-glycosaminoglycan anti-coagulant
-found endogenously in mast cell granules (but normally undetectable in plasma)
-appears to be required for histamine storage w/in mast cells
-can be detected in systemic mastocytosis
-massive mast cell drgranulation --> may lead to a mildly prolonged aPTT
-prolongs aPTT & Thrombin Time (TT) --> see mechanism below
-Onset Of Action:
-rapid (< 0.1s)
-Molecular Weight:
-750,000 - 1,000,000 Daltons
-Structure:
-Mechanism:
-structure contains multiple sulfate groups which facilitate binding to anit-thormbin III (heparin cofactor)
-anti-thrombin III rapidly (1/2-life < 0.1s) inhibits thrombin (IIa) ONLY in the presence of heparin
-also inhibits Factors IXa, Xa & XIa --> intrinsic pathway inhibition --> prolongs aPTT & Thrombin Time (TT)
-heparin catalyzes formation of anti-thrombin III / thrombin (IIa)-complex then heparin is released to act again
-heparin is NOT thrombolytic --> Thrombin (IIa) & Factor Xa already clot-bound are protected from anti-thrombin III
-heparin can only prevent clots from forming or enlarging --> it cannot dissolve clots already formed
-Uses:
1) Venous Thrombosis
-give heparin initially then switch to oral anti-coagulants
-must continue IV heparin for 4-5 days to allow oral anti-coag levels to become therapeutic
2) Pulmonary Embolus (PE)
-give heparin initially then switch to oral anti-coagulants
-must continue IV heparin for 4-5 days to allow oral anti-coag levels to become therapeutic
3) Unstable Angina
4) Acute MI
5) During & after PTCI (Percutaneous Transluminal Coronary Intervention)
-Ex.) angioplasty or stent placement
6) Operative procedures requiring CP Bypass
7) DIC
8) Venous thromboembolism prophylaxis
9) DOC for anti-coagulation during pregnancy
-heparin (unlike warfarin (coumadin)) does NOT cross the placenta
-should stop heparin admin. ~24 hrs. prior to delivery --> minimizes post-partum bleeds
-1/2-Life
-depends on dose (longer 1/2-lives for LMWH's):
A) 100 units / kg IV --> 1 hr.
B) 400 units / kg IV --> 2.5 hrs.
C) 800 units / kg IV --> 5 hrs.
-Clearance:
A) Reticuloendothelial System (RES) --> ~97%
B) Renal --> ~3%
-Admin:
A) IV --> immediate onset of action (< 0.1s)
B) Sub-Q --> onset of action: 1-2 hrs.
-used for long-term anti-coagulation when warfarin (coumadin) contraindicated (Ex.) pregnancy)
-maintain aPTT's of ~1.5x normal mean
-total daily dose = 35,000 units divided into Q8H or Q12H
-measure aPTT's 1/2 way b/w doses (either Q4H or Q6H)
-once aPTT levels are consistently (for > 2 days) @ ~1.5x normal mean --> no routine lab monitoring needed
-use low doses for DVT & thromboembolism prophylaxis
-5000 units sub-Q Q8H-Q12H --> will NOT prolong aPTT's --> no routine lab monitoring needed
1) Venous thromboembolism:
-5000 units IV bolus then 1200-1600 units / hr.
-monitor aPTT's Q6H initially until levels are therapeutic then QD aPTT's
-MUST achieve therapeutic levels w/in 24 hrs. --> otherwise increased risk of recurrent thromboembolism
-therapeutic aPTT --> 1.8 - 2.5x normal mean aPTT
-therapeutic heparin plasma levels --> 0.3 - 0.7 units / mL
2) CP Bypass:
-very high amounts of IV Hep used
-large prolongation of the aPTT so instead monitor coag function w/ activated clotting time (ACT)
-Heparin Resistance:
-consider in pts. w/ normal therapeutic heparin plasma levels w/ normal aPTT's
-Mechanism --> competitive inhibition of heparin (or heparan sulfate) / anti-thrombin binding by:
A) Histidine-rich glycoprotein
B) Vitronectin
C) Platelet Factor 4 (PF4)
-pro-coagulant
-promotes localized clot formation @ the site of vessel injury
-assoc. conditions:
1) Massive Pulmonary Embolus (PE):
-induces heparin clearance
2) Hyper-Factor VIII-emia:
-pts. have elevated Factor VIII levels @ baseline
-so pts. not actually resistant to heparin --> they just have very short aPTT's @ baseline
3) Acquired Anti-Thrombin Deficiency:
-pts. have only ~25% of normal anti-thrombin levels (vs. 40%-60% in Inherited Anti-Thrombin Deficiency)
-pts. may require increased IV Hep dosing to achieve usual aPTT increases
-seen with:
1) Hepatic Cirrhosis
2) Nephrotic Syndrome
3) DIC
4) Inherited Anit-Thrombin Deficiency:
-pts. have only ~40%-60% of normal anti-thrombin levels (vs. 25% in Acquired Anti-Thrombin Deficiency)
-most pts. respond normally to IV Hep dosing
-Side Effex:
1) Bleeding: --> most common side effect
-occurs in < 3% of pts. tx'd w/ IV Hep (similar for LMWH's)
-risk increases w/ increased aPTT's & higher doses
-heparin interferes w/ platelet aggregation --> may prolong bleeding time (BT)
-heparin also induces TFPI release: --> inhibits the extrinisic pathway
A) inhibits Factor Xa
B) inhibts Factor VIIa / TF-complex
-comorbid d/o's usually present:
A) recent surgery
B) trauma
C) peptic ulcer dis. (PUD)
D) platelet dysfunction
-anti-coag effex of heparin disappear w/in hrs. of drug d/c --> short 1/2-life (see 1/2-Life above)
-if life-threatening bleed --> tx w/ slow IV infusion of protamine sulfate
-reverses effex by binding & neutralizing heparin
-anaphylaxis in ~1% of diabetics on protamine-containing insulin:
-Ex.) NPH or protamine-zinc insulin
-Protamine Dosing:
-1 mg/100 units of heparin remaining in pt. @ slow IV rate of 50 mg/10 mins
-Protamine Side Effex:
A) pulmonary vasoconstriction
B) RV dysfunction
C) systemic hypotension
D) transient neutropenia
2) Heparin-Induced Thrombocytopenia (HIT):
-dx. requires either:
A) new onset platelet count < 150,000 or
B) 50% decrease of platelet count from pre-tx values
-Incidence:
-occurs in ~3% of pts. (less in LMWH's)
-1/3 of these 3% (overall 1%) will develop thrombotic complications
-usually arises 5-10 days after initiation of heparin tx.
-Mechanism:
-heparin triggers IgG & IgM Ab response (if given for > 4 days)
-the Ab response is triggered by the heparin/PF4-complex on the platelet surface
-the Ab's bind to the heparin/PF4-complex and:
A) Activates the platelet --> platelet aggregation & premature removal from circulation
B) Induces increased PF4 release --> pro-coagulation
C) Induces prothrombin (Factor II) to thrombin (Factor IIa) activation --> pro-coagulation
-leading to thrombosis & thrombocytopenia --> major clinical risks of HIT
-Diagnosis:
-HIT-Ab level
-Tx:
-d/c heparin immediately if pt. develops clinical signs (Ex.) thrombosis or thrombocytopenia) > 4 days after heparin initiation
-thrombotic complications may still occur even after drug has been d/c'd --> must anti-coagulate w/ another drug:
A) Direct Thrombin Inhibitors:
1) Lepirudin (Refludan)
2) Bivalirudin (Angiomax)
3) Argatroban
B) Non-Heparin Glycosaminoglycan Anti-Coagulants:
1) Danaparoid (Orgaran)
-AVOID in pts. w/ HIT (possible cross-reactivity w/ heparin):
1) LMWH's:
-very often cross-react w/ heparin
2) Warfarin (Coumadin):
-may cause venous limb gangrene in pts. w/ HIT
2) LFT Changes:
-may see mild elevations in ALT & AST
3) Osteoporosis:
-may present as spontaneous vertebral fractures
-usually seen w/ daily dosing > 20,000 units/day for > 3 months
4) Hyperkalemia:
-heparin can infrequently inhibit adrenal aldosterone synthesis even @ low doses
5) Anaphylaxis:
-very rare
6) Rebound Hyperlipidemia:
-heparin induces LPL release --> hydrolyzes: trigs --> glycerol + FFAcids
-may see rebound hyperlipidemia when drug is d/c'd
7) Prolonged Bleeding Times (BT):
-heparin interferes w/ platelet aggregation --> may prolong the bleeding time (BT)
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References:
Goodman & Gilman's: The Pharmacologic Basis Of Therapeutics - 10th Edition - 2001. Chapter 55.