Part 21. Disease of Blood

PART 21.Diseases of the Blood

Section 1. Development of the Hematopoietic system

# 성인과의 차이점

    1. constant, dramatic changes in hematopoiesis

    2. low oxygen tension but high metabolic rate

    3. sterile intra-amniotic environment

# three anatomic stage

    1. mesoblastic

           ; yolk sac

           ; begins between 16th and 19th days

           ; ceases by 10th~12th wks

    2. hepatic

           ; begins 6 wks

           ; premominant until last trimester

    3. myeloid

           ; *begins by 10th~12 wks

# ★not simply transfer from yolk sac to liver to marrow

    ; houses quite distinct hematopoietic population

           - at 18-20wks

                   / more than 85% of fetal liver - erythroid

                   / bone marrow

                           : less than 40% - erythroid

                           : up to 15% - neutrophils

★Table XXI-1

Granulocytopoiesis

; no neutrophil until midtrimester

; abundant CFU-GM in liver, bone marrow, blood

    - adult 20~300 CFU-GM/ml

    - term infant 2000 CFU-GM/ml

    - not indicate large total body quantity of CFU-GM

    - low concentration in liver & bone marrow

; low production of G-CSF

    - monocyte generates small quntities of G-CSF & mRNA after LPS or IL-1

    - but same G-CSF receptor

; ★no granulocytopoiesis in human embryo

    - *due to relative lack of the major neutrophil regulatory growth factor, G-CSF

Erythropoiesis

Erythropoietin (Epo)

    ; regulate erythrocyte production

    ; produced in cell of monocyte/macrophage origin & epithelial cell of glomerular tuft

    ; lack of importance of renal contribution in fetus

BFU-E

    ; more differentiate normoblast

    ; different fashion from adults

           --> more rapidly, more normoblasts

           --> Epo alone

Hemoglobin

; oxygen combination

    - no expenditure of metabolic energy

; α₂β₂

♥ Classification (=six hemoglobin)

    1. Gower-1 ; ζε

    2. Gower-2 ;

  3. portland ; ζ

  4. Hb F

  5. Hb A

  6. Hb A2

; αpolypeptide - chromosome16

; β, γ, δpolypeptide - chromosome11

Embryonic Hemoglobins 

;

Fetal Hemoglobin

; ★At Birth

    - *70% of total hemoglobin

; 6-12mo

    - only trace

; ★older children & adults

    - *less than 2%

Normal Relationships Among The Hemoglobins

Alteration Of The Hemoglobins By Diseases

Ｏ2 와 Hb의 결합 또는 해리는 metabolic energy 가 필요 없음

# Hb F 증가 (2%↑)

  ; normal infant

  ; β-thalassemia trait

  ; thalassemia major (cooley anemia)

  ; other hematologic stress

  ; hemolytic anemia, leukemia, aplastic anemia

# ※Hb A2 증가 (normal : 2.4∼3.4%)

  ; β-thalassemia trait

    ; *megaloblastic anemia

# Hb A2 감소

  ; iron deficiency anemia

  ; α-thalassemia

Metabolism Of The Red Blood Cell

# mature RBC

    ; no mitochondria

    ; ATP generation *cannot occur by oxidative phosphorylation in Krebs cycle reactions

           --> *but by Embden-Meyerhof pathway(mostly) & Pentose phosphate pathways

# ♥5 Function Of ATP Essential To Normal Cell Viability

    ; maintenance of electrolyte gradients

  ; initiation of energy production

  ; maintenance red blood cell membrane and shape

  ; maintenance heme iron in the reduced(ferrous) form

  ; maintenance of the levels of 2,3-DPG ＆ ATP within RBC

Thrombopoiesis

  colon forming units - megakaryocyte

  (CFU - MEG) 관여

Chapter 405 The Anemias

; 7∼8g/dl 이하 : pallor in the skin and mucosa

; physiologic adjustment to anemia

   c. o 증가

  oxygen extraction 증가

  vital organ 과 tissue 로의 blood flow shunting

  2.3∼DPG 농도 증가

  oxygen dissociation curve의 shift to the right

; RPW (RBC distribution width)

  - the coefficient of variation RBC size

   (standard deviation of the MCV  mean MCV   100)

   MCV and RDW can be helpful in the initial classification of the anemia

; peripheral blood smear  :RBC morphology 가 underlying dz에 point

㉿Table 405-1

㉿Table 405-2

㉿Table 405-3

Section 2. Anemia of Inadequate production

Chapter 406. Congenital Hypoplastic Anemia (Diamond - Blackfan Syndrome)

; 50% of children : 2mo 에 DX

; 75% : 6mon 에 DX

Etiology

; 20% familial occurrence

; male : female equally

; elevated EPO even more than expected for degree of anemia

; ★Primary Defect

    - *erythroid precursor defect

    - *not immunologic damage

; possible defects

    - defects in cytokine & their receptor on red cell

           / EPO, SCF, IL-3, GM-CSF

           / not positive investigation

Clinical Manifestation

; profound anemia

    - 2-6mo

; *liver ＆ spleen not enlarged initially

; *asso. with congenital anomaly

    - 1/3

    - *dysmorphic face, detect of upper extremity(e.g. triphalangeal thumb)

Laboratory Finding

; *macrocytic

; folic acid ＆ vitamine B12 증가

; *“young” erythrocyte population

    - *increased Hb F, increased expression of "i" antigen

; *increased ADA activity

    - congenital RBC aplasia 와 acquired transient erythroblastopenia DDx

; thrombocytosis, neuetropenia

   Reticulocyte 감소

   Red blood cell precursor

   serum iron level 증가

; Bone marrow culture   

    - markedly reduced CFU-E, and BFU-E

Differential Diagnosis

: low reticulocyte count 의 anemia와 DDX

   convalescent phase of hemolytic disease of newborn

  aplastic crises of other hemolytic anemia

  transient enythroblastopenia

Prognosis

; *best prognosis on responder to corticosteroid therapy

; *spontaneous remission

    - *14%

; hemosiderosis due to frequent transfusion

  - liver ＆ spleen enlarged

  - secondary Hypersplenism

  - leukopenia and tbrombocytopenia

Treatment

; ★corticosteroid

    - *beneficial if begin early

    - 3/4에서 반응

    - prednisone 2mg/kg/24hr # 3 or 4

    - therapy 후 1∼3주에 Bone marrow에서 Red blood cell precursor 나타남

  4∼6주에 Hb 이 normal level

  Hb 10g/dl  이상 유지할 때까지 steroid tapering

; transfusion : interval of 4∼8 주

  Chelation therapy : deferoxamine

  Androgen, cyclosporin A, cyclophosphamide antithymocyte globulin,

  high dose intravenous immunoglobulin, erythropoietin, IL-3

  splenectomy

  Bone marrow transplantation

406. 1  Pearson Marrow - Pancreas Syndrome

  marrow failure : neonatal period에 나타남

  macrocytic normochromic anemia Hb F 증가, red cell adenosine deaminase 증가

  vacuolated erythroblast가 증가 , myeloblast 증가

  neutropenia 와 thrombocytopenia

  failure to thrive, insulin - dependent DM, exocrine dysfunction, lactic acidosis,

 renal fanconi syndrome, muscle ＆ neurologic impairment

  mitochondrial DNA deletion이 원인

Chater 407. Acquired Pure Red Blood Cell Anemia

(1)cause : uncertain

   association of thymoma

   complement - dependent antibody cytoxic for erythroblast : high-dose IV IG or     immunosuppressive therapy 관여

   Large dose of chloramphenicol

   -erythropoiesis 방해

    Reticulocytopenia, erythroid hyperplasia vacuolated pronormoblast in marrow

   various viral infection

   -Blg parvovirus

    single stranded DNA virus

   -self limited last only 10∼14 days

   -hepatitis virus (non-A, non-B, non-C)

    Epstein - Barr vinus, cytomegalovirus, human immunodeficiency virus

Chapter 408. Transient Erythroblastopenia Of Childhood(TEC)

; severe transient anemia in previously healthy children

; ★6mo-3yr, mostly 12mo

    - DDx point from congenital hypoplastic anemia

; more common than congenital hypoplasetic anemaia

; cause

    - not clear

    - *frequently follow viral illness (parvovirus 는 관계없다)

; *markedly decreased reticulocyte and bone marrow erythroid precursor

; ★normal MCV, HbF, ADA

    - DDx poinst from congenital hypoplastic anemia

; Treatment

    - *recovery within 1-2mo

    - rare recurrence

    - Red cell transfusion (Hb<3.5g/dl 시)

    - corticosteroid

           / not valuable

Chapter 409. Anemia Of Chronic Disorders And Renal Disease

; chronic pyogenic infection (bronchiectasis, osteomyelitis), chronic inflammatory process, (rheumatoid arthritis, SLE, ulcerative colitis), Malignancy, advanced renal dz

Etiology

    ; decreased production of EPO

           - major componant

    ; decreased RBC destruction by hyperactive RES

 a relative BM failure : BM Hypoactivity

 inadequate erythropoietin production

 abnormal iron metabolism  : defective from release from tissue

Clinical Manifestation

:underlying dz에 따라 다르다

Lab finding

  Hb : 6∼9g/dl

  Anemia : normochromic, normocytic

  absolute reticulocyte : normal or low

  leukocytosis

  FEP 증가

  serum iron 감소, TIBC 감소

  -valuable diagnostic feature

  serum ferritin 증가

  bone marrow ; normal cellularity

Treatment

  not respond to iron theray

  transfusion : rare

  Recombinant human erythropoietin

  JRA 경우 iron therapy 시행시 GI bleeding 유발하여 iron deficiency 더 악화

  underlying systemic dz 가 control 시 Anemia 저절로 조절

Chapter 410. Congenital Dyserythropoietic Anemia

:rare inherited normocytic or macrocytic anemia

  multinuclearity and abnormal chromatin pattern in RBC precursors

  ineffective erythropoiesis and abnomal Uptake of iron

  chronic hemolysis

 →jaundice, gallstone, splenomegaly

(1) 4가지 type

type 1 : binuclearity and megaloblastic

                  : 15%

type 2 : multinuclearity and positive Ham test

                  : 60%

type 3 : pronounced multinuclearity and huge RBC precursor in BM

                  :15%

type 4 : resemble type 2 but Ham test (-)

                  : rare

(2) TX

  Blood transfusion

  splenectomy

  Restriction of iron intake and iron chelation theray

Chapter 411. Physiologic Ameia Of Infancy

Full Term Infant

# ㉿Causes

    ; abrupt cessation of erythropoiesis with onset of respiration at birth

           - why?

                   / liver is major site of EPO production in neonatal periods

                           --> insensitivity to EPO release with tissue hypoxia

                   / decreased half-life of EPO but increased volume of distribution in newborn

    ; shortened survival of fetal RBC

  ; sizable expansion accompanying rapid weight gain during the 1st 3mo

    ; red cell function is influenced by the higher level of serum phosphate

           --> increase red cell phosphate & 2,3 DPG

           --> facilitating oxygen release

           --> decreasing tissue hypoxia

==> ㉿“marginal erythropoietic eqilibrium”

Premature Infant

    ; *more extreme & rapid

           - 7-9g/dl by 3-6wks commonly

           - ♥why ?

                   / frequent phlebotomies

                   / inability to produce compensatory amounts of EPO

                   / dietary factor

                           : folic acid deficiency

                           : vitamin E deficiency

                           : iron deficiency

    ; Treatment

           - recombinant human EPO

                   / 200IU/kg tiw 200-250IU/kg tiw sc

Treatment

   packed RBC transfusion

 :very low Hb level (7g/dl)

  complicating medical condition

  frequent blood sampling

  apnea 와 failure to gain weight

   r-Huepo 과 iron therapy

 첫 6주동안

Chapter 412. Megaloblastic Anemnia

; deficiency of folic acid & vitamin B12

    - *more common in folic acid deficiency

412.1 Folic Acid Deficiency

Megaloblastic Anemia Of Infancy

Etiology

# folate (=pteroylmonoglutamate)

    ; abundant in green vegetables, fruit, animal organ(e.g. liver, kidney)

    ; *absorbed through small intestine

    ; not biologic activity

    ; reduced by dihydrofolate reductase

           - *tetrahydropteroylglutamate(tetrahydrofolate) : biologic active

# dietary deficiency

  ; *goat milk or powered milk feeding

    ; rapid growth or infection 은 dietary deficiency를 더욱 조장

# *ascorbic acid deficiency

  ; impairs availability of dietary folic acid

Clinical Manifestation

; *4-7mo - Peak

; irritable, fail to gain weight, chronic diarrhea

; thrombocytopenia

; kwashiorkor, marasmus, sprue와 동반

Laboratory Finding

; macrocytic (MCV>100fl)

    - RBC shape 과  size 의 variation

; *reticulocyte : low

; *Neutropenia, thrombocytopenia

; *Neutrophil - large, hypersegmented nuclei

; folic acid < 3ng/mg (5-20 ng/mg)

; RBC folate level 이 chronic deficiency 의 지표

    (150-600 ng/mg : normal)

; iron, Vitamin B12 : normal or 중가

; LDH 증가

; BM

    - *Hypercellular (erythroid hyperplasia)

Treatment

   folic acic: 1-5mg/24hr.

   72 시간 안에 hematologic response

   -anemia 가 심각시에만 transfusion)

   folic acid therapy: 3-4주

  <Megaloblastic anemia of pregnancy>

:lmg/24h (특히 last trimester)

Megaloblastic Anemia Of Pregnancy

; *increased folate requirements during pregnancy

Folic Acid Deficiently In Malabsorption Syndrome

; *celiac disease, chronic infectious enteritis, enteroenteric fistula

Congenital Folate Malabsorption

 :megaloblastic anemia

  convulsion

  mental retardation

  cerebral calcification

Folic Acid Deficency Associated With Anticonvulsant And Other Drug

; Anticonvulsant drug

    - *phenytoin, primidone, phenobarbital

; oral contraceptives

; *MTX

    - bind to dihydrofolate reductase

           --> prevent formation of tetrahydrofolate

; *pyrimethamine, trimethoprim

Congenital Dihydrotolate Reductase Deficiency

 : unable to form biologically active tetrahydrofolate

412.2 Vitamin B12 (Cobalamine) Deficiency

Etiology

# vitamin B12 (=cobalamin)

    ; derived from cobalamin in food

    ; secondary production by microorganism

    ; kinetics

           1) cobalamin released in acidity of stomach

                   --> conbine there with IF & R proteins

                   --> transverse duodenum

                   --> pancreatic proteases break down R proteins

                   --> *absorbed in terminal ileum via specific receptors for IF-cobalamin

                   --> cobalamin bound to TCII

           2) diffuse through mucosa in intestine and mouth

# inadequate intake, surgery involving the stomach or terminal ileum, lack of secretion of intrinsic factor by the stomach, consumption or inhibition of the B12-IF complex, abnormalities involving the receptor site in terminal ileum, abnormalities of TCII

Juvenile Pernicious Anemia

; AR

; cause

    - inability to secrete gastric intrinsic factor or secretion of functionally abnormal IF

; 위의 조직학적 소견이나 위산은 정상

Clinical Manifestation

    ; *9mo-11yr

    ; weakness, irritability, anorexia, listlessness

  ; ★tongue - smooth, red, painful

  ; Neurologic manifestation

           - ataxia, paresthesia , hyporeflexia, Babinski (+), clonus, coma

Laboratory Finding

  anemia ; macrocytic (macro-Ovalocytosis of RBC)

  Neutrophil : large, hypersegmanted

  Neutropenia thrombocytopenia

  s-vit B12 : 100 pg/mg 이하

  s-iron, folic acid : normal or 증가

  s-LDH  : 증가

  s-bilirubin 증가  (2∼3mg/dl)

  excessive excretion of methylmalonic Acid in the urine (0∼3.5mg/24hr)

-reliable and sensitive index

    ; ★no Ab against parietal cell or IF

           - DDx from adult type

10 Gastric acidity 감소

11 Schilling test : vit B12 가 전혀 흡수 안됨

Treatment

  vit B12 : lmg (parenteral)

  5∼10ug을 매일 근육주사

  신경 증상 있으면 매일 1mg 근육주사(최소 2주간)

  oral therapy 은 contraindicated

Transcobalamin Deficiency

  Autosomal recessive

  thranscoblamine II의 cong, def 가 원인

  영아 초기부터 severe megaloblastic anemia

  TX : massive parenteral dose of vit B12

Vit B12 Malabsorption Due To Intestinal Cause

  surgical resection or inflammatory dz of ileum

  overgrowth of intestinal bacteria (diverticulum or duplication)

  fish tapeworm : diphyllobothrium latum

Vitamin B12 Deficiency In Older Children

 : atrophy of gastric mucosa,  achlorhydria

   Ab against IF

 : cataneous candidiasis, Hypoparathyroidism, 또는 내분비 결핍증과 동반

412.3 Rare Megaloblasstic Anemia

# *oroticaciduria

    ; a genetically determined defect in pyrimidine Biosynthesis

    ; severe megaloblastic Anemia

    ; Neutropenia

    ; crystalluria

# *Lesch-Nyhan syndrome

# thiamine-responsive and thiamine-dependent megaloblastic anemia

# cobalamine variant

Chapter 413. Iron Deficiency Anemia

; *▲common hematologic dz of infancy and childhood

; 신생아 출생시 0.5g의 iron 존재→성인시 5gm으로 증가

; 식품에 함유된 철분은 10% 만이 장에서 흡수

Etiology

; low birthweight and perinatal hemorrhage

    - decreases in neonatal hemoglobin mass and store of iron

; *common at 9-24mo

# Pt's Dietary Pattern

    ; large amount of milk and carbohydrate supplemented with iron

# Blood loss

    ; old children

  ; petic ulcer, Meckel diverticulum, polyp or hemangioma

  ; hook-worm infestation

  ; *pulmonary hemosiderosis

  ; *chronic diarrhea

  ; *chronic blood loss induced by exposure to a heat-labile protein in whole cow's milk

           - *prevention by reducing quantity of whole cow’s milk to 1pint/24hr or by using heated or evaporated milk or by milk substitute

Clinical Manifestation

    ; pallor

           - *▲important clue

  ; Blue sclera

  ; *pagophagia

           - desire to ingest unusual substance such as ice or dirt

    ; less than Hb 5g/dl

           - irritability, anorexia, tachycardia, cardiac dilatation, systolic murmur

  ; spleen enlarged : 10-15%

  ; widening of dipole of skull

  ; obese or underweight

  ; ★neurologic and intelectual disturbance

           - disturbance in attention span, alertness, learning of both infants and adolescents

           - *MAO, iron-dependent enzyme이 원인역할로 여겨짐

Laboratory Finding

# ★Progression of IDA

    ; decreased BM hemosiderin

          --> decreased serum ferritin

           --> decreased serum iron

           --> increased TIBC

           --> decreased transferrin saturation

           --> increased FEP(free erythrocyte protoporphyrins)

           --> microcytic, hypochromic poikilocytosis

           --> increased RDW

# *normal reticulocyte, nucleated RBC, normal WBC count

# thrombocytosis or thrombocytopenia

# BM

    ; *Hypercellular with erythroid hyperplasia

  ; hemosiderin not demonstrated in marrow specimens by prussian blue stainining

# stool occult blood (+) :1/3

Differential Diagnosis

; lead poisoing

; β-thalassemia traint

; α-thalassemia traint

; chronic inflammation and infection

# elevation of FEP

    ; IDA, lead poisoning, chronic Hemolytic anemia, anemia associated with chronic disorder, porphyria

Treatment

    ; *elemental iron : 6mg/kg/day #3 given between meals

    ; parenteral iron preparation

           - ※no more rapid or complete

    ; limited milk : 500ml/day or less

           - ※93객 why? dual effect

                   / increased iron-rich foods

                   / prevented blood loss from intolerance to cow’s milk

㉿Table 413-1 Responses to Iron Therapy in Iron Deficiency

Time After Iron Administration	Response
12-24hr	Replacement of intraceluular iron enzymes; subjective improvement; decreased irritability; increased appetite
26-48hr	Initial bone marrow response; erythroid hyperplasia
48-72hr	Reticulocytosis, peaking at 5-7days
4-30days	Increase in hemoglobin level     ; 0.5g/dL/24hr
1-3mo	Repletion of stores

    ; *원칙은 Hgb이 정상이된 후 8주간 더 치료함.

    ; ※87★Failures of iron therapy

         - not received the prescribed medication

        - given a poorly absorbed form

        - unrecognized blood loss

        - incorrect original DX

    ; ※86,89★Indication Of Transfusion

    - *very severe anemia : Hb 4g/dL 이하

           - superimposed infection : iron therapy response 저해

    ; Method of transfusion

           - *2-3ml/kg of packed cell and then furosemide

           - modified exchange transfusion if congestive heart failure

Chapter 414. Other Microcytic Anemia

Sideroblastic Anemia

  heterogeneous group of hypochromic, microcytic anemia

  basis defect : heme metabolism 이상

  serum iron 증가

  BM : ringed sideroblast

  pearson syndrome 시 나타난다

  acquired sideroblastic anemia

-inflammatoy and malignant process,

 Alcoholism 시 나타난다

  X-liked recessive trait

  splenomegaly

  FEP 정상 or low

10 X-linked pyridoxine responsible sideroblastic anemia 와 pyridoxine refractory

 sideroblastic anemia

Lead Poisoning

RARE Type Of Hypochromic Microcytic Anemia

  congenital absence of iron-binding protein

  lymphatic tumor or lymphatic Hyperplasia

Section 3. Hemolytic Anemia

# Hemolysis

    ; premature destruction of red cell

    ; *shortened red cell survial, increased marrow activity

           --> *increased reticulocyte

# reticulocyte index

# if more severe anemia

  ; erythropoietin stimulation of erythropoiesis

    ; reticulocytosis

    ; BM : erythroid hyperplasia

    ; Hypertrophy of marrow expand medullary space

           - skull ＆ long bone의  X-ray 상 이상

# ★Direct Assessment Of Severity Of Hemolysis

  ; measurement of red cell survival

    ; *use RBC targeted with radioisotope Na₂⁵¹ CrO4 

 degradation of Hb : fecal Urobilinogen 증가

                    S-uncojugated bilirubin 증가

 gall stone

 specific iron binding protein : haptoglobulin

                              hemopexin

-> haptoglobulin-Hb complex cleared from circulation by RES

->decreased serum haptoglobulin and hemopexin

 Hct during hemolysis

:dependent on severity of hemolysis ＆ on increased marrow production of red cell

 aplastic or hypoplastic crises

    : parvovirus, Infection

 retculocytopenia, erythroid marrow failure

★Table XXI-2 Hemolytic Anemia And Their Treatment

Chapter 415. Hereditary Spherocytosis

; ▲common among person of northern European origin (1: 5000)

Etiology

; autosomal dominant in 75%

  - occasionally autosomal recessive

  - sporadic (new mutation) in 25%

; basic defict

    - *abnormality of spectrin (provide stabilty to the RBC memb )

    - recessive defect

           / *α-spectrin

    - dominant defect

           / *β-spectrin & protein 3

    - dominant & recessvie defects

           / *ankyrin

; ★Result Of Deficiency Of Spectrin, Protein 3, Ankyrin

    - *uncoupling in the vertical interactions of lipid bilayer skeleton

           --> *loss of membrane microvesicles

           --> *increase in cation, permeability, cation transport, ATP utilization, glycolytic metabolism

★Fig. 415-1

Clinical Manifestation

# neonatal period

    ; hemolytic disease

    ; *anemia and hyperbilirubinemia requierd phototherapy or exchange transfusion

# variable severity

    ; some asymptomatic

    ; severe anemia

           - pallor, jaundice, fatigue, exercise intolerance

           - expansion of the diploi of the skull and the medullary region of other bones

# *usually splenomegaly

    ; after infancy

    ; as early as 4-5yr

# pigmentary gallstones after late childhood (50% of unsplectommized pt)

# *susceptible to aplastic crisis due to parvovirus & hypoplastic crisis due to a variety of other infection

# Erythroid marrow failure

    ; profound anemia(Hct<10%)

  ; high output heart failure, hypoxia, cardiovascular collapse, death

Lab finding

-evidence of hemolysis; reticulocytosis

                       anemia

                       Hyperbilirubinemia

-MCHC ;elevated --MCV is normal

-BM ;erythroid hyperplsia

-osmofragility test (in hypotonic saline)---confirm

-autohemolysis test ; incubation under sterile condition for 48hrs at 37 ℃

                     -->normal RBC ; 15-45% hemolysis

                     -->abnormal autohemolysis corrected by addition of small amounts                          of glucose to the blood before incubation

★Differential Diagnosis

    ; immune hemolysis

           - esp. ABO incompatibility

    ; rare disease

           - *thermal injury, clostridia septicemia with exotoxemia, wilson’s disease

Treatment

# *folic acids 1mg/24hr

# splenectomy

    ; after 5-6yr age or older(for avoid postsplenectomy sepsis)

    ; *Hgb < 10 g/dl, reticulocytes > 10% 이면 실시

# Changes after splenectomy

  ; prevents gallstone and eliminates aplastic crisis

  ; jaundice and reticulocytosis rapidly disappear

  ; Hb level attains the normal range

  ; *the spherocytosis and osmotic fragility more pronounced

    ; hemochromatosis and hepatic failure in adult without splenectomy

# postsplenectomy sepsis

    ; vaccines for encapsulated organism such as pneumococcus, H-influenza and meningococcus  should be given prior to splenectomy 

    ; Prophylatic penicillin therapy

# post splenectomy thrombosis

    ; 흔히 발견 그러나 치료 필요없고 자연 치유됨         

Chapter 416. Hereditary Elliptocytosis

; most commonly found in West africa

   where the abnormality may provide resistance to malaria infection

Etiology

; inherited as a dominant disorder

; ★abnormalities of α- and β-spectrin and defective spectrin heterodoxies self-association

    --> gross membrane fragmentation (esp homozygous HPP)

; mutation in protein 4.1 and glycophorin C

    - less common

Clinical Manifestation

; *incidental & not asso. with singnificant hemolysis

; newborn

    - *neonatal jaundice

    - *no characteristic elliptocytosis

           / bizzare poikilocytosis, pyknocytosis

; usually features

    - later onset

    - anemia, jaundice, splenomegaly, and osseous change

; Cholelithiasis

    - later childhood

; aplastic crisis

; severe form

    - HPP

           : extreme microcytosis (MCV;50-60fl/cell)

           : *microspherocytosis than elliptocytsis

Diagnosis

; *PBS findings, AD inheritance, absence of other causes of elliptocytosis

Lab finding

; PBS

    - *▲important test

    - various degree of elongation (rod shape) of RBCs

    - microcytes, spherocytes, poikylocytes

; southeast asian ovalocytosis

    - ovalocytes

    - mutant protein 3

    - no hemolysis

; reticulocyte count reflicts severe of hemolysis

; erythroid hyperplasia

; indirect hyperbilirubinemia

; ★increased thermal instability

    - characteristic of HPP

    - *cell lyse at 45-46℃

Treatment

-no hemolysis, no treatment

-chronic hemolysis ; folic acid 1mg/24hr to secondary folic acid defience

-splenectomy ; Hb <10g/dl and reti >10%

Chpter 417. Hereditary Stomatocytosis

-red cells are cup shaped, circular area of centeral pallor(fig 415-2D)

 * Acquired stomatocytosis---liver disease

- Hereditary Stomatocytosis associated with red cell hydration status

  or with deficiency in Rh artigens , abnormalities within the region of protein 7

Tx

 -Splenectomy; not consistently effective as treatment

Chapter 418. Other Membrane Defects

Paroxysmal Noctunal Hemoglobinuria(PNH)

Etiology

    ; clonal abnormalities of a marrow stem cell that affects multiple blood cell lines

    ; not inherited

    ; acquired disorder of hematopoiesis

# underlying defect

  ; *vaious mutations in the PIG-A gene

           --> *glycolipid anchor defect

           --> defect in proteins of cell memb.

                   / *decay accellerating factor, C8 binding protein etc

           --> the red cell susceptible to damage by serum complement

           --> hemolysis

Clinical Manifestation

-mean age ;13yr(0.8-21.4yr)

-marrow failure (60% of patients)

-Noctunal and morning hemoglobulinuria

-pyogenic infection

-thrombosis

-abd, back, head pain

-드물게 ALL 로 진행

-생존률 ; 5년 80%, 10년 60%, 20년 28%

-mortality is related primarily to the development of aplastic anemia or thrombotic complication

Laboratory Finding

 -Ham test or sucroe lysis test

 -hemosiderinuria

 - marked reduced levels of red cell acetylcholinesterase

Treatment

 -splenectomy is not indicated

 -Glucorticoid; Prs(2mg/kg/24hr)

 -prolonged anticoagulant therpy

 -iron therapy due to urinary loss of the hemosiderin

 -Androgens( halotestin and danazol)

 -antithymic globulin

 -Bone marrow transplantation

Acanthocytosis

-characterized by red cells with irregular circumferencial pointed  projection

-liver disease, congenital a betalipoproteinemia, neuromuscular abnormalities

  ,retinitis pigmentosa 에서 보인다

 그외 late onset myopathy ,splenomegaly, hemolysis with acanthocytosis에서도 나타남

Chapter 419. Hemogloblin Disorder

Hemoglobin Structural Abnormalities

 -500 structural variants of Hb have been identified

 -many abnormal Hb identified by electrophoresis but cannot be specifically identified by      this              means alone

419.1 Sickle Cell Hemoglobulinopathy

 -A substitution of glutamic acid at the 6th position of its beta chain by valine

 -In the oxygenated state HbS functions normally

 --->spiny, brittle character of sickle erythrocytes under condition of hemoglobin is          deoxygenated

-erythrocytes of sickle cell trait resistent to invasion by                

 malaria parasites (plasimodium falciparum)

Sickle Cell Anemia

 -characterized by severe chronic hemolytic disease

 -attributable to ischemic changes resulting from vascular occlusion  by masses of sickled cells

Clinical Manifestation

    ; hemolytic anemia gradually develops over the 1st 2-4mo

    ; other features

           - *uncommon prior to 5-6mo

    ; *hand foot syndrome

           - Acute sickle dactylitis

    - *1st overt evidence of sickle cell ds in infancy

    ; ★acute painful vaso-occlusive episodes

       - *▲frequently and prominent manifestation

           - in young children : involves the exetremities

           - in olrer children : involves head, chest, abdomen, back

    ; more extensive vaso-occlusive events

       - infarct of bone marrow and bone

       splenic infarct->autosplenectomy

       cerebrovascular occlusion

       ischemic damage to myocardium, liver,and kidneys

    ; ★Acute Splenic Sequestration

           - *infants & young children

        - large amounts of blood acutely pooled in the spleen

                   --> massive enlarged spleen

         --> signs of circulatory collapse rapidly developed

    ; increased susceptibility to infection

           - meningitis, sepsis

           - *mainly pneumococcal, H. influenza

           - due to

                   ① altered splenic function

                   ②deficient level of serum opsonin against pneumococci

Laboratory Finding

-PB smear; target cell, poikilocytosis,and sickle cells

-abn  LFT

-diffuse hypergammaglobulinemia

-BM; erythroid hyperplasia

-X-ray ; expanded marrow spaces and osteophorosis

Diagnosis

-electrophoresis at the alkaline pH

-hemoglobin solubility test ; confirm test

 -->HbS 80-95%

     HbF 2-20%

     HbA2 ;normal

     HbA ;absent

Differential Diagnosis

    ; rheumatic fever, rheumatic arthritis ,osteomyelitis, leukemia

Treatment

    ; maintaining full immunization

           - polyvalant pneumococcal vaccine

           - H-influenza and hepatitis B immunization

    ; prophylactic penicillin G

           - highly effective

           - orally twice daily

           - starting in early infancy to at least 6yr

    ; packed RBC transfusion

    ; splenectomy

           - repeated episodes of splenic sequestration

419.2 Sickle Cell Trait

(Heterozygous Hb S; HbAS)

-Heterozygous expression of the sickle hemoglobin gene is usually associted with a totally                                  benign clinical course

-8% of American blacks have sickle cell trait, with 35∼45% of their hemoglobin consisting   of Hb S

-This low level of Hb S is insufficient to produce sickling manifestations under usual                          circumstances, but under conditions of severe hypoxia vasoocclusive                       complications

-The diagnosis is established by hemoglobin electrophoresis, with confirmatory sickle testing

419.3 Other Hemoglobinopathies

Hemoglobin C

    ; α₂ β₂⁶lysine

    ; 2% of American blacks

    ; homozygous individual (Hb CC disease)

           - moderately severe hemolytic anemia with hemoglobin levels from 8to 11g/dL

           - reticulocytosis of 5-10%

           - splenomegaly

    ; peripheral blood

           - striking numbers of target cells and occasional spherocytes

Hemoglobin E

    ; α₂β₂²⁶lysine

    ; prevalent from southeast asia

    ; homozygous individual (Hb EE diseases)

           - hemolytic anemia with prominent target cells

           - microcytosis

           - moderate to severe splenomegaly

419.4 Unstable Hemoglobin Disorders

(congenital Heinz Body Anemia)

- characterized by molecular instability, leading to denaturation and precipitaion of hemoglobin within the red cells

-In the more severe forrms of amorphous masses of the denatured hemoglobin known as                                      Heinz bodies, attach to the red blood cell membrane, damaging the cell                     and shortening           its survival

-autosomal dominant hemolysis first becomes apparent at 3-6 mo after birth Hb F is replaced            by adult hemoglobin

419.5 Abnormal Hemoglobins Causing Cyanosis

    ; *Hb Kansas and Hb Beth Israel

    ; *Hb M group

419.7 Hereditary Methemoglobinemia

# normal iron of oxygenated and deoxygenated hemoglobins

    ; ferrous state

# methhemoglobin

    ; ferric state iron

    ; less than 2% in normal

Hereditory Methemoglobinemia With Deficiency Of NADH Cytochrome B5 Reductase

# all type ; AR

# Type I

    ; ▲frequent

    ; deficiency of cytochrome b5 reductase is limited to erythrocytes

    ; cyanosis is the only consequence

# Type II

    ; progressive disorder

    ; approximately 10% of patients with hereditary methemoglobinemia

    ; *deficiency of cytochrome b5 reductase in all tissues

    ; methemonglobinemia with severe encephalopathy before 1yr

    ; mental retardation, microcephaly, retarded growth, attacks of bilateral athetoid movements, strabismus, oposthotonus, generalized hypertonia

# Type III

    ; deficiency of cytochrome b5 reductase in erythrocyte,lymphocyte, platelet and granulocyte

    ; cyanosis is the only manifestation

# Type IV

    ; disease from a deficiency of erythrocyte cytochrome b5 and is associated with chronic cyanosis

Treatment

    ; *Daily oral treatment with ascorbic acid (200-500 mg in divided doses)

           - chronic high doese of ascorbic acid

                   --> hyperoxalura and renal stone formation

    ; *Methylene blue given intravenously (1-2mg/kg) daily

         - oral administration of methylene blue (3-5mg/kg)

419.8 Syndromes Of Hereditary Persistence Of Fetal Hemoglobin (HPFH)

-characterized by the production of elevated levels of Hb F beyond the neonatal period

419.9 Thalassemia Syndromes

★Table 419-2

Honozygous β°-Thalassemia (=Cooley Anemia, Thalassemia Major)

Clinical Manifestation

; *severe progressive hemolytic anemia during 2-6mo

; regular transfustion이 필요하다.

    - without transfusion : death within a few yr

; hypertrophy of erythropoietic tissue in medullary and extramedullary locations

    - bones : thin, athologic fractures

; *characteristic facies, pallor, hemosiderosis, jaundice

    --> ★Greenish-Brown Complexion

; spleen and liver are enlarged by extramedullary hematopoiesis and hemosiderosis

; Growth is impaired in older children; puberty is delayed or absent because of secondary                                    endocrine abnormalities

; diabetes mellitus Cardiac complications, severe hypochromia and microcytosis many          bizarre, fragmented poikilocytes and target cells are present

Laboratory Finding

-Large numbers of nucleated red blood cells circulate

-The unconjugated serum bilirubin level is elevated  the serum iron level is high, with                      saturation of the iron-binding capacity

Treatment

-Transfusions to maintain the hemoglobin level above 10 g/dL

-Transfusions of 15-20 mL/kg of packed cells are usually necessary every 4-5wk

-Hemosiderosis--splenectomy exceeding 240 mL/kg of packed red blood cells/yr

-bone marrow transplantation

-Skeletal deformities and hepatosplenomegaly develop hemoglobin levels ar usually mainained at 6-8g/dL without transfusion

Other β-Thalassemia Syndromes

    ; most forms of heterozygous B-thalassemia

           - mild anemia

    ; Hypochromic and microcytic, poikilocytosis, ovalocytosis, often basophilic stippling

    ; Target cells

    ; The mean corpuscular volume (MCV) is low, averaging 65fL, the mean corpuscular hemoglobin (MCH) values are also low (26 pg)

    ; The serum iron level is normal or elevated

# β-thalassemia trait

    ; 90% of patients

           - *diagnostic elevations of Hb A2 of 3.4-7%

  ; 50% of patients

           - *slight elevations of HbF 2-6%

α-Thalassemia

-Deletions of α-globin genes account for most of these abnormalities

-All four of these genes (see Table 419-2)

-The most severe form of α-thalassemia, accompanied by a total absence of α-chain                       synthesis

419.10 Hemocbromatosis

-Excessive storage of iron, the form of hemosiderin in parenchymal cells, liver, heart, gonads,           skin, and joints

①-Idiopathic hemochromatosis, autosomal recessive mode the classical clinical triad of                                       cirrhosis bronzing of the skin, and diabetes mellitus

-Serum ferritin characteristically greatly elevated, with increased transferrin saturation

-HLA types A-3, B-7, and B-14 

-With treatment by repeated phlebotomy, organ damage can be prevented

②-Neonatal hemochromatosis

③-Transfusion - induced hemosiderosis

Chapter 420. Enzymatic Defects

420.1 Pyruvate Kinase Deficiency

-Generation of adenosine triphosphate (ATP) within the red cell is impaired and low levels of ATP, pyruvate, and NAD+ are seen 

-As a consequence of decreased ATP, the red cell cannot maintain the potassium and water             considerably reduced

-The human PK gene mapped to chromosome 1q21, and a variety of mutations involve from a severe neonatal hemolytic anemia to mild , Severe jaundice and anemia may occur and, kernicterus has been reported, hemoglobin values from 8 to 12 g/dL 

    Polychromatophilia and mild macrocytosis reflect the elevated reticulocyte count

    Spherocytes are usually present

-Autohemolysis is moderately or markedly increased, of a marked reduction of pyruvate                                       kinase (PK) activity or an increase in the Michaelis Menten dissociation                   constant (KM)              for its substrate

-Exchange transfusions may be indicated for hyperbilirubinemia in the newborn

-Transfusions of packed red cell

 -splenectomy should be performed after 5-6 yr

420.2 Other Glycolytic Enzyme Deficiencies

deficiency of enzymes of the pentose phosphate pathway and related compounds

420.3 Glucose-6-Phosphate Dehydrogenase (G-6-Pd) And Related Deficiencies

; *▲important disease of pentose phosphate pathway

# ★Two Clinical Syndromes

    ; episodic hemolytic anemia

           - induced by infection or certain drugs

    ; spontaneous chronic nonspherocytic hemolytic anemia

; X-linked

; balanced polymorphism

; resistance to Falciparum malaria

; ★Normal Enzyme

    - *G-6-PD B+ : mostly

    - *G-6-PD A+ : normal variants in african-american populations

Episodic Or Induced Hemolytic Anemia

Etiology

    ; more frequently in males

    ; 13% of male

           - *african-americans with mutant gene : G-6-PD A-

           - 5-15% or less of normal

    ; *italian, greeks, other mediterranean, middle eastern, african, asian ethnic group

           - high incidence : 5-40%

           - *G-6-PD B-

Clinical Manifestation

    ; *develop 24-48hr after ingestion of substances

㉿Table 420-1 Agents Precipitating Hemolysis In Glucose-6-Phosphate Dehydrogenase Deficiency

    ; “favism”

           - after ingestion of fava bean(mediterranean dietary staple)

    ; hemolysis

           - *variable with inciting agents

Laboratory Finding

    ; Heinze bodies (precipitated hemoglobin)

           - visible in unstained or supravital stain

           - *invisible after first 3-4days illness

    ; PBS

           - a few fragmented cells, polychromatophilic cells (bluish large red cells)

    ; reticulocytosis

Diagnosis

    ; *direct or indirect demonstration of reduced G-6-PD activity in red cells

    ; enzyme activity in affected persons

           - 10% of normal or less

    ; ★Satisfactory Screening Tests

           - decoloration of methylene blue

           - reduction of methemoglobin

Prevention and Treatment

-The usual does of aspirin and trimethoprim sulfamethoxazole do not cause clincally aspirin          administered for acute rheumatic fever (60-100 mg/kg/day) may produce a severe                                 hemolytic episode

-When hemolysis has occured, supportive therapy may require blood transfusions

Chapter 421. Hemolytic Anemias Resulting From Extracellular Factors

Autoimmune Hemolytic Anemias

# Hallmark

    ; ★positive coomb’s test

Autoimmune Hemolytic Anemias Associated With “Warm” Antibodies

Etiology

 -Chronic nonspherocytic hemolytic anemia isoimmune hemolytic anemia 

-abnomal antibodies are directed against red cells  but the pathogenetic

-The autoantibody may be produced as an inappropriate immune response to a red cell -

-If the autoimmune hemolysis associated with an underlying disease such as

     a lymphoprolifeative disorder, systemic lupus erythematosus, or immunodeficiency

-In as many as 20% of cases of immune hemolysis, drugs may be implicated

    "hapten" mechanism (e.g, penicillin or sometimes cephalosporins)

-Antibodies to the drug either newly or previously formed, bind, such as quinine and                         quinidine,

-"tertiary complex  α-Methyldopa true autoantibodies

-The onset may prostration pallor, jaundice pyrexia, and hemoglobinuria, primarily fatigue and pallor

-The spleen is usually enlarged primary site for destruction of Ig-G- coated red cells

-A consistent response  to glucocorticoid therapy, low mortality, and full recovery are                      characteristic of the acute form

-a prolonged and chronic more frequent in infants and in children older than 12yr

-Hemolysis may continue for many months or response to glucocorticoids is variable -Mortality is about 10% often attributable to an underlying systemic disease

-In many cases the anemia is profound, hemolglobin levels <6g/dL

-Considerable spherocytosis and polychromasia are present

-More than 50% of the circulating red cells may be reticulocytes, nucleated red cells

-Leukocytosis

-The platelet count is usually normal, concomitant immune thrombocytopenic purpura

(Evans     syndrome) 

-The prognosis of patients with Evans syndrome is poor, many develop chronic disease,

 including some with systemic lupus erythematosus

-The direct Coombs test is strongly positive, belong to the IgG class

-particularly C3b, may be detected on the red cells in conjunction with IgG

Treatment

    ; Transfusions usually are only of transient benefit

    ; *Glucocorticoids

           - Prednisone 2 mg/kg/24hr

                   / some patients with severe hemolysis, does up to 6mg/kg/24hr

    ; intravenous immunoglobulin and danazol

           - if hemolytic anemia remains severe despite glucocorticoid therpapy

                   or very large doses are necessary to maintain a reasonable hemoglobin

    ; splenectomy

    ; immunosuppressive agents

    ; plasmapheresis

Autoimmune Hemolytic Anemias Associated With “Cold” Antibodies

-Red cell antibodies that are more active at low temperature agglutinated red cells at        temperatures below 37  C have "cold" antibodies  They are primarily of the IgM

    Cold antibodies specificity for the oligosaccharide antigens of the I/i system

-idiopathic cold agglutinin secondary to infection such as Mycoplasma pneumoniae and                                    infectious mononuclesis, or secondary to lymphoproliferative

-The mean corpuscular volume (MCV) mav be spuriously elevated   The severtiy of the                                      hemolysis is related to the thermal amplitude of th antibody

-Cold agglutinin disesse is less common in children than in adults, and it more frequently                results in an acute, self-limited episode of hemolysis

-Glucocorticoids are much less effective in cold aggulutinin dz

 -should avoid esposure to cold and be treated for any undrelying disease

-infrequent patients with severe hemolytic disease the treatment immunosuppression and plasmapheresis

-splenectomy is not useful in cold agglutinin disease

-mediated by the donath Landstediner hemolysin, an IgG cold-reactive autoantibody with                                   anti-P specificity

-self-limited and are associated with viral infections, and they are now rarely seen            associaed with congenital or acquired syphilis

-Treatmaent include transfusions for severe anemia and avoidance of cold ambient          temperatures

Chapter 422.  Hemolytic Anemias Secondary To Other Extracellular Factors

Fragmentation Hemolysis

; Red cell destruction occurs in this grop of diseases because of mechanical injury as the cells traverse a damaged vascular bed

    hemolyticd-uremic syndrom or thrombotic thrombocytopenic purpura

    Kasabach-Merritt syndrome

Thermal Injury 

Renal Disease

    Erythropoietin production may be decreased marrow suppressed by toxic metabolites

Liver Disease

Toxins And Venoms

 Haemophilus influenzae, staphylococci, streptococci, clostridial                         infections, cobras, vipers, and rattlesnakes,

Wilson's Disease

Section 4. Polycythemia

 : RBC count, hemoglobin level, total RBC volume 모두 정상치 이상일  

  in postpubertal children ; Hb＞16 g/dl & RBC mass＞35 ml/kg 이상 적용

  true polycythemia ; total RBC 와 total Blood volume 양쪽 다 증가시

  acute dehydration and burns ; plasma 양이 감소하여 Hb 과 Hct 수치 증가

  DDx : radioisotopic techniques 필수

Primary Polycythemia ( Polycythemia Rubra Vera )

  진단 기준은 total RBC volume 의 증가, arterial 02 saturation ≥92%, 비장 비대이다

  supportive lab abnormalies include : thrombocytosis, leukocytosis, leukocyte alkaline

          phosphatase 증가, vit B12 증가, unsaturated B12 binding capacity 증가 포함

  Tx ; phlebotomy, antiproliferative chemotherapy

Seconday Polycythemia

★Table XXI-3

  chronic arterial oxygen desaturation -> hypoxia of kidney-> erythropoietin 생산 증가

   -> 적혈구 생산 증가

  hematocrit 가 65%이상시 Phlebotomy 필요

  1000 m 높이가 높아질수록 Hb 은 4%증가 (고지대)

  선천성 methemoglobinemia 은 cytochrome b5 reductase의 감소로 오는것으로 cyanosis 와

   polycythemia 의 원인이 된다 

 대부분은 무증상이 상염색체 열성유전을 한다

  hematocrit 가 65-70%(hemoglobin ＞23 g/dl)일때 blood viscosity 가 두드러지게 증가한다

Section 5. the Pancytopenias

Chapter 423. The Constitutional Pancytopenias

Etiology

㉿Table 423-1

Epidemiology 

; Fanconi anemia 의 heterozygote frequency 는 1:100-1:300 이다

Pathology and Pathogenesis

# Fanconi anemia

    ; ★spontaneous or clastogenic-induced chromosomal breaks(100%)

           - *hallmarks of fanconi anemia

    ; cytogenic abnormalities in lymphoid, hematopoietic and fibroblast cell         

           - defective DNA repair, increased susceptibility to oxidant stress

    ; abnormal cytokines networks

           - *depressed level of GM-CSF, stem cell factor, IL-6

# dyskeratosis congenita

    ; 10% chromosomal breaks

Clinical menifestation

# Fanconi anemia

    ; *hyperpigmentation, cafe-au-lait spots, skeletal abnormalitis(esp. absent or hypoplastic thumb) short stature, wide array of integumentary & organ abnormality

# Dyskertosis congenita

    ; hyperpigmentation, nail dystrophy of both the hands and foot, leukoplakia epiphora, blepharitis cataracts

Laboratory Finding

  macrocytosis (mild poikilocytosis and anisocytosis) 나타나며, RBC 에는 hemoglobin-F 증가

   말초성 pancytopenia 가 나타날때 acquired aplastic anemia와 구분하기위해 BM Exam 필요

    -> hypoplastic or aplastic

Diagnosis

    short stature와 함께 skeletal and cutaneous 이상을 가지고 hematologic problem 이 없을때 congenital pancytopenia 제시

Complication

   consequences of bone marrow failure-> leukemia and other cancer

   Organ Cx ; liver problem-Fanconi anemia, malabsorption -Shwachman-Diamond syndrome

   bleeding & infection

Treatment

    ; traditional backbone of Tx

           - *steroids & androgens(특히 oxymetholone or nandrolone)

           - 50-75% improvements

           - *수개월후에 효과가 나타난다.

           - common relapse & complications

                   / hepatic tumor, obstructive liver disease

    ; BMT

           - only curative therapy

    ; GM-CSF

    ; multiple cytokines (EPO, IL-3, IL-6)

    ; gene therapy

Prognosis

   안좋음

Chapter 424. The Acquired Pancytopenias

Etiology & Epidemiology

㉿Table 424-1

Patholoy & Pathogenesis

# ♥Severe Aplastic Anemia

  ① absolute neutrophil count ＜500/mm³

  ② Platelet count＜20000/mm³

  ③ Reticulocyte count＜1% after correction for the hematocrit

Clinical menifestaton, Lab finding, DDX

    ; anemia, leukopenia, thrombocytopenia 있으면서 fatigue, cardiac failure, Infection  bleeding 의 risk가 증가

   fetal hemoglobin 은 congenital pancytopenia 을 제시하나 진단을 내리지는 못한다

# Ham test

    ; rule-out PNH

# BM biopsy

    ; ★lymphocyte > 70%

           --> *poor prognosis

Complication

  bleeding & infection

Treatment

    ; ★Antithymocyte Globulin(ATG)

           - major therapy

           - *45% response rate

           - *60% survival rate similar to BM transplantation

    ; corticosteroid, cyclosporine, bone marrow transplantaton

Pancytopenias Caused By Marrow Replacement

  BM replace혹은 infiltrate 과정이 acquired pancytopenia 를 초래할수 있다

Chapter 425. Infectious And Other Complication Of Pancytopenia

Risk Factor For Infection

   neutropenia(polymorphonuclear neutrophil count＜500/mm3) ; most important risk factor

Predominant Organisms Responsible For Infection

  pancytopenic 환자에게는 bacteria,fungi,viruses,parasites들에 대해 감염의 위험이 증가한다

   during the last decade, gram-positive bacteria (coagulase negative staphylococci,Staphy

    aureus,enterococci,streptococci) 가 gram-negative organisms (pseudomonas aeruginosa)보다 더 많다

   neutropenia가 오랫동안 있었던 환자에선 fungus 의 감염이 많다

High-And Low Risk Patients

  7-10 일 이하의 neutropenia를 가진환아는low risk patient이고, 그이상의 시기동안 일때

   high risk patient이다

  transient neutropenia : drug & infection

    -drug ; antimicrobial agents ( penicillins,cephalosporins,trimethoprim-sulfamethoxazole)

            antiviral agent ( gancyclovir )

            antineoplastic agents ( anthracyclines,antimetabolites,antifols,alkylators)

    -virus infection : rubella, influenza, CMV, E-B virus,

Initial Management Of The Neutropenic Patient Who Becomes Febrile

Initial Therapy

  neutropenic 환자가 열이 날때(single oral temperature >38..5。C

                               or three elevations > 38。c   during a 24hr period)

                               광범위 항생제를 즉각 투여 하여야 한다.

Criteria For Modifying Initial Treatment

  fever and neutropenia를 1주일이상 지속될때 antifungal agent start

  Asfergillus 경우 ; higher dose of ampho( 1.5mg/kg/24hr) 투여

Management Of Sites Of Infection

Catheter-Associated Infections

; gram-positive bacteria( coagulase negative staphylococci

                                 or S.aureus) dominant

                                 gram-negative bacteria (P.aeruginosa,acinetobacter,

                                 Enterobacteriaceae)

                                 fungal infection

Pneumonias

; neutropenic patient가 경험적 항생제 투여에도 72시간 이후 더 심해지면

                more aggresive procedure가 필요

               ; interstitial pneumonia 의 가장 대표적인 것은viral infection or pneumocystis

                 carinii 이다

GI Infection

; neutropenia에서 회복하고 있는 환자에서 지속적이거나,반복적인 열이동반될                   때 hepatosplenic candidiasis가 가장 흔하다

                흔히 rebound leukocytosis,elevated alkaline phosphatase, RUQ abdominal                      discomfort증상이 있고, Ultra, CT, MRI 상 특징적인 bull`s eye 소견이

                보인다

                 치료는 Ampho-B 투여

                 - typhlitis (cecitis); appendicitis와 유사하게 RLQ pain, tenderness

                 나타나며, 원인은 G-negative infection on cecum site

                 - perianal cellulitis ; mixed infection

Section 6. Blood and Blood Component Transfusion

Chapter 426. Red Blood Cell Transfusions

♥Table 426-1

; IDA는 Hgb 5mg/dl라 하더라도 일단 oral iron therapy를 먼저 실시한다.

# ♥Consideration For Transfusions

    ; patients symptoms, signs, functional capacities

    ; presence or absence of cardiorespiratory and CNS disease

    ; cause and anticipated course of the anemia

    ; alternative therapies

# RBC products

    ; suspension of RBCs isolated from whole blood

           - Hct 60%

           - choice for children and adolescents

    ; packed RBCs

           - Hct 70-90%

           - choice for neonates

           - 15ml/kg for 2-4hr

Chapter 427 PLT Transfusions

♥Table 427-1

# ★Ideal Goal

    ; > 50 x 10⁹/L for children

    ; > 100 x 10⁹/L for neonate

# 10ml/kg이상은 수혈하지 않는다.

Chapter 428 Neutrophil (Granulocyte) Transfusions

♥Table 428-1

# ★Dose of fresh leukapheresis

    ; neonate and infants less than 10kg

           - 1-2 x 10⁹/kg/GTX

    ; larger infants and children

           - 1 x 10¹⁰/GTX

    ; adolescents

           - 2-3 x 10¹⁰/GTX

Chapter 429 Transfusions Of Fresh Frozon Plasma

♥Table 429-1

; deficiencies of clotting factor Ⅱ,Ⅴ,Ⅶ,Ⅹ,? 있을때 유용

; factor VIII and fibrinogen의 결핍에는 cryoprecipitate투여

; 수혈은 15 ml/kg 로 준다.

# ♥Indication For FFP In Neonate

    ① reconstitution of RBC conccentrates to simulate whole blood for use in massive transfusion

  ② hemorrage secondary to vit K deficiency

  ③ DIC with bleeding

  ④ bleeding in congenital coagulation factor deficiency

; prophylactic FFP transfusion은 권장되지 않는다.

Chapter 430 Risk Of Blood Transfusions

; transfusion-associated human immunodeficiency virus

    - 1:300,000-1:1,000,000 donor exposure

; risk of viral hepatitis

    - 1:3000-1:5000 donor exposure

; infection

    - syphilis, parvovirus B19, EB virus, Chagas`disease

; *fluid overload, graft-versus-host disease, electolyte and acid-base imbalances, iron overload, increased susceptibility to oxidant damage, exposure to plasticizers, hemolysis when T-antigen activation of red blood cells(RBCs) has occured, immunosuppression, alloimmunization

Section 7. Hemorrhagic and Thrombotic disease

Chapter 431 Hemostasis

Schema Of Hemostasis

# ♥Classic Schema Of Hemostasis

  ; vascular response and platelet plug formation (primary hemostatic mechanism)

    ; formation of a stable fibrin clot (the 2ndary hemostatic mechanism)

# ♥Three Phase Of Coagulation(Secondary Hemostatic Mechanism)

    ; phage 1

           - thromboplatin formation by interaction of certain coagulation factor, phospholipids and tissue juice

    ; phage 2

           - prothrombin --> thrombin

  ; phage 3

           - soluble fibrinogen --> fibrin

# ★Coagulation Inhibitors

  ; antithrombin III - inhibits thrombin, factor Xa, IXa, XIa, XIIa

    ; protein C - inhibits factor VIII, V

    ; protein S - cofactor of protein C

Table 431-1

★Figure 431-1

Evaluation Of The Patient With A Suspected Hemostatic Defect

History And Physical Examination

# ★Characteristics Of Defective Primary Hemostatic Mechanisms

    ; mucous membrane bleeding

           - epistaxis, hematuria, menorrhagia, gastrointestinal

    ; petechiae in skin and mucous membrane

  ; multiple small ecchymotic lesions

# ★Characteristics Of Defective Secondary Hemostatic Mechanism

    ; deep bleeding into joint and muscles

  ; large spreading ecchymotic lesions

  ; hematomas

Laboratory Tests

Bleeding Time

    ; *▲best test for the vascular and platelet of hemostasis

Platelet Count

         - a linear relationship between the bleeding time and platelet count

         - BT(min)=30.5 - (platelet count(per ul)/3850)

         - BT와 platelet count 가 서로 비례하지 않으면,a qualitative platelet defect를

           의심할수 있다.

Platelet Aggregation And Other Tests

# ♥Platelet Function Tests

 - platelet aggregation test

 - clot retraction test

 - prothrombin consumption test

 - ATP and serotonin release

Thrombin Time

    ; *evaluation of phase III

    ; prolongation of thrombin time

           --> hypofibrinogenemia

         --> dysfibrinogenemia

         --> by heparin ; 따라서 heparin의 영향을 배제하기위하여

     thrombin like enzyme 의 일종인 reptilase를 사용하기도 한다.

Prothrombin Time

    ; *evaluation of phase II                           

    ; if intact phase III

           - *deficiency of factor II, V, VII, X

Activated Partial Thromboplastin Time

    ; evaluation of phase I

    ; *assessment of adequacy of factor XII, XI, IX and VIII

Mixing Study

    ; abnormal aPTT를 보이는 환자의 Plasma 와 normal plasma를 섞는다.

         - correction of the abnormal aPTT in a patient with a bleeding disorder

           --> deficiency of factor VIII, IX or XI

           - correction of the abnormal aPTT in a patient without a bleeding disorder

           --> a deficiency of XII, prekallikrein, high molecular weight kininogen

         - incorrection of abnormal aPTT in a patient with bleeding disorders

           --> *presence of an inhibitor

         - incorrection of abnormal aPTT in a patient without bleeding disorders

           --> *presence of the inhibitor so-called lupus anticoagulant

Other Tests

# ★Euglobulin Clot Lysis Time (ELT)

    ; assess fibrinolysis

  ; short ELT

           - increased plasminogen activator

    - reduced fibrinogen

  ; prolonged ELT

           - reduced plasminogen

    - reduced activator

    - extremely increased fibrinogen concentration

Chapter 432. Phase I Disorders : The Hemophilias

432.1 Factor VIII Deficiency (Hemophilia A)

; hemophilia 의 80% 차지

; defective gene on the X chromosome

; patients with hemophilia and carrier women

    - reduced factor VIII activity

  - normal plasma level of the von Willebrand protein

; normal persons

   ; the plasma ratio of VIII activity to von Willebrand protein

     -> most female carriers : less than 1

     -> used for carrier detection and genetic counselling

 - family history is positive in 80% of cases

 - sporadic cases <- by a new mutation

# ※93★Clinical Severity

    ; *severe - less than 1% (1 unit/dl) of normal activity

  ; moderate - 1-5%

  ; mild - 6-30%

  ; normal - 50-150%

Clinical manifestation

    ; bleeding tendency in neonatal period

           - *due to no cross placenta of factor VIII

    ; severe disease 의 90%에서 1세경까지 clinical bleeding 이 나타난다.

    ; ★hemarthrosis

           - *hallmark

    ; factor VIII 의 activity가 6%이상되면 spontaneous symptoms은 나타나지 않는다.

Laboratory Finding

    ; *greatly prolonged PTT

    ; normal platelet count, PT

Treatment

    ; prevention of trauma

  ; avoidance of aspirin and other drugs that affect platelet function

  ; *immunization against hepatitis B virus

Replacement Therapy

    ; essential treatment

    ; iv infusion of FFP or plasma concentration

# ★Calculation Of Dosage

    ; 50%이상 증가시켜야 한다.

    1) FFP

           ; ㉿1unit of factor VIII/1ml of normal plasma(plasma volume 45ml/kg)

           ; 25-50 units/kg of factor VIII

            --> raise the recipient`s level to 50-100%

    2) factor VIII concentrations

           ; ★75-125units of factor VIII/1bag of cryoprecipitate

# ※93 Hemarthrosis

    ; *replacement threapy가 가장 중요하다.

  ; raise factor VIIIlevel to about *50%(50units/dl) and *maintain at least above 5% for 48-72hrs

    ; initial immobilization

           - but *passive exercise within 48hrs to prevent joint stiffmess and fibrosis

# when hemorrhage in vital areas such as brain or neck or when major surgery

    ; intensive replacement therapy

           - *plasma level above 50% for 2wks

           - *use factor VIII concentrates

# oral mucous membrane hemorrhage and tooth extraction

    ; *replacement therapy with EACA (ε-aminocaproic acid) 50-100mg q 6hr

# ※89 Long Term Complication

     -> abnormal hepatic enzyme activities

     -> chronic active hepatitis and cirrhosis

     -> hepatitis B & C

     -> AIDS

Desmopressin(DDAVP)

    ; *minor bleeding episodes에만 사용

           - oral bleeding, dental extractions, small hematomas

           - ineffective in hemarthrosis, CNS bleeding and after major surgery

    ; 0.3 ug/kg once every 1-2 days

    ; raise the factor VIII level 25-50% above the baseline

※92 Factor VIII Inhibitors

    ; 10-15% of patients

           --> refractory to factor VIII therapy

    ; *not related to the number of plasma transfusion

           --> *should not be withhold replacement therapy

    ; Ig G globulin으로 구성

    ; ♥1 “bethesda unit”

           - *factor VIII level from 1 to 0.5unit in 1ml normal plasma

    ; ♥Treatment

           - massive doses of factor VIII concentrates

           - plasmapheresis with replacement with factor VIII 

           - *factor IX concentrates(Konyne; Autoplex; Feiba)

           - porcine factor VIII

           - immune tolerance

                   / IV immunoglobulin, cyclophosphamides, factor VIII의 comination therapy

  ; immunosuppressive therapy ; no value

Prenatal Diagnosis

   - each male fetus of a mother who carries hemophilia -> 50% risk

   - fetal plasma assay : a markedly higher von Willebrand protein level compared to

                         the factor VIIIc level

432.2 Factor IX Deficiency (=Christmas Disease, Hemophilia B)

 Factor Ⅸ은 liver에서 생산되며, vit k dependent coagulation factors 이다.

  Christmas Disease ; Hemophilia B

Clinical manifestation

  - about 12-15% of hemophilia

   .vit-k dependent coagulation factors .부족에 의해 12∼15％에서 Hemophilia가 발병됨. 

  - clinically indistinguishable from factor VIII deficiency

  - joint and muscle hemorrhages ; characteristic

  - X-linded recessive trait

   .임상적으로 factor VIII def.(hemophilia A)와 구분이 힘듬 - factor Ⅸ는 factor VIII 달리 정성적으로 신생아기에서는 감소되어 있기때문에

    .detection using monoclonal antbody or DNA analysis

Lab findings

   .plasma 내에서  coagulant activity의 정도에 따라 질병의 severity가 결정됨                 - PTT - prolonged

   - BT and PT ; normal

 

   .분류-    CRM+

             CRM-(OR CRMred) ; 75% 

   CRM- mutation:  .large gene deletions

          . frameshift mutation            종류       

            . space-site mutation 

            . nonsense mutation

Treatment

  - FFP (1ml of FFP contain 1 unit of factor Ⅸ) or factor Ⅸ concentrates

      - 1 unit of factor Ⅸ/kg -> raise the plasma factor Ⅸ by 1.0-1.2%

                 .factor IX는 factor VIII 달리 정상적으로 신생아기에서는 감소되어 있기                -> 따라서 severe case에서 100% 올려주기 위해서 100unit/kg 를 주어야 한다.

432.3 Factor XI Deficiency (=Hemophilia C)

   - the least common type of hemophilia ; 2-3%

   - incomplete autosomal recessive ; affect males and females

   - porlonged PTT, normal PT and BT

   - Tx ; half life 40-80hrs

          FFP 10-15ml/kg every 24hrs

432.4 Factor Xii Deficiency (= Hageman Factor Deficiency)

   - abnormal phase Ⅰ coagulation : PTT and clotting times prolonged,but no clinical

     abnormalities

432.5 Von Willebrand Disease (=Vascular Hemophilia )

; more frequent than hemophilia B

Etiology

    ; underproduction of von willebrand protein

  ; von willebrand protein

           - contains a platelet adhesive component (von willebrand factors)

           - protein function to carry factor VIII

Clinical Manifestation

# Classification

    type Ⅰ

           ; classic form, autosomal dominant

       ; normal multimer structure of the von willebrand protein on gel eloectrophoresis

  type Ⅱ

           ; A & B

           ; autosomal dominant

           ; *loss of large and intermediated-sized multimer

  type Ⅲ

           ; *autosomal recessive

    ; normal multimer structure of the von willebrand protein

Laboratory Finding

㉿Table 432-3

; *bleeding time - prolonged

; normal PT, platelet count

; PTT - may be normal but usually mildly to moderately prolonged

; type Ⅰ

    - *reduced plasma levels of von willebrand protein, von willebrand factor activity, and factor VIII activity

Treatment

; *FFP, cryoprecipitate ( 2-4 bags/10kg every 12-24hrs)

; DDAVP

Chapter 433. Phase II Disorder

   - phase Ⅱ coagulation에 포함되는 factors;

       ; factor Ⅱ(prothrombin), Ⅴ,Ⅶ and Ⅹ -> prothrombin complex

   - deficiency of a factor in the prothrombin complex -> autosomal recessive

   - dysprothrombinemia -> a functionally abnormal factor Ⅱ

 * Lab  ; PT ; prolonged

          PTT ; prolonged

Chapter 434. Phase III Disorders

Congenital Afibrinogenemia

   - autosomal recessive

   - no severe spontaneous hemorrhage or hemarthrosis but severe bleeding after trauma

      or surgery

   - Tx ; 100mg/kg of fibrinogen

          plasma half life of fibrinogen ; 3-5 days

          cryoprecipitate 1 bag : contains 225-250mg of fibrinogen

Congenital Dysfibrinogenemia

   - autosomal dominant

   - thrombin time ; prolonged

   - normal level of fibrinogen

Factor XIII deficiency

; *▲often infancy

; Clinical Manifestation

    - bleeding after separation of umbilical cord stump

    - G-I, intracranial, intra-articular hemorrhages

           / ▲common clinical manifestations

; Diagnosis

    - normal routine coagulation study

    - ★abnormal solubility of clot in 5M urea solution

; Treatment

    - FFP or cryoprecipitate

Chapter 435. Postneonatal Vit-K Deficiency

; rarely after the neonatal period

; ★Etiology

    - “late” hemorrhagic disease in breast-fed children

    - intestinal malabsorption of fats

    - prolonged adminstration of broad-spectrum antibiotics

; Treatment

    - *prophylactic water-soluble oral vitamin K

           / 2-3mg/24hr : children

    / 5-10mg/24hr : adolescents, adults

; anticoagulant (dicumarol, superwarfarin)

  - vit-k 합성억제

  - factor II, VII, X 합성억제

; vit-k def의 검사실 소견

  - *PT ＆ PTT↑

  - platelet count, BT, plasma fibrinogen level ; Nl

Chapter 436. Liver Disease

; liver dz 환자에게 coagulation abnormalities 가 common

   -그중 , 15%환자만이 의미있는 clinical bleeding states 보임 

; 원인 coagulation factor 합성저하

; factor VIII을 제외한 모든 factor는 liver에서 생성됨

; severe liver dz

  - *normal to increased levels of factor VIII activity in plasma

; Treatment

    - FFP ＆ cryoprecipitates

             FFP (10∼15ml/kg) ; correct all clotting factor except fibrinogen)

             fibrinogen correction 위해서는 cryoprecipitates 필요

                                       (4∼5 bags / 10kg) 

    - vit-k (PO, SC, IV)not IM

            -infant ; 1mg/24hr

            -children ; 2∼3mg/24hr

            -adolescents, adults ; 5∼10mg/24hr

Chapter 437. Inhibitors.

# Acquired circulating anticoagulants (inhibitors)

  ; abnormal endogenous components of blood로서 normal blood의  coagulation을 억제시킴

    ; specific types of gamma globulin

  ; autoantibodies

# mechanism of circulating anticoagulant effect

    ; by neutralizing a specific coagulation factor directly

  ; by acting against certain reaction sites in the coagulation pathway

# ★Asso. Conditions

    ; *SLE, lymphoma, incidental viral infection, penicilline or other drug reaction

Laboratory Findings

    ; *usually affect factor VIII, IX, XI (a phase I defect)

    ; *PTT↑, PT- normal

    ; ★▲common inhibitor

           - *lupus anticoagulant

    ; 이러한 anticoagulant는 bleeding을 유발하기 보다는 역설적으로 thrombotic tendency와 관련성 이 있음이 보고 되어지고 있다.

    ; 드물게 hypoprothrombinemia (reduced factor II)와 관련이 있을수 있다

Treatment    

 hemophilia 환아와 비슷한 치료방법이 사용됨

       prothrombin complex concentrate (Konyne)

       activated prothrombin complex concentrate (Autoplex)

        -심각한 출혈을 조절하는데 필요하다

 viral infection 후의 spontaneous inhibitor는 대개 수주에서 수개월  사이에 없어진다.

Chapter 438. Consumption Coagulopathy (DIC Syndromes)

; 광범위한 혈관내 fibrin 축척이 tissue ischemia, necroisis, hemorrhagic state, hemolytic anemia 유발시킴

Etiology

# ★Pathologic Process

  - hypoxia

  - acidosis

  - tissue necrosis

  - shock

  - endothelial damage

# ★Associated Disease

  - incompatible blood transfusion

  - gram negative septic shock

  - rickettsial infections

  - snakebite

  - purpura fulminans

  - giant hemangioma

  - malignancies

  - acute promyelocytic leukemia

Laboratory Finding

㉿Table 438-1

# ★Consumption Factors

    ; II, V, VIII, fibrinogen

    ; platelets

# microangiopathic

    ; schizocytes (burr and helmet-shaped red cells)

# D-dimer

    ; *more specific for DIC than FDP

    ; *neo-antigen formed following thrombin-initiated generation of fibrin from fibrinogen

           --> *cross-linking of fibrin by factor VIII and plasmin digestion of the cross-linked fibrin

Treatment

 infection, shock, acidosis, hypoxia, and underlying problem control

 platelet infusions for thrombocytopenia

 cryoprecipitate for hypofibrinogenemia

 FFP

# anticoagulants

    ; heparin

           - drug of choice

           - intermittent intravenous schedule

                   / 75-100 units/kg every 4hr

       - continuous schedule

                   / *50-75 units/kg given as abolus followed by continous infusion of 15-25 units/kg/hr

        - duration and effectivenes judged by platelet count and plasma fibrinogen concentration

           - ★effective on purpura fulminans, promyelocytic leukemia

                   / 10-15 units/kg/hr without loading

           - ineffective in septic shock, snakebite, heat stroke, massive head injury, and incompatible blood transfusion reaction

Chapter 439. Platelet And Blood Vessel Disorders

. non-nucleated, cellular fragments

. BM의 megakaryocytes에서 생성

. life span ; 7∼10일

            -integrity of the vascular endothelium

            -collagen과 같은 extravascular component 와 contact가 있어야 platelet adhesion                이 시작된다.

            - thromboxane(PG)와 endogenous ADP가 firm aggregation 시켜줌.

            -5-HT, Histamine가 분비되어져 local vasoconstriction

            - platelet는 partial thromboplastin activity의 phospholipid를 함유하는데, 이것이  coagulation에 중요한 역할을 한다.

            -other blood coagulation factor들을 운반

            -necessary for normal clot retraction

. Nl ; 15만∼40만/ml

. thrombocytopenia

            -by inadequate production

            -by excessive destruction or removal of platelet.

. Inadequate production

            -result of marrow dysfunetion

            -megakaryocytes 수 감소

. Increased destruction

            -megakaryocytes 수 정상 혹은 증가

# BM aspiration

  - unexplained thrombocytopenia 때 indication

    - severe thrombocytopenia 환아에서도 serious bleeding을 유발하지 않고 가능

         / ★why ?

                   : *thromboplastins in tissue juice

439.1 Congenital Thrombocytopenias

Wiskott-Aldrich Syndrome

; consist of

  - eczema

  - thrombocytopeinc hemorrhage

  - increased susceptibility to infection

; X-linked recessive

; BM 

    - megakaryocytes 수 정상이지만 many bizarre nuclear morphology

; autologus platelet

   - shortened life span and small size

. thrombocytopenia의 원인은 megakaryocytes의 수는 정상이지만 platelet formation라  release의    장애에 기인됨

. Splenectomy

     -Significant improvement in thrombocytopenia

     -postsplectomy후 예방적 penicillin 사용이 필요함

. 5% W-A-S에서 lymphoreticular malignancy 발생됨

Other Inherited Thrombocytopenias

. x-linked, autosomal transmission

. young male에 있어서 ITP로 진단 후 splenectomy를 포함한 통상의 치료에 잘 반응하지 않    고 예후가 나쁜 경우 의심해야 한다.

Thrombopoietin Deficiency

. chromic thrombocytopenia를 가진 소수의 환자에서 megakaryocyte maturation factor의 def      에 의할수 있다.

. episodic thrombocytopenia와 microangiopathic hemolysis는 plasma infusion에 의해

  reverse된다.

Thrombocytopenia With Cavernous Hemangioma (=Kasabach-Meritt Syndrome)

. large, cavernous hemangiomas of the trunk, extremities, or abdominal viscera.

. severe thrombocytopenia and evidence of intravascular coagulation.

. peripheral blood ; thrombocytopenia,  RBC fragments

 BM; adequate numbers of megakaryocytes.

. histologic and isotopic studies ;

     -platelet are trapped and destroyed within extensive vascular bed of the tumor

. Tx ;   

     - 6∼8 Gy radiation therapy → vascular channel 의 thrombosis obliteration을

       spontaneous recovery를 촉진시켜줌

     - corticosteroids and interferon

     - splenectomy ; contraindicated

Congenital Hypoplastic Thrombocytopenia With Associated Malformations (=Thrombocytopenia Absent Radius Syndrome ; TAR Syndrome)

; severe thrombocytopenia

; and cardiac and renal anomalies

; familial

; severe hemorrhagic manifestation are evident in the lst days of life.

; Hb - Nl

. BM ; absent megakaryocytes.

. 혈액학적 소견이Fanconi pancytopenia 와 비슷하나 Fanconi에서 와는 달리 혈액학적 이상이  3-4세 이전에는 나타나지 않는다

 Chromosome - Nl

439.2 Congenital platelet function defects

. congenital disorders of platelet function에 의한 출혈성 질환은 흔하지 않다.

. adhesion, aggregation, coagulant activity의 역할

Clinical Manifestations

    . thrombocytopenia

    . mucous membrane bleeding ( epistaxis, oral cavity bleeding etc)

    . skin petechiae

    . small ecchymoses

Laboratory Findings

    . BT ↑

    . PT, PTT : normal

    . platelet count ; 정상 혹은 약간 감소

    . can be defined by specific in vitro platelet function test

    . platelet factor 3 def.

            - BT : normal

            - abnormal prothrombin consumption test

Treatment

 . platelet transfusion

Bernard-Soulier Syndrome

 . AR

 . 특성 - moderate thrombocytopenia

        - large platelets

        - decreased ristocetin - induced platelet agglutination

 . not corrected by the addition of von Willebrand factor

Glanzmann Thrombasthenia

 . AR       

 . platelet count - normal

 . absent in vitro aggregation with all agonists

 . absent clot retraction

Other Defects

 . defect in normal platelet release reaction

    - 원인 : ① platelet granule def.

             ② impaired platelet arachidonic acid metabolism

            ③ impaired secretion of intraplatelet agonists

 . Lab

     -normal platelet count

     -abnormal in vitro aggregation

439.3 Inherited Blood Vessel Defects

. childhood시기의 defective blood vessel 에 의한 이차적인 출혈은 흔하지 않다.

. hereditory hemorrhagic telangiectasia와 Ehlers - Danlos syndrome은 심한

     mucous membrane과 skin의 bleeding을 일으킬수 있다.

. all Lab - 대개 정상

439.4 Acquired Thrombocytopenias

Idiopathic Thrombocytopenic Purpura

; *▲common thrombocytopenic purpuras of childhood

; petechia, mucocutaneous bleeding, hemorrhage into tissues

Etiology

; related to sensitization by viral infections

  - *70% antecedent diseases : rubella, rubeola, viral URI

    - average 2wks

; immune mechanism

    - platelet에 bound된 IgG가 증가된것은 platelet surface에 면역 복합체가 absorbed된 것       을 나타냄

Clinical Manifestation

; acute onset

; bruising, generalized petechial rash

    - 1-4wks after viral infection

    - *asymmetric, most prominent over legs

; hemorrhages in mucous membranes

  - *hemorrhagic bullae of the gums and lips

; intracranial hemorrhage

    - *▲serious Cx

    - *less than 1%

; *no enlargement of liver, spleen, lymph node

; acute phase asso. with spontaneous hemorrhage

    - lasts 1 -2wks

; *after acute phase, subside of spotaneous mucocutaneous hemorrhage even though thrombocytopenia

Laboratory Findings

 platelet count : 20만/ml 이하

 PB smear상 megathrombocyte : reflect increased marrow production

 BT, clot retraction test : abnormal

 WBC count 정상이며 anemia없음

# ★BM

    ; normal granulocyte and erythrocytic series

    ; frequently , modest eosinophilia

    ; normal or increased numbers of megakaryocytes

    ; *no pathologic or diagnostic megakaryocte morphology

Differential Diagnosis

aplastic or infiltrative process of BM

SLE

AIDS

lymphoma

X-linked thrombocytopenia ; in male infant with low platelet count.

Treatment

    ; excellent prognosis, even when no specific therapy.

    ; *75%

           - *recover completely within 3 mo

  ; 90%

           - recover completely within 9-12 mo

    ; when the disease is mild and hemorrhage of the retina or mucous memb are not present

           --> no specific therapy

Gamma Globulin

    ; 400 mg/kg/24hr for 5 days or 1g/kg/24hr for 1 or 2 days

Corticosteroid Therapy

    ; not decreased the number of chronic cases

    ; steroid therapy 의 효과

           - reduced the severity

         - shortens the duration of the initial phase

    ; PRS 1-2 mg/kg/24 hr until the platelet count is normal or for 3 wk

    ; *3wks 이상은 사용하지 않는다.

           - if prolonged corticosteroid therapy

                --> may depress the bone marrow, cushingoid changes, growth failure

# ★if thrombocytopenia persists for 4-6 month

    --> *2nd short course of corticosteroid therapy or IV gamma globulin therapy

# splenectomy

  ; chronic cases (persistent for more than 1 yr)

  ; for severe cases that do not respond corticosteroid.

# ★severe hemorragic manifestation or intracranial hemorrhage

    ; *larger doses of prednisolone(5-10 mg/kg/24hr) & intravenous gamma globulin

Drug Induced Thrombocytopenia

        . by immune mediated process or megakaryocyte injury

        . 소아과 영역에서 쓰는 약제중 thrombocytopenia를 유발하는 것

          -carbamazepine (Tegretol), phenytoin (Dilantin), sulfonamide, bactrim,

           chloramphenicol

Hemolytic-Uremic Syndrome

             see 474

 

. AGE 증상의 episode 있은 후 머지않아 hemolytic anemia, thrombocytopenia,

   acute renal insufficiency의 증상을 나타낸다.

. Lab. findings.

    :특징적인 bizarre RBC morphology.

     ( contracted and distorted with prominance of spherocytes, burr cells and

       helmet-shaped forms )

. BM : nl

  PB : depressed platelet count ---> indicates excessive peripheral destruction

. tests of the coagulation mecanism-nl.

. urinary sediment에 protein, RBC, cast 가 존재함.

. Tx.

     -severe anemia 시 transfusion.

     -corticosteroid 와 heparin therapy 는 별 효과 없다.

Thrombotic Thrombocytopenic Purpura

. rare and serious disease.

. diffuse embolism and thrombosis of the small vessels of the brain

      : neurogenic sign

        1) aphasia

        2) blindness

        3) convulsions

. 예후 : grave

. LAB. finding

       :thrombocytopenia

        hemolytic anemia

 

. Tx.

   - plasmapheresis and plasma infusion

      ; 60-70 % 에서 효과적.

   - corticosteroid and splenectomy

     ; reserved for refractory cases.

Other Causes

   - thrombocytopenia

     ;common complication of viral and bacterial infection, DIC, rarely, heparin therapy.

Neonatal Thrombocytopenia

     - primary disease in the infant's hematopoietic system or transfer of

       abnormal factors from mother.

Association With Infection

  - thrombocytopenia occur in various fetal and neonatal infections

    ---> serious spontaneous bleeding.

  - viral infection: rubella and cytomegalic inclusion disease.

  -protozoal infection : toxoplasmosis

  -syphilis

  -bacterial infection; caused by gram negative bacilli

  - hemolysis with prominent anemia and jaundice.

  - enlarged liver and spleen

  - BM: variable, but reduced numbers of megakaryocytes.

Immune Neonatal Thrombocytopenia

  1) active ITP를 가진 산모에게서 태어난 신생아의 30 %에서 thrombocytopenia

    발생. <--- by transplacental transfer of antiplatelet antibodies.

    - no hepatosplenomegaly

    - duration : 2-3 mo

    - Tx. : - IV immunoglobulin

           - exchange transfusion

           - PLT transfusion

           - corticosteroid : not benificial

 

           - 분만 1주 전에 산모에게 corticosteroid 를 투여하거나, 임신 후반기에

              산모에게 IV immunoglobulin을 투여하면 산모나 아기에게 도움이

              될 수 있다.

           - splenectomy : contraindicated.

  2) alloimmunization :

     - 산모에게 없는 PLT antigens 을 fetus 가 가지고 있을 때, fetal platelet

      Ag 에 대하여 maternal Ab가 생성되어 placeta 를 통과하여 thrombocyto

       penia 가 발생한다.

      - familial, and 1st born infants are frequently affected.

      . clinical signs

        - petechiae and other hemorrhagic manifestations

      . Antiplatelet Ab

        - 50 % 에서 발견됨.

.the PLA-1 antigen is most frequently involved.

.Tx ;

    - exchange transfusion (지혈을 위한 일시적 효과)

    - IV gamma globulin (도움)

    - compatible platelet transfusion ( by preparing washed platelet concentrates from the                                           mother )

    - c-section ; delivery 도중 신생아의 head trauma 방지.

    - 심한 bleeding 소견 보이면 corticosteroid therapy 나 exchange transfusion 고려함.

3) when the mother has drug induced thrombocytopenia.

    => both Ab and drug cross the placenta

    => neonatal thrombocytopenia.

439.5 Acquired Platelet Function Disorders

* Acquired disorders of platelet function caused by ;

    -toxic metabolic products ; in uremia

    -autoantibodies

    -immune complexes

    -fibrin split products ( FSPS )

    -drugs ; most common, esp aspirin.

     => prolonged BT and abnormal platelet aggregation tests.

.  aspirin ;

    -not dose related

    -adult의 경우에 있어서 300mg 의 aspirin을 먹은지 1시간 내에 abnomal platelet                 aggregation을 나타낼수 있다.

    -The abnormality persists for 4-6 days.

    -usually no clinical problem, although prolongation of BT.

      => underlying bleeding disorder 있거나 surgery 후에는 출혈을 초래.

    -contraindicated 경우 acetaminopen등으로 대체

    -transplacental effect 가 있어 newborn의 platelet function에 영향을 끼쳐 neonatal              hemorrhage가 드물게 발생하기도 하므로 임신말기의 aspirin 사용은 피하는 것이 좋다.

 

    439.6 Acquired Vascular disders.

.  most common cause of a vascular type of nonthrombocytopenic purpura

       - H-S syndrome 혹은 anaphylactoid purpura

.  unknown origin

.  involves the small blood vessels of the skin, joints ,gut, kidney

.  rash는 centrifugal distribution

       - legs and buttocks are characteristic

         (특히 arthritis, nephritis, GI bleeding 과 같이 나타날때)

.  petechiae

       - early meningococcemia 혹은 septicemia 에 의한 것과 구별해야함

.  toxic vasculitis

       - arsenical, iodides 같은 약제에 의한 hemorrhagic rash.

.   Tx

       - self-limited

       - corticosteroids ; painful edema, G-I pain, arthritis에는 효과적이지만 vasculitic skin            rash 에는 별로 효과가 없다. 

439.7 Thrombocytosis

 정의 ; 75만/ml 이상

 thrombocytosis 가 동반되는 경우

       -.hemorrhage

        .iron deficiency anemia

        .hemolytic anemia

        .primary myeloproliferative disorders

        .acute and chronic inflammatory states

        .Kawasaki disease

         sickle cell anemia

         after splenectomy for ITP or hemolytic anemia

     Tx ;

        -no specific therapy, because thrombosis is extremely rare

        -aspirin or dipyridamole if factors predisposing to thrombosis are present

          (inhibit platelet function)

Chapter 440. Thrombotic Disorders

Clinical Manifestation And Diagnosis

          capillary and small vessel occlusion

           -> vasculitis and DIC

          occlusion in medium sized vessel

           -> -homocystinuria

               -cyanotic congenital heart disease

               -dehydration

               -polyarteritis nodosa

          occlusion in larger vessel

           -> -aortic thrombosis

               -superior vena cava thrombosis in the newborn

               -deep venous thrombosis

               -sickle cell anemia

               -pulmonary embolism

          the mechanism   -vessel injury (leading to the thrombosis)

        +-abnormal platelet adhesiveness-aggregation

        | activated coagulation mechanism

     ＋ | inactive inhibitor system

        | inactive fibrinolytic mechanism

        +-reduced blood flow

           -arterial thrombosis:vessel injury + platelet activation

           -venous thrombosis:

                  -low flow conditions

                   with activation of the coagulation mechanism or

                   an impaired inhibitor-fibrinolytic system

     Dx:   -angiography: confirm

           - ultrasound and radionuclide scanning: for screening

           - other lab study:진단에 별로 도움을 주지 못함

CONGENITAL AND INHERRITED DEFECTS

# complex inhibitor system of coagulation

    ; antithrombin III

  ; protein C

  ; protein S

  ; cofactor for APC

1) congenital hypoplasminogenemia  & dysplasminogenemia

        - reduced ability to remove fibrin clots

2) congenital dysfibrinogenemia

        - formation of an unusual fibrin clot

        -> 1),2) can lead to thrombotic disease

          thromboembolic disease는 venous system에 잘 침범하며 arterial form은 드물다

           frequent manifestations

          - deep vein thrombosis of the legs

          - pulmonary embolism

          - pelvic & mesenteric vein thrombosis

          - sagittal sinus thrombosis

         1st thromboembolic event

          - 10-25세 사이에서 발생

Antithrombin III Deficiency

# AT III

; plasma inhibitor  protein으로서  some serine protease coagulation factors 의 enzymatic activity를 block 시킨다

           synthesized in liver , not vitamin K dependent

           activity of this inbitor increased by heparin

           patients have AT III activity levels between 20 and 60% of normal

           autosomal dominant, both sexes, all races

           Dx ; by detection of reducded AT III activity in plasma

           two types ;

                      type 1 - most common

                               lack both AT III functional activity and protein

                      type 2 - lack functional activity,

                               normal level of the protein (dysfunctional protein)

           Tx;

              - mildly deficient patients ; intravenous heparin

              - severe deficient patients ; plasma (a source of AT III) + heparin

              - early initiation of long term warfarin therapy (recommended)

              - danazol ; raise AT III levels

Protein C Deficiency

           protein C ; plasma inhibitor protein 으로서 일단 activated 되면 clot formation을                       억제시키고 fibrinolysis를 촉진시킨다

           APC 가 plasminogen activator inhibitor를 억제시켜서 protein S (as a cofactor)와          더불어 fibrinolysis를 촉진시키고 limited proteolysis에 의해 factor V과 VIII의                 clotting ability를 억제시킨다

           liver에서 생성

           Vit-K dependent

           AD

           Dx ; by detection of reduced protein C activity in plasma

           Type I (most common)

           - both activity and protein reduced

           Type II

           - functionally recuced activity

           - but, normal amount of protein

     Tx  - heparin (anticoagulation for thrombosis)

               - warfarin to prevent recurrence of thrombosis

               - danazol (androgenic drug) ; increase protein C level

Purpura Fulminans Neonatalis

; homozygous protein C-deficient infants에서 발생

; abrupt, early onset of subcutaneous ecchymoses and necrosis and widespread thrombosis of blood vessels

; Treatment

    - *FFP

  - long term warfarin therapy

Protein S Deficiency

           protein S ; Vit-K dep  plasma protein

                      liver에서 생성 (by endothelial cells)

                      activated protein C 의 cofactor 작용

                      2 forms  +-1  protein - bound

                               +-2  free (biologically active)

           AD

           Tx ; heparin (for thrombosis)

                oral anticoagulants (for prevention of further thrombosis)

Resistance To Activated Protein C(APC)

            due to def  of a cofactor to APC

            AD

            factor V : -cofactor

                      -procoagulant and anticoagulant function

            ↓ activity of anticoagulant function

            Tx : Anticoagulant therapy

Plasminogen And Fibrinogen Abnormalites

             rare

             dysfibrinogenemia :-many abnormal fibrinogens

                               -AD

            Tx : -heparin and long-term warfarin

ACQUIRD DEFECTS

            uncommon

   

        Table440-1

           arterial events:

                  -stroke, cold and pulseless lower extremity

                  -with or without renal involvement

                  -myocardial infarction

            venous event:

                  -deep venous thrombosis with or without phlebitis,pulmonary embolism

                   and renal vein thrombosis

             antiphospholipid antibody syndrome(lupus anticoagulant)

            - ① primary(idiopathic)

            - ② associated with SLE,infection,drug reactions or other autoimmune diseases

            - associated features

                 livedo reticularis

                 thrombocytopenia

                 recurrent fetal loss and thrombosis

                 - aPTT  increase

            -  Tx: warfarin with or without aspirin

                 Treatment of TED

            - remove the thrombus or embolus

            - 약제(anticoagulant)에 의한 thrombus 생성과 propagation 억제

        8)Venous Thrombosis and Thrombophlebitis

               ①superficial thrombophlebitis 치료

                 -anti-inflammatory drug(NSAID)

                 -heat compress

                 -rest and elevation of the affected part

               ②deep venous thrombophlebitis 치료

                 -anticoagulation

                 -with thrombolytic agents

  Heparin:(in pt  with proximal venous thrombosis)

     -anticoagulation

     -full dose(7-10일)

     -with warfarin(2-3개월)

  Calf vein thrombosis

     -heparin(7일) + Sc heparin(6주)

     -heparin (7일) + warfarin (6주)

Pulmonary Embolism

  treated with heparin or thrombolytic drugs

  thrombolytic therapy가 heparin therapy보다 빠른 임상증상의 호전을 보이지만

  long-term pulmonary function에는 거의 차이가 없다

  1시간내로 약물치료가 실패시에는 embolectomy가 강력히 고려되어져야 한다 

Arterial Thrombosis

  acute arterial thrombosis 혹은 embolism은 clot의 surgical remove가 최선의 치료방법이다

  수술이 불가능할 때에는 intra-arterial 혹은 intravenous thrombolytic drug

  platelet-inhibiting drugs가 유용한 경우

 (arterial disease that predispose to thrombosis)

     - aneurysm

     - cardiomyopathy(mural thrombi)

     - cardiac prosthesis

Stroke

  embolization from heart

  venous thrombosis of cerebral vessel

    with - cyanotic heart disease

         - inflammatory lesions of the brain

         - hyperviscosity states

  anticoagulation and/or platelet inhibitor drugs

  hemorrhagic infarct 때는 anticoagulant therapy는 CIx

ANTICOAGULANT AND THROMBOLYTIC THERAPY

Anticoagulants

Heparin

  enhances the effect of antithrombin III

  half life;

    - about 60 min in adult,

    - 30 min in the newborn

    - half life of heparin is dose dependent

        ---> the higher dose, the longer the circulating half life

    - shorter than normal in patients with thromboembolitic ds

    - longer than normal in patients with cirrhosis and uremia

  contraindication;

    - a preexisting coagulation defects or bleeding abnormality

    - recent central nervous system hemorrhage

    - bleeding from inaccessible sites

        - bacterial endocarditis

    - malignant hypertension

  - previous surgery of the eye, brain, or spinal cord

    - current adm  of regional or lumbar block anesthesia

  route;

    - intravenous or subcutaneous, not effective orally

       should not be given as an IM injection

    - 2가지 투여 방법

      1) intermittent schedule : 75-100 mg units/kg by bolus every 4 hr

      2) continuous infusion; a bolus injecting of 50-75 units/kg

                   followed by a continuous infusion of 10-25 units/kg/hr

                   - continuous method가 anticoagulant-related bleeding이 적은 것으                          로 알려져 있다

  monitoring;

  -aPTT;

    the most frequently used test for monitoring heparin therapy

    maintained at 1 5-2 times the patient's own preheparin control a PTT

1) the intermittent schedule;

  ->  aPTT determined 1 hr after initial infusion; greatly prolonged at that time

  ->  the next aPTT performed at the 4th hr just prior to the next dose 0

       at that time, should be 5-10 sec longer than the  normal control time

  ->  if the aPTT very prolonged, reduced by 10%

    if the aPTT within the normal range, increased 10%

   -> the test repeated 4 hr later

 2) the continuous schedule;

   -> aPTT performed at any time 4 hr after the continuous infusion

   -> the desired result is 1.5-2.0 times the patients pretreatment value

       dose adjustment of 5-10% during this period

  heparin can be neurtralized immediately by using protamine sulfate

   1 mg of protamine sulfate neutralizes 90-110 units of heparin

   ->그러나 heparin은 rapid clearance rate를 가지기 때문에 대개는 heparin infusion을 중지       하는 것으로 충분하고, protamine을 쓴다면 계산된 양의 1/2을 사용해도 충분하다

Warfarin

; the coumarin derivates, oral anticoagulant drug

# ★Action Mechanisms

    ; *inhibition of vitamin K-dependent carboxylation of precursor coagulation proteins

           --> *decreasing the rate of synthesis of the vitamin K dependent coagulation factors II, VII, IX, and X & increase of protein C and protein S

# warfarin을 투여하여 anticoagulation의 효과를 보려면 일반적으로 4-5일 소요된다

  PT; assess warfarin anticoagulation

    - mechanical prosthetic heart valve and recurrent systemic embolism

       ---> 1.5-2.0 times the normal control.

    - treatment of the deep vein thrombosis or pulmonary embolism

       ---> 1.3-1.5 times

    - prevention of systemic embolism in patients with atrial fibrillation,

      valvular heart disease, or tissue heart valves

       ---> 1.3-1.5 times

  most serious side effect : hemorrhage

  - often related to changes in the dose or metabolism of the drug

    - warfarin의 효과를 상승시키는 약물;

                             antibiotics

                             salicylates

                             anabolic steroid

                             chloral hydrate

                             laxatives

                             allopurinol

                             vitamin E

                             methylphenidate HCl

    - warfarin의 효과를 감소시키는 약물

                             barbiturates

                             vit  K

                             oral contraceptives

                             phenytoin

    - Tx of warfarin induced bleeding;

          discontinuation the drug

          adm  of vit  K

           -->the amount of vit  K equal to the amount of the daily warfarin dose

         if a significant bleeding problem,

            -->FFP 15 ml/kg + vit  K

  cross the placenta --> should not given during pregnancy

  although breast milk contains warfarin, the quantity is insignificant,

    -->the drug can be used in the lactating mother

 

# THROMBOLYTIC THERAPY;

  generation of plasmin  <-- plasminogen activators

         ===> thrombolytic effect

                        1) urokinase               

                   2) tissue type plasminogen activator(TPA)

                        3) streptokinase

  urokinase and TPA; direct activators

  streptokinase ; formation of streptokinase-plasminogen complex

           ---> activation of plasminogen

  thrombolytic therapy가 효과를 보려면 blood clot이 형성된지 7-10일 이내에 약물이 투여

                 되어야 한다

section 8. The spleen

Anatomy

# white pulp ; lymphoid compartments

# red pulp ; filtering system

Function

; reservoir function : not very great

; hematopoiesis:during fetal life(3-6mo)

              but, thalassemia and osteopetrosis-->hematopoiesis is resumed postnatally

; culling: RBC and platelet coated by the spleen

                  --->selectively sequestered and destroyed

; pitting: remove or pit intracytoplasmic inclusion such as Howel-Jolly bodies

          or siderotic granules from within the RBC

; destruction of old RBC

; membrane effect; when the spleen is absent,

           --> RBCs are flatter and thinner,

                increased numbers of target cells,

                osmotic fragility is decreased

; filtering and immunologic functions;

    - primary site of clearance of microorganism such s pneumococci in the

      absence of specific antibody

    - antibody formation

    - synthesis of Ig M, properdin,

                       tuftsin( a phagocytosis-promoting tetrapeptide)

; hormonal function

Chapter 441. Splenomegaly

 

Physical Exam

# palpable spleen

    ; *15% neonates, 10 % children, 5% adolescents

# superficial abdominal venous distention

    ; portal hypertension에 의한 splenomegaly때 나타남

# imaging studies

    ; U/S, abdominal CT, ^99mTc-sulfur colloid scan

Differential Diagnosis

★Table 441-1

Pseudosplenomegaly

  abnormally elongated mesenteric connections

    - produce a wandering or proptic spleen

  enlarged left lobe of liver of LUQ mass

    - mistaken for splenomegaly

  splenic cysts

   1) congenital(epidermoid)

   2) acquired(pseudocyst) ; after trauma or infarction

  congenital polysplenism(syndrome)

   1) cardiac defects

   2) left-sided organ anormalies                                       

   3) biliary atresia

   4) pseudosplenomegaly

Hypersplenism

  특성: increased splenic function(destruction of circulating cells)

    - PB cytopenias

    - increased BM activity

    - splenomegaly

  usually secondary to another disease

        --> underlying condition을 치료하면 치료가능

Congestive Splenomegaly(Banti Syndrome)

; *splenomegaly resulting from hepatic, portal, splenic vein obstruction

Etiology

    ; Wilson disease, galactosemia, biliary atresia, alpha 1-antitrypsin deficiency도 hepatic inflammation, fibrosis, vascular obstruction을 야기한다.    

    ; masses of sickled erythrocytes

           - splenic venous flow obstruction

    ; congenital anomalies of portal or splenic veins

    ; *septic omphalitis

    ; *umbilical venous catheterization

Treatment

    ; splenectomy

    ; portocaval shunting

Chapter 442. Hypersplenism, Splenic Trauma, Splenectomy

# Congenital absence of the spleen

    - ★Ivemark Syndrome

       1) congenital absence of spleen

       2) complex cyanotic heart defects

       3) dextrocardia

       4) heterotopic abdominal organs

# ★Functional Hyposplenism

  ; normal infant, esp. premature infant

  ; sickle cell hemoglobinopathy

  ; malaria

    ; after LUQ irradiation

  ; severe hemolytic anemias

    ; metabolic storage disease

  ; functional hyposplenism환아에서는 이유가 뭐든 간에 encapsulated organism sepsis의 위험성이 증가한다.

Trauma

  Small splenic capsular tears

    - abdominal or referred left shoulder pain as a result of peritoneal irritation by blood

   Larger capsular tears

    - severe blood loss에 의한 hypovolemia때 나타나는 유사한 pain과 signs을 나타낸다

  Tx:    - small capsular injury

          :   careful observation

              serial Hb determination-RBC transfusion(25ml/kg in48hr이하)

              10-14일간 입원

              수개월간 활동제한

        - laparotomy with or without splenectomy indication(trauma때)

          1) marked abdominal bleeding

          2) clinical instability or deterioration

          3) other organ damage is suspected

Splenectomy

# ♥Indication

    1) splenic rupture

  2) anatomic defects

  3) hemolytic anemias

  4) immune cytopenias

  5) metabolic storage diseases

  6) secondary hypersplenism

# Major risk of splenectomy

    ; infection(sepsis or meningitis)

  ; *high in younger than 5yr

    ; ★less risk for sepsis

           - *trauma, RBC membrane defects, immune cytopenia

# Postsplenectomy sepsis의 원인균

    ; *streptococcus pneumonia(more than 60%), H. influenzae, N. meningitidis, E. coli

    ; protozoal infection(malaria, babesiosis)

  ; 빨리 진행되어 12-24시간 내에 사망

# ★Preoperative,Intraoperative & Postoperative Managements

    ; *▲important Tx

           - certain of necessity for splenectomy

    ; if possible, postpone until 5yr

    ; vaccination with pneumococcal ( H. influenza, meningococcal) vaccines before splenectomy

    ; splenic repair or partial splenectomy in trauma

    ; *surgical splenosis

           - heterotopic autotransplantation of splenic tissue onto the surface of the peritonem

           - *inadequate function

    ; penicillin (or amoxacillin) prophylaxis

           - 250mg twice a day

       - 투여기간은 unknown, may be lifelong

SECTION 9. The lymphatic system

 구성;  1) circulating lymphatocytes

        2) lymphatic vessels

        3) LN

        4) spleen, tonsils, adenoids

        5) Peyer patches, thymus

  present in all organs except the brain and heart

Chapter 443. Abnormalities Of Lymphatic Vessels

* Lymphangiectasia

       dilation of the lymphatics

       pulmonary lymphangiectasia

        - causes respiratory distress 

        involvement of the intestinal lymphatics

        - causes hypoproteinemia and lymphocytopenia

          ( secondary to loss of lymph into the intestines)

* lymphangioma ( cystic hygroma )- mass of dilated lymphatics

* lymphatic dysplasia

       - may cause multisystem problems

       - lymphedema, chylous ascites, chylothorax, lymphangioma of bone, lung, or other               locations

* lymphedema

   - by obstruction of lymph flow

   -  ① congenital : Turner syndrome, Noonan syndrome, AD inherited Milrory disease 

      ② others association with : intestinal lymphangiectasia etc

* lymphangitis

   - inflammation of the lymphatics

   - on examination

      ① tender red streaks  

      ② regional nodes enlarged and tender

    - 원인론 : S aureus, group A streptococci

Chapter 444. Lymphadenopathy

; no consideration until cervical or axillary nodes 1cm, inguinal nodes 1.5cm

  neck에서 발견되는 nonlymphoid mass

     -cervical rib, thyroglossal cyst, branchial sinus or cyst, etc

  tumor- bearing nodes

     ; - usually firm and nontender

       - matted or fixed to the skin or underlying structures

1) Generalized adenopathy

     -often accompanied by abnormal physical findings

         Table 444-1

2) Localized adenopathy

     -most frequently due to infection and/or its drainage area

         Table 444-2

  10-14일 경과 후에도 크기가 줄지 않으면 좀더 검사가 필요함

# ㉿ LN Biopsy Indication

    ; persistent or unexplained fever

  ; wt. loss

  ; night sweats

  ; hard nodes

    ; fixation of the nodes to surrounding tissues

  ; supraclavicular adenopathy

  ; mediastinal adenopathy

  ; increase size over baseline in 2wks

    ; no decrease in size in 4-6wks

    ; no regression to normal in 8-12wks

    ; development of new sign & symptoms