Heparin Anticoagulants I Flashcards
where is heparin naturally found
in the granules of MAST cells (along with histamine and serotonin)
chemically what is heparin made up of
strongly acidic (highly ionized) mucopolysaccharide composed of repeating units of sulfated glucuronic acid and sulfated glucosamine.
is heterogenous - found in different weights
what part of heparin is required to bind its co-factor
penta-saccaride sequence
why is there variation in heparin
comes from swine and different species produce different potencies of heparin
what 2 methods are used to standarize heparin
anti-Xa and anti-IIa assays
how is heparin dosed
in units
1 unit equals 8-12mg depending on potency
Actions of Heparin
Inhibits the action of activated factor Xa and factor IIa (Thrombin).
Inhibits the action of several other serine protease enzymes (XIIa, XIa).
Inhibits the aggregation of platelets (at high concentration).
Plasma clearing effect
Binds to vascular lining and neutralizes the positive charge.
Causes a release of Tissue Factor Pathway Inhibitor (TFPI).
heparin mainly affects which pathway
intrinsic (contact activation) pathway
heparin’s MOA
Heparin binds to AT III and induces a conformational change in AT III resulting in 1000x greater binding affinity to clotting factor proteases.
heparin requires what co-factor
antithrombin III
plasma clearing affect of heparin
Turbid plasma is rapidly cleared of fat chylomicrons by a release of lipase from the blood vessels.
heparin’s route of administration
IV and subcutaneous (mostly used inpatient)
not absorbed orally or rectally
APTT therapeudic range for heparin
2- 2.5 times baseline
how do you monitor heparin
APTT (effects are not well correlated with patient weight)
what enzyme metabolizes heparin
heparinase in the liver
how is heparin excreted
20-25% of heparin is excreted in urine
what happens to heparin that is not excreted
Some heparin is picked up by mast cells
Endothelium is able to bind heparin
what is the duration and onset of heparin
Biologic T 1/2 of intravenous heparin is 1-3 hours, depending on the dose. (dose dependent effect)
Onset of action is 5-10 minutes (as measured by APTT method).
Endogenous modulators of heparin action (what affects heparin’s actions)
AT(main heparin co-factor) needed for heparin to have affects
Heparin cofactor II (second cofactor) can only inhibit thrombin when heparin binds
Tissue Factor Pathway Inhibitor (TFPI)
Platelet factor 4 (heparin neutralizing protein)
Side Effects of Heparin
Hemorrhagic complications
(Adrenal, gut, etc.)
Heparin induced thrombocytopenia (HIT)
Osteoporotic
Alopecia
Heparin induced thrombocytopenia (HIT)
Generation of antiheparin platelet factor 4 antibodies. (Ab to the complex) These antibodies activate platelets and endothelial cells.
can lead to limb loss - monitor platelet counts for drops of around 50%
clinical uses of heparin
Therapeutic anticoagulation Surgical anticoagulation Prophylactic anticoagulation Unstable angina and related coronary syndromes Adjunct therapy with thrombolytic drugs Thrombotic and ischemic stroke
Protamine
is a powerful heparin antagonist. It has a low molecular weight and is a highly basic protein found in the sperm of certain fish.
It combines with strongly acidic heparin to form a stable salt with loss of anticoagulant activity. (an advantage to using heparin is that an antagonist is available)
how much protamine is needed to neutralized 1 unit of heparin?
about 10 ug
2500 units is neutralized by 25 mg
Low Molecular Weight Heparins & Synthetic Heparin Pentasaccharide are made by
Prepared by fractionation or depolymerization of native heparin.
bioavailability of LMW heparin vs heparin
LMW heparin 100% (advantage it can be given orally)
heparin
Clinical Advantages of LMW Heparins
- Better bioavailability
- Longer duration of action
Less bleeding
Lesser thrombocytopenia
do LMW heparins require a co-factor
yes! they still require AT III
clinical uses of LMW heparin
Prophylaxis of DVT (once a day dosing advantage over heparin)
Treatment of DVT (can be sent home on it)
Management of acute coronary syndromes
Other uses such as anticoagulation for surgical and interventional cardiovascular procedures
Antithrombin- Concentrates (AT) uses
Antithrombin-concentrate is used to treat patients with acquired or congenital antithrombin-deficiency AT is also useful in *sepsis and *disseminated intravascular coagulation
pts with AT III deficiencies are more prone to DIC and sepsis
Hirudin
is a protein from the saliva of the medicinal leech (Hirudo medicinalis) which contains several pharmacologically active substances.
direct thrombin inhibitor
refludan
commercial preparation of r-hirudin is used in the anticoagulant management of heparin induced thrombocytopenic patients.
Argatroban
Thrombin Inhibitor, a synthetic anti-thrombin agent which is currently used as an anticoagulant in patients who can not be treated with heparin, special usage in the management of heparin induced thrombocytopenia.
Bivalirudin
is a synthetic antithrombin agent. This agent is a hybrid molecule between a component of hirudin and a tripeptide. This drug is approved for PTCA anticoagulation.
used for stent placement
LMW heparins MOA
Complex with AT and inhibit factors Xa and IIa
fondaparinux (pentasaccaride) MOA
complex with AT and inhibits factor Xa
argatronban MOA
directly inhibits IIa
Bivalirudin MOA
directly inhibits IIa
Hirudin MOA
directly inhibits IIa
Antithrombin concentrate MOA
Directly inhibits IIa
protamine sulface MOA
heparin antagonist
Argatroban, Bivalirudin, and Hirudin indications
Anticoagulant management of HIT patients
Antithrombin concentrate indications
DIC, sepsis, thrombophilia, hypercoagulable state
fondaparinux (pentasaccharide) indications
management of a DVT
protamine sulfate adverse effects
Bradycardia, hypotension
