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

THANK YOU