ANEMIA

LEUKEMIA
BLEEDING DISORDER

LOSEN ADNYANA

DIVISI HEMATOLOGI-ONKOLOGI
MEDIK BAG/SMF ILMU PENYAKIT
DALAM FK UNUD-RSUP SANGLAH
ANEMIA
 Menurunnya massa eritrosit yang beredar sehingga
tidak mampu menjalankan tugasnya sebagai oxygen
carrying power
 Ditandai oleh menurunnya kadar hemoglobin,
hematokrit, dan hitung eritrosit di bawah normal
Kriteria anemia menurut WHO 1968:
 Laki dewasa : < 13 g/dl
 Wanita dewasa : < 12 g/dl
 Wanita hamil : < 11 g/dl
Kriteria Klinik : Hb < 10 g/dl
KLASIFIKASI ANEMIA
Klasifikasi Morfologi
a. Anemia hipokromik mikrositer
(MCV < 80 fl, MCH < 27 pg)
b. Anemia normokromik normositer
( MCV 80-95, MCH 27 – 34)
c. Anemia makrositer
( MCV > 95 fl)
 Klasifikasi Etiopatogenesis
A. Gangguan Produksi Eritrosit
1. Kekurangan bahan pembentuk darah
a. Anemia defisiensi besi
b. Anemia defisiensi B12 & asam folat
2. Gangguan Utilisasi Besi
a. Anemia akibat penyakit kronik
b. Anemia sideroblastik
3. Kerusakan sumsum tulang
a. Hipoplasia  Anemia aplastik
b. Infiltrasi  anemia mieloptisik
4. Gangguan eritropoetin
a. Anemia pada GGK
5. Disfungsi sumsum tulang
a. Anemia diseritropoetik
b. Anemia pada sindroma mielodisplastik
Klasifikasi Etiopatogenesis

A. Gangguan Produksi Eritrosit

1. Kekurangan bahan pembentuk darah
2. Gangguan Utilisasi Besi
3. Kerusakan sumsum tulang
4. Gangguan eritropoetin
5. Disfungsi sumsum tulang

B. Perdarahan
a. Anemia pasca perdarahan akut
b. Anemia pasca perdarahan kronik

C. Anemia akibat hemolisis

1. Faktor ekstrakorpuskuler
2. Faktor intrakorpuskuler

D. Bentuk Campuran

E. Unclassified
Klasifikasi Etiopatogenesis (lanjutan)
B. Perdarahan
a. Anemia pasca perdarahan akut
b. Anemia pasca perdarahan kronik
C. Anemia akibat hemolisis
1. Faktor ekstrakorpuskuler
a. Akibat proses imun
b. Hipersplenisme
c. Akibat bahan kimia/fisik
d. Akibat infeksi bakteri atau parasit
e. Akibat faktor mekanik
2. Faktor intrakorpuskuler
a. Gangguan membran eritrosit (membranopati)
Hereditary spherocytosis
b. Gangguan ensim eritrosit (ensimopati)
Defisiensi G6PD
c. Gangguan pembentukan hemoglobin (hemoglobinopati)
Hemoglobinopati struktural: HbS, HbE, dll
Thalassemia
D. Bentuk Campuran
PATOFISIOLOGI
Penyebab Anemia

Penurunan Hb, Hct, Eritrosit

Kapasitas angkut oksigen menurun

Hipoksia organ target Mekanisme

Kompensasi

Gejala Anemia
GEJALA ANEMIA
 Gejala umum anemia (sindroma anemia)
 Gejala khas masing-masing anemia

Anemia defisiensi besi

Anemia aplastik
Dan lain-lain
 Gejala komplikasi anemia
 Gejala penyakit dasar (underlying disease)
DIAGNOSIS ANEMIA
Diagnosis anemia dibuat berdasarkan:
 Gejala klinik (terutama gejala khas dan
gejala penyakit dasar)
 Pemeriksaan Laboratorium

1. Pemeriksaan skrining
2. Pemeriksaan dasar hematologi
3. Pemeriksaan khusus hematologi
 Pemeriksaan penunjang lain
TAHAPAN DALAM DIAGNOSIS ANEMIA
 Tahapan untuk menentukan adanya anemia
 Diagnosis jenis anemia
 Penentuan beratnya anemia atau adanya
keadaan gawat darurat
 Penentuan etiologi
PRINSIP TERAPI
 Terapi hendaknya berdasarkan diagnosis yang
benar yang telah ditegakkan terlebih dahulu,
kecuali pada keadaan gawat darurat

JENIS TERAPI
1. Terapi darurat
2. Terapi suportif/simtomatik
3. Terapi spesifik
4. Terapi kausal
5. Terapi ex juvantivus
ACUTE LEUKEMIA
Etiology
 A number of environmental factors and clinical conditions are
associated with acute leukemia
 Ionizing radiation is a known leukemogen
 Benzene is known to cause AML, myelodysplastic
syndrome, and aplastic anemia
 Patients with Down syndrome (trisomy 21) and chromosome
breakage disor­ders (e.g., Fanconi anemia, Bloom syndrome)
are at increased risk for devel­oping acute leukemia.
 The myeloproliferative disorders and myelodysplastic
syndromes may progress to AML.
 Chemotherapy can cause treatment-related AML.

 In most patients with acute leukemia, no predisposing

condition or agent can be identified.
Clinical presentation
 Bone marrow failure
 Fatigue and weakness

 Thrombocytopenic hemorrhage

 Neutropenic infections are potentially life

threatening complications of acute leukemia
 Bone marrow infiltration may result in severe bone
pain.
 Leukostasis
 Stasis of blood flow may occur in the cerebral and
pulmonary vasculature when the blast count is
above 50,000/mL.
Clinical presentation (con’t)
 Coagulopathy

 Extramedullary acute leukemia.

 Patients with ALL are likely to present with
adenopathy and splenomegaly due to infiltration of
these lymphoid organs.
 AML with monocytic differentiation is most often
associated with extra-medullary disease.
Diagnosis and classification

 Classification guidelines.

French-American-British (FAB)
classification system
Blasts must account for more than
30% of the nucleated cells
Initial management and supportive
care
Transfusion support. Curative therapy of acute leukemia
depends on effective transfusion support.
 The threshold for RBC transfusion depends on the patient's
physiologic state; younger patients generally tolerate a
lower hemoglobin level than elderly patients with
cardiopulmonary disease.

 Recent studies of patients with acute leukemia have

established a platelet count of 10,000/mL as a reasonable
threshold for prophylactic platelet transfusion, except for
patients with fever, chemotherapy-induced mucositis, and
DIC, in which case more than 20,000/mL is appropriate.
 Kemoterapi
 BMT
PENDEKATAN PASIEN

DENGAN PERDARAHAN
NORMAL HEMOSTASIS

 Primary Hemostasis
Vascular & Platelet  Platelet Plug
 Secondary Hemostasis

Coagulation proteins  Fibrin Plug

 Fibrinolysis Lysis of fibrin
COAGULATION PROCESS

 Coagulation Cascade
 Three pathways:

a. Intrinsic pathway
b. Extrinsic pathway
c. Common pathway
The Four Key Steps
1. Contact Activation (generation of F.IXa)
2. The generation of factor Xa
3. The generation of thrombin (F. IIa)
4. The generation of fibrin
SCREENING TESTS FOR BLEEDING DISORDERS

When these assay are performed simultaneously the results

indicate almost all
The diagnostic catagories of bleeding disorders

Activated partial thromboplastin time (APTT)

Prothrombin time (PT)
Platelet count
Bleeding time
Thrombin clotting time
 PENDEKATAN DIGANOSIS
TROMBOSITOPENIA

W Losen Adnyana

HEMATOLOGY & MEDICAL ONCOLOGY DIVISION

INTERNAL MEDICINE DEPARTMENT, UDAYANA UNIVERSITY-
SANGLAH HOSPITAL
 Overview

• Normal Physiology
• Categories of Thrombocytopenias
 Normal Physiology-
Production and Number
• Platelets are normally made in the bone
marrow from progenitor cells known as
megakaryocytes.
• Normal platelet lifespan is 10d. Every day,
1/10 of platelet pool is replenished.
• Normal platelet count is between 150,000
and 450,000/mm3

Mehmet et al. J Hemato 2012;1(2-3)44-53

 Platelet Response
Platelets adhere to
vessel wall, then
aggregate, leading
to formation of a
platelet plug

Platelets provide phospholipid scaffold for

thrombin generation
Mehmet et al. J Hemato 2012;1(2-3)44-53
 Thrombocytopenia-
How low is too low?
• 150,000 - 50,000: no symptoms
– No treatment generally required.
• 50,000 - 20,000: first symptoms
– Generally need to begin therapy
• 20,000-10,000: life-threatening
– Generally requires hospitalization
• < 10,000: risk for spontaneous intracranial
hemorrhage
Rodeghiero et al. Blood 2009

Roberto Stasi. Blood 2013

 Thrombocytopenia
3 broad categories of causes
• Pseudothrombocytopenia
• Underproduction
• Splenic sequestration
• Peripheral Destruction

Rodeghiero et al. Blood 2009

Roberto Stasi. Blood 2013
 Pseudothrombocytopenia

• Platelet clumping is of no clinical significance

• No increased risk of bleeding or clotting
CLASSIFICATION OF THROMBOCYTOPENIA
IMPAIRED OR DECREASED PRODUCTION OF PLATELET

Congenital
May-Hegglin Anomaly
Bernard-Soulier Syndrome
Fechtner Syndrome
Sbeastian Syndrome
Epstein Syndrome
Montreal Platelet Syndrome
Fancone Anemia
Wiskott-Aldrich Syndrome
Thrombocytopenia with absent radii (TAR) Syndrome
Congenital amegakaryotic thrombocytopenia
Autosomal dominant and X-linked thrombocytopenia
Neonatal
Acquired
Viral
Drug induced
Roberto Stasi. Blood 2013
CLASSIFICATION OF THROMBOCYTOPENIA
INCREASE PLATELET DESTRUCTION
Immune
Acute and chronic immune thrombocytopenic purpura
Drug induced; Immunologic
Heparin induced thrombocytopenia
Neonatal autoimmune (Isoimmune neonatal) thrombocytopenia
Neonatal autoimmune thrombocytopenia
Posttransfusion isoimmune thrombocytopenia
Secondary autoimmune thrombocytopenia
Nonimmune
Thrombocytopenia in pregnancy and preeclampsia
Human immunodefficency virus infection
Hemolytic disease of the newborn
Thrombotic thrombocytopenia purpura
Disseminated intravascular coagulation
Hemolytic uremic syndrome
Drug induced
Roberto Stasi. Blood 2013
CLASSIFICATION OF THROMBOCYTOPENIA
ABNORMALITIES OF DISTRIBUTION OR DILUTION

Splenic sequesteration

Kasabach-Meritt syndrome

Loss of platelets :

Massive blood transfusion, extracorporeal circulation

Rodeghiero et al. Blood 2009

Roberto Stasi. Blood 2013
 Thrombocytopenia -
Peripheral Destruction
• Non-immune mechanisms:
– Platelet activation and consumption
– e.g. TTP and DIC

• Immune Mechanisms:
– antibody-mediated platelet destruction
– may be primary, secondary, or drug-
induced.
Rodeghiero et al. Blood 2009
Provan D et al. Blood 2010
 ITP - Immune/Idiopathic
Thrombocytopenic Purpura
• Definition: isolated thrombocytopenia with no
clinically apparent associated conditions or other
causes of thrombocytopenia.
• Etiology: autoantibodies directed against platelets
coat platelet surface. IgG-coated platelets are taken
up by RE system.
• Incidence: approximately 100 per million; half of
these are children. In adults, two peaks:
– one are young (<40) with female predominance,
– one are older (>60), no gender predominance.

Rodeghiero et al. Blood 2009

Provan D et al. Blood 2010
Childhood (acute) ITP

Adult (chronic) ITP

Rodeghiero et al. Blood 2009
Provan D et al. Blood 2010
 ITP - Diagnosis

• ITP is a Diagnosis of Exclusion

• No laboratory test can diagnose ITP
• Need to exclude other causes of
thrombocytopenia

Rodeghiero et al. Blood 2009

Provan D et al. Blood 2010
Medication induced
Thrombocytopenia
 Drugs Commonly Implicated in
Thrombocytopenia
• Beta-lactam antibiotics.
• Trimethoprim-sulfamethoxazole and other sulfa
drugs.
• Vancomycin.
• Quinine/quinidine.
• Heparin.
• Abciximab (ReoPro®).
• H2 blockers
• If a patient’s platelets fall, ALL unnecessary drugs
need to be stopped.
Gorge JN et al. Haemetology Am Soc Program 2009

Rousan TA et al. Am J Hematol 2013

COMMON DRUGS CAUSING IMMUNE
THROMBOCYTOPENIA
Analgesics
Salicylates
Acetaminophen
Phenylbutazone

Antibiotics
Cephalothin
Penicillin
Streptomycin
Aminosalicylic acid
Rifampin
Novobiocin

Various Sulfa drugs (Chlortalidone, furosemide)

Alkaloids
Quinidine
Quinine Gorge JN et al. Haemetology Am Soc Program 2009
Rousan TA et al. Am J Hematol 2013
COMMON DRUGS CAUSING IMMUNE
THROMBOCYTOPENIA
Sedative, anticonvulsants
Methoin
Troxidone
Chlorpromazine
Diphenylhydantoin
Meprobamate
Phenobarbital
Carbamazepine
Oral Hypoglycemics
Chlorpropamide
Tolbutamide
Heavy Metals
Gold
Mercury
Bismuth
Organic arsenicals
COMMON DRUGS CAUSING IMMUNE
THROMBOCYTOPENIA
Miscellaneus
Chloroquine
Chlorothiazide
Insecticides

Gorge JN et al. Haemetology Am Soc Program 2009

Rousan TA et al. Am J Hematol 2013

Gorge JN et al. Haemetology Am Soc Program 2009
 Drug Induced ITP
• Usually, removing the offending agent is
enough to allow the platelets to rise on
their own.
• If platelets are severely low, platelet
transfusions may be required.
• IVIg is particularly helpful in quinine-
induced ITP.

Gorge JN et al. Haemetology Am Soc Program 2009

Rousan TA et al. Am J Hematol 2013

 Heparin-Induced Thrombocytopenia
• Seen in 1-3% of patients treated with heparin
• Usually, 7-10 d after heparin started, platelets fall by at least
1/3 to 1/2.
– Patients do not have to be thrombocytopenic.
– Can occur earlier in patients who have been previously
exposed to heparin, even as SQ injections.
• Caused by antibodies against the complex of heparin and PF4.
These antibodies activate platelets.
• Can lead, paradoxically, to THROMBOSIS, in up to half of
patients.
• More common in patients with vascular disease

Hui P et al. Chest 2014

Rausan TA et al. Am J Hematol 2013

 Alternate Presentations of HIT/T
• Small drop in platelet count (especially with
skin necrosis)
• Earlier onset thrombocytopenia with
heparin re-exposure
• Delayed-onset thrombocytopenia/
thrombosis after stopping heparin
• Thrombosis after heparin exposure

Gorge JN et al. Haemetology Am Soc Program 2009

Rousan TA et al. Am J Hematol 2013
Heparin-Induced Thrombocytopenia
(HIT): Pathophysiology1
IgG antibody
PF4 Heparin
Formation of
immune complexes
(PF4-heparin-IgG)
Formation of
PF4-heparin
Microparticle complexes
release
EC injury
Platelet PF4
release

Platelet
activation*
Heparin-like
Fc receptor molecules

Blood vessel

*Places patient at greater risk from primary thrombotic problem.

1. Adapted from Aster RH. N Engl J Med. 1995;332(20):1374-1376.
 TTP - Diagnostic Features
• Microangiopathic Hemolytic Anemia (MAHA)
– Elevated LDH, elevated bilirubin
– Schistocytes on the peripheral smear
– MUST BE PRESENT
• Low platelets - MUST BE PRESENT
• Fever
• Neurologic Manifestations - headache, sleepiness,
confusion, stupor, stroke, coma, seizures
• Renal Manifestations - hematuria, proteinuria, elevated
BUN/Creatinine
• Abdominal Pain - can see elevated lipase/amylase
Roberto Stasi. Blood 2013
Hui P et al. Chest 2014
 TTP - etiology
• May be associated with an antibody against or a
deficiency of the protease which cleaves the ultra-
high molecular weight multimers of von Willebrand’s
factor. These very high molecular weight vWF
multimers cause abnormal platelet activation.
• Can be induced by drugs, including ticlopidine,
quinine, cyclosporine, tacrolimus, mitomycin C.
• Increased incidence with pregnancy or HIV

Roberto Stasi. Blood 2013

Hui P et al. Chest 2014
TTP - Course and Prognosis
• 95% fatal prior to therapy, now 5% fatal.
• Treatment relies on PLASMA EXCHANGE.
– Plasma exchange is superior to plasma infusion, but if PLEX is
delayed, give FFP.

• Remove all inciting agents.

• Platelet transfusions contra-indicated.

– Multiple case reports of stroke and/or death during or
immediately after platelet transfusion.

– Can consider giving if life-threatening hemorrhage is present,

but avoid routine platelet transfusions.

• Secondary measures if no response to plasma exchange

include splenectomy, vincristine

Roberto Stasi. Blood 2013

Hui P et al. Chest 2014
 HUS - Hemolytic Uremic Syndrome

• Usually classified along with TTP as “TTP/HUS”

• Has fewer neurologic sequelae, more renal
manifestations.
• Usually precipitated by diarrheal illness, especially E.
coli O157:H7 or Shigella
• Seen more in pediatric patients, usually has better
prognosis. May respond less well to plasma
exchange.

Roberto Stasi. Blood 2013

Hui P et al. Chest 2014
 THROMBOCYTOPENIA AND PREGNANCY

• Benign thrombocytopenia of pregnancy

 Occurs in up to 6 – 15 % of term pregnancies
 Accounts for about 75% of cases of thrombocytopenia
 Asymptomatic, mild, occurs late in gestation
• Microangiopathy (Preeclampsia/eclampsia, HELLP)
• ITP (increased incidence in pregnancy)
• GT

Bockendetdt et al. Haematol oncol Clin North Am 20011

 Disseminated intravascular
coagulation: characteristics
• Widespread activation of coagulation
 intravascular formation of fibrin
 thrombotic occlusion of small vessels
 contributes to multiple organ failure in conjunction
with haemodynamic and metabolic consequences
• Depletion of platelets and clotting factors
 severe bleeding

Taylor FB et al. Thromb Haemost 2001

 Systemic activation
of coagulation

Intravascular Depletion of platelets

deposition of fibrin and coagulation factors

Thrombosis of small
and midsize vessels
and organ failure Bleeding
Bachelor of Chinese Medicine
 DIC
• Peripheral blood picture:
– Anaemia
– Thrombocytopenia
– Fragmented red cells (schistocytes)
• A feature common to several conditions:
– DIC
– Thrombotic thrombocytopenic purpura
– Haemolytic Uraemic Syndrome

Taylor FB et al. Thromb Haemost 2001

Disseminated intravascular
coagulation
 Evaluation of Patient with Low Platelets
• History
– Has the patient ever had a normal platelet count?
– Carefully review medications
• Antibiotics, quinine, anti-seizure medications
– Ask about other conditions which may be associated with low
platelets
• Liver Disease/hepatitis
• Thyroid Disease - both hypo- and hyper-
• Infections: viral, rickettsial
• Pregnancy
– Ask about other conditions which may be associated with ITP
• Lupus, CLL, lymphoma
Roberto Stasi. Blood 2013
Evaluation of Patient with Low Platelets
• Physical
– Evaluate for lymphadenopathy and splenomegaly
– Look for stigmata of bleeding
– Blood blisters and oral petechiae
• Laboratory Data
– Other blood counts should be normal.
– Check B12 and folate levels.
– Look at peripheral smear to exclude
pseudothrombocytopenia, also exclude TTP (especially if
anemia also present.)
– Send coagulation screens (PT/PTT) to exclude DIC
– Send HIV, hepatitis serologies and TSH
• Consider doing a bone marrow biopsy
– Megakaryocytes should be present.

Roberto Stasi. Blood 2013

 Work up (continued)
Bone marrow biopsy?
– More definitively answers the “production vs.
destruction” question
– Generally indicated in unexplained
thromocytopenia
*UNLESS age < 60, thrombocytopenia is
isolated, and history, and smear suggest the
diagnosis (of exclusion) of ITP.
*If age > 60, and suspect likely ITP, BM biopsy
generally indicated to r/o myleodysplasia
Roberto Stasi. Blood 2013
Robert LG. American Family Physician 2012
Robert LG. American Family Physician 2012
CONGENITAL BLEEDING DISORDER
The most frequently congenital bleeding disorders are def in factor VIII, IX
and XI ( as Hemophilia A, B, and C), VON WILLEBRAND DISEASE
Factor VIII and IX def are most common congenital bleeding disorders
because they are sex-linked defects ( X chromosome)
PATHOPHYSIOLOGY OF CONGENITAL BLEEDING
DISORDER

Deficiencies in coagulation factor result in a decreased rate and

amount of thrombin produced  decreased of fibrin plug
Quality fibrin plug is poor
 CLINICAL EVALUATION ON CONGENITAL BLEEDING
DISORDERS

characteristic primary hemostasis Secondary hemostasis

platelet/vascular factor coagulation
Onset Spontaneus, immediately Delayed after trauma
after trauma
Sites Skin, mucous, membran Deep tissues
Form Petechiae, ecchymoses Hematomas
Mucous membran Common Rare
Other sites Rare Joint, muscle, CNS,
retroperitoneal
Clinical example Thrombocytopenia, Def factor, acquired
platelet defect, vWB, inhibitor, liver disease
scuvy
Factor VIII deficiency (Hemophilia A)
1. Overview :
F VIII def is most common of the hemophilias with
incidence 1 – 2 case per 10.000 male birth.
F VIII essensial cofactor F IXa- mediated F Xa
2. Genetic :
Def F VIII  sex linked recessive disorder
All patients with hemophilia A  F VIII a < 50 %,
reduced activity and antigen level F VIII
30% hemophilia have no family history of hemophilia 
inherent de novo spontaneous mutation chromosome X
3. Clinical presentation

Bleeding manifestations in hemophilia

Bleeding after circumcision
Delayed oozing from deep lacerations
Protracted bleeding after dental extraction
Intramuscular hematomas
Intraarticular hemorrhage
Central nervous system bleeding
Hematuria
DIAGNOSIS

a. History: types of trauma and sites of spontaneous bleeding

and interval time injury and bleeding
b. Laboratory evaluation : aPTT prolonged,
F VIII < 30 % and PT, bleeding time, clotting time are normal,
Predictive value of Factor VIII level

F VIII (%) Type specific Symptoms

<1 severe spontaneous intraarticular
and intramuscular bleeds

1–5 moderate predominantly soft tissue

bleeding

5 – 10 mild risk of bleeding after surgery,

trauma, reduced risk of
spontaneous hemorrhage
Specific problems in hemophilia A and B

1. Acute hemarthrosis  most frequent type bleeding in patiens

severe hemophilia
2. Chronic hemophilia arthropaty
3. Intramuscular hemorrhage  second frequent bleeding in
patienns severe hemophilia
4. Central nervous system bleeding
5. Mouth, throat, and nose bleeds
6. Dental procedure
7. Mayor surgery
8. Other procedure
FACTOR IX DEFICIENCY ( HEMOPHILIA B)

F IX def occounts ± 10 % of hereditery coagulation factor

X linked recessive disorder, 30% mutation spontaneous
Clinical presentation identical F VIII def (hemophilia A)
Laboratorium evaluation : level factor IX below 50% result in a prolonged
aPTT and level factor identical F VIII def
 Diagnostic Criteria

Family_history_of_coagulation_disorders:positive
Factor_IX_assay:abnormal
APTT:abnormal
Diagnosis by factor IX levels
 Treatment

For patients with mild form of factor IX deficiency

with non-life-threatening bleeding, the treatment of
choice is FFP.
Treat with recombinant IX
TERIMAKASIH