Parenteral Anticoagulant
BY : Maha khalidBY : Maha khalid
Supervisor : Pro Dr Seham Hafez Supervisor : Pro Dr Seham Hafez
Parenteral Anticoagulant
UFH LMWH
Fondaparinux
UFH & LMWH all consist of high
MW molecules that Are highly ionized (they don'tabsorbed from GIT they must
given byIV infusion or
deep SC injection. (never IM(
Objective of anticoagulation
To prevent death & recurrent To prevent death & recurrent event with acceptable rate of event with acceptable rate of bleeding complicationsbleeding complications..Considering the high mortality Considering the high mortality rate (30 %) in untreated patient rate (30 %) in untreated patient with suspected PE with suspected PE anticoagulant treatment anticoagulant treatment should be consider while a should be consider while a waiting definitive diagnostic waiting definitive diagnostic
confirmationconfirmation..
Goals of anticoagulation therapy
1-The efficacy of heparin therapy depends on achieving a critical therapeutic level of heparin within the first 24 hours of treatment. The critical therapeutic level of heparin is 1.5 times the baseline control value or the upper limit of normal range of the activated partial thromboplastin time
(aPTT) .This level of anticoagulation is expected to correspond to a heparin blood level of 0.2-0.4 U/mL by the protamine sulfate titration assay and
0.3-0.6 by the antifactor X assay .
UFH Vs LMWH • 1-Standard heparin is comprised of an 1-Standard heparin is comprised of an
unfractionated heterogeneous mixture of unfractionated heterogeneous mixture of polysaccharide chains with mean molecular polysaccharide chains with mean molecular weights ranging from 12 000 to 16 000 daltons.weights ranging from 12 000 to 16 000 daltons.
2-LMWHs are formed by depolymerization of 2-LMWHs are formed by depolymerization of unfractionated heparin side chains, producing unfractionated heparin side chains, producing “smaller” heparin fragments, with mean molecular “smaller” heparin fragments, with mean molecular weights ranging from 1000 daltons to 10 000 weights ranging from 1000 daltons to 10 000 daltons. daltons.
UFH Vs LMWH • 1- Both types of heparin inactivate factor Xa by 1- Both types of heparin inactivate factor Xa by
interacting with antithrombin (AT)interacting with antithrombin (AT)• 2- unfractionated heparin 2- unfractionated heparin ((UFHUFH) ) is able to inactivate is able to inactivate
factor IIa through formation of a tertiary complex.factor IIa through formation of a tertiary complex.• 3- UFH inactivates factors IIa and Xa and affects the 3- UFH inactivates factors IIa and Xa and affects the
apTT (activated partial thromboplastin time )apTT (activated partial thromboplastin time )• 4-LMWH inhibits factor Xa and minimally affects 4-LMWH inhibits factor Xa and minimally affects
factor IIa; thus activated partial thromboplastin time factor IIa; thus activated partial thromboplastin time is not used to measure its anticoagulant activityis not used to measure its anticoagulant activity
Anticoagulant Properties of UFH
4-Inhibits activated factors XII, XI, IX, X and II
3-Inhibits activation of fibrinstabilizing enzyme
2-Inhibits the aggregation of platelets by thrombin
1-Inhibits the thrombin-mediated conversion of fibrinogen to fibrin
Does not actively lyse but is able to inhibit
further thrombogenesis. Prevents
reaccumulation of clot after spontaneous
fibrinolysis
When unfractionated heparin is used, the aPTT should not be
checked until 6 h after the initial heparin bolus because an
extremely high or low value during this time should not provoke
any action.
UFH weight based dose:
UFH Vs LMWH1-Heparin half life is 1 hrs
but it shorter in patient with PE It
excreted by both hepatic & renal ways
it would take 5 hrs )five half lives
to reach steady state ,a loading dose is
required to reduced the time
to achieve adequate anticoagulation
LMWH have potential desirable PK than heparin
,they excreted renally & have longer half lives
have morepredictable dose
response than UFH.,they can give once or at the most
twice daily in fixed dose.
UFH Vs LMWH
Hem
orrhage
commoner in patients
with sever heart or liver disease
,renal disease , general debility
&women aged over
60 years. The risk of hemorrhage
is increased in those
with prolonged clotting times
Heparin
LMW
Hrisk
of hemorrhage is
increased in those
given heparin by
Intermittent intravenous
bolus rather than
by continuous
intravenous administration .
LMWH may
produce fewer
hemorrhagic complication & monitoring
of effect is
not routinely required
More less
Throm
bocytopenia
HeparinH
IT
LMW
H
LMWH are less likely to produce thrombocytopenia this complication only in :Patient only previoulsly developed thrombocytopenia
after UFH .
Heparin induced thrombocytopenia“ HIT “
the first occurs after 3-5 days
after initiate of treatment
the second type occure after 6 days
of FIRSTtreatment orhours to 2-3 days
with re-exposure .
doesnot result in complication
often result in much more reduction in
plateletscount & increased risk of thromboembolism .
HIT ( Mechanism )
• HIT is the most common drug-induced thrombocytopenia HIT is the most common drug-induced thrombocytopenia in adults, complicating 1-4% of full-dose exposures to in adults, complicating 1-4% of full-dose exposures to standard heparin. Unlike other thrombocytopenias, HIT standard heparin. Unlike other thrombocytopenias, HIT carries a high thrombotic morbidity (30-50%) and carries a high thrombotic morbidity (30-50%) and mortality (10-15%) because it is a syndrome of platelet mortality (10-15%) because it is a syndrome of platelet activation. Heparin forms a complex with platelet factor 4 activation. Heparin forms a complex with platelet factor 4 (PF4) which is released from platelets by platelet (PF4) which is released from platelets by platelet activation. Antibody directed against the heparin-PF4 activation. Antibody directed against the heparin-PF4 complex binds via its Fab region. The antibody-heparin-complex binds via its Fab region. The antibody-heparin-PF4 immune complex binds to the Fc receptor on the PF4 immune complex binds to the Fc receptor on the surface of the platelet leading to activation of the platelet. surface of the platelet leading to activation of the platelet.
Criteria for Diagnosing HIT
Complications of HIT
1-•Deep vein thrombosis•1-•Deep vein thrombosis•• 2-Pulmonary embolism•2-Pulmonary embolism•• 3-Myocardial infarction•3-Myocardial infarction•• 4-Occlusion of limb arteries (possibly resulting in 4-Occlusion of limb arteries (possibly resulting in
amputation)•amputation)•• 5-Cerebrovascular accidents (stroke )5-Cerebrovascular accidents (stroke )• 6-Skin necrosis•6-Skin necrosis•• 7-End-organ damage (e.g., adrenal, bowel, spleen, 7-End-organ damage (e.g., adrenal, bowel, spleen,
gallbladder or hepatic infarction; renal failure)•gallbladder or hepatic infarction; renal failure)•• 8-Death8-Death
Treatment of HIT :
1-ALL heparin (lines, flushes, heparin-coated catheters, LMWH ) must be stopped
Platelet transfusion) transfusion may precipitate thrombosis ( should be AVOIDED
warfarin in the acute phase of HIT) its use may precipitate venous gangrene and thrombosis .( C/I
Treatment of HIT :
[1-lepirudin (rDNA) for injection
highly specific directinhibitor of thrombin
indicated as an anticoagulant for prophylaxis or treatment of
thrombosis in patients with HIT
and associated thromboembolic
diseasein order to prevent further
thromboembolic complications .
2-Argatroban is a synthetic direct
thrombin inhibitorindicated as an anticoagulant
for prophylaxis or treatment
of thrombosis in patients with HIT
For how long UFH &LMWH should be used ?
• 1-Heparin used in immediate stages of venous1-Heparin used in immediate stages of venousthrombosis & PE until the effect of warfarin thrombosis & PE until the effect of warfarin • become apparent .become apparent .• In the past it has been continued for 7-10 daysIn the past it has been continued for 7-10 days• but recent evidence indicate that 3-5 days of but recent evidence indicate that 3-5 days of
therapy maybe sufficient in many instances :therapy maybe sufficient in many instances :• this will reduce the risk of HIT which normally this will reduce the risk of HIT which normally
occurred after 6 days.occurred after 6 days.• 2- LMWH are used for similar length but they 2- LMWH are used for similar length but they
are give SC without loading dose & without are give SC without loading dose & without routinely monitoring.routinely monitoring.
Enoxaparin
Only LMWH approved by FDA for both treatment and prophylaxis of DVT and PE.
Dose Adult :DVT/PE: 1 mg/kg SC q12h or 1.5 mg/kg SC qd
Prophylaxis of DVT: 30 mg SC q12hProphylaxis in abdominal surgery: 40 mg SC qd,
first dose given 2 h prior to surgery PediatricDVT/PE: 1 mg/kg SC q 12h
Interactions:Platelet inhibitors or oral anticoagulants (eg, dipyridamole
,salicylates, aspirin, NSAIDs ,sulfinpyrazone, ticlopidine) may increase risk of bleeding
Enoxaparin(Con”d)
contraindicationDocumented hypersensitivity; major bleeding; thrombocytopenia
PregnancyB - Usually safe but benefits must outweigh the risks
PrecautionsIf thromboembolic event occurs despite LMWH prophylaxis ,discontinue drug and initiate alternate therapy; elevation of
hepatic transaminases may occur but is reversible; HIT may occur; 1 mg protamine sulfate
reverses effect of approximately 1 mg enoxaparin if significant bleeding complications develop
When LMWH will need dose adjustment :
in patient with renal failure dose adjustment according to
anti-Xa level.If crcl less than 30ml/min
heparin is preferred
very thin or very obese patient
dose adjustment
According to factor Xa
Also patient at high risk of
bleeding heparin should
be considering as it effect
is easy to reversed.
pregnancy.
FONDAPARINUX
Synthetic anticoagulant that works by inhibiting factor Xa a key component involved in blood clotting. Provides
highly predictable response.
Bioavailability is 100%. Has a rapid onset of action and a half-life of 14-16 h,
allowing for sustained antithrombotic activity over 24-h period
Does not affect prothrombin time or activated partialThromboplastin time, nor does it affect platelet function
Dose : 2.5 mg SC qd
DRUG INTERACTIONS: None reported; increased risk of bleeding possible
with concurrent administration of platelet inhibitors ,
oral anticoagulants, or thrombolytic agents
Contraindication Documented hypersensitivity; seriously impaired kidney function
or in patients who weigh <110 lb; patients given spinal anesthesia
or spinal puncturePregnancy
C - Safety for use during pregnancy has not been established.
PrecautionsWhen spinal anesthesia or spinal puncture
used, may develop blood clot in spine ,which can result in long-term or permanent paralysis
Finally which one is better UFH or LMWH ?
Several meta-analyses have indicated that:1-LMWH
is associated with less bleeding
and fewer episodes of
heparin-Induced
thrombocytopenia Than
UFH
2-patients receiving
LMWH reported a higher quality
of life in terms of
physical and social
function and sense
of well-being.
3 -Treatment of DVT with LMWH was more
cost-effective than therapy with
UFH because
the length of The hospital
stay was reduced by 60to 70 percent without
an increase in the cost of home health care
But Two recent studies of patients with DVT :
•To compare the effect of LMWH given on an outpatient basis SC twice daily with that of UFH given by continuous IV infusion in the No significant different was hospital found in rates of recurrent venous thromboembolism, hemorrhagic complications, development of thrombocytopenia or mortality. LMWH were as safe and effective as UFH and most patients were managed at home immediately after diagnosis or a brief hospitalization.
With warfarin
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