• sulfated mucopolysaccharide stored in granules of mast cells
• Categorized into the standard unfractionated (UFH) and low molecular weight heparin (LMWH)
• acts as a cofactor and accelerates actions of antithrombin (AT)
• To inactivate thrombin, heparin must bind simultaneously to both thrombin and AT
• end result of UFH and LMWH action is inhibition of thrombin (factor IIa) and factor Xa

• natural anticoagulant that inactivates facotrs II, , IX, X, XI and XII

Low molecular weight heparin (LMWH)

• have sorter chains, so catalyze inactivation of factor X more efficiently than factor II (3:1)
• current products:
  • Enoxaparin (Lovenox)
  • Dalteparin (Fragmin)
  • Tinzaparin (Innohep)

• Standard prep (> 18 monosaccharide units)
• has longer chain, so catalyzes inactivation of factor II more efficiently than factor X (1:1)

• measures efficacy of both intrinsic and common coagulation pathways
• much more sensitive to changes in factor II levels. Therefore monitors UFH. The higher the anti factor X activity of LMWH the lesser the impact on the PTT

• elimination:
  • UFH = heparinase and RE system
  • LMWH = mostly renal
• Monitoring
  • UFH = PTT, ACT
  • LMWH = not necessary
• Bioavailability
  • UFH = 20%
  • LMWH = 90-100% (use for acute thrombosis)

• Therapeutic use with SC route makes it convenient for outpatient use and bridge therapy
• slightly lower incidence of HIT
• no need to monitor PTT
• ideal agent during pregnancy, since warfarin is contraindicated 

• conversion of one agent to another
• warfarin stays in system longer, so stop its use 5 days prior to procedure and start LMWH days 4-1 prior
• post procedure give both agents for 6 days so warfarin can take effect then discontinue LMWH

• Prophylaxis of thromboembolic disease (small dose)
• Treatment of thromboembolic disease (full dose)

• Therapeutic doses based on body weight
• Prophylactic doses tent to be fixed and not based on body weight
• dosing of LMWH is also dependent on renal fxn. (may need to extend dosing interval)

1. bleeding 
2. Heparin induced thrombocytopenia (HIT)

• immunologically mediated
• drop in platelet count usually > 50%
• incidence: UFH = 2%, LMWH < 1%
• prothrombotic condition
• onset commonly seen after day 4 of therapy. Early or delayed onset also seen
• discontinue all heparin and use direct thrombin inhibitor

• heparin forms an antigenic complex with platelet PF-4
• IgG recognizes and binds complex
• platelet activation occurs, promoting release of prothrombotic microparticles an platelet aggregation
• activated platelets aggregate and are removed prematurely from circulation = ↓ platelet count

• variable onset (rapid, typical, delayed)
• ↓ platelet count of ≥ 50% from baseline (even if count is > 150,000)
• median platelet count nadir = 50,000
• thrombosis occurs in 20-50% of untreated HIT pts. Must use another agent to prevent clots until platelet count returns to normal
• degree of thrombocytopenia is inversely related to presence of thrombosis
• the lower the platelet count the greater the risk of thrombosis
• more venous thrombosis than arterial
• thrombosis may precede thrombocytopenia
• acute systemic reactions
• skin lesions at heparin injection sites

• can occur within 30 min of heparin bolus administration
• inflammatory: fever, chills
• cardiorespiratory: hypertension, tachycardia, dyspnea, chest pain, cardiorespiratory arrest

• Immunologically mediated ↓ in platelets,
• no thrombosis

• HIT and associated thrombosis syndrome

• Immunologically mediated ↓ in platelets, with thrombosis 

• Heparin associated thrombocytopenia 
• non-immunologically mediated ↓ in platelets

the 4 Ts system

1. Thrombocytopenia
2. Timing
3. Thrombosis
4. Other causes of platelet fall (ie chemotherapy)

Current Direct thrombin inhibitors (DTI) agents

only agents to work directly on thrombin, all others affect antithrombin

• Lepirudin (Refludan)
• Argatroban
• Bivalirudin (Angiomax)

• approved indications: 
  • alternative anticoagulants or pts with HIT
  • as anticoagulants in acute coronary syndromes (e.g in cath lab)
• other uses:
  • general anticoagulation in place of indirect anti-Xa antagonists
  • antithrombin deficiency (all other agents act on antithrombin)
  • hypersensitivity to heparin, LMWH or Fondaparinux
• must be given IV

Fondaparinux (Arixtra) is only agent marketed in US

• selective indirect factor Xa inhibitor
• compared to UFH and LMWH, has no direct effect on thrombin (factor IIa) activity
• does not bind to platelet factor 4 (PF4) or affect platelet fxn

• synthetic pentasaccharide binds AT and inducing conformational change in AT to bind factor Xa. End result = inhibition of Xa (similar to UFH and LMWH)
• neutralization of factor Xa disrupts the blood coagulation cascade, which inhibits thrombin formation and thrombus development

• Excretion = renal: up to 77% excreted an unchanged drug
• contraindicated if Clcr < 30 ml/min 
  • do not give to renal pts or elderly 
• t_1/2 = 17-21 hrs
• Distribution: 94% bound to antithrombin
• absorption: SC 100%

• good alternative to UFH or LMWH
• possibly safer profile on platelets
• given SC once a day (DTI given as IV)possibly more effective than enoxaparin in prevention of thromboembolism post major orthopedic procedures

• treatment or prophylaxis of venous thromboembolism
• distant 2nd treatment for HIT (after DTIs), considered safe but has caused HIT like syndrome

• causes hepatic production of partially carboxylated or decarboxylated proteins (vit k dependent clotting factors) having reduced procoagulant activity
  • blocks conversion of vit k epoxide to vit K₁ (active form), and therefore all further steps that lead to the activation of clotting factors 
• also inhibits synthesis of natural anticoagulants protein C and S (both are vit k dependent)
• does not inhibit activity of existing clotting factors
• interferes with other vit k dependent proteins in bone, cartilage... etc (can lead to osteoporosis)

factors II, VII, IX, and X

• require gamma carboxylation of their precursors to produce their procoagulant effect
• vit k antagonists ↓ the levels of these clotting factors   

not established until catabolism of existing clotting factors and replacement with newly synthesized dysfunctional clotting factors occurs

• warfarin does not inhibit activity of existing clotting factors

decreases both thrombotic (factors II, VII, IX, and X)and antithrombotic proteins (proteins C and S)

• net effect is still thrombotic 
• requires 5 days to take effect due to long t_1/2 of factors II and X, until enough fxnal factors are depleted
• levels of protein C and S are reduced before factors II and X, can cause a theoretical hypercoagulable state. Injectable immediate acting anticoagulant (UFH or LMWH) often required when immediate anticoagulation is needed
• do not give loading dose, this would cause more thrombosis

• This gene encodes vit k epoxide reductase, which is inhibited by warfarin
• pts with A haplotype may produce smaller amounts of VKORC1 (the warfarin target protein) than pts with B. 
  • reduced response
• This association is independent of CYP2C9 genotype

• bleeding 
• skin necrosis (rare, but can be life threatening)
• purple toe syndrome (rare)

• thrombosis of venules and capillaries within SC fat
• may be associated with protein C deficiency
• more common in middle aged, obese females

• warfarin ay induce formation of cholesterol micro-emboli with subsequent occlusion and infarction of dermal arterioles with concomitant cyanosis

Drugs that cause ↑ in INR: 

Sulfamethoxazole-trimethoprim (Bactrim), amiodarone, metronidazole

Drugs that cause ↓ in INR:

Nafcillin, carbamazepine, Babiturates

international normalized ratio (INR)

• adjusts the PTT according to reagent sensitivity. 
• for most indication s therapeutic INR = 2-3
• the higher the INR the thinner the blood
• therapeutic INR reached in 5 days
• true steady state in 12-14 days

• vit k containing foods may antagonize the effects of warfarin. Pts need to maintain consistent daily intake of these foods
• enteral supplements (feeding tube) contain soy protein which binds to warfarin in the gut and prevents its absorption. Separate by at least 4 hrs

• ↑ INR
• liver dysfunction
• Hyperthyrodism
• Protracted diarrhea (↓ vit K production due to vit k producing bacteria being flushed out of the system)
• HF
• acute infections

• ↓ INR
• Hypothyroidsm 
• short gut syndrome

• dose not well correlated to weight
• no loading dose necessary
• dose based on age, drug interactions, diet, disease states, and genetics
• small weekly dosage adjustments of 5-15% are adequate for most pts

• for immediate reversal use fresh frozen plasma (contains all clotting plasma)
• vit k₁ is otherwise used. Route of Vit k₁ admin determines onset of action
  • IVPB (over 30 min) = 8 hrs
  • PO = 24 hrs
  • SC = up to 72 (but has erratic and delayed absorption, not used)

• acts as plasminogen activators and catalyze plasminogen to plasmin conversion, which in turn cleaves fibrin (all other agents only prevent extension of a clot)
• used to lyse already-formed clots, and thereby to restore patency of an obstructed vessel before distal tissue necrosis occurs

• alteplase (activase)
• peteplase (retevase)
• Tenecteplase (TNKase)

• ST segment elevation myocardial infarction (STEMI)
• Stroke (alteplase only)
• Pulmonary embolism (alteplase only)
• acute atrial occlusions (low dose intra-arterially)
• catheter clearance (or IV line clearance)

• Intracranial disease
• uncontrolled hypertension
• major surgery or trauma

1. cyclooxygenase inhibitors
2. adenosine Diphosphate (ADP) receptor antagonists
3. GP IIb-IIa inhibitors

• irreversible inhibition of platelet cyclooxygenase (COX) 
• this enzyme inhibition blocks the formation of thromboxane A₂ from arachidonic acid and reduces platelet aggregation

• one of the end products of the arachidonic acid pathway (arach. acid → →thromboxane A₂ via cyclooxygenase 1 and thromboxane synthase)
• Promotes platelet aggregation (its inhibition prevents clot formation)

• Anti-platelet: irreversibly inhibit platelet TXA₂ production, therefore inhibits platelet aggregation for the life span of platelets (7-10 days). Platelets lack capability to synthesize new proteins (e.g. COX enzyme)
• Anti-inflammatory: irreversibly inhibits COX activity 
• Analgesic: inhibits pain stimulation at subcortical level. May be used for mild to moderate pain, but safer agents available
• Antipyretic: Effective, but safer agents available
• better agents available for last 3 indications

Practical applications of aspairn

• recently identified and presents as recurrent ischemic events
• Possible causes:
  • aspirin-NSAID interaction (compete for binding)
  • genetic polymorphism rendered COX-1 less sensitive to aspirin
  • alternate pathways of TXA₂ synthesis
  • poor pt compliance
• any possible concomitant NDAIS therapy must be discontinued. A higher aspirin dose may be necessary

• most common: GI intolerance, bleeding or ulcers

mech of action of ADP receptor antagonists

Clopidogrel

• irreversibly blocks ADP receptor P2Y₁₂ on platelets - inhibits aggregation by blocking glycoprotein IIb/IIIa pathway

• pro-drug
• mainly by CYP3A4 and CYP 2C19
• polymorphism of CYP2C19*2 is possible and leads to non-responsiveness (higher cardiovascular death, nonfatal myocardial infarction and urgent revascularization)
• 2-3% caucasian and african american pts
• 10-15% asian pts

slower than ASA

can be avanced by giving a loading dose:

300mg ≥ 6 hrs

600 mg = 2 hrs

900 mg = 2 hrs

give 600 mg

Proton pump inhibitors (PPI): inhibit CYP2C19 hepatic enzyme, which is involved in bioactivation of clopidogrel

do not give together

1. genetic factors (polymorphisms)
2. Clinical factors (absorption, drug-drug interactions)
3. Cellular factors

• ADP receptor antagonist
• a pro-drug
• rapid oral absorption
• greater anti-platelet effect than clopidogrel (not as many confounding factors)
• metabolized by CYP3A4

• Very potent IV antiplatelet drugs
• blocks binding of fibrinogen to IIb/IIIa receptor on activated platelets
• used in catheterization lab for percutaneous coronary interventions

• bleeding (1-4%) higher than other agents
• Thrombocytopenia (3-5%) higher risk with abciximab than others