MIND MAP 1.

BASIC SCIENCE
1. BASIC SCIENCE
Ada di DS Basic Science
A. PLATELET 2. CLINICAL SCIENCE
1. Definition A. BLEEDING DISORDER
2. Morphology
No Klasifikasi Jenis
3. Structure 1 Platelet Kuantitatif
4. Function 1. Thrombocytopenia
B. HEMOSTASIS a. Defisiensi Produksi Platelet
1. Definition Myelophthisic (cth: Leukemia)
2. Classification Aplasia (Anemia aplastic)
a. Primary Hemostasis Ineffective Thrombopoiesis
- Blood Vessel (vascular system) (Defisiensi Vit B12)
- Platelet plug formation b. Distribusi Platelet Abnormal
b. Secondary Hemostasis Hypersplenism (splenomegaly)
- Coagulation Hemangioma
- Fibrinolysis c. Peningkatan Destruksi Platelet
Immune, Primary (Idiopathic
2. CLINICAL SCIENCE
thrombocytopenic purpura [ITP],
A. BLEEDING DISORDER
Posttransfusion purpura)
B. HEMOPHILIA A Immune, Secondary (SLE)
3. BHP & IIMC Microangiopathic
4. PATHOMECHANISM Thrombocytopenia
2. Thrombocytosis
a. Primary thrombocytosis,
Myeloproliperative disorder
b. Reactive thrombocytosis
Kualitatif
1. Platelet Membrane Defects
a. Glanzmann’s thrombasthenia
b. Bernard-Soulier syndrome
2. Platelet Release (Secretion Defects)
a. Storage pool deficiency (granule
defects)
b. Primary secretion defects (enzymatic
pathway defects)
3. Platelet coagulant defects
 4. Von Willebrand Disease - Fletcher trait
Fitzgerald factor (high molecular weight
kininogen/HMWK)
2 Vascular Primary Purpura - Fitzgerald defisiensi
1. Simple purpura Plasminogen
2. Mechanical purpura - Abnormal functional plasminogen
3. Senile purpura Protein C
- Protein c defisiensi
4. Factitious purpura
Secondary Purpura
4 Fibrinolytic - Disseminated Intravascular Coagulation
1. Infectious purpura
Disorder - Primary fibrinolysis
2. Metabolic purpura
3. Psychogenic purpura

3 Coagulation Factor I (fibrinogen) B. HEMOPHILIA A

Disorder - Afibrinogenemia
- Hypofibrinogenemia 1. DEFINITION
- Dysfibrinogenemia Hemofilia a (classic hemofilia) merupakan hereditary coagulopathy, memiliki
Factor II (prothrombin) frekuensi tertinggi kedua setelah Von Willebrand disease. Hemofilia
- Hypoprothrombinemia
merupakan sex-linked recessive bleeding disorder.
Factor V (proaccelerin)
- Parahemophilia **Reference: Denise M. Harmening clinical hematology and fundamentals
Factor VII (proconvertin) of hemostasis 5th edition.
- Hypoproconvertinemia
Factor VIII (antihemophilic factor)
Hemophilia A refers to the inherited coagulation disorder characterized by
- Hemophilia a
- von Willebrand’s syndrome deficiency of function of the coagulation protein called factor VIII.
Factor IX (Christmas factor/ plasma **Reference: Wintrobe’s Clinical Hematology, 13th edition.
thromboplastin
component) Hemophilia A is an X chromosome-linked hereditary disorder caused by
- Hemophilia b defective synthesis or by synthesis of dysfunctional factor VIII molecules.
Factor X (stuart-prower factor) **Reference: William Hematology, 7th edition
- Stuart-prower defect
Factor XI (plasma thromboplastic antecedent)
- Hemophilia c 2. EPIDEMIOLOGY
Factor XII (Hageman factor) Approximately 1 in 5000 to 10.000 affected males.
- Hageman trait **Reference: Denise M. Harmening clinical hematology and fundamentals
Factor XIII (fibrin stabiling factor) of hemostasis 5th edition.
- Factor XIII defisiensi
Fletcher trait (prekallikrein)
 3. ETIOLOGY - Missense mutation  Change amino acid  dysfunctional FVIII
 Penurunan sintesis F VIII atau disfungsi F VIII yang diakibat oleh
missense mutation, nonsense mutation, abnormal splicing, deletion
of all or portion of gene and insertsion of element yang terjadi pada
kromosom X pada q28 pada intron 22 .

- Insertsion extragenic F8A ke F8A yang di exon 22 **Reference: William Hematology, 7th edition.

4. CLASSIFICATION
- Severe, <1%
- Moderate, 1% to 5%
- Mild, 6% to 24%
**Reference: Betty Ciesla: hematology in practice

**Reference: Wintrobe’s Clinical Hematology, 13th edition

5. BIOMOLECULER HEMOPHILIA

Hemophilia A akibat dari multiple alteration pada gen faktor VIII diantaranya:
- Nonsense mutation  stop codon sintesis FVII menurun gene rearrangements, missense mutations, subtitution single base, nonsense
mutation, abnormal splicing gen, delesi gen, insersi elemen genetic.
 gen factor VIII berada di q28 kromosom X
didalam intron 22 terdapat 2 gen yang unik : gen F8A dan F8B
gen F8A ditranskripsi ke arah 3 berlawanan arah dengan transkripsi gen factor VIII
sedangkan gen F8 ditranskripsi ke arah 5 searah dengan transkripsi gen factor VIII
selama meiosis terjadi crossing homolog antara gen F8A di intron 22
ketika gen F8A akan ditranskripsi maka terjadi translokasi dan inversi yang menyebabkan
transkripsi sequence faktor VII terganggu
adanya suatu mutasi gen faktor VII pada basa nucleotida CpG dikarenaka tidak adanya
retriction fragment enzim TaqI
mutasi sering terjadi pada kodon CGA (arginin) large delesi small delesi
(severe hemophilia) (mild hemophilia)
terjadi mutasi pada CG doublets
transisi pada basa C transisi pada basa G
maka C  T  TGA maka G A  CAA (glisin)
TGA itu KODON STOP MISSENSE MUTATION
akan menghentikan proses perubahan asam amino
pembentukan protein F.VII dari argini menjadi glisin
(severe hemophilia) (mild moderate severe hemophilia)
**Reference: William hematology, 7th edition.

kurangnya protein F. VII yang disintesis

menurunnya jumlah faktor VII
proses [embentukan thrombin lambat
terjadi pembentukan clot yang mudah rapuh, mudah terlepas dan fibrinolysis meningkat
EXCESSIVE BLEEDING
 Pathogenesis and pathophysiology
Multiple Alteration of F VIII gene
Missense Nonsense Abnormal Deletion of all or Insertsion of
mutation mutation splicing portin of gene element
“Pada kromosom X di q28 pada intron 22 “
Defect synthesis of FVIII Dysfunctional of FVIII
Penurunan Level FVII: Not Forming a functional factor X activity complex ( “tenase or Xase”)
 ≤ 0,01 U/ml (severe)
 0,01-0,05 U/ml (moderate) Defect to secondary hemostasis
 0,05-0,3 U/ml (mild)
Delay clot formation
Spontaneous hemorrhage Trauma
(jarang terjadi pada mild )
Pendarahan Pendarahan susah diberhentikan
6. PATHOGENESIS & PATHOPHYSIOLOGY

Hemartrosis hematoma Perdarahan Perdarahan hematuria hematuria Dental

(sendi lutut intramuscular Intrakranial retroperitoneal and
,siku,pergelang (pada otot 2 dan retrofaringeal surgical
an kaki dan fleksor besar Urine Epistaxis bleeding
Kematian terlihat ,hemoptys
tangan , bahu) ,ex:otot betis
,illiopsoa Membahayakan kecoklatan is and
danlengan jalan nafas dan peptic
kemerahan ulcer
bawah)
Compartment Nerve palsy Muscle
syndrome contracture
 7. CLINICAL MANIFESTATION  bone necrosis

a. Mild (5-30%)  Subcutaneous dan intramuscular hematoma

 Petechiae - Ecchymoses besar

 Prolonged bleeding after circumsision - Subcutaneous dan intramuscular hematom

 Intraocular hemorrage(bleeding conjuctiva/orbit) - Pada originnya : jaringan keras, meninggi, hitam keunguan

 Bleeding after surgery - Pendarahan pada lidah, tenggorokan, leher bisa sangat
berbahaya karena dapat menggangu pernafasan
 Continous bleeding
- Gangrene
b. Moderate (2-5%)
 Psoas dan retroperitoneal hematoma
 Trauma
- Spontaneous hemorrage pada internal facial space dan otot-
 Continous bleeding otot pada abdomen
c. Severe (<1%) - Pendarahan pada otot iliapsoas menyebabkan nyeri yang
 Hemarthrosis progresif dan tenderness bila terjadi pada sisi kanan, bisa
menstimulus terjadinya apendicitis
- Terjadi karena pendarahan dari synovial vessel (terjadi secara
spontan/trauma yang tidak terasa/trauma yang diremehkan  Gastrointestinal dan genitourinary bleeding

- Hemorrage yang terjadi di joint cavity/ke diapysis dan epipysis - Hemorrage pada mulut, gusi, bibir, dan lidah
tulang - Sumber darah biasanya pada upper gastrointestinal tract :
 Acute stage peptic ulcer, gastritis

 Synovial space menggelembung karena darah - Hematouria

 Muscular spasm meningkat, intrasynovial pressure

meningkat, pada stage ini fungsi joint masih normal
 Chronic stage
 Absorbsi darah intraarticular incomplete, darah tersebut
menyebabkan kronik inflamasi di synovial membran
 Joint bengkak, sangat nyeri
 Terminal stage
 fibrous/joint anxylosis complete destruction sehingga
struktur sendi tulang jadi lebih kecil dan tipis
8. DIAGNOSIS
Evaluation of a patient for a hemostatic defect generally entails the following:
1. Detailed History
- Symptoms: epistaxis, gingival bleeding, easy bruising, menorrhagia,
hematuria, gastrointestinal bleeding, hemarthrosis, prolonged bleeding
after lacerations.
- Response to hemostatic challenge: circumcision, surgery, phlebotomy,
immunization/intramuscular injection, suture placement/removal.
- Underlying medical conditions: known associations with hemostatic products, D dimers), and in the presence of thrombin-
defects (liver disease, renal failure, vitamin K deficiency). inhibiting drugs. Useful when both the PT and PTT are
- Medications: antiplatelet drugs (nonsteroidal anti-inflammatory drugs), prolonged.
anticoagulants (warfarin, heparin, low-molecular-weight heparin), o Mixing studies (performed to evaluate a prolonged PT or PTT): the
antimetabolites (L-asparaginase). respective assay is performed following addition of normal plasma to
- Family history: symptoms, response to hemostatic challenge (siblings, patient plasma. Normalization indicates a clotting factor deficiency that
parents, aunts, uncles, grandparents). was corrected by addition of normal plasma. Continued prolongation
2. Complete Physical Examination indicates presence of a coagulation inhibitor. Such inhibitors may be
Signs consistent with past coagulopathy: petechiae, ecchymoses, physiologically relevant or only of in vitro significance.
hematomas, synovitis/joint effusion, arthropathy, muscle atrophy. o Clotting factor activity assays: performed to identify clotting factor
3. Laboratory Evaluation deficiencies if mixing studies normalize. FXII, FXI, FIX, and FVIII assays are
A. Initial screening test: useful if the PTT normalizes in mixing studies. The FVII assay is useful if the
Complete blood count (CBC): quantitative assessment of PT normalizes in mixing studies. FX, FV, FII, and fibrinogen assays are
platelets. useful if both PT and PTT normalize in mixing studies. (Note: Factor XIII
B. Assessments of platelet function: deficiency does not result in prolongation of the PT or PTT.)
o Bleeding time: prolonged with impaired platelet function,
platelet counts reduced below 80,000–100,000/mm3 or
impaired vascular integrity.
o Platelet function analyzer (PFA 100): assesses flow through a
membrane; membrane closure time is measured in response
to ADP and to epinephrine. Often prolonged with impaired
platelet function
C. Coagulant Factor Screening:
o Prothrombin time (PT) assay (assesses the extrinsic system):
utilizes tissue thromboplastin and calcium chloride to initiate
the formation of thrombin via the extrinsic pathway.
o Partial thromboplastin time (PTT) assay (assesses the intrinsic
system): utilizes a phospholipid reagent, a particulate
activator (e.g., ellagic acid, kaolin, silica, soy extract), and
calcium chloride to start the enzyme reaction that leads to the
formation of thrombin via the intrinsic pathway.
D. Common confirmatory coagulation assays:
o Fibrinogen: quantitative measurement of fibrinogen, useful **Reference: Lanskowsky: Manual of Pediatric Hematology and Oncology,
when both the PT and the PTT are prolonged 4th edition.
o Thrombin time: prolonged when fibrinogen is reduced or
abnormal, in the presence of inhibitors (fibrin degradation
  Laboratory Result
 PTT substitution test: deficient factor VIII
 Specific assay for coagulation factor:
Normal: 50-150 U/dl
 Factor VIII < 1% (severe)
 Factor VIII 1-5% (moderate)
 Factor VIII 6-40% (mild)

 Screening hemostasis
 Bleeding Time : normal
 CT Memanjang
 PT normal (normal: 12-15.5 sec)
 aPTT is elevated, due to the reduced factor VIII. ( normal:
26-36 sec)

**Reference: Wintrobe’s Clinical Hematology, 13th edition.

**Reference: Wintrobe’s Clinical Hematology, 13th edition.

 Laboratory diagnosis of inherited coagulation disorders.

**Reference: Wintrobe’s Clinical Hematology, 13th edition

- Prothrombin Time(PT)
Digunakan untuk mengukur factor extrinsic pathway dan common pathway
coagulation (factor VII, X, V, II dan I). **Reference: Wintrobe’s Clinical Hematology, 13th edition.
- Activated Partial Thromboplastin Time (APTT)
Test yang digunakan untuk mengukur coagulation factor pada intrinsic
pathway (factor VII, IX, XI dan XII) dan common pathway (factor I, II, V dan X).
Evaluation of a patient with bleeding and an isolated, prolonged partial 9. MANAGEMENT
thromboplastin time (PTT).
General Principle
 Faktor VIII replacement harus tersedia.
 Mencegah perdarahan dan bila terjadi harus segera ditangani.
 Hindari obat aspirin, NSAID, dan yang lainnya yang mengganggu
aggregasi platelet (Anti platelet).

Faktor VIII Replacement Therapy

 Terdapat 3 generasi: generasi 1 (fresh frozen plasma dan
cryoprecipitate), generasi 2 (recombinate, kogenate, dan helixate),
dan generasi 3 (Monarc-M dan hemofil-M).
 Replacement product diberikan saat terjadi perdarahan, dapat
diberikan berdasarkan berat badan atau plasma volume.
 Cara pemberiannya :
 Prophylactic
Dose 40-50 U/Kg BB, 3x/minggu.
 On demand
 Mild hemorrhage (early hemathrosis, epistaxis,
gingival bleeding): pertahankan kadar factor VIII
pada 30%.
 Moderate hemorrhage (hemathrosis, epistaxis
severe, muscle bleeding): pertahankan kadar faktor
**Reference: Wintrobe’s Clinical Hematology, 13th edition. VIII pada 50%.
 Major hemorrhage (Surgery, head trauma, GI
bleeding): pertahankan kadar factor VIII pada 100%.
 Pemberiaan diatas dengan formula: kg BB x 50 ml/kg
x 1 U x % yang dibutuhkan.

DDAVP (I-deamino-8-D-arginine vasopressin, desmopressin)

 ↑ faktor VIII dengan cara menstimulus vascular endothelial cells
untuk merelease beberapa protein termauk vWF dalam jumlah yang
cukup untuk meningkatkan plasma level protein dan faktor VIII
sebanyak 2-5 kali lipat.
  Digunakan untuk mild – moderate hemophili A. Replacement Therapy in Hemophilia A and Hemophilia B
 Dose : 0,3 mikrogram/kg BB, 2-3 kali/hari. Minor bleeding (i.e., major bleeding
uncomplicated (hematomas in critical
hemathroses; locations; traumatic
Antifibrinolytic Agent hematomas in injures; multiple tooth
 Inhibisi fibrinolysis (mempertahankan hemostasis). noncritical area; extraction; major surgical
 Kontraindikasi untuk hematuria. hematuria; dressing procedures)
changes; arthrocentesis;
 Dose and drugs : epsilon – aminocaproic acid (EACA) 4 gr/4-6 jam, 2- removal of sutures and
8 hari dan tranexamic acid 1 gr, 4 kali/hari. drains)
Disorder Therapeutic loadin Maintenan Loading Maintenan
Fibrin Glue product g dose ce dose dose ce dose
 Disebut juga dengan fibrin tissue adhesives. 1 Hemophi Cryoprecipit Not 1.25-1.75 3.5 1.75
 Kandungan nya terdiri dari : fibrinogen, thrombin, dan faktor XIII. . lia A ate requir bags/10kg bags/10 bags/10kg
 Terutama digunakan untuk hemostasis pada pasien yang sedang (factor ed every 12 h kg every 8 h
VIII for 1-3 d for 1-2 d;
melakukan dental surgery dan bisa juga digunakan pada orthopedic
deficienc every 12 h
procedure dan sirkumsisi. y) thereafter
Purified Not 10-15 30-40 30-40
Gene Therapy
factor VIIIC requir IU/kg IU/kg IU/kg
 Digunakan pada severe hemophili.
ed every 12 h every 12 h
 Jarang digunakan karena peningkatan kadar faktor VIII nya rendah for 2-4 d
dan banyak resiko. 2 Hemophi Prothrombin 20-30 15 IU/kg 40-60 20-25
. lia B complex IU/kg every 24 h IU/kg IU/kg
**Reference: Williams Hematology 7th edition. (factor IX for 2-4 d every 24 h
deficienc
y)
Purified 20-30 15 IU/kg 60-70 20-40
factor IX IU/kg every 24 h IU/kg IU/kg
for 2-4 d every 24 h
**Reference: Wintrobe’s Clinical Hematology, 13th edition.

10. COMPLICATION

Komplikasi terjadi tergantung tingkat keparahan, namun secara umum

dapat dijumpai
- Deformitas persendian
- Intracranial Bleeding yang dapat menyebabkan kelainan neurologis
 - Perdarahan pada saluran nafas atas atau bawah yang menyebabkan
dyspnea
- Perdarahan GI tract dan urinary tract akibat mucous membrane
bleeding

11. PROGNOSIS

Prognosis dari penderita hemophilia A adalah baik apabila mengikuti FVIII

(Factor VIII) replacement therapy secara teratur, seperempat penderita
hemophilia A dalam rentang usia 6-18 tahun mengalami gangguan motorik,
kognitif, dan perilaku.

Mortalitas dari penderita hemophilia ringan dan sedang adalah dua kali lebih
tinggi dari populasi normal, sedangkan penderita hemophilia berat
meningkat menjadi empat kali lebih tinggi.

3. BHP & IIMC

4. PATHOMECHANISM