Hemostasis

Shufrie Effendy
Subbagian Hematologi-Onkologi Medik, Bagian Ilmu Penyakit Dalam, Fakultas Kedokteran Universitas Indonesia, RSUPN-Cipto Mangunkusumo / RS Kanker Dharmais, Jakarta

Hemostasis
The process which spontaneously arrest the flow carrying out of blood from vessels under pressure, to maintains the blood in intraluminary vascular system.
Diathesis Hemorrhagic Carrying out of blood from vessels

Proses hemostasis
Primer
Tahap vaskular Tahap trombosit

Sekunder
Tahap faktor koagulasi

PROSES HEMOSTASIS
Robekan vaskuler Gangguan endothel Hemostasis sekunder Prekalikrein Fletcher Kalikrein PAI-1 Plasminogen Plasmin Aktifasi KBMT Fitzgerald Jalur Intrinsik
t-PA

Hemostasis primer
VCAM-1 ECAM

Kontrol Tissue factor Hemostasis released Jalur Ekstrinsik Trombin Fibrinogen Fibrin polimer Fibrin Cross link FPA+FPB FDP X,Y,D,E FDP X,Y,E D-Dimer

Reflek vasokonstriksi Sticky platelet collagen ADP, TXA2 released Aggregasi trombosit Trombosit plug semipermiable

Recanalisasi

endothelial proliferation

PD-ECGF, VEGF bFGF

Hemostasis primer
Vascular injury Expose Collagen, elastin & Membrana basalis
Vasokonstriksi
vWF Retarded bloodflow TXA2 Aktifasi jalur ekstrinsik Tissue factor ADP Tissue thromboplastin

Release ADP Aktifasi KBMT Fitzgerald

Adhesi Platelet-collagen Aggregasi Platelet-primer

Aktifasi jalur intrinsik Fibrinogen

PF-3 PF-4 PF-2

Aggregasi Platelet-sekunder
Alfa granule

ADP, Epinephrin, 5OH-Tryptamine

Dense granule

Fibrin

PF-2 = aktifator fibrin dan inhibitor AT-III, PF-3 phospholipid procoagulan PF-4 = anti-heparin

Adhesive Protein receptors on Platelet

Receptor
GPIa-IIa Collagen GPIb-IX Ristocetin-vWF, and (Direct Platelet associated IgG) GPIc-IIa Fibrinocetin, Laminin GPIIb-IIIa Ristocetin-vWF, Collagen, Fibrinogen, Fibrinocetin, Vitronectin, Complemen.

Ligand

GPIIIb Collagen, Trombospondin ADP ADP TXA2 Tromboksan A2 Epinefrin Epinefrin Direct Platelet associated IgG : Sticky platelet syndrome

Sekresi dan aksis trombosit

Promoters Reseptor vWF, IgG GPIb-IX colagen GPIa-IIa / GPIIIb Fibrinocetin ADP GPIc-IIa ADP TXA2 TXA2

G-Protein Tyrosine kynase

Serotonin PgE2 ADP TXA2 PF-2 PF-3 PF-4

Protein kynase C

Sekresi
Dense granule a granule

vWF, Collagen, Fibrinogen, Fibrinocetin, Vitronectin, Complemen

MGDF Megakaryocyte Growth and Development platelet Formation

GPIIb-IIIa

Cascade hemostasis
XII KBMT XIIa Kalikrein KBMT (Fitzgerald) Prekalikrein (Fletcher) Collagen VIIa Ca** VIIIa PL X V Va PL Ca** Protrombin II Fibrinogen I Fibrinopeptida A Fibrinopeptida B Plasmin Ca** Fibrin Monomer Fibrin Polimer XIIIa Fibrin Ikat Silang Trombin Ca** Xa VII

KBMT
XI IX VIII

Platelets XIa

III TF

AT-III Cofactor II Protein C

IXa

Ca** PL (PLA2)

F1, F2

LA
XIII

ACA

Fragmen X,Y,D,E

Fragmen X,Y,E D-Dimer

Coagulation cascade

Factor VII

Vitamin K antagonist Anti-thrombin III Activated Protein C

Kontrol hemostasis
Penghambat
AT III - Heparan Cofactor II - Heparan APC (Protein C active) b2GPI (antifosfolipid)

Dihambat
Xa, IIa, IXa, XIa, XIIa IIa Va, VIIIa Fosfolipase A2 (PL)

a1 Antitripsin
a1 Makroglobulin C1

XIa, IIa
Kalikrein, IIa, Plasmin Kalikrein, XIIa, XIa

Extrinsic or Tissue factor pathway inhibitor VIIa, Tissue thromboplastin

Causes of Diathesis Hemorrhagic

Vascular fragility Platelet count and/or function Coagulation factor

Clinical Features of Bleeding Disorders

Platelet disorders
Site of bleeding Skin Mucous membranes (epistaxis, gum, vaginal, GI tract) Yes Small, superficial

Coagulation factor disorders

Deep in soft tissues (joints, muscles)

Petechiae Ecchymoses (bruises)

No Large, deep

Hemarthrosis / muscle bleeding

Bleeding after cuts & scratches Bleeding after surgery or trauma

Extremely rare
Yes Immediate, usually mild

Common
No Delayed (1-2 days), often severe

Petechiae
(typical of platelet disorders)

Do not blanch with pressure (cf. angiomas) Not palpable (cf. vasculitis)

Ecchymoses
(typical of coagulation factor disorders)

Hemarthrosis (acute)

Prosedur diagnostik diatesis hemoragis

Masa perdarahan memanjang
Trombopenia Normal or Trombositosis Normal or Hyperagregasi

Masa pembekuan memanjang

Campur dengan plasma normal 1:1

ADP-IPA
Hypoagregasi

Tetap Memanjang
Antikoagulan dalam sirkulasi

Normal

FVIII-v
Normal vWD

Iatrogenik

Periksa Cascade hemostasis

Defisiensi faktor pembekuan spesifik

Fragilitas Vaskuler

Autoimmune Releasing anticoagulant

Fragilitas vaskuler meningkat

Sering
Penurunan kadar estrogen (post menopause) Defisiensi vitamin C Infeksi Sakit berat (hipoproteinemia) Hipotiroidisme

Reaksi alergi
Demam, meriang Efusi sendi (Schoenliens) Efusi visceral akut (Henochs)

Teleangiektasis herediter Psikoneurosis

Sensitisasi autoeritrosit (Gardner-Diamond)

Penyakit collagen

Trombositopenia
Produksi berkurang
Megakaryosit
Infiltrasi sel kanker ke sumsum tulang Lekemia, Limfoma Infiltrasi Fibrosis, Lemak

Penghancuran meningkat
Sirkulasi antibodi
ITP
Primer Sekunder

Imunologik Defsiensi Trombopoietin

TPO/MGDF (3q26-27) IL11 (19q13.3-13.4)

Hipersplenisme Konsumsi
DIC Sindroma Hemolisis TTP (Thrombotic thrombopenic Purpura)

Megakaryosit /N
Distrombopoesis
MDS

Trombopenia purpura
ITP
Penghancuran berlebihan intra/extravaskuler Primer
Hamil Pada kehamilan

Sekunder

HUS (Hemolytic Uremic Syndrome) TTP DIC

ITP
Hamil
Target Mempertahankan kehamilan
Bl.T < 10 menit
Kortikosteroid

Pada kehamilan
Pengobatan
Kortikosteroid IvIg
Jika berhasil: Splenectomi Jika gagal: Vinkristin

Mencegah neonatal trombopenia

IvIg antepartum

Persalinan Sectiocaesaria
Persiapan khusus:
Trombosit Kortikosteroid

Target Mempertahankan kehamilan Persalinan Sectiocaesaria

Persiapan khusus:
Trombosit Kortikosteroid

Reaktifitas aggregasi Trombosit

ADP Disease von Willebrand
Bernard-Soulier

Defect Slope -1 Slope -2 vWF N N

GPIb-IX N N N

Colagen Ristocetin N N N

Storage pool Secretion

Thrombasthenia GPIIb-IIIa
Platelet type vWD GPIb-IX*

* Reaktif terhadap glikoprotein nonspesifik, mengaktifkan GPIIb-IIIa sehingga seolaholah seperti defisiensi GPIb-IX dan GPIIb-IIIa.

Slope-1: reaktifitas akibat ADP external Slope-2: reaktifitas akibat ADP internal (10 detik setelah ADP external)

Hipoagregasi trombosit
Defisiensi vWF Thrombasthenia (Glasnmanns) Sindroma BernardSoulier Disfungsi ADP familial Kelainan metabolik
Uremia

Iatrogenik
Antiagregasi trombosit
Aspirin Cilostazol Ticlopidin/Clopidogrel Moab GPIIb-IIIa

NSAID Antibiotik dosis tinggi

von Willebrand disease

Type 1 Type 2A
N/

Type 2B
N/ N/

Pl-vWD
N/ N/

Type 2M Type 2N
N N/ N N/ N/

Type 3

Bl.T FVIIIa vWFa Rc

RIPA**
Clinically
Treatment

N/ N/

mild
mild
DDAVP Cryo

moderate
absent moderate
DDAVP Cryo

non
present mild Cryo

severe
present

moderate
absent
DDAVP Cryo

mild
absent mild
DDAVP Cryo

severe
absent severe Cryo

LDRIPA* absent

moderate moderate TC

Antibodi vWF: Multiple mutation Kelas 2 dan/atau kelas 3 antibodi

RIPA : 0.5 dan 1mg/mL LDRIPA : 0.1 dan 0.25 mg/mol Pl-vWD : Platelet type vWD Bl.T : Bleeding Time Rc : Ristocetin cofactor * reactivity, ** hyporeactivity

Bedah pada ITP

Akut/Segera/Emergency
Target:
Bl.T (Ivy) < 4 menit Trombosit > 75.000/mm3

Berencana
Target:
Bedah Bl.T (Ivy) Trombosit

Kecil < 7 menit > 20.000/mm3 Sedan 5 menit > 50.000/mm3 g Besar < 4 menit > 75.000/mm3

Bedah pada pengguna antiagregasi trombosit

Emergency/Segera
Stop obat Transfusi TC 15 U
1U TC 100/mm3/kgBB D/(100 x BB) U

Berencana
Aspirin stop 7 hari Ticlid/Plavix stop 3 hari Target:

Target: Bl.T (Ivy) < 4 menit

Bedah Bl.T (Ivy) Kecil < 7 menit Sedang 5 menit Besar < 4 menit

Defisiensi faktor pembekuan

Hipofibrinogen
Primer (idiopatik) Sekunder
Sindroma HELLP Fibrinolisis primer DIC

Hemofilia
A (Faktor VIII) B (Faktor IX) C (Faktor XI)

Faktor VII dan II

Sirosis hati

Antibodi FVIII 5-10BU (40U/kgBB)

Molecular basis of hemophilia

Hemophylia A
Chromosome X q28 (Factor VIIIc)
Containning 26 exon Defect on exon between 22-23

Hemophilia B
Chromosome X q26 and q27 (Factor IXc)
Containig 8 exon Defect on exon between 1-8

Hemophilia C
Chromosome 4 q35 (Factor XIc)
Defect on exon between 5-14

Von Willebrand disease

Chromosome 12 p (Factor VIIIv)
Type 1 vWD Type 2 vWD
Subtype 2A, 2B, 2N, 2M

Type 3 vWD

Platelet type vWD (Pseudo vWD)

Penatalaksanaan perdarahan perlukaan vaskular

Lokal vasokonstriksi
Aktifasi faktor kontak
Penekanan Epineprin lokal Spongestan

Pengganti (Substitusi)
Nonspesifik
PBS (kecuali trombosit)
Minimal F-VIII, Absent F-V) Factor = D x BB/10 mL

Penghambat fibrinolisis
Suplement
eACA Asam traneksamat

Spesifik

Cryopresipitate (Fibrinogen, VIII)

50-80U/bag (VIII) Fibrinogen = D x BB/1000 bag VIIIc = D x BB/2 U atau 25U/kgBB Antibodi human VIII: 5-10 BU: 40U/kgBB 10-50 BU: porcine VIII

Vitamin K (II,VII,IX,X)

Koate, Profilate, Haemate (VIII) Konyne, Berinine (IX)

F-IXc = D x BB U

Coagulation factor characteristics in plasma

Coagulation factor T in vitro T postinfusion (h)
VII vWF IX V X Prothrombin XI Fibrinogen XIII Stable Stable Stable 3-5 days Stable Stable Stable Stable Stable 4-6 8-12 11-12 22 24 35 60 60 96 144 VIII 1-2 weeks

Coagulation factor characteristics in cryoprecipitate single 10-15 mL bag

Coagulation factor vWF 100-150U T in vitro T postinfusion (h) Stable Stable Stable 8-12

VIII
XIII

80-100 U 1-2 weeks

50-75 U

11-12
96 144

Fibrinogen 150-250 mg

Guidelines replacement
Target Site of bleed Prophylaxis Oral mucosa Muscle/joint 30% Initially 50-30% until healing Initially 80-30% until healing Level aPTT <3 <2 <1.5 Dose 25U/kgBW o/tw 30U/kgBW as necessary 35U/kgBW and 20U/kgBB/d as necessary 40U/kgBW and 25U/kgBW/d 50U/kgBW and 25U/kgBW/12h

Epistaxis/GI/GU Initially 100-40% until healing <1.5 CNS/Surgery Initially 100-40% until 2wks or full healing <1.3

Bedah pada pengguna antikoagulant

Warfarin stop 72 jam sebelumnya, ganti dengan heparin, berikan vit.K 3 x 10 mg/iv LMWH hentikan 12 jam sebelumnya Heparin hentikan 4-6 jam sebelumnya
Kecil Sedang Besar Bl.T (Ivy) 7 menit 5 menit 4 menit INR PT 2 2 x kontrol aPTT 2 x kontrol

1,5 1,5 x kontrol 1,5 x kontrol 1,3 1,2 x kontrol 1,2 x kontrol

Penyulit transfusi
Resepien
Reaksi hemolisis Reaksi demam Reaksi alergi Overload Cold effect
Arrythmia Arrest

Janin
Reaksi hemolisis
HUS DIC

Transmisi penyakit
Virus Bakteri Parasit

Citrate overload Transmisi penyakit

Antibodi dan antigen eritrosit

Antibody
A B A and B Rho+ Rho(C,D,E) Kell (K) Duffy (Fy) hr (c,e) IgG labeled erythrocyte C3b labeled erythrocyte

Antigen
B A None None None None None None ? ?

Blood type
B A O RhRhC,D,E KFyhrc,e -

Immunogenisitas Eritrosit ABO & Rhesus

Eritrosit
Reagen Ab-A Ab-B + + Ag None A B

Serum
Reagen Ag-A Ag-B + + + + Ab A&B B A

Blood Type ABO O A B

+
+ -

A &B
Rho None

None
None Rho+

AB
Rhesus Rh+ Rh-

Ab-Rho

Ag-Rho

Incompatibilitas ABO & Rhesus

Transfusi darah
Resepien Donor O A O B AB Ibu O A O + -/+ -/+ -/+

Ibu & Janin

Janin B + AB +

A
B AB

+
+ +

+ +

+
+ Rh-

+
+ -

A
B AB

+ Rh+

+
Rh-

+
+ -

Rh+

Rh+
Rh-

-/+

+
-

Rh+
Rh-

-/+
-

Antibodi: Donor Antigen: Donor

Resepien Resepien

Antibodi: Ibu Antibodi: Janin

Janin Ibu

Thank you