes -2 . % platelets antibodies : detected in 70 -3 : Treatment steroids : prednisone 60 mg/d with cautious ↓ of dose after -1 .remission is achieved splenectomy : for non-responder to steroids or requires high -2 doses to maintain platelet count < 50,000 / cmm ( most adults will ( need splenectomy high dose Ig : → block FC receptors of macrophages → -3 removal of sensitized platelets. This must be reserved for .emergency conditions only → as it's expensive immunosuppressive drugs : e.g. azathioprine ( for refractory -4 ( cases : platelet transfusion -5 . in life-threatining bleeding 77

however, because of the presence of antibodies; transfused .platelets do not survive longer than Pt's own platelets danazol : ( = non-virilizing androgen ) → 600 mg /d. → useful -6 .in some cases failing to respond to steroids & splenectomy

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