HAEMORRHAGIC

DISEASE

Suspected of hemorrhagic disease :

1. Spontaneous bleeding
2. Prolonged bleeding/massive

3. More than one site bleeding

PATHOGENESIS
Hemostasis process :
- maintaining blood in a state of dilution
- maintaining blood in vascular
- to stop bleeding vascular damage

3 components of hemostasis:

HEMOSTASIS
THROMBOCYTE

Disturbance one of components homeostasis

bleeding

TRAUMA/INJURY
VASOCONSTRICTION

BLOOD

CLOTTING

ADHESION OF THROMBCYTE

THROMBINE

ADP/SEROTONINE

FIBRINE

AGREGATION OF THROMBOCYTE

STABILE HAEMOSTATIC BLOCKAGE

DETECTION OF HAEMORRAGIC DISEASE

Step I

- good history taking

- physical examination

- Trauma: - History of trauma chronologically

- Mild trauma bleeding
- Severe spontaneous bleeding
- Quantity and duration of bleeding
- Recurrent bleeding

- trauma always bleeding

Congenital hemorrhagic disease
- Deep tissue bleeding
( large hematom or hemarthrosis)

Congenital hemorrhagic disease

- Petechie not congenital hemorrhagic disease
- Congenital hemorrhagic disease usually
coagulation disorder

Laboratory examination :
- Screening examination
- Specific examination

Screening examination :
1. Platelet count
2. Bleeding time ( thrombocyte function)
3. Prothombine time (PT)
4. Activated partial tromboplastin time (APTT)
5. Clotting observation / clotting retraction

Specific examination :
1. Coagulation factor (factor assay)
2. Thrombocyte function :
aggregation, release reaction etc.

VASCULAR DISORDER
Mostly : secondary vascular pupura :
- Immunology: Schenlein-Henoch syndrome
- Infection: Virus, Rickets, Bacteria
- Drugs
- Deficiency of Vit. C
- Uremia

Congenital:
- Hereditary hemorrhagic telangiectasia
(Osler-Weber-Rendu)

- Cutis hyperelastica (Ehler-danlos)

Clinical :

- usually petechiae skin & mucosa

spontaneous
- Tourniquet test positive
- symptoms & signs of primary disease

Laboratory:
- platelet count normal
- bleeding time normal
- PT & APTT normal

SCHENLEIN-HENOCH SYNDROME
- Allergic Purpura
- Anaphylactic Purpura
Incidence :

- 3 -7 years of age
- Male : female = 3 : 2

Etiology:
Immunologic Reaction:
- Infection: beta hemolytic Streptococcal, Viral
- Food : milk, egg, tomato, fish etc.
- Drug : erythromycin, sulfa, penicillin, ect.
- Insect bite

-Hemolytic Streptococcal Infection important

- 75% cases History of respiratory tract
infection 1-3 weeks before
- 50% cases positive throat swab culture
- 30% cases titer ASO

PATHOGENESIS
Immune complex :
- vasculitis increase permeability
- perivasculer inflammation

CLINICAL MANIFESTATION
1. Skin involvement:
- erytema, maculopapuler
- petechie & echymosis
Distribution of lesion: symmetric:
- extensor lower extremity
- gluteus, hip
- extensor arm elbow

2.Articular involvement:
- 75% case
- polyarthralgia/polyarthritis non-migrants
- periarthriculer swelling
- especially knee & ankle
- full recovery

3. Stomach involvement:
Colic (50%) with : vomiting, diarrhea, melena

- mild to severe umbilicus

- cause : edema & bleeding intestinal mucosa

4. Kidney involvement:
- 25-50% case 2-3 weeks
- proteinuria & hematuria (micro/macroscopic)

- often in male
- 5 -10% chronic

MANAGEMENT

self limiting symptomatic treatment

- Corticosteroid:
- intestinal mucosa edema colic & invagination
- arthricular involvement
- Bed rest avoid intracranial bleeding

PROGNOSTIC
- Good if no complication
- Full recovery in 4 weeks
- Residive
- Complication rare:
- invagination, intestinal perforation
- intracranial bleeding
- renal failure

THROMBOCYTE DISORDER

A. QUANTITATIVE DISORDER
1. Thrombocytopenia bleeding
2. Thrombocytosis thrombus formation
Normal:

platelet count 150.000 - 400.000/mm3

< 50.000/mm3 spontaneous bleeding

THROMBOCYTOPENIA:
a. Production disorder:
- Hypoproliferation: aplastic anemia, ATP
- Ineffective thrombopoesis :
- Megaloblastic anemia
- ANLL M7

b. Distribution disturbance:
- Splenomegali: pooling thrombocyte
- Lymphoma

c. Dilution:
- Massive blood transfusion

d. Abnormal destruction
- Non-immune: - DIC
- Infection: DHF, sepsis
- Immune:
- Idiopathic Thrombocytopenic Purpura (ITP)
- Drugs: Kina, kinidin, sulfa, dilantin, ect.
- Neonatal thrombocytopenia
- Purpura post-transfusion

e. Abnormal consumption:
- DIC, DHF

B. QUALITATIVE DISORDER

= Trombastenia or thrombopati
1. Adhesion disturbance
2. Aggregation anomaly

Diphenydramin:
- prevent platelet aggregation
3. Disturbance of platelet release reaction
Asetil salisilic ac.:
- distrub release of ADP
- asetilasi platelet membrane

IDIOPATHIC/IMMUNE
THROMBOCYTOPENIC PURPURA (ITP)

Destruction of platelet shorter age

immunologic mechanism:
- antibody (IgG) platelet
- C3 complement
- cellular immunity activation:
macrophage & cytotoxic cell

CLASSIFICATION
1. Acute ITP (85-90%): self limiting children
2. Chronic ITP (10-15%): adult

ACUTE ITP
- Age : 2 - 8 years
- 50% of cases : 1 - 6 weeks before
viral infection: ARTI, hepatitis, mumps,
mononucleosus infectiosa,
cytomegaloviral etc.)

Clinic symptoms:

- hemorrhagic skin & mucous membrane

petechie & ecchimosis
melena, hematury
- hemorrhagic of inner organ rare
- severely thrombocytopeni cerebral bleeding

- tourniquet test is positive

Blood picture:
- thrombocytopeni

- blood smear:
abnormal platelet form,
big size, separately
- decrease of clot retraction
- prolonged of bleeding time
- PT & APTT normal

Bone marrow:
Important exclude:
- aplastic anemia
- leukemia
Megakaryocyte:
- Normal in quantity or increase
- Morphology:
- immature
- cytoplasm: more basophile
- less granulation

Acute ITP therapy

- Rest & avoid trauma
- Mild case doesn't need therapy
- Severely case massive hemorrhagic:
- corticosteroid
- platelet suspension not suggested
- blood transfusion (PRC): on indication

Prognose:
- Mostly (85 - 90 %) recover
- 10 - 15% chronic

Chronic ITP
- Thrombocytopeni (< 100.000/mm3) 6 months
- Spontaneous remission is very rare
- Age > 10 years, female > male

Therapy:
1. Corticosteroid
2. Immunosuppressive if 1 failed
3. IgG or Danazol

3. Sphlenectomy if 1, 2 & 3 failed

COAGULATION
DISORDER
Coagulation component:
1. Blood Coagulation System
blood coagulation mechanism

2. Anticoagulation System
prevent intravascular coagulation
maintain blood fluidity
3. Fibrinolytic System
fibrinolysis keep open the lumen of
blood vessels

BLOOD COAGULATION SYSTEM

Blood Coagulation Factors :
International Name

Synonym

Fibrinogen

II

Prothrombin

III
IV

Tissue factor,
Tissue thromboplastin
Calcium (Ca)

Proacelerin, Labile Factor

VII

Proconvertin, Stable factor

VIII

Antihemophilic Factor, AHF-A

BLOOD COAGULATION SYSTEM

IX

Plasma Thromboplastin Component

(PTC), Christmas Factor, AHF-B

Stuart Prower Factor

XI
XII

Plasma Thromboplastin Antecedent

(PTA), AHF-C
Hageman Factor, AHF-D

XIII

Fibrin Stabilizing factor (FSF)

Prekalikrein

Fletcher Factor

Kininogen

Fitzgerald factor

ANTICOAGULATION SYSTEM :
Coagulation Inhibitor:
- Antithrombin III
- C Protein & S Protein
- Alpha-2 macroglobulin

FIBRINOLYTIC SYSTEM :
Plasminogen system- plasmin:
- Plasminogen
- Plasminogen activator
- Anti plasmin

Blood coagulation process :

1.Prothrombin activator formation

(Protrombinase):
- Intrinsic
- Ekstrinsic
2. Prothrombin trombin

3. Fibrinogen fibrin

Tissue damage

Surface Contact

XII
I
N
T
R
I
N
S
I
C

XIIa
XI

III
+
VII

XIa

IX

IXa
VIII
X

Ca++

PROTHROMBINASE

Xa

Ca++

V
F.Tr-3

Prothrombin

Ca++

Thrombin

Fibrinogen

Fibrin
XIII
Fibrin polymer

E
x
T
R
I
N
S
I
C

COAGULATION DISORDER
1. Coagulation System
2. Anticoagulation system

3. Fibrinolytic system

Disorder of coagulation system/mechanism

one or more deficiency :
coagulation factor

1. Decreased of synthesis :
- Genetic/congenital : Hemophilia

- Vit. K deficiency II, VII, IX & X, C Protein

- Severe liver disease

2. Increase of demand
- Consumption coagulopathy
Disseminated Intravascular Coagulation
(DIC)

Coagulation Disorder Characteristics :

1. Bleeding mild injury, rarely spontaneously
2. Rarely petechie
3. Bleeding joint & deep tissue
large hematoma, large ecchymoses
4. Bleeding from wound :
- not immediately occur
- often recurrent
- prolonged (> 48 hours)
- oozing

Laboratory:
- PT & PTT: one or both increase
- Normal bleeding time
- Coagulation observation: fragile

HEMOPHILIA

HEMOPHILIA
Bleeding disorder:
- Coagulation disorders
Coagulation factors deficiency
- congenital, inherited

Hemophilia:
Hemophilia A factor VIII deficiency
Hemophilia B factor IX deficiency

INCIDENCE
1 : 10.000
Hemophilia A most common
GENETICS AND PATHOPHYSIOLOGY
- Factor VIII Gen X chromosome
- Gen mutation (substitution & deletion)
defects in factor VIII synthesis
Inherited recessively in connection with
sex chromosomes : X-linked

GENETICS AND PATHOPHYSIOLOGY

Male (Xh Y) affected
female (Xh X) carrier
Usually by marriage:
Normal father (X Y)
Carrier mother (Xh X)
Hemophilia almost entirely in boys

GENETICS AND PATOPHYSIOLOGY

Women could be affected:
- father = (Xh Y) & mother = (Xh X)
- Inactive gene of VIII factor
- Spontaneous mutation gene of VIII factor
F VIII: protein plasma are needed in
prothrombin activator synthesis process
F VIII deficiency coagulation cascade
disturbance

CLINICAL MANIFESTATION:
Depends on F VIII levels
Severe Hemophilia : F VIII < 1%
spontaneous bleeding
hemarthrosis, muscle bleeding,
gastrointestinal, hematuria & brain
Moderate Hemophilia : F VIII 1 5 %
bleeding after minor trauma

Mild Hemophilia : F VIII 6 25 %

bleeding after major trauma,
surgery

DIAGNOSIS
History:
- History of repeated bleeding joints
- Brothers with the same illness
- Brothers from mother with the same illness
Physical examination:
- hemarthrosis, hematoma, etc
Laboratory:
- normal platelet & bleeding time
- Prolonged PTT & normal PT
- TGT & AHF assay F VIII deficiency

COMPLICATION
Because of the disease:
hemophilia arthropathy
contracture and paresis/paralysis
of muscle
hemophilic pseudotumor
Because of treatment:
Formation antibody against F VIII
thrombosis
ITP
Viral hepatitis

TREATMENT
1. Stop the bleeding:
Administration of F VIII:
- cryoprecipitate
- F VIII concentrate (KOATE)
Bed rest
Immobilizes bleeding area:
cold compress, tampon

2. Correction of bleeding consequence:

- Treatment of anemia & shock
- synovectomy
- joints & muscles rehabilitation

TREATMENT

3. Bleeding prevention:
- prevention of trauma
- addition of F VIII before surgery
- contraindication: aspirin

VITAMIN K DEFICIENCY

Is found in:
1. Hemorrhagic disease of the newborn (HDN)
2. Disorder of Vit. K absorption:
- Biliary tract obstruction
- Chronic diarrhea
- Severe liver disease

3. Intestinal sterilization by antibiotics

HEMORRHAGIC DISEASE OF THE NEWBORN

(HDN)
Hemorrhagic disease in newborn baby due to:
Deficiencies of factor II, VII, IX & X vitamin K

Physiology (normal):
Coagulation factor II,VII,IX & X:
- decrease in newborn
the lowest rate at 2 - 5 days of age
- increase at 7 14 days of age

Etiology:
- Uncomplete colonization of intestinal flora
the synthesis of vit K in gut is still low
- decrease of vit K in placenta

If decreasing of coagulation factor excessive

HDN

May result from :

1.Very low amounts of vitamin K storage
2.No synthesis of vit. K in gut
sterile intestinal flora
3. Absorption of vit K in gut very low
4. Disorder of vitamin K metabolism:
- Damaging of vit. K :
barbiturat, phenytoin, diazepam, INH,
Rifampisin
- disturbance of vit.K usage by liver:
dicumarol, salicylat

FUNCTION OF VITAMIN K
Protein (II, VII, IX & X)

Vitamin K

Carboxylation

Functional of coagulation factor

(II, VII, IX & X)

The process were done in liver

Incidence:
- Age: 2 - 5 days

Clinical manifestations:
Bleeding in various location:
- gastrointestinal tract: melena
- umbilical cord, skin, mucosa
- cephalhematom, brain bleeding

BLOOD HEMOSTASIS
ABNORMAL/PROLONGED

NORMAL

PT (Factor II, VII, X)

Thrombin time (TT)

APTT (Factor II, IX, X)

Fibrinogen

Thrombotest,
Normotest (F. II, VII, X)

Activity F. V, VIII, XI

Activity F. II, VII, IX, X

Antigen F. II,VII,IX,X

There are PIVKA II

Platelet count & BT

Practical:
HDN: bleeding manifestation in baby <12 weeks with :
- Prolonged of PT & APTT
- Normal platelet and BT

TREATMENT
HDN self limited
Bleeding can stop spontaneously
but needs long time
- Massive hemorrhagic
- Continuous hemorrhagic
- intracranial hemorrhagic
Threaten the newborns life
Needs immediate & the right treatment

HDN
Vit. K 1-2 mg im/times
-Continous bleeding or
recurrent
-Prolonged PTT

Severe hemorrhagic
shock

Repeat Vit. K
(3 times, every 6 hours)
-Continous bleeding or
recurrent
- Prolonged PTT
Plasma or
Fresh frozen plasma (FFP)

Anemia

PRC transf

Plasma or
fresh frozen plasma (FFP)
20 ml/kgBW

PROPHYLAXIS
Vitamin K 1 mg

High risk newborn :

- Premature
- Twins
- Assisted labor
- Asphyxia

DIC

= DISSEMINATED INTRAVASCULAR

COAGULATION

- Intravascular coagulation spread

everywhere in blood vessel (systemic)
pathologic activation of
haemostatic mechanism
DIC:
Defibrination syndrome = Consumption coagulopathy
complication: many condition / disease
initiate DIC

- WIDE ENDOTHEL DAMAGE

- TISSUE THROMBOPLASTIN CIRCULATION

WIDE ACTIVATION OF
COAGULATION PROCESS
BLOOD VESSEL
OCLUTION

MAHA

INTRAVASCULAR
TROMBI-FIBRIN

USAGE:
- COAGULATION FACTOR
- PLATELET

FIBRINOLISIS

DEFICIENCY
- COAGULATION FACTOR
- PLATELET

FDP
COAGULATION
DISORDER

ISCHEMIA

HEMORAGE

ETIOLOGY:
- Massive vascular endothel damage
- Tissue Factor (tromboplastin) circulation

1. Trauma:
- burn, crush injury, heat stroke

2. Infection:
- Viral: DHF, Variola
- Bacterial: sepsis
- Fungus: candidiasis

3. Metabolic:
- Acidosis, alkalosis, ketosis
- Hyperthermia, hypothermia

4. Immunologic:
- Blood transfusion reaction (massive hemolisis)
- Anaphylactic, Immune complex diseases.

5. Malignancy:
- Leukemia (ANLL-M3)

6. Others:
- Shock
- Anoxia

DIAGNOSIS
CLINICAL:
Primary Severe Disease
Duration of illness with:

- hemorrhage
- tissue/organ ischemia :
acral necrosis
renal failure

LABORATORY
- Blood smear microangiopathy:

burr cells, helmet cells

- Thrombocytopenia & prolonged bleeding time
- PT, PTT & prolonged thrombin time
- coagulation factor Fibrinogen
- FDP (FSP)

THERAPY
1. Treat etiology factor

2. Blockade process
3. Blood/plasma component substitution