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