Coagulation Disorder

Luciana
 Contoh kasus
 Ny BS usia 81 tahun dengan BB : 56 kg/ TB : 155 cm, masuk RS dengan
keluhan lemas. Riwayat penyakit dahulu : CKD on HD, DM tipe 2, riwayat
PCI 1 tahun 2017 dan PCI 2 tgl 20/7/19 . Riwayat penggunaan obat :
novorapid sc 3x sehari.
 Kesadaran : cm, TD : 114/58 mmHg; nadi : 76x/menit; RR : 19x/menit;
SatO2 : 99%. Hasil lab : Hb : 10,1; Leukosit : 13.800; Trombosit : 167.000;
Ureum : 228; creatinine : 6,28; SGOT : 61; SGPT : 70; CRP : 79,57; Albumin :
3,6 g/dL. Dokter mendiagnosis DM tipe2, CAD post PCI dan CKD. Terapi
saat ini : Brilinta 90 mg 2x sehari, Xarelto 10 mg 2x sehari; simvastatin 20
mg 1x sehari malam, meropenem 500 mg tiap 24 jam. Dobutamin 10
mcg/kgbb/menit dan norepinephrine 0,1 mcg/kgbb/menit. Pasien
mengeluh pegal-pegal, dan hasil pemeriksaan feses ditemukan darah
samar +1. Lakukan evaluasi terapi dan rekomendasi apa yang dapat
anda sampaikan?
 Introduction

 Coagulation disorders result from a decreased of platelets,

decreased function of platelets, coagulation factor deficiency,
or enhanced fibrinolytic activity
 Maintenance of blood flow involve 4 major components :
• The vessel wall
• Platelets
• The coagulation system
• The fibrinolytic system
 Coagulation could be initiated via either the intrinsic or
the extrinsic pathway
 The extrinsic pathway is initiated by exposure of tissue
during trauma
 The intrinsic pathway is initiated when circulating factor
XII contacts with the subendothelial membrane
Coagulation Factors

 The coagulation factor can be divided into three groups

on the basis of biochemical properties :
 Vit K-dependent factors : ( II, VII, IX and X )
 Contact activation factors ( XI and XII, prekallikrein, high-
molecular-weight kininogen )
 Thrombin-sensitive factors ( V, VIII, XIII, and fibrinogen )
 Laboratory Procedures
 Coagulation test
Drug used in Coagulation Disorders
Anticoagulants

 Inhhibit the formation of fibrin clots

 3 types of anticoagulants :
a) Heparin and related products
b) Direct thrombin and factor X inhibitors
c) The orally active cumarin derivatives ( warfarin )
 Heparin :
• MW: 15.000-20.000
• Heparin is highly acidic and can be neutralized by basic molecules
( protamine )
• Heparin is given iv or sc
• UFH is an indirect thrombin inhibitor, UFH binds to antithrombin III
form the heparin-ATIII complex and irreversibly inactivates thrombin,
particularly factor Xa
• The action of heparin is monitored with aPTT laboratory test.
 LMWH ( enoxaparin, dalteparin, and tinzaparin )
• MW: 2.000-6.000
• Have greater bioavailability and longer durations of action than UFH
• Doses can be given once or twice a day sc
 Fondaparinux
• A small synthetic drug that contains the biologically active
pentasaccharide present in UFH and LMWH
• Administered sc once daily

 Bind ATIII form complexes have the same inhibitory effect on factox Xa as
the UFH-ATIII complex.
 The aPTT test does not reliably measure the anticoagulant effect of LMWH
and fondaparinux
 Clinical use
 Heparin is used when anticoagulation is needed immediately (
treatment DVT, pulmonary embolism, and acute MI )

 Toxicity :
• Increased bleeding and may result in hemorrhagic stroke
• UFH causes moderate transient thrombocytopenia and severe
thrombocytopenia
• LMWH and fondaparinux are less likely to cause this immune-
mediated thrombocytopenia.
• Prolonged use of UFH is associated with osteoporosis

 Protamine can lessen the bleeding risk, protamine only partially

reverse the effects of LMWH and does not effect the action of
fondaparinux
Direct Thrombin Inhibitors

 Example : lepirudin ( no longer available ), argatroban (

a small molecule with a short half life ), dabigatran ( the
only orally active direct thrombin inhibitor
 Dabigatran ( Pradaxa ) 150 mg
 Mechanism action : direct thrombin inhibitor that inhibits
both free and fibrin-bound thrombin. Inhibits
coagulation by preventing thrombin-mediated effects
and inhibition of thrombin-induced platelet
aggregation.
 Clinical use :
 Prevention of stroke and systemic embolism in
nonvalvular AF
Dosage : oral : 150 mg twice daily
 Prophylaxis of VTE following hip or knee replacement
surgery
 Dosage Total hip arthroplasty : oral : initial 110 mg given
1 to 4 hours after completion of surgery or when
dabigatran is not initiated on day of surgery, give an
initial dose of 220 mg after hemostasis has been
achieved. Maintenance dose of 220 mg once daily for
minimum 10 to 14 days.
 Dosage for total knee arthroplasty : initial : oral initial 110
mg given 1 to 4 hours after completion of surgery or
when dabigatran is not initiated on day of surgery, give
an initial dose of 220 mg after hemostasis has been
achieved. Maintenance dose of 220 mg once daily for
minimum 10 to 14 days.
 Dosage for DVT : after at least 5 days of initial therapy
with parenteral anticoagulant, 150 mg twice daily

 Reduction of the risk of recurrent VTE

 Toxicity :
• Bleeding risk
• Dyspepsia, gastritis-like symptoms
Direct Oral Factor Xa inhibitors
 Oral Xa inhibitors : rivaroxaban, apixaban and
edoxaban
 Have a rapid onset of action and shorter half-lives
 These drugs are given as fixed oral doses and do not
require monitoring
 Mechanism : directly bind to and inhibit both free factor
Xa and factor Xa bound in clotting complex
 Clinical use :
• For prevention and treatment of VTE following hip or knee surgery
• For prevention of stroke in patients with AF without valvular heart
disease
 Dosage for :
 Deep vein thrombosis ( DVT ) : oral : 15 mg daily with food for 21
days
 Superficial vein thrombosis, acute symptomatic ( off-label use ) :
oral : 10 mg once daily for 45 days
 Nonvalcular AF ( to prevent stroke and systemic embolism ); oral 20
mg once daily with the evening meal
 Acute coronary syndrome ( ACS ) : oral : 2,5 mg twice daily,
administer in combination with low dose aspirin plus clopidogrel
 Heparin-induced thrombocytopenia ( off label use ); with or without
thrombosis : oral : 15 mg twice daiy with food for 21 days or until
platelet count recovery
Warfarin and other Coumarin Anticoagulants
 Warfarin and other coumarin anticoagulants are small,
lipid-soluble molecules
 Warfarin is highly bound to plasma proteins ( > 99% )
 Mechanism : interfere clotting factors in the liver. The
drugs inhibit vit K epoxide reductase , which converts vit
K epoxide to reduced vit K. Vit K-dependent factors
include : thrombin and factors VII, IX, and X
 The effect of warfarin is monitored by the Prothrombin
time ( PT ) test
 Clinical use :
 Thromboembolic complications ( prophylaxis/treatment ) or
MI : oral : consider the patient ( hepatic function, cardiac
function, age, nutritional status, risk of bleeding ). Start 2 to 5
mg once daily .
 Adjust dose according to INR results, usual maintenance dose
ranges from 2 to 10 mg daily
 Duration therapy :
• Provoked DVT : 3 months minimum
• Anterior MI with LV thrombus or at high risk for LV thrombus : 3
months after MI
 Thromboembolic complications ( prophylaxis/treatment
) in geriatric : oral : initial dose or MI ≤ 5 mg, usual
maintenance dose : 2-5 mg mg/day
 Toxicity :
• Bleeding is the most important adverse effect of warfarin
• Bone defects
• Hemorrhage in the developing fetus
 Drug interaction of warfarin ( increased warfarin”s clearance
and reduce anticoagulant effects ):
 Carbamazepin
 Phenytoin
 Rifampicin
 Drug interaction of warfarin( reduced warfarin clearance and
increased anticoagulant effects ):
 Amiodaron
 Cimetidin
 SSRI : fluoxetine
Thrombolytic agents

 The most commonly are either forms of the endogenous

tissue plasminogen activator (t-PA : alteplase,
tenecteplase and reteplase ) or a protein synthesized by
streptococci ( streptokinase ).
 All are given iv.
 Mechanism of action : plasmin is an endogenous
fibrinolytic enzyme that degrades clots by splitting fibrin
into fragments. The thrombolytic enzyme catalyze the
conversion plasminogen to plasmin
Diagram of the fibrinolytic system
 Tissue plasminogen activator

 An enzyme that directly converts plasminogen to plasmin. It

has little activity unless it is bound to fibrin.
 At the pharmacologic levels of t-PA used in thrombolytic
therapy, clot specificity is lost.
 Alteplase is recombinant human plasminogen activator
 Dosage :
0,6 mg/kg bb ( diberi dengan dosis 10% secara bolus dan 90%
secara drip hbis dalam waktu 1 jam )
 Streptokinase :
• Obtained from bacterial cultures.
• Streptokinase forms a complex with endogenous plasminogen
in this complex allows it to rapidly convert free plasminogen
into plasmin.
• Streptokinase does not show selectivity for fibrin-bound
plasminogen
Clinical Use :

 Alternatif to percutaneous coronary angioplasty in the

emergency treatment of coronary artery thrombosis.
 Very prompt use ( within 3 h in the first symptoms ) of t-PA
with ischemic stroke.
 The thrombolytic agents used in cases of severe
pulmonary embolism
Toxicity

 Bleeding risk
 Cerebral hemorrhage is the most serious manifestation
 For streptokinase, a bacterial protein, can evoke the
production of antibodies, cause it to lose it effectiveness
and induce severe allergic reaction.
Antiplatelet Drugs

 Platelet aggregation contributes to the clotting process.

 Platelets appear to play a central role in pathologic
coronary and cerebral occlusion
 Platelet aggregation is triggered by a variety of
endogenous mediators ( thromboxane, ADP, thrombin
and fibrin )
Classification

Antiplatelet drugs include aspirin, NSAIDs,

glycoprotein IIb/IIIa receptor inhibitors (
abciximab, eptifibatide ), antagonist of ADP
receptors ( clopidogrel, ticlopidine, prasugrel ),
inhibitors of phospodiesterase3 ( dipyridamole,
cilostazol )
 Mechanism of action :
 Aspirin and NSAIDs inhibit thromboxane synthesis by
blocking the enzyme cyclooxygenase . Thromboxane A2
is a potent stimulator of platelet aggregation.
 Aspirin is irreversible COX2 inhibitor

 Clopidogrel, prasugrel and the older drug ticlopidine

inhibit the platelet ADP receptor and prevent ADP-
mediated platelet aggregation.
 Ticgrelor is anewer drug that inhibits the platelet ADP
receptor
 Dipyridamole and cilostazol have dual mechanism :
 Prolong the platelet-inhibiting action of intracellular cAMP by
inhibiting phodphodiesterase enzyme that degrade cyclic
nucleotides,cAMP ( inhibitor of pltlet aggregation ), cAGMP (
vasodilator )
 Inhibit the uptake of adenosine by endothelial cells and
erythrocytes, increase the plasma concentration of
adenosine. Adenosine acts inhibit aggregation
Clinical use :
 Aspirin is used to prevent infarcts in persons or
myocardial infarct, to prevent TIA, ishemic stroke and
thrombosis events
 Dosage :
 ACS, Myocardial infarction : initial 162-325 mg ,
maintenance 81-325 mg once daily, when used with
ticagrelor the recommended dose of aspirin is 81
mg/day.
 The glycoproteins IIb/IIIa inhibitors prevent restenosis after
coronary angioplasty and for short periods in ACS ( unstable
angina )
 Dosage :
 PCI : iv : 0,25 mg/kg bolus administered 10-60 minutes prior to
start PCI followed by an infusion of 0,125 mcg/kg/minute for
12 hours
 ST-elevation myocardial infarction ( STEMI ) undergoing PCI :
loading dose : 0,25 mg/kg bolus administered at the time of
PCI. Maintenance infusion : 0,125 mcg/kg/minute continued
for up to 12 hours
 Clopidogrel and ticlopidine are effective preventing TIA
and ischemic strokes, especially in patients who cannot
tolerate aspirin. Clopidogrel is routinely used for 6-12
months with aspirin to prevent thrombosisin patient after
placement of a coronary artery stent
 Dosage :
 Unstable angina, ACS : loading dose oral 300 mg or 600
mg, followed 75 mg once daily for up to 12 months in
combination with aspirin.
 CAD : oral 75 mg oncedaily
 PCI , non ACS : 600 mg loading dose, followed by 75 mg
OD ( in combination with aspirin )
 Cilostazol is used to treat intermittent claudication, a
manifestation of peripheral arterial disease.
 Dosage :
 Primary coronary intervention ( PCI ) : oral 100 mg twice
daily combination with aspirin and clopidogrel
 Secondary prevention of noncardioembolic stroke or TIA
: oral 100 mg twice daily ac
 Toxicity :
 Aspirin and other NSAIDs cause gastrointestinal and CNS
effects
 The major toxicities of the glycoprotein Iib/IIIa receptor-
blocking drugs are bleeding, thrombocytopenia
 Ticlopidine is used rarely because it causes bleeding up
to 5%, severe neutropenia, thrombocytopenia
 Clopidogrel is less hematotoxic
 Ciostazole and dipyridamole cause headaches and
palpitations
 Drugs Used in Bleeding Disorders

 Inadequate blood clotting can result from vit K deficiency,

genetically determined errors of clotting factor synthesis (
hemophilia ), thrombocytopenia
 Treatment involves administration of vit K or antiplasmin drugs
 Vitamin K
 Deficiency vit K is most common in older person with
abnormalities of fat absorption and in newborn
 Large dose of vitamin K are used to reverse the
anticoagulant effect of excess warfarin

 Antiplasmin agents
 Valuable for the prevention or management of acute
bleeding episodes in patients with hemophilia
 Tranexamic acid : inhibit fibrinolysis by inhibiting by
plasminogen avtivation
TERIMA KASIH