Disorder of Clotting Factor

DISORDER OF CLOTTING FACTOR

DARAHKOMPOSISI :

SEL DARAH MERAHSEL DARAH PUTIHTROMBOSITPLASMA

FAKTOR PEMBEKUAN PROTEIN LAINNYA

FUNGSITRANSPORTASI

NUTRISI (PROTEIN, KH, LEMAK, MINERAL, VIT)

O2 DAN CO2

MEMPERTAHANKAN TEKANAN DARAH

DARAH

DALAM KEADAAN NORMAL DARAH NORMAL, BENTUK CAIR DAN BERADA DALAM SISTEM SIRKULASI (P.DARAH)

FAKTOR YG BERPERAN DLM TROMBOSIS-HEMOSTASIS1. P.DARAH2. FAKTOR KOAGULASI 3. TROMBOSIT4. ANTIKOAGULAN5. SISTEM FIBRINOLISIS

Trombosis : Dikenalkan Virchow (abad 19) “ Triad of Virchow “ 3 faktor berperan : 1. Pembuluh darah tidak normal. 2. Perubahan aliran darah / stasis. 3.Perubahan komposisi darah ( hiperkoagulabilitas )

HEMOSTASIS, (Virchow’s Triad)

Function of HEMOSTASIS

ARREST BLEEDINGMAINTAIN BLOOD IN FLUID STATE

HOMEOSTATIC HEMOSTASIS

Physiologic function Maintain blood in fluid state

Hemostatic Balance

ATIII

Clotting Factors

Tissue factor*

PAI-1

AntiplasminTFPI

Prot. C

Prot. S

ProcoagulantProcoagulant AnticoagulantAnticoagulant

Fibrinolytic System

Hemostasis an equilibrium of physiological activators and inhibitors of coagulation

The equilibrium is fragile and several causes put patient at risk

The equilibrium is fragile and several causes put patient at risk

HEMOSTASISPrimary Hemostasis

Blood vessel contractionPlatelet Plug Formation

Secondary HemostasisActivation of Clotting Cascade Deposition & Stabilization of Fibrin

Tertiary HemostasisDissolution of Fibrin ClotDependent on Plasminogen Activation

HemostasisBV Injury

PlateletPlateletAggregation

Blood VesselBlood Vessel Constriction

CoagulationCoagulation Cascade

Stable Hemostatic Plug

Fibrin formation

Reduced

Blood flow

Tissue Factor

Primary hemostatic plug

Neural

Lab Tests•CBC-Plt•BT,(CT)•PT•PTT

Plt StudyMorphologyFunctionAntibody

Platelet Adhesion

and Activation

Clinical Manifestation of Hemostatic defect

PtechiaPurpuraEchymosisHematomaHematemesisMelenaHemathrosisHemoptysisHematuriaEpistaxisGum bleeding

Petechia : a minute, rounded spot of haemorrhage on a surface, such as skin, mucous membrane, serious membranePurpura : a condition in which haemorrhage occur in the skinEcchymosis: extravasasion of blood into the subcutaneous tissue. It is marked by purple discoloration of the skin, the color gradually changing to brown green and yellowHematemesis : the vomiting bloodHemoptysis : the spitting of blood from larynx ,pharynx, trachea, bronchi or lung

Hematoma : a focalized extravasation of blood which soon clot to form a solid mass and readily became encapsulated by connective tissueMelena : the discharge of stool colored black by altered bloodHemathrosis : extravasation of blood into a jointHematuria : the discharge of urine containing bloodEpistaxis : bleeding from noseHematoschezia : the discharge of stool colored red or brown

Disorders of HemostasisVascular disorders –

Scurvy, easy bruising, Henoch-Schonlein purpura.

Platelet disordersQuantitative - ThrombocytopeniaQualitative - Platelet function disorders – Glanzmans

Coagulation disordersCongenital - Haemophilia (A, B), Von-WillebrandsAcquired - Vitamin-K deficiency, Liver disease

Mixed/Consumption: DIC

VASCULAR

VascularPurpura, echymosisConnective tissue Ehler-Danlos SyndromeAging process senile purpura (Bateman’s disease)Infectious Meningococcus Rocky Mountain’s syndrometyphoid fever Roseola spotVit C deficiency scurvyImmunologic Henoch-Schonlein purpura

↑ fragility capillary infectious, vasculitis

Senile PurpuraSenile Purpura

Petechiae in Petechiae in VasculitisVasculitis

((RockyRocky MountainMountain SpottedSpotted FeverFever))

Henoch-Schonlein purpura

20y Male, fever, painful symmetric polyarthritis for a day. During the next two days, edema and palpable purpura developed.

Henoch-Schonlein purpuraImmune disorder

Children

Follows infection

Petechiae with edema and itching.

VascularNon palpable purpura senile purpura scurvy use corticosteroidPalpable purpura Henoch-Schonlein syndrome

THE ROLE OF PLATELET IN THE ROLE OF PLATELET IN HEMOSTASISHEMOSTASIS

THE ROLE OF PLATELET IN HEMOSTASISTHE ROLE OF PLATELET IN HEMOSTASIS

Platelet dysfunction:

Inherited Disorders: Bernard-Soulier disease

large platelets, failure of adhesion

Glanzmann’s thrombasthenia normal size, failure of aggregation

Acquired Disorders:Drugs : Aspirin AlcoholUremia,

Platelet dysfunction

Quantitatif : - thrombocytemia - ITP - aplastic anemia - DHF - acute leukemia - hypersplenism

Platelet Disorders - Features:

Mucocutaneous bleedingPetechiae, Purpura, Ecchymosis.Spontaneous bleeding after traumaCNS bleeding (severe, Plt)Prolonged bleeding time (BT)

Dengue Hemorrhagic fever

Platelet deficiency..

Petechiae

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

(typical of platelet disorders)

Idiopathic Thrombocytopenic Purpura (ITP)

Acute - children (post infection)Chronic - adults ( females, 20-40 yrs)autoimmune disorder antiplatelet antibodies (IgG)IgG coated platelets removed by spleenUsually megakaryocytes in BM

COAGULATION DISORDERS

Coagulation DisordersCoagulation Disorders

Heparin is a cofactor that allows antithrombin III to inactivate thrombin and Factor Xa

Thrombomodulin binds to thrombin, making it an anticoagulant whichthen activates anti-coagulant protein C.Protein C cleave factors Va and VIIIa

Hemophilia B (ChristmasDisease) results from deficiency of factor IX

Hemophilia A (classic)is due to reduced amount or reduced activity of Factor VIII

Coagulation disorders:

Deficiencies of Clotting factorsOnset - delayed after traumaDeep bleeding

Into joints - Hemarthroses Into deep tissues – Hematoma large skin bleed – Ecchymoses

Ecchymoses(typical of

coagulation factor disorders)

Coagulation Disorders

Laboratory findings:

Normal bleeding time & Platelet count

Prolonged prothrombin time (PT)

deficiencies of II, V, VII, X

Prolonged thrombin time (aPTT)

all factors except VII, XIII

Mixing studies - normal plasma corrects PT or aPTT

HEMOFILIA

How do you get it?Hemophilia is a genetic disease and is passed on by the X chromosome (the chromosome that carries the clotting factor).If a boy gets the X chromosome that carries the hemophilia gene he will become a hemophiliac.If a girl get the gene, she will become the carrier of the gene, not showing symptoms of the disease though she may have a long or heavy menstrual cycle. The carrier has a 50% chance of passing the gene on to her children every time she gets pregnant.

How do you get it ctd.

– This is a diagram of the joints most commonly affected by Hemophilia. It most often occurs at the knees, hips, ankles, shoulders, and elbows

– The most common muscles that bleed with Hemophilia are those in the the upper arm, upper leg (front and back), the calf and the front of the groin

Classification

% normal factor level

Causes of bleeding

Severe < 1% bleeding after trivial injury or spontaneous

Moderate

1 - 5% bleeding after minor injury; occasional spontaneous bleeds

Mild 6 - 30 % following major trauma, surgical or dental procedures

Factor VIII DeficiencyClassic hemophilia (hemophilia A):

X-linked disorder (affects 1º males)Most common - severe bleedingNormal : 50 – 150%Def mild = 5-30%; moderate = 2-5%, severe = <1% Abnormal aPTT – Intrinsic path.Diagnosis - factor VIII assayTreatment - factor VIII concentrateCryoprecipitate (less desirable)Concentrat factor VIII KoateRecombinat factor VIII

PATOGENESE

Faktor VIII adalah suatu glikoprotein yang mengaselerasi kompleks pembekuan darah. Pematangan faktor VIII disintesa sebagai single chain polypeptide yang mengandung 2332 residu asam amino dan terdiri dari tiga rantai yang tersusun A1-A2-B-A3-C1-C2.

Sebagai hasil proses proteolitik, dibentuk oleh suatu heavy chain (HCh) yang dibentuk dari A1, A2, dan B sedangkan light chain (LCh) dibentuk dari A3, C1, dan C2.

Faktor VIII disebut juga dengan anti hemophilic factor (AHF) merupakan ko faktor yang efektif untuk membentuk faktor IXa. Dimana faktor VIIIa dan faktor IXa bersama dengan faktor trombosit yang sudah aktif membentuk suatu kompleks yang disebut functional factor X activating compleks.

Adanya faktor VIIIa kecepatan aktifasi faktor X oleh faktor IXa akan meningkat secara drastis

Pada penderita hemofilia pembentukan pembekuan darah tertunda sehingga pembentukan trombin juga tertunda

Factor IX Deficiency

Christmas disease (Hemophilia B):

X-linked recessive disorder Indistinguishable from classic hemophilia (F VIII)Requires evaluation of factor VIII and IX activity levels to diagnoseNormal : 50 – 150%Def mild = 5-30%; moderate = 2-5%, severe = <1%Treatment - factor IX concentrateCryoprecipitate if factor IX unavailable

Laboratorium

Pemeriksaan aktivitas faktor VIII dan IX, pemeriksaan koagulasi menunjukkan aPTT yang memanjang dan PT normal, bentuk ini juga dapat disebabkan oleh pemberian heparin atau adanya lupus antikoagulan. Adanya heparin dapat diekslude dengan pengobatan Hepzyne (suatu inaktive heparin) dan kemudian pemeriksan aPTT ulangan atau trombin time.

PENATALAKSANAAN

Prinsip umum penatalaksanaan pasien ini adalah pencegahan terjadinya

perdarahan yaitu dengan menghindari trauma dan hindari penggunaan

obat-obatan yang mempengaruhi agregasi trombosit (aspirin) dan non

steroid anti inflamasi serta penyuntikan I.m

Berbagai produk darah telah digunakan untuk menjamin hemostasis;

Porcin FVIII, FEIBA dan konsentrasi aktivasi protrombin kompleks lain

telah digunakan beberapa tahun yang lalu dengan sukses.

Other Medical Treatment Analgesics (no aspirin) Anti-inflammatory medications Good dental care Education – life long management Psychological counseling Acute and long term management of

musculoskeletal problems

Von-Willebrand Disease:

Coagulation + PLT disorder:

Congenital disorderDeficiency of vWF molecule Part of FVIII, Mediates platelet adhesionProlonged Bleeding timeLow Factor VIII & long aPTTMucocutaneous bleeding

Von-Willebrand Disease:

vWF: F-VIII & Plt function.Defective Platelet AdhesionSkin Bleeding Prolonged Bleeding time.Low Factor VIII levels.

VON WILLEBRAND DISEASESPONTANEOUS BLEEDING FROM MUCOUS MEMBRANESEXCESSIVE BLEEDING FROM WOUNDSMENORRHAGIAOFTEN PROLONGED BLEEDING TIME WITH NORMAL PLATELET COUNT

VON WILLEBRAND DISEASEAUTOSOMAL DOMINANT, USUALLYRARELY AUTOSOMAL RECESSIVEOFTEN MILDDIAGNOSIS MAY BE DIFFICULT AND REQUIRE SOPHISTICATED TESTS.POSSIBLY IS THE MOST COMMON INHERITED BLEEDING DISORDER.

VON WILLEBRAND DISEASETYPE I IS MOST COMMON.

REDUCED QUANTITY OF CIRCULATING VON WILLEBRAND FACTOR (vWF)SECONDARY DECREASE IN FACTOR VIII BECAUSE vWF STABILIZES FACTOR VIIIAPPROXIMATELY 70% OF ALL CASES OF VON WILLEBRAND DISEASERELATIVELY MILD

VON WILLEBRAND DISEASETYPE II HAS SEVERAL SUBTYPES, ALL WITH SELECTIVE LOSS OF HIGH MOLECULAR WEIGHT MULTIMERS OF vWF. (Functional deficiency)

IIA: HIGH MOLECULAR WEIGHT MULTIMERS ARE NOT SYNTHESIZED.IIB: ABNORMAL HIGH MOLECULAR WEIGHT MULTIMERS ARE SYNTHESIZED.

TYPE II VON WILLEBRANDDISEASE, CONTINUED

TYPE IIB HIGH-MOLECULAR-WEIGHT MULTIMERS ARE RAPIDLY REMOVED FROM CIRCULATION.HIGH-MOLECULAR-WEIGHT MULTIMERS MAY CAUSE SPONTANEOUS PLATELET AGGREGATION (SIMILAR TO TTP).IN TYPE IIB MAY SEE MILD CHRONIC THROMBOCYTOPENIA LIKELY CAUSED BY PLATELET CONSUMPTION.

VON WILLEBRAND DISEASECLINICAL/LAB FEATURES

PROLONGED BLEEDING TIMEUSUALLY NORMAL PLATELET COUNTPLASMA VWF LEVELS ARE REDUCED.SECONDARY DECREASE IN VIII LEVELSJOINT BLEEDS ARE SEEN ONLY IN SEVERE CASES.

1. Gambaran klinis2. Pemeriksaan Laboratorium

Pemeriksaan Laboratorium Kombinasi hasil px Pemanjangan bleeding time (BT) Penurunan kadar FVW plasma Penurunan aktivitas F VIII Penurunan kadar kofaktor ristosetin

Penanganan segeraPenanganan jangka panjang

Penanganan segera :Stop obat yg menghambat fungsi trombositPemberian FVWTransfusi tombosit.

Penanganan Jangka Panjang:Hindari pemakaian obat yang memperberat kelainan trombosit (aspirin)Pemakaian kartu identitas penderita atau gelang peringatan.DDAVP (desmopresin)FVWKriopresipitatObat lain : Imunoglobuli intravena, premarine, Epsilon aminocaproic acid (EACA), Estrogen.

Analog sintetik hormon antidiuretik, vasopresin.Pemberian IntravenaMeransang pengeluaran FVW dari sel endotel, agar FVW & F VIII cepat ↑ dlm plasma.Dapat diberikan untuk pasien PVW tipe 1 & 2ADosis 0,3 ug/kg BB, Pengenceran dgn 20-30 cc saline, IV selama 10-20 menit.

Melalui transfusi plasma segar atau konsentrat plasma yg mengandung komplek FVW-F VIII.Kriopresipitat;

Dapat segera memperpendek BT, namun bertahan relatif singkat (6-12 jam).

Sediaan konsentrat F VIII/FVW: Humate P, Alphanate.

Imunoglobulin Intravena:Dosis 1 gr/kg/ hari selama 2-3 hari, dapat ↓ kadar antibodi anti FVW.

EACAInhibitor fibrinolitikMencegah perdarahan pada pembedahan minor.Dosis 3-4 gr tiap 4-6 jam IV atau per oral, dimulai sesaat sebelum prosedur & dilanjutkan 5-7 hari.

Estrogen↑ produksi FVW oleh endotelKehamilan normal sering kadar FVW & F VIII normal.

Secondary Hemostatic Disorders

Acquired coagulation disorder:

Vitamin K deficiency- neonates - decreased intestinal flora and dietary intake- oral anticoagulants (coumadin)- fat malabsorption syndromes

Required for factors II, VII, IX, X Prolonged PT and aPTT

Combined Primary and Secondary Hemostatic Disorders

Severe Liver Disease: Primary - dysfunctional platelets and/or thrombocytopenia (

BT) Secondary - decrease in all coagulation factors except vWF (

PT, aPTT) Vitamin K will promote synthesis of factors II, VII, IX, X

Clinical Features of Bleeding Disorders

Platelet Coagulation disorders factor disorders

Skin Deep in soft tissuesSite of bleeding Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe

Platelet Coagulation

Petechiae, Purpura Hematoma, Joint bl.

TROMBOSISDEFINISI : BEKUAN DI DALAM P.DARAH YG TERDIRI KOMPOSISI DARAH, FAKTOR PEMBEKUAN, SDM, DAN TROMBUSADA 2 JENIS : -TROMBUS MERAH

-TROMBUS PUTIH PENYEBAB KEMATIAN NO.1

DI AMERIKA SERIKAT / NEGARA BARAT

PATOGENESISFAKTOR YG MENSTIMULASI TROMBOSISFAKTOR YG MENCEGAH TROMBOSIS

FAKTOR YG MENSTIMULASI TROMBOSIS

ENDOTEL YG RUSAKAKTIFASI KOAGULASIAKTIFASI TROMBOSITSISTEM FIBRINOLISIS MENURUN

COA GULATION, INHIBITOR AN D FIBRINOLYSISCOA GULATION, INHIBITOR AN D FIBRINOLYSIS

C a**

H M W K(F itz ge rald)

X II Ia

X III

HM W K

K al ikre in

X II

F ibrin ope ptid a A

F ibrin ope ptid a B

Fibri n M onomer Cross -l inke dFibr in

Fibrin Polymer

F ibrino gen I

P rekal ikrein(F let che r)

XI Ia

X I X Ia

IX IX a

P ro thrombin II Thrombin

V II IaV III

V V a

X aX

V II

VI Ia + TFHM W K

C a**

C a**

D-Dimer

C a**P L

P L

C a**

activate dProt C

Protei n C

Protein S

TM

Anticoagulant

ExtrinsicIntrinsic

Aktivatio n

Inhib itio n

Hepar in

Plasmin

FAKTOR YG MENCEGAH TROMBOSIS

ENDOTEL UTUHANTIKOAGULAN ALAMIAH

AT IIIPROT CPROT SALPHA 1ANTITRIPSINALPHA 2 MAKROGLOBULIN

MANIFESTASI KLINIS

STROKEINFARK MIOKARDTROMBOSIS MESENTRIALTROMBOSIS VENAEMBOLI PARU

Dangers of Arterial Thrombosis

PENATALAKSANAANPENGOBATAN

PRINSIP P.DARAH DIPERBAIKI MANIPULASI KOMPOSISI DARAH

BEDAH TROMBEKTOMI ARTERI BYPASS

MEDIS TROMBOLISIS ANTIKOAGULAN ANTIAGREGASI TROMBOSIT

PENCEGAHANMENGHILANGKAN FAKTOR RISIKO

DIDAPAT HIPERTENSI ATEROSKLEROSIS DISPLIPIDEMIA OBAT KONTRASEPTIVE ORAL MEROKOK

MENGATASI AKIBAT DEF. AT III DEF. PROT C DEF. PROT S DISFIBRINOGENEMIA

T E R I M A K A S I H