Antithrombotic therapy
Thrombophilia – clinical criteria
• trhombosis in younger age:
– venous under age 45 years
– arterial under age 35 years
• recurrence of thrombosis
• atypic localization of thrombosis
• positive family history of VT
• repeated fetal loss
Acquired risk factors of thrombosis
• Specific risk factors
• Aging
• Long-lasting immobilization
• History of thromboembolism
• Overweight
• Varicosity
• Heart failure
• Stroke
• Hip & leg fractures
• Infections of colon
• Nefrotic syndrome
• Oestrogens
• Malignancy
Risk factors of DVT - thrombofilias
• hereditary:
– factor V Leiden
– protrombin 20210A
–  antitrombin III
–  protein C
–  protein S
– dysfibrinogenemia
• mixed etiology:
– factor VIII 150%
–  fibrinogen
–  homocystein
• acquired:
– antiphospholipid syndrome
Hereditary thrombotic states
Prevalence (%) Rel. Risk of DVT
prothrombotic factor DVT Normal population
FV Leiden heterozygot 20 5 6.0
FII20210A 6.2 2-3 3.0
PS def. 2.2 0.2 2-10
PC def. 2.1 0.3 5-10
ATIII def. 1.1 0,2 50
dysfibrinogenemia 0.8 ? ?
Elevation of FVIII* 20 11 3.0
Hyperfibrinogenemia* 15 8 2.0
Hyperhomocysteinemia*+ 10 5 2.0
* Mixed etiology + dietetic influences
Coopera a Krawczacka
Factor Va
• cofactor of FXa
• cofactor of aPC for degradatio of FVIIIa
• by aPC is cleaved at site:
– Arg 506
– Arg 306
– Arg 679
Faktor V – mutation
(chromosome no 1)
• Leiden Arg 506G ln
• Cambridge Arg 306 Thr
• Hong Kong
– 1 Arg 485 Lys
– 2 Arg 306 Gly
• HR2 haplotype His 199 Arg
Faktor V Leiden
(G1691A » Arg506Gln)
In Caucasian population:
• All population 5%
• DVT without selection 20%
• DVT clinical thrombophilia 40%
Seligsohn U., N Engl J Med, 2001
Factor V Leiden
(heterozygots)
DVT risk is increased: 5-6x
• homozygotes 50-100x
• in pregnancy 5-15x
• + OC III. generation 20x (OC only 3-4x)
• + HRT 15x (HRT OC only 2-4x)
Mutation of prothrombin 20210A (20210 G A)
• missence mutation in non-translated part of gene
• DVT risk is incerased 3x
•  plasma level of FII
• 2-3 % in all population
• 6 % DVT without selection
• 7-18 % DVT and positive family history of DVT
Protrombin - G20210A
(heterozygotes)
DVT risk is increased: 3x
• homozygotes:
1/3 without DVT 1/3 spont. DVT 1/3 sec. DVT
• Heterozygotes with FVL 50-100x
• in pregnancy 10x
heterozygotes with FVL 100x
• + OC III. generation 3-16x (OC only 3-4x)
• + OC + smoker: risk of VT of CNS: 150x
Metabolis of homocysteine
•METHIONIN
• HOMOCYSTEIN
•Cystathion
•cystein
•THF
•Methionin
•syntáza
•Cystathionin b-syntetáza
• MTHF
•Vit.B12
•Folát
•Vit.B6
•Metylen
•tetrahydrofolát
•reduktáza
•serin
•betain
•dimetylglycin
•Betain-homocystein
•metyltransferáza
•homocystin
Mild hyperhomocysteinemia
• 15-30 mol/l
- 5% of all population
-10-20 % of DVT
- 2 x  risk of DVT, AT
- folate deficiency is in 5 -15 % of population
• polymorfism C677T in gene for MTHFR
- TT: 10-15% - T/C: 40-45% - C/C: 50-55%
- TT: 1/4-1/3 has mild hyperhomocysteinemia
• Treatment:
– Folate: 0.5 mg
– B12: 0.4 mg
– B6: 3-10 mg
Antithrombotic therapy
• prevention of thrombus formation
• prevention of thrombus progression
• thrombus dissolution
• prevention of rethrombosis
• prevention of secondary changes
Actual requirements for antithrombotics:
• simple administration (oral, no laboratory monitoring, no
diet restrictions, no concomittant therapy restrictions)
• safe therapy (without bleeding, without adverse events)
• inexpensive
Antithrombotic therapy
• anticoagulant (anti-IIa):
– indirect thrombin inhibitors (antithrombin-mediated):
heparin, LMWH
– coumarins – reduce levels of vitamin-K dependent factors:
warfarin
– direct thrombin inhibitors: hirudin, dabigatran
• antithrombotic (anti-Xa):
– indirect factor Xa inhibiotris: LMWH, pentasacharides
– direct factor Xa inhibotors: xabans (rivaro-, api-, edoxaban)
• antiaggregation (antiplatelet):
– ASA
– clopidogrel, prasugrel, ticagrelor, cangrelor, etc.
– GP IIb/IIIa inhibitors
• thrombolytic: rt-PA
• substitution: AT, PC
Coagulation cascade and antithrombotic therapy
XII XIIa TF TFPI VII
XI XIa VIIa
IX IXa Pl
X X
Va XIII
II IIa
XIIIa
Fbg Fs Fi
Plg PL
t-PA FDP (DD)
Pl
VIIIa
Xa
Pl
Va
IIa
ATH
K
APC
•ATIII
•+ Xa + IIa
•1:1 ratio
•Heparin
•1930s
•ATIII
•+Xa
•Indirect FXa
inhibitors
•2002
•IIa
•Direct oral
thrombin
inhibitors
•2004
•ATIII
•+ Xa + IIa
Xa > IIa
•LMWH
•1980s
•II, VII, IX, X
(PC,PS)
•Vitamin K
antagonists
•1940s
•Xa
•Direct oral
FXa
inhibitors
•2008
Antithrombotics development
•IIa
•Thrombin
inhibitors
•1990s
Indication for anticoagulant therapy
- heparins, coumarins
• venous thrombosis and embolism
• atrial fibrillation
• heart valve replacement
• artificial surfaces – HD, extracorporeal
circulation
• antiphospholipid syndrome
• DIC
Risk of VTE in surgery
• Cathegory Pelvic Proximal Fatal PE
• High 40-80% 10-30% 1-5%
(large orthopedic surgery, urologic surgery (age >40), history of VTE,
extensive pelvic & abdominal surgery for malignancy)
• Intermediate 10-40% 2-10% 0,1-0,8%
(common surgery & age >40 & duration > 30 minutes, surgery &
contraceptives, urgent sectio Cesarea)
• Low < 10% <1% <0,01%
(small surgery, young patient, no risk factors)
The classification of risk profile
• Low risk
• Non-complicated surgery lasting <30 min in a patient aged < 40 years
• Intermediate risk
• Surgery in a patinet aged 40-60 years without any risk factor
• Larger surgery in a patient aged > 40 years without any risk factor
• Small surgery in patients with risk factor/s
• High risk
• Larger surgery in a patient aged >60 years without risk factors
• Larger surgery in patient aged 40-60 years with risk factor/s
• The highest risk
• Large surgery in a patient aged >40 years with history of VTE and/or
recent malignancy
• Hypercoagulable states, polytrauma, heroic surgery
Indication of antithrombotic
prevention according to the risk
• Low risk – bandage (other according to the circumstancies)
• Intermediate risk
– (common & chest surgery, gynecological surgery)
– LMWH, LD UH
• High risk
• Elective total hip replacement LMWH, anti-IIa, anti-Xa
• Elective knee replacement LMWH, amti-Iia, anti-Xa
• Hip fracture LMWH
• Polytrauma LMWH
• Acute posttraumatic paralysis LMWH
Occurence of postoperative VTE
depending on time interval after
high risk surgery
9
16
13
9
4
0
0
2
4
6
8
10
12
14
16
0 - 7. 8. - 14. 15. - 21. 22. - 28. 29. - 35. 36. - 42. dny
GLYCOSAMINOGLYCAN
HEPARIN
O
COOO
OH
OH
O
O
CH2OSO3H-
OH
NHCOCH3
GLUCURONIC
ACID
IDURONIC ACID
N-ACETYL-D-GLUCOSAMINE-
6-O-SULPHATE
Heparin function
• Antithrombin-mediated:
– reversible binding to AT
– potentiates binding of AT to FIIa a FXa (inactivation):
• heparin binding to FXa is not necessary
• heparin binding to FIIa is necessary
• Releases TFPI into circulation (tissue factor pathway inhibitor)
• Stimulates t-PA release
• Binds also to cellular surfaces:
– Platelets : DF 4
– Endothelium
– Leukocytes
Mechanisms of effect of
UH a LMWH
LMWH
FX FII
AT FX FII
UFH
AT
< 18 saccharide units
> 18 saccharide units
Dosing and monitoring of heparin
treatment
VTE treatment:
• bolus 80 U/kg
• 18 U/kg/hour continual IV infusion
• aPTT:
– prolonged aPTT 1.5-2.5 R (2-3x)
– anti-IIa: 0.2-0.4 U/ml
– anti-Xa: 0.35-0.7 U/ml
•  TT, normal reptilase time
VTE prophylaxis:
• 5000 U 2-3 times/day SC
Heparin treatment monitoring
ACT (Activated Clotting Time)
• Activation of coagulation by contact surfaces, e.g.
kaolin
• Whole blood: „bed side“ test
• Thoracic surgery in extracorporeal circulation
• Normal range: 120 - 180 s
• Therapeutic range: 300 - 600 s
Low Molecular Weight Heparins
Generic name Trade name anti-Xa / anti-IIa
Nadroparin Fraxiparine 3.0
Dalteparin Fragmin 2.0
Enoxaparin Clexane 3.3
Bemiparin Zibor 8.0
Parnaparin 4.0
Tinzaparin 1.8
Certoparin 4.2
Monitoring and dosing of LMWH
treatment
VTE therapy:
• 100 U anti-Xa/kg twice daily SC
– except for Zibor (115 U anti-Xa/kg once daily SC)
• routine monitoring not required
• anti-Xa (blood collected 3-4 hours after SC application):
– 0.5 – 1.0 U/ml
– anti-Xa monitoring:
• renal insufficiency
• body weight > 100 kg or < 50 kg
• pregnancy
• high risk of bleeding
• only borderline prolonged aPTT at therapeutic dosing
Monitoring and dosing of LMWH
prophylaxis
VTE prophylaxis:
• 2000 – 5000 U anti-Xa SC once daily
• routine monitoring not required
• anti-Xa (blood draw 3-4 hours after SC application):
0.2 – 0.4 U/ml
• specific dosing for each LMWH
→DOSING ACCORDING TO SmPC!
LMWH as a „bridging“ therapy
Indirect FXa inhibitors
● Pentasacharides (fondaparinux) – prefered over UFH
● Dosing 7,5 mg once daily SC
(5 mg in patients < 50 kg and 10 mg > 100 kg)
● Contraindications:
● CKD with CrCl < 30 ml/min.
● bacterial endocarditis
GlaxoSmithKline: Prescribing information, Arixtra (fondaparinux sodium) injection. Available
at http://us.gsk.com/products/assets/us_arixtra.pdf (accessed October 26, 2012
Coumarins – warfarin
● Coumarins therapy usually follows after initial treatment with
heparins – overlap required for at least 5 following days
● Dosing individual – 1.5–12.5 mg/day
● Specific laboratory monitoring: INR 2.0–3.0
● Significant drug and diet interactions
● Monitoring every 4 – 6 weeks
Schulman S, Parpia S, Stewart C, Rudd-Scott L, Julian JA, Levine M. Warfarin dose
assessment every 4 weeks versus every 12 weeks in patients with stable international
normalized ratios: a randomized trial, Ann Intern Med 2011;155:653-9, W201-3
Schwarz UI, Ritchie MD, Bradford Y, et al: Genetic determinants of response to warfarin
during initial anticoagulation. N Engl J Med 2008;358(10):999-1008
Vitamin K dependent coagulation factors
• FII, FVII, FIX, FX
• glutamic acid carboxylation
- necessary for phospholipids
binding through Ca bridges
• coagulation factors are
produced but they are not
coagulation active - PIVKA
forms (Protein Induced by
Vitamin K Absence /
Antagonist)
Coumarins
generics half-life
ethylbiscumacetate (Pelentan) 2 hours
warfarin (Warfarin) 72 hours
phenprocoumon (Marcoumar) 160 hours
Coumarin therapy monitoring
Prothrombin time (PT):
• therapeutic range:
2.0 – 3.0 INR (international normalized ratio)
• „normal range“ :
0.8 – 1.2 INR
t pac.
ISI (international sensitivity index)
-------
t norm.
Bleeding on warfarin
Trial N INR risk %
Hull (82) 96 3.0-4.05 22.4
2.0-2.5 4.3
Turpie (88) 210 2.5-4.0 13.9
2.0-2.5 5.9
Saour (90) 247 7.4-10.8 42.4
1.9-3.6 21.3
Altmann (91) 99 3.0-4.5 24.0
2.0-2.9 6.0
Halftime of factors influenced by coumarines
(hours)
• FII 60 - 96
• FVII 4 - 6
• FIX 18 - 30
• FX 30 - 48
• PC 5 - 6
• PS 60
0 50 100 150 200
PS
PC
FX
FX
FVII
FII
Warfarin dosing
• Warfarin 5 mg daily (7,5 mg on Day 1)
• PT monitoring from Day 3
• overlap with LMWH for min. 4-5 days, not only until PT 2-
3 INR:
– from Day 2 decreasing FVII, PC
– from Day 3 decreasing FII, FIX, FX, PS
– risk: rethrombosis, coumarin necrosis
• multiple drug interactions!!!
• influence of vit. K from diet (grean leaves, herbal tea…)
• diferences in metabolism:
– doses from 1.5 mg daily up to over 15 mg daily
• 100 Sunnybrook Anticoagulation Clinic Patients
DVT treatment duration
depends on risk of recurrence, which is higher in the following
circumstances:
• Male
• Elderly
• Higher BMI
• Neurological impairment (limb paresis)
• Malignancy
• Antiphospholipide syndrome
• IndiopaticVTE
• Positive family history
• Trombophilia (inhibitors defficiency, trombophilic gene mutations)
• Persistent D-dimer elevation
• Permanent inferior vena cava filter
DVT provoked by a transient risk – 3 months, otherwise „long-term“ treatment
Duration of coumarin therapy
• Distal or provoked thrombosis – 3 months
• Proximal thrombosis – 6 months
• Complicated thrombosis (PE) – 6–12 months
• Hypercoagulable state:
– severe (ATIII, homozyg. FVL, double heterozyg. FVL a PT)
• long lasting (life long)
– FVL, PT20210A polymorphism
• after the first episode of VTE standard duration of therapy
• Critical situation management – transient targeted
Higher sensitivity to warfarin
Propeptid FIX mutation
Ala (GCC) -10Thr(ACC) - Chu et al., 1996
Ala (GCC) -10Val (GTC) - Oldeburg et al., 1997
Cytochrome P450 polymorphism
cytochrom P450(2C9), P450(3A4)
cytochrom P450(1A2), P450(3A4)
VKORC1 mutation
Interactions of coumarines with
drugs & food
• Potentiation of warfarin effect (NSA)
• Lowering of warfarin effect (barbiturates, broccoli)
• Influence on absorption (antacides)
• Influence on vit K production (antibiotics)
• Potentiation of bleeding risk (ASA)
• (Extreme) wide range of daily dose:
– 5 – 7.5 mg usually
– 1.5 mg / low – 15 mg / high metabolizer
Quantity of vit K in selected foodstuffs (ug/100g)
• Broccoli 270
• Celery 300
• Cabbage 817
• Dill 400
• Cauliflower 300
• Chives 380
• Parsley 700
• Spinach 500
• Kale 1540
• Olive oil 400
• Soya oil 542
• Sunflower oil 10
• Green tea 712
• Chicken meat 300
Complications of warfarin
therapy
• Bleeding ( overdose, mutation of propeptide of FIX,
polymorphisms of cytochrome P450)
Bleeding up to 7%, fatal 0.5%
• Coumarine skin necrosis
• Failure of therapy (resistance, neoplasma)
• Teratogenic effect ( mainly from 6th to 12th week of
pregnancy)
• heparin induced • coumarine induced
*Bichler A.J. et al: Hypersensitivity reactions to
anticoagulant drugs: diagnosis and managment option.
Allergy 2006: 61: 1432-1440
Skin necrosis
Which values of INR are
acceptable?
• Clinical situation target INR
• Minor bleeding & high risk of VTE 2-2.1
• Major bleeding & intermediate risk of VTE 1.5
• Life threating bleeding & low risk of VTE 1.0
Schulman S, NEJM 2003
Possibilities of INR
correction
• Lowering or ommiting of warfarin dose
• Application of prothrombin complex
factors (FFP, PCC, APCC)
• Administration of K vitamine
Recommended management of coumarin
overdose
• INR 3.0 - 5.0 dose reduction/delay until INR < 3.0
• INR 5.0 - 9.0 dose delay until INR < 3.0
– High risk of bleeding: oral vitamin K 1-5 mg (drops)
• INR > 9.0 dose delay and oral vitamin K 2-5 mg
– High risk of bleeding: oral or IV vitamin K 5-10 mg
• major bleeding or emergency surgery:
– prothrombin complex concentrate (PCC) 25-50 U/kg
• full effect lasts only 6 hours (halftime of FVII)
– IV vitamin K 5-10 mg (allways to be applicated together with
substitution – PCC)
Heparin induced thrombocytopenia - HIT
Etiology:
• complex heparin-PF4 + antibody stimulates platelet Fc receptor
– Induce platelets aggregation
– Venous and arterial thrombosis in  50% patients with HIT
• day 4 - 10 after onset of heparin treatment
• decline of platelet count more than 50%
Scoring system of HIT diagnosis:4 T´s
*Lo et al: JTH 2006; 4: 759-765
2 points 1 point 0 points
Thr-penia; plt
count
> 50%
nadir >20 x109/l
30-50%
nadir 10-19 x109/l
< 30%
nadir < 10 x109/l
Timing 5-10D;
≤1D (H 30D before)
5-10D ? plt; >14D; ≤1D
(H 30 - 100D)
4D
Thrombosis New, skin necrosis progression, recurrence,
non-necrotic skin lesion
none
Thr-penia;
other reason
none possible yes
• > 3 points  laboratory examination, discontinuation of UFH or LMWH
• 4-5 point - moderate, 6-8 points – high suspicion of HIT
HIT: diagnosis
• Clinical + laboratory:
– Decline of plt count (thrombosis, skin necrosis)
– HIPA:
• Aggregation of healthy platelets + patient‘ s PPP + heparin
• Low (50%) sensitivity, almost 100% specificity
– ELISA:
• complex heparin - PF4 antibodies
• High sensitivity, low specificity
– Release of 14*C-serotonine
• the highest sensitivity and specificity
HIT: treatment
– Cross-reactivity between UFH and LMWH:
– argatroban – IIa inhibitor (1C)
– bivalirudin – IIa inhibitor (2C)
– danaparoid – heparinoid with predominant FXa inhibition (1B)
– Fondaparinux (Arixtra®) - oligosacharid with FXa inhibition (2C)
– Warfarin after normalization of plt count 150
– If no thrombosis – prophylactic dosage for 30 days
HIT – platelets‘ count according to the risk
•  0,1%:
–  4 days
– internal and gyneacological indication:
• LMWH for  4 days
• 0,1 – 1%:
– Internal a gyneacological: - after surgery:
• UFH  4 days * LMWH  4 days
•  1%:
– After surgery:
• UFH  4 days
Thrombolytic therapy
• streptokinase (Streptase, Kabikinase, Awelyzin)
• urokinase (Ukidan), prourokináza (scu-PA)
plasminogen
Streptokinase + plazminogen urokinase
plasmin
– monitoring: TT 30-90 s
• r-tPA (Actilyse)
– binds to fibrin and activates plasminogen
– rtPA 100 mg via 2-hour i.v. infusion
– no monitoring (fibrinogen)
Substitution therapy with coagulation
inhibitors
(direct measurment of functional activity)
Antithrombin (Antithrombin III)
1 unit increases AT level by 1 - 1.5 %
– hereditary defficiency:
• perioperative prophylaxis, in pregnancy LMWH/UFH prophylaxis
• VTE treatment together with LMWH/UFH
– acquired defficiency with AT levels < 50 %
• sepsis
• VTE
Protein C (Ceprotin, Xigris)
– inherited homozygous defficiency with purpura fulminans
– or severe acquired defficiency – meningococcal sepsis
Direct thrombin inhibitors
(not AT III-mediated)
• hirudin
• recombinant - lepirudin (Refludan)
• synthetic - argatroban – (Novastan)
- dabigatran – oral (Pradaxa)
monitoring:
– Hemoclot
– aPTT
– Ecarin clotting time (ECT): ecarin cleaves FII to FIIa
indepently from Ca and phospholipids
Factor Xa inhibitors
• indirect
– antithrombin-mediated
– synthetic pentasacharides
– fondaparinux (Arixtra)
– idraparinux – prolonged action (once per week SC)
• direct (xabans)
– NOT antithrombin-mediated
– rivaroxaban (Xarelto)
– apixaban (Eliquis)
– edoxaban (Lixiana, Savaysa)
• monitoring: anti-Xa
60
UFHAT
Targets for antithrombotic drugs
direct indirect
Xa
IIa
TF/VIIa
X IX
IXa
VIIIa
Va
II
FibrinFibrinogen
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
Otamaxaban
Darexaban
YM466
LMWHAT
Fondaparinux,
Idraparinux
AT
Weitze et al, 2005; Weitz et al, 2008
Dabigatran
AZD 0837
Hirudin, des-
lepirudin
bivaluridin
Argobatran
VKA
Direct inhibitors of factor IIa and Xa
PT (INR) aPTT fibrinogen TT monitoring
dabigatran
PRADAXA®
could be
influenced
Anti-IIa
(g/l)
rivaroxaban
XALERTO®
apixaban
ELIQUIS®
not
influenced
not
influenced
Anti-Xa
(g/l)
* plasma half-life: * renal elimination: * daily dose
- dabigatran 12-17 h - 80% - 220 – 300 mg
- rivaroxaban 5-11 h - 1/3 - 10 - 30 mg
- apixaban 8-15 h - ¼ - 5 - 10 mg
Pradaxa
(dabigatran etexilate)
Xarelto
(rivaroxaban)
Eliquis
(apixaban)
Mechanism of action Thrombin inhibitor FXa inhibitor Inhibitor Xa
Doses 2x150 mg (red. 110) prev. 10, th 20 mg 2 x 2,5/5 mg
Bioavailability 6,5% 80-100% aprox. 50%
Prodrug Yes No No
t1/2 12–14 hours 9–13 hours aprox. 12 hours
Tmax 0,5–2 hours 2–4 hours 3–4 hours
Possible interactions
Strong P-gp
inhibitors
Strong CYP3A4/Pgp
inhibitors
Strong CYP3A4/Pgp
inhibitors
Plasmatic proteins
binding
34-35% 92–95% 87%
Elimination 80% renal 33% renal 27% renal
Novel Oral Anticoagulants (NOAC)
Bauer KA. J Thromb Haemost 2011; 9 Suppl 1:12-9; SPC Pradaxa 02/2012; SPC Xarelto ; SPC Apixaban
Monitoring of NOAC: usually not necessary
• Pradaxa: roughly aPTT, TT, plasma level - test „Pradaxa anti-IIa“:
2x150 mg daily 220 mg 1x daily
– Peak: 175 (117-275) g/l 71 (35-162) g/l (percentil 25-75)
– Nadir: 91 (61-143) g/l 22 (13-36) g/l (percentil 25-75)
• Xarelto: really roughly PT, plasma level of anti-Xa:
20 mg 1x daily 10 mg 1x daily
– Peak: 215 (22-535) g/l 125 (91-195) g/l
– Nadir: 32 (6-239) g/l 9 (1-38) g/l
• Eliquis: really roughly PT, plasma level of anti-Xa:
2x5 mg daily 2x2.5 mg daily
– Peak: 128 g/l (CV 10%) 62 g/l (CV 37%)
– Nadir 50 g/l (CV 20%) 21 g/l (CV 17%)
Bleeding in patients treated by direct IIa / Xa inhibitors
• to stop therapy – t1/2
: 5-17 h
• specific antidotes – now only for dabigatran, single dose of Prax-bind
– Anti-direct Xa inhibitor: only in studies
• drug elimination:
– activated carbon
– haemodialysis (not rivaroxaban – binding on plasma proteins)
– haemoperfusion
– plasmapheresis (fondaparinux, dabigatran)
• nespecific hemostyptic therapy:
– aPCC (activated prothrombin complex concentrate)
• Content: FII, FVIIa, FIX, FX
– rFVIIa
– antifibrinolytics
Antidotes for anticoagulant therapy
• Heparin, LMWH:
– Protamine (1 mg / 100 U UFH)
• Binds to heparins
• Not sufficient neutralization after SC aplication of LMWH
• Warfarin:
– vitamin K (2-5 mg)
– prothrombin complex concentrates (PCC)
• FII, VII, IX, X
– FFP
• Factor IIa and Xa inhibitors:
– specific antidotes ongoing clinical trials, only Prax-binde for use
– PCC, rFVIIa
– dialysis (only dabigatran)
Surgical interventions
● Embolectomy – massive PE, possibly documented by
angiography
● 20% operative mortality (before1985 32 %)
Stein PD, Alnas M, Beemath A, Patel NR: Outcome of pulmonary embolectomy. Am
J Cardiol 2007;99(3)
● vena cava filters
indicated when contraindication to anticoagulant therapy,
complications of anticoagulant therapy, recurrent VTE
despite adjusted anticoagulant therapy and prior to
pulmonary embolectomy
ACCP guidelines
• 9th edition (2012)
Platelet activation pathways
cell membrane phospholipids
inflammation
arachidonic acid
PGH2 Synt 1
Cyclooxygenase
Aspirin
NSAID
PGG2/H2
Prostacyklin TxA2 Thrombin ADP
platelet activation
GpIIb/IIIa exposition
IIb/IIIa inhibitors
platelet aggregation
PGH2 Synt 2
PGG2/H2
illoprost
beraprost
ticlopidin, clopidogrel
Acetylsalicylic acid
• Irreversible serin acetylation 529 AA in COX-1
• → decreased production of:
• platelet activator thromboxane (TX)A2
• its metabolite thromboxane TXB2 in serum
• 11-dehydro-thromboxane B2 in urine
• aprox. 30% is of non-platelet origin
• 150-fold less afinity to COX-2:
• serin 516 acetylation
• 10% of circulating platelets contain COX-2
• possible origin of TXA2
COX-1 inhibition
~ acetylsalicylic acid (ASA):
~ Anopyrin, Godasal, Acylpyrin, Aspirin
~ 100 (200) mg daily
~ effective during the whole life span of platelets
~ must be stopped 5-10 days before surgery
~ other non-steroidal anti-inflammatory drugs
(NSAIDs):
• indobufen (Ibustrin)
- 200 mg twice daily
- reversible effect 12-24 hours
- no evidence for clinical benefit
Thienopyridines
• Irreversible block of ADP receptors P2Y12:
– disulphide bonds formation between the drug and receptor
cysteine
– acts in megacaryopoiesis phase – must be stopped 5-10 days
before surgery
• Prodrug:
– the active form is produced by liver cytochrome P450
• Affected also by other drugs
• CYP2C19*1, slower metabolism with alleles *2, *3
• CYP3A4
• CYP1A2
• CYP3A5:
• Inhibition:
– CYP2B6
• Higher variability in effect on platelets than ASA
Thienopyridines
~ Ticlopidin (ApoTic) - agranulocytosis
~ 250 mg twice daily
~ Clopidogrel (Plavix, Trombex): oral
~ 75 mg daily
~ Prasugrel (Efient) : oral
Direct drugs, not prodrugs, effect less variable:
~ Ticagrelor (Brilique): oral
~ Cangrelor: i.v.
~ Elinogrel: oral or i.v.
PAR antagonists – voraxapar, atopaxar
Antiaggregation therapy monitoring-
ASA
Clinical:
– relapse of MI, stroke, chronic limb ischemia
Laboratory – definition (?) of efficacy-resistence:
• ADP-induced platelet aggregation 10 mol/l in PRP:
– max. aggregation < 70%
• ARA-induced platelet aggregation 0,5 mg/ml in PRP:
– max. aggregation < 20%
• Cathionic propyl gallate aggregation in PRP:
– decreased slope of aggregation curve < aprox. 50%/min.
– time to 50% of maximum aggregation > aprox. 100 sec.
• PFA-100:
– prolonged closure time with Col/Epi above upper limit of normal
–  metabolite: thromboxane-b2 in serum (11-dehydro in urine)
Antiaggregation therapy monitoring-
clopidogrel
ADP-induced platelet aggregation 5 or 20 mol/l in
PRP:
– decrease by 10-30% of absolute value compared to the
value before treatment
VASP-P:
– phosphorylation of vasodilator (PGE1) stimulated phosphoprotein
– stimulation of P2Y12 receptor blocks VASP phosphorylation
– evaluation of VASP phosphorylation after addition of ADP, following
previous PGE1 stimulation
– if P2Y12 is blocked by clopidogrel, addition of ADP will not reduce
VASP phosphorylation
– effective therapy – phosphorylation after addtion of ADP will not
be reduced  50%
Antiaggregation therapy monitoring
- whole blood aggregation Multiplate®
• impedance aggregometry
• whole blood
• induction of aggregation
– ARA (ASPI test) - monitoring: ASA
– ADP clopidogrel
– ADP+PGE1 clopidogrel
– thrombin (TRAP test) IIb/IIIa inh.
Gp IIb/IIIA inhibitors monitoring
~ monoclonal antibodies, peptides and small
molecules
• Platelet aggregation in whole blood –
impedance method Multiplate®:
• TRAP test:< 30 U
• VerifyNow Assay®:
– Platelet Aggregation Units (PAU)
– abciximab (ReoPro®) eptifibitide (Integrilin®)
• 0-44 PAU - > 80% inhibice 0-31 PAU - > 80% inhibice
• 0-13 PAU - > 95% inhibice 0-10 PAU - > 95% inhibice
Summary
• At the present time standard monitoring and dose
adjustment of antiaggregation therapy is not
recommended.
• Recommended only in clinical trials.