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ISSUES IN TREATMENT OF ACUTE PULMONARY THROMBOEMBOLISM. Asc.Prof. SERHAT FINDIK, MD FCCP Ondokuz Mayis University Faculty of Medicine Department of Pulmonary Medicine. ACUTE PULMONARY THROMBOEMBOLISM. One of the most common causes of death Mortality without treatment : 30%

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issues in treatment of acute pulmonary thromboembolism

ISSUES IN TREATMENT OF ACUTE PULMONARY THROMBOEMBOLISM

Asc.Prof. SERHAT FINDIK, MD FCCP

Ondokuz Mayis University

Faculty of Medicine

Department of Pulmonary Medicine

acute pulmonary thromboembolism
ACUTE PULMONARY THROMBOEMBOLISM
  • One of the most common causes of death
  • Mortality without treatment : 30%
  • Most of the deaths within first hours
  • Mortality with treatment : 2 – 8 %
acute pulmonary thromboembolism1
ACUTE PULMONARY THROMBOEMBOLISM
  • Variable clinic picture asymptomatic – severe hipoxemia, right ventricular failure, shock, death
  • Treatment depends on clinical picture of the patient
slide4

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

absolute contraindications
ABSOLUTE CONTRAINDICATIONS

ACTIVE MAJOR HEMORRHAGE

  • Intracranial hemorrhage
  • Retroperitoneal hemorrhage
  • Intrathoracic hemorrhage (lungs- pleura)
  • Hemorrhages causing > 2 gr / dL in hemoglobin
relative contraindications
RELATIVE CONTRAINDICATIONS
  • Recent surgery (within two weeks)
  • Recent trauma (within two weeks)
  • Bleeding diathesis
  • Uncontrolled severe hypertension (systolic blood pressure > 200 mmHg, diastolic >120 mmHg)
  • Peptic ulcer
wells ndex
WELLS İNDEX

POINT

  • Age > 65 1
  • History of gastrointestinal bleeding 1
  • Stroke 1
  • At least one of the below ; 1 Hematocritet < %30 Creatinine > 1.5 mg/dl Diabetes mellitus Recent acute myocard infarction
  • Evaluation Low risk : 0 point, Moderate risk : 1 – 2 points High risk : ≥ 3 points
slide10

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

diagnostic evaluation
DIAGNOSTIC EVALUATION
  • DIAGNOSIS : PULMONARY THROMBOEMBOLISM
  • CONTRAINDICATION FOR ANTICOAGULATION
indications
INDICATIONS
  • Contraindication for anticoagulation
  • Recurrent PTE despite anticoagulation
  • Major hemorrhage as a side effect of anticoagulation
  • Severe compromisement of pulmonary vascular bed such as massive PTE, CTEPH.
slide15

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

slide16

ANTICOAGULANT MUST BE GİVEN ?

  • Give in a patient with a high clinical risk for PTE
  • Mortalite without treatment is 30%
  • Risk for major hemorrhage is 3%
  • Patients with low – moderate clinical risk for PTE ?
  • Effectiveness of treatment depends on its effect within 24 hours
slide17

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

diagnostic evaluation1
DIAGNOSTIC EVALUATION
  • DIAGNOSIS : PULMONARY THROMBOEMBOLISM
slide19

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

acute pulmonary thromboembolism2
ACUTE PULMONARY THROMBOEMBOLISM
  • MASSIVE ?
  • SUBMASSIVE ?
massive pte
MASSIVE PTE ?
  • Hemodynamic evaluation
  • Physical examination
  • ECG
  • Spiral CT pulmonary angiography
  • ECHO
  • Troponin / BNP
  • Arterial blood gases
hemodynamic evaluation
HEMODYNAMIC EVALUATION
  • HYPOTENSION systolik blood pressure < 90 mmHg *, sudden decrease (at least 40 mmHg) in systolic blood pressure
  • TACHYCARDIA > 130 – 140 pulses / min
  • TACHYPNEA > 30 / min
  • SHOCK / COMA
physical examination
PHYSICAL EXAMINATION
  • SIGNS FOR COR PULMONALE Prominence of neck veins Orthopnea Tachypnea Systolic murmur on tricuspid area(“Carvello maneuvre”) Prominence of S2 on pulmonary area Cyanosis
electrocardiography
ELECTROCARDIOGRAPHY
  • Right ventricular strain pattern on anterior leads (V1-V4)
  • S1Q3T3
  • Right bundle block
  • Right axis deviation
  • Tachycardia*
  • P pulmonale
  • Normal signs and / or nonspecific ST/T changes
spiral ct pulmonary angiography
SPIRAL CT PULMONARY ANGIOGRAPHY
  • Emboli burden
  • Pulmonary hypertension
  • Right ventricular dysfunction
  • Leftward shift of interventricular septum
  • Thrombus within right atrium or right ventricule
  • Patent foramen ovale
  • Thrombus within inferior vena cava
echocardiography
ECHOCARDIOGRAPHY
  • Dilatation of right ventricule
  • Leftward shift of interventricular septum
  • Decrease in ejection fraction (<%50)
  • Thrombus within right ventricule or right atrium
  • Pulmonary hypertension ( > 45-50 mmHg)
  • Patent foramen ovale
troponine bnp
TROPONINE / BNP
  • High BNP, early mortality
  • Elevation of troponine increase mortality
  • Troponine I > 0.5 ng/mL in submassive PTE : Mortality within three months increases 3.5 times
  • Heart-type fatty acid binding protein (H-FABP)”
arterial blood gases
ARTERIAL BLOOD GASES
  • PaO2 < 60 mmHg
  • Sat O2 < %90
  • Hypercapnia
slide42

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

absolute contraindications1
ABSOLUTE CONTRAINDICATIONS
  • Active major hemorrhage
  • History of hemorrhagic stroke
  • Active intracranial neoplasm
  • Recent (within two months) intracranial surgery or trauma
  • Active (or within past 6 months) internal organ bleeding
relative contraindications1
RELATIVE CONTRAINDICATIONS
  • Bleeding diathesis
  • Uncontrolled severe hypertension (systolic blood pressure >200 mmHg, diastolic blood pressure > 120 mmHg)
  • History of nonhemorrhagic stroke within 2 months
  • Surgery within 10 days
  • Thrombocytopenia (100.000 / mm 3)
slide46

ABSOLUTE CONTRAINDICATIONS

ACTIVE MAJOR HEMORRHAGE

  • Intracranial hemorrhage
  • Retroperitoneal hemorrhage
  • Intrathoracic hemorrhage (lungs- pleura)
  • Hemorrhages causing > 2 gr / dL in hemoglobin
slide48

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

thrombolytic drugs
THROMBOLYTIC DRUGS
  • STREPTOKINASE
  • UROKINASE
  • TISSUE TYPE PLASMINOGEN ACTIVATOR (TPA)
thrombolytic drugs1
THROMBOLYTIC DRUGS
  • Plasminogen → Plasmine
  • Direct lyzis of thrombus
streptokinase
STREPTOKINASE
  • C groupe ß- hemolytic streptococcus
  • Polypeptide
  • Makes complex with plasminogen

Activates plasmine

  • The cheapest thrombolytic
  • The most frequent side effects
  • Plasma clearance time : 18 – 25 minutes (the longest)
streptokinase administration
STREPTOKINASE ADMINISTRATION
  • 15-30 minutes before streptokinase acetaminophen + prednisolone + anti-histaminic
  • Bolus: 250.000 units iv (30 minutes)
  • Continuous infusion : 100.000 ünite / hr (24 hours)
  • Monitorisation (hypotension, allergic reactions, anaphylaxis, asthma)
  • Only decrease rate of infusion in mild allergic reactions
slide53
TPA
  • Recombinant
  • Binds to fibrine

Increases affinity of fibrine to plasminogen Increases activation of plasmin Intravascular fibrinolyzis

  • The most expensive
  • Plasma clearance time : 2 – 6 minutes (the shortest)
tpa administration
TPA ADMINISTRATION
  • 100 mg iv infusion (2 hours)
urokinase
UROKINASE
  • Human urine, human embrion, kidney cell culture
  • Plazminogen activator
  • High concentrations in urine
  • Major activator for extravascular fibrinolyzis
  • Plasma clearance time: 13 – 20 minutes
  • Not available in our country
urokinase administration
UROKINASE ADMINISTRATION
  • Bolus: 4400 units /kg, iv (10 minutes)
  • Continuous infusion: 2200 units / kg / hr (12 hr)
which thrombolytic drug
WHICH THROMBOLYTIC DRUG ?
  • History of streptokinase administration within 6 – 12 months ; others should be given
  • Money ? Streptokinase
  • Cardiac arrest (occured or imminent) ; bolus TPA
administration of thrombolytic drugs bolus infusion
ADMINISTRATION OF THROMBOLYTIC DRUGS BOLUS INFUSION
  • Bolus infusion ? Two hours infusion ?
  • If cardiac arrest occured (or imminent), bolus ?
administration of thrombolytic drugs pulmonary artery catheter
ADMINISTRATION OF THROMBOLYTIC DRUGS PULMONARY ARTERY CATHETER
  • Thrombolytic drugs are given directly into pulmonary artery via catheter
  • No difference in effectiveness from administration through peripheral vein
  • Intraembolic administration may be more effective ?
thrombolytic treatment monitorisation
THROMBOLYTIC TREATMENT MONITORISATION
  • Pre-treatment CBC, biochemistry blood group match fresh frozen plasmataze (at least 6 units) transamine
thrombolytic treatment monitorisation1
THROMBOLYTIC TREATMENT MONITORISATION
  • Too short clearance rates
  • Complications appear during or just after tadministration
  • The most serious complications are anaphylaxis and major hemorrhage
thrombolytic treatment monitorisation2
THROMBOLYTIC TREATMENT MONITORISATION
  • Monitorisation should be done during treatment, (vital signs and conscious state)
  • Be alert, especially for major hemorrhage (intracranial, intrathoracic, retroperitoneal, gastrointestinal)
thrombolytic treatment monitorisation3
THROMBOLYTIC TREATMENT MONITORISATION
  • Any suspicion for hemorrhage; hemoglobin, hematocrite hemoptyzis ? hematemezis? epistaxis? hematuria ? hematochesia melena ? Physical examination, Chest x-ray, Kranial CT, neurosugery consultation
  • Intramuscular hematomas, extensive ecchymoses !
thrombolytic treatment complication
THROMBOLYTIC TREATMENT COMPLICATION

ACTIVE MAJOR HEMORRAHAGE

  • Intracranial, %3
  • Retroperitoneal
  • Thorax (lungs – pleural space)
  • > 2 gr / dL decrease in hemoglobin level
  • The most frequent bleeding sites are the sites where invasive procedures performed ( pulmonary angiography, arterial blood gases)
thrombolytic treatment hemorrhage
THROMBOLYTIC TREATMENT HEMORRHAGE

RİSK FACTORS

  • Cathecolamine administration for systemic arterial hypotension (odds ratio 115, %95 CI 9.4 – 1411)
  • Malignancy (odds ratio 16, %95 CI 3.2 – 180
  • Diabetes Mellitus (odds ratio 9.6, %95 CI 1.7 – 54)
  • High INR (odds ratio 6, %95 CI 1.5 – 22)
thrombolytic treatment complication treatment
THROMBOLYTIC TREATMENT COMPLICATION – TREATMENT
  • İmmediately stop thrombolytic administration
  • Monitorisation, close control of vital signs and consciousness
  • Fresh frozen plasma (at least 6 units) or cryoprecipitate (10 units)
  • Transamine
  • Blood or erythrocyte suspension, if needed
thrombolytic treatment complication treatment1
THROMBOLYTIC TREATMENT COMPLICATION- TREATMENT

Origin of bleeding ; Intracranial bleeding : Neurosurgery Hemothorax : Chest tube

Retroperitoneal bleeding : General surgery- urology

thrombolytic treatment complication1
THROMBOLYTIC TREATMENT COMPLICATION

STREPTOKINASE

  • Antigenic
  • Immunologic sensitisation and allergic reactions
  • Major reactions are rare
  • Anaphylaxis : < 0.5%
  • Shivering, pyrexia, rashes ;10%
  • Anti-streptococcal antibodies remain 7.5 years in blood
thrombolytic treatment complication2
THROMBOLYTIC TREATMENT COMPLICATION

STREPTOKINASE

  • Hypotension
  • Infusion rate > 500 units / kg /min

TREATMENT

  • Decrease or stop rate of infusion
  • Give iv fluid
  • Give vasopressors
slide71
Diagnosis of PTE should be confirmed certainly
  • Effective within 14 days of symptoms
  • Should be administered in patients in whom PTE was diagnosed and had hypotension due to PTE (without any absolute contraindication) GRADE 1B
slide72
Decision is made by clinician in other patients
  • Patients without hemodynamic instability and/or respiratory failure (severe hypoxemia) should not be administered thrombolytic treatment GRADE 1B
slide73

There is no difference in between thrombolytic drugs at the respect of efficacy and major bleeding*

  • Peripheral veins should be selected for administration GRADE 1B
  • Infusion duration ≤ 2 hours ; better thrombolyzis and lesser bleeding GRADE 2B
slide74

Cardiac arestes , if occured or imminent: Bolus TPA

  • If economic cost is major concern ; streptokinase
  • If streptokinase has been given within 6 – 12 months, others should be selected
  • In case of absolute contraindication for thrombolytic drugs, embolectomy
slide76

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

embolectomy
EMBOLECTOMY
  • Surgical embolectomy
  • Catheter embolectomy
surgical embolectomy
SURGICAL EMBOLECTOMY
  • Specialised center – experienced surgeon
  • Mortality is too variable
catheter embolectomy
CATHETER EMBOLECTOMY
  • Interventional radiology
  • Small series
  • Limited experience
slide81

PTE ?

Contraindication to anticoagulation

Yes

No

Diagnostic evaluation

sc LMWH or IV Heparin

Diagnostic evaluation

PTE -

PTE +

Other diseases

Inferior vena

cava filter

PTE -

PTE +

Massive PTE ?

Stop anticoagulation

Yes

No

Contraindication to

thrombolytic

Yes

Anticoagulation

Embolectomy

No

Thrombolytic treatment

which anticoagulant
WHICH ANTICOAGULANT ?
  • Low-molecular weight heparin (LMWH)
  • Heparin (iv or subcutaneous)
  • Fondaparinux
  • Warfarin
slide85
LMWH
  • Synthesis by enzymatic or chemical depolymerization of heparin
  • Effect through antithrombin
  • 1000 times more Anti Xa activity than heparin
slide88
LMWH
  • Better bioavailability
  • Longer plasma clearance rates (one or two times a day )
  • Fixed dose (no need for monitorization*)
  • Less incidence of thrombocytopenia
slide89
DOSE
  • Enoxaparine
  • 1 mg / kg, bid
  • 1.5 mg/kg/day
  • Malignancy, extensive thrombus burden, 101-150 kg, BMI:30-40 (1 mg / kg, bid)
slide90
DOSE

Tinsaparine

  • 175 IU/kg, one a day
  • Contraindication : > 90 age, moderate-severe renal failure (creatinine clearance < 60 mL/min)
slide91
DOSE

Dalteparine

  • At the beginning 200 IU/kg, once a day (<18.000 IU) 30 dyas
  • Maintainance 150 IU/kg, once a day (<18.000 IU)
  • > 90 kg → Enoxaparine or Tinsaparine
lmwh monitorization
LMWH MONITORIZATION

NO NEED FOR MONITORIZATION EXCEPT BELOW:

  • Morbid obesity (BMI> 40)
  • Low body weight male < 57 kg female < 45 kg
  • Renal failure creatinine clearance < 30 mL/dk 1- Heparin 2- LMWH (50% of daily dose)

Monitor anti-Xa activity

slide93

WHICH LMWH ?

  • No randomised controlled study
  • Tinsaparine vs Dalteparine , 5 days, 505 patients 31
  • Major bleeding, recurrent PTE or DVT : No difference
  • Any LMWH can be choosen
hepar n1
HEPARİN
  • Narrow therapeutic index
  • Close monitorization
  • Plasma half life is 30 minutes to 3 hours
  • Interacts with endothelium and thrombocytes
  • Binds to plasma proteins
  • Continuous iv infusion
  • Subcutaneous administration
dose and administration
DOSE AND ADMINISTRATION

CONTINUOUS INTRAVENOUS INFUSION

A- Body weight – dose administration

  • 80 U/kg bolus, followed by 18 U/kg/hour infusion
  • After 4-6 hours check aPTT
  • Aim : aPTT (1.5-2.5 N)
  • To achieve target APTT within first 24 hours is 97%
heparin dose monitorization
HEPARIN DOSE MONITORIZATION

FIRST DOSE 80U/kg bolus, 18 U/kg/hr

aPTT<35 s (1.2xBazal) 80U/kg bolus, + 4U/kg/hr

aPTT 35-45 s (1.2-1.5xBazal) 40U/kg bolus, + 2U/kg/hr

aPTT 46-70 s (1.5-2.3x Bazal) SAME DOSE

aPTT 71-90 s (2.3-3.0x Bazal) - 2U/kg/hr

aPTT > 90 s (>3.0 x Bazal) Stop infusion(1 hr), - 3U/kg/hr

dose and administration1
DOSE AND ADMINISTRATION

CONTINUOUS INTRAVENOUS INFUSION

B- Fixed dose

  • 5000 U bolus, followed by 1000 U-1300 U/hr infusion
  • After 4-6 hr, check aPTT
  • Target aPTT (1.5-2.5 N)
  • To achieve target APTT within first 24 hours is 77%
dose and administration2
DOSE AND ADMINISTRATION

SUBCUTANEOUS APPLICATION

A- 17.500 U or 250 U/kg (bid)

  • Target aPTT (1.5-2.5 N)
  • 4-6 hr after second dose, check aPTT
  • Change in doses ; 10-30% + or –
  • 3-4 days after achievement of stabil dose, check aPTT, then, weekly check aPTT
dose and administration3
DOSE AND ADMINISTRATION

SUBCUTANEOUS APPLICATION

B- First dose : 333 U/ kg, followed by 250 U/kg (bid)

  • No need for measurement of aPTT
monitorization
MONITORIZATION
  • Check aPTT
  • Target aPTT ; 1.5 - 2.5 APTT (control)
  • To reach target value in first 24 hours is too important

Recurrence rate ; 3 % vs 23%

Risk of recurence goes three months

monitorization1
MONITORIZATION
  • There is no always correlation between aPTT and plasma heparin level
  • If there is no achievement of target APTT although high doses of heparin (> 35.000 U/day) administration (heparin resistance), check anti-Xa level
slide107

LMWH >> HEPARIN

  • Better bioavailability
  • Longer plasma half life (od or bid)
  • Fixed dose (no need for monitorization *)
  • Lesser incidence of thrombocytopenia
  • Low risk for osteoporosis
slide108

LMWH >> HEPARIN

  • Low mortality (odds ratio: 0.76) 8054 pt, 18 study
  • Low recurrence (odds ratio:0.68) 8867 pt, 22 study
  • Lesser major bleeding
  • Stronger efect (rate of thrombus lyzis ) (odds ratio:0.69), 12 study
slide109

HEPARIN >> LMWH

  • Persistant hypotension due to PTE
  • High risk for bleeding
  • Plan for thrombolytics ?
  • Inadequate absorbtion for subcutaneous way ? Morbid obesity Severe anasarca
slide111
Synthetic pentasaccaride (binding site o heparin to antithrombin)
  • Effect via antithrombin (without inhibition of thrombin)
slide112
2213 pt, fondaparinux vs heparin recurrence 3.8% 5% major bleeding 2% 2.4% nonmajor bleeding5.7% 8.4% thrombocytopenia 0.9% 1.2% death 5.2% 4.4%
contraindication
CONTRAINDICATION
  • Active bleeding
  • Acute bacterial endocarditis
  • < 17 age (effectivity ?)
  • Severe renal failure (cr cle < 30 mL/min)
  • Pregnancy ?!
  • Breast feeding is not recommended
dose and administration4
DOSE AND ADMINISTRATION
  • Subcutaneous
  • Once a day
  • Body weight – dose < 50 kg 5 mg 50-100 kg 7.5 mg >100 kg 10 mg
monitorization2
MONITORIZATION

No need for monitorization

Periodically check

  • Renal functions
  • Hemoglobin
  • Hematocrite
  • Thrombocyte count
oral anticoagulants1
ORAL ANTICOAGULANTS
  • Vitamin K antagonists
  • Inhibit synthesis of vitamin K dependent coagulation factors (II, VII, IX ve X)
  • Warfarin is the best known and most commonly used
first doses
FIRST DOSES
  • At the same time or within 72 hours of parenteral anticoagulants
  • Three times more recurrences if given before parenteral anticoagulants
  • At least given for 5 days with parenteral anticoagulants + INR must be 2.0 – 3.0 at least in two successive days
effects
EFFECTS
  • Its effects begin in 36 – 72 hr
  • Initial increase in INR level due to decrease in level of factor VII
  • At least 5 days of treatment are needed for inhibition of intrinsic pathway
dose and monitorization
DOSE AND MONITORIZATION
  • 5 mg in first two days
  • Lower doses in elderly
  • Daily INR
  • Target INR: 2.0 – 3.0
dose and monitorization1
DOSE AND MONITORIZATION
  • Maintainance dose is too variable
  • Age, metabolism, İdame doz çok değişken
  • Yaş, metabolizma,drugs, diseases, diet
  • Skin necrosis due to Protein C deficiency
dose and monitorization2
DOSE AND MONITORIZATION
  • After reaching target values, weekly in first month, then biweekly at second month
  • Monthly in third month
  • Close monitorization*
  • Many drug interactions
side effects
SIDE EFFECTS
  • TERATOGENIC
  • Impairment of hepatic function tests
  • Skin necrosis
  • Alopecia
  • Dermatitis
  • Urticeria
slide125
BLEEDING
  • HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA
major bleeding heparin
MAJOR BLEEDING HEPARIN
  • < 3%

High risk for bleeding

  • ↑ aPTT
  • Recent surgery
  • Recent trauma
  • Elderly (>70 years
  • Treatment (aspirin, clopidogrel)
  • Renal failure
major bleeding heparin treatment
MAJOR BLEEDING HEPARIN TREATMENT
  • Immediately stop heparin infusion
  • Start PROTAMİN
  • Neutralizes heparin dose within last 2 hours
  • Slow iv injection or infusion (one dose ≤ 50 mg)
  • Repeat injections if needed
  • Immediate action lasting 2 hours
major kanama heparin treatment
MAJOR KANAMA HEPARIN TREATMENT
  • Available in our country as 5.000 IU/5mL, protamin 1000 IU: 10 mg protamin
major bleeding heparin treatment1
MAJOR BLEEDING HEPARIN TREATMENT
  • Protamin side efects
  • Hypotension
  • Anaphylaxis
  • Protamin allergy : Toluidin blue (5 mg/kg iv, slow) or hexamidin
major bleeding lmwh
MAJOR BLEEDING LMWH
  • 1-2 %
  • Meta-analysis, 22 randomised studies 8867 patients LMWH vs Heparin Less major bleeding in LMWH (Odds ratio: 0.57 CI :0.39-0.83)
slide132

MAJOR BLEEDING LMWH TREATMENT

  • Stop LMWH
  • Start PROTAMİN
  • Neutralizes 30-70% of LMWH
major bleeding fondaparinux
MAJOR BLEEDING FONDAPARINUX
  • Limited data
  • Same as LMWH
major bleeding warfarin
MAJOR BLEEDING WARFARIN
  • < 3% mortality 13%

High risk for bleeding

  • > 65 years
  • History of stroke
  • History of gastrointestinal bleeding
  • Severe hepatik failure
  • Severe renal failure
  • Anti-platelet treatment
major bleeding warfarin treatment
MAJOR BLEEDING WARFARIN TREATMENT

INR < 5.0 + no severe bleeding

TREATMENT

  • Decrease dose or skip
  • Close follow-up
  • Begin lower dose when INR reaches therapeutic range
major bleeding warfarin tretment
MAJOR BLEEDING WARFARIN TRETMENT

INR < 9.0 > 5.0

TREATMENT

  • Skip first or first two doses
  • Close INR control
  • More careful dose titration when INR reaches therapeutic dose
  • Severe bleeding risk : Vitamin K (1-2.5 mg oral)
  • Emergent correction (surgery): Vitamin K (< 5 mg oral)
  • Still high INR ; Vitamin K (1-2 mg oral)
major bleeding warfarin treatment1
MAJOR BLEEDING WARFARIN TREATMENT

INR > 9.0, no severe bleeding

Stop warfarin

More vitamin K

More frequent controlDaha sık kontrol

Repeat vitamin K if needed,

Be more careful on titration when INR reaches therapeutic range

major bleeding warfarin treatment2
MAJOR BLEEDING WARFARIN TREATMENT

ANY INR VALUE BUT SEVERE BLEEDING

  • Stop warfarin
  • Vitamin K (10 mg, iv slow infusion)
  • Depending on the acuteness ; fresh frosen plasma, prthrombine complex concentrate, or recombinant factor VII may be given
  • Vitamin K, can be repeated every 12 hours, if needed
major bleeding warfarin treatment3
MAJOR BLEEDING WARFARIN TREATMENT

LIFE THREATINING BLEEDING

  • Stop warfarin
  • Vitamin K (10 mg, iv slow infusion)
  • Depending on acuteness of the patient; fresh frosen plasma, prothrombin complex concentrate or recombinant factor VII may be given
  • Vitamin K , according to INR
heparin induced thrombocytopenia1
HEPARIN INDUCED THROMBOCYTOPENIA

TYPE 1 TYPE 2

  • INCIDENCE 10-20% 1-3%
  • TIME 1 – 4 day 5 – 10 day
  • Platelet 100.000 >20.000
  • Antibody - +
  • Thromboemboli - +
  • Hemorrhage - +
  • Treatment Observation Stop heparin Other drugs
heparin induced immune thrombocytopenia hit
HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA (HIT)
  • Type II
  • 1 – 5 %
  • IgG mediated
  • 5. – 10. days*
slide143

HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA ?

Stop heparin,all forms

Confirm diagnosis

HIPA

Serotonin release assay

Heparin-PF4 Ab ELISA

+

-

Anticoagulation is needed ?

Think other causes of thrombocytopenia

Yes/No

Yes

Yes

Other indications

for anticoagulation

Only thrombocytopenia

No thrombozis

Arterial or venous thrombosis

Observation?

Lepirudin veya Argatroban

Fondaparinux ?

slide144

HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA (TYPE 2)

  • Thrombocytes decrease to 50% of pretreatment count or

at least 30% decrease in thrombocyte count and count< 100.000/ mm3

slide145

HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA ?

PATIENTS TO WHOM HEPARIN HAS BEEN GIVEN IN LAST 5 – 10 DAYS

  • Thrombocytopenia (>20.000/mm3) FIRST SIGN
  • Thrombozis (DVT , PTE) and thrombocytopenia
  • ≥ %50 decrease in thrombocyte count
  • Necrotic lesions at injection sites
  • Spontaneous bleedings are RARE
heparin induced immune thrombocytopenia risk factors
HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA RISK FACTORS

RR

  • Heparin* 5.3
  • Female patients 3.2
  • Surgical patients 2.4
  • Surgery + female + heparin : 17
  • Risk in heparin use 2.6% in LMWH use 0- 0.2%
heparin induced immune thrombocytopenia treatment
HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA TREATMENT
  • Stop heparin
  • Warfarin is not given only
  • No LMWH
  • Direct thrombin inhibitors in cases of need for rapid coagulation
heparin induced immune thrombocytopenia treatment1
HEPARIN INDUCED IMMUNE THROMBOCYTOPENIA TREATMENT
  • No available direct thrombin inhibitors in our country
  • FONDAPARINUX
  • Add warfarin to treatment when thrombocyte count reaches normal level
  • Continue treatment with warfarin
pte in pregnancy
PTE IN PREGNANCY
  • High risk patients : Begin anticoagulation before diagnostic tests
  • Moderate – low risk : CLINICIAN
  • Contraindication to anticoagulation; firstly, diagnostic tests, then, if PTE was confirmed, IVC filter
pte in pregnancy1
PTE IN PREGNANCY
  • First choice : LMWH
  • Hipotension caused by PTE or high risk for bleeding : iv HEPARIN
  • Severe renal failure: iv or sc HEPARIN
  • Warfarin : Contraindication*
  • Fondaparinux: Contraindication*
pte in pregnancy lmwh
PTE IN PREGNANCY LMWH
  • Dalteparine 200 u /kg od
  • Tinzaparine 175 u/kg od
  • Dalteparine 100 u / kg bid
  • Enoxaparine 1 mg/kg, bid
pte in pregnancy iv heparin
PTE IN PREGNANCY iv HEPARIN
  • 80 U / kg bolus
  • 18 U / kg/saat (maintainance)
  • aPTT every 6 hours
  • Daily aPTT
  • LMWH or sc Heparin*
pte in pregnancy sc hepar n
PTE IN PREGNANCY sc HEPARİN
  • 17.500 U bid
  • aPTT (6 hr after second dose)
  • 10 – 30 % - / +
  • Given after 5 – 10 days iv Heparin
massive pte in pregnancy
MASSIVE PTE IN PREGNANCY
  • THROMBOLYTIC TREATMENT 172 patients, maternal mortality 1% fetal loss 6%, maternal hemoraji 8%
delivery
DELIVERY
  • Stop LMWH and sc Heparin 24-36 hr before delivery
  • Give iv heparin in high risk patients
  • Stop iv heparin 4 – 6 hr before delivery and IVC filter
delivery1
DELIVERY
  • Do not Prefer Aspinal anesthesia in anticoagulated patients
  • Stop LMWH or sc heparin and give iv heparin at 36th week of pregnancy in cases of preterm
after delivery
AFTER DELIVERY
  • 12 hr after ceserian section
  • 6 hr after vaginal delivery
  • LMWH or heparin
  • At least 5 days with warfarin
  • Warfarin is safe during lactation
duration of treatment in pregnancy
DURATION OF TREATMENT IN PREGNANCY
  • Anticoagulant treatment must be given at least 6 weeks postpartum
  • If there is transient risk factor, AT LEAST 6 MONTHS
  • For persistant risk factors > 6 MONTHS
pte and malignancy
PTE AND MALIGNANCY
  • 1303 patients, 264 malign recurrent VTE 3 times more in malign patients major hemorrhage 6.5 times more in malign patients
treatment of pte in malignancy
TREATMENT OF PTE IN MALIGNANCY
  • LMWH
  • Warfarin
  • Duration ?
  • If paraneoplastik sendrom; LMWH
slide164

ANTIPHOSPHOLIPID SYNDROME

  • HEPARIN

LMWH

HEPARIN

  • WARFARIN
  • ANTIPLATELET GROUPE

ASPIRIN

CLOPIDOGREL

  • INITIAL TREATMENT IS SAME
  • MAINTAINANCE TREATMENT IS SAME
  • DURATION İS LIFELONG
  • PROFILAXIS
  • SLE and aPL but no manifestations, the combination of low-dose aspirin and hydroxychloroquine
slide166

DURATION VTE

3 MONTHS One event (reversible risk factor)

> 3 MONHTS One event, idiopathic VTE

12 – 24 months- Recurrent VTE Lifelong

slide167

HEREDITARY THROMBOPHILIA

Duration of anticoagulation 6 – 12 months

High risk groupe Lifelong ?

  • ≥ 2 spontaneous thrombozis 1 spontaneous thrombozis (AT-III deficiency, antiphospholipid syndrome)
  • 1 spontaneous life threatining thrombozis (massive PTE, cerebral thrombozis, portal vein thrombozis)
  • Thrombozis at unusual sites (cerebral, mesetheric)
  • 1 spontaneous thrombozis and more than one thrombophlic condition