Anticoagulants and antiplatelet

Mechanism

Aspirin: See Antiinflammatory

Acetylsalicylic acid

Low-dose's irreversibly block the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8—9 days)

Thromboxane are responsible for the aggregation of platelets that form clots

Pharmacokinetic

About 50—80% of salicylate in the blood is bound to albumin, while the rest remains in the active, ionized state; protein binding is concentration-dependent
Half-life 20 min in circulating blood
Because platelets cannot generate new COX, the effects of aspirin last for the duration of the life of the platelet.
After a single dose of aspirin, platelet COX activity recovers by 10% per day in parallel with platelet turnover.
It has been shown that as few as 20% of the platelets have normal COX activity, haemostasis may be normal
Up to 28% are none responders to aspirin

Side effects

All of them cause water and sodium retention and potential nephrotoxicity.
Via IV route does not reduce gastrointestinal (GI) side effects;

Must be taken with meals

Clopidogrel

Uses

NICE recommended use in heart disease and stroke for disease prevention;
Following placement Of arterial stents (cardiac, intracranial) +1- aspirin

Clopidogrel is a prodrug, which is activated in two steps → The active metabolite then specifically and irreversibly inhibits the P2Y₁₂ subtype Of ADP receptor (important in activation Of platelets and eventual cross-linking by the protein fibrin)

Up to 10% are non responders

Pharmacokinetic

After a single, oral dose Of 75 mg, clopidogrel has a half-life Of approximately 6 hours.
It takes 5.5 x half-life of a medicine for it to be removed from one's system,

Therefore it be eliminated from a system in 5.5 x 6 = 33 hours
The active metabolite has an elimination half-life of about 0.5 to 1.0 h

Ticagrelor

Another P2Y₁₂ inhibitor

Uses

NICE recommended use in heart disease for disease prevention POST MI; or following placement of arterial stents (cardiac) usually with aspirin

In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible

The PLATO trail showed decreased mortality vs clopidogrel (9.8% vs. 11.7%, p<0.001) post cardiac event, but increased risk of bleeding (16.1% vs. 14.6%, p=0.0084)

While the patient group on ticagrelor had more instances of fatal intracranial bleeding, there were significantly fewer cases of fatal non-intracranial bleeding, leading to an overall neutral effect on fatal or life-threatening bleeding vs. clopidogrel (p=0.70)

The mean half-life is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.

Emergency neurosurgery

Aspirin

Due to it's active metabolites short half life, platelet transfusions will restore a volume of functioning platelets provided last dose was >1hour prior
No published proven benefit in emergency neurosurgery for patients actively on aspirin therapy receiving platelet transfusion
Theoretical benefit only, supported by published clinical trails that show restoration of platelet function with platelet transfusions in patients on aspirin therapy
Very widespread variation in practice UK wide
See Taylor et al 2013, Lee et al 2017

Ticagrelor

Due to its prolonged half-life, even at 18 hours post dose, 25% of its active metabolite will remain in the circulatory system
All platelets transfused will be immediately inhibited
An emergency surgical patient would require a continuous infusion in order to have potentially functioning platelets (case reports of 15+ units, limited efficacy)
Units of platelets given >24hrs following the most recent dose have a potential role in coagulation
See Bhatt et al 2019

Reversal agents for current drugs

Drug	Target	Reversal Agent(s)	Dose
Aspirin	Cyclooxygenase-1	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 1U • DDAVP 0.3 μg/kg slow IV q12h
Dipyridimole	Phosphodiesterase type 5	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 1U • DDAVP 0.3 μg/kg slow IV q12h
Cilostizol	Phosphodiesterase type 3	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 1U • DDAVP 0.3 μg/kg slow IV q12h
Clopidogrel	P2Y₁₂ receptor	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 2U • DDAVP 0.3 μg/kg slow IV q12h
Prasugrel	P2Y₁₂ receptor	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 2U • DDAVP 0.3 μg/kg slow IV q12h
Ticagrelor	P2Y₁₂ receptor	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 2U • DDAVP 0.3 μg/kg slow IV q12h
Abciximab	Glycoprotein IIbIIIa	• Platelet transfusion • Desmopressin (DDAVP)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 1U • DDAVP 0.3 μg/kg slow IV q12h
Eptifibatide	Glycoprotein IIbIIIa	• Platelet transfusion • Desmopressin (DDAVP) • Fresh frozen plasma (FFP) • Prothrombin complex concentrate (PCC)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 1U • DDAVP 0.3 μg/kg slow IV q12h • FFP 1U • PCC 50 IU/kg
Tirofiban	Glycoprotein IIbIIIa	• Platelet transfusion • Desmopressin (DDAVP) • Fresh frozen plasma (FFP) • Prothrombin complex concentrate (PCC)	• Apheresis or pool platelets (>3×10⁹ platelet/L) 1U • DDAVP 0.3 μg/kg slow IV q12h • FFP 1U • PCC 50 IU/kg
Heparin	IIa; Xa	• Protamine	• Protamine 1 mg IV per 100 U of heparin over last 4 h (max 50 mg)
Enoxaparin	Xa; IIa	• Protamine	• Protamine 1 mg IV per 1 mg LMWH (max 50 mg)
Fondaparinux	Direct Xa	• Prothrombin complex concentrate (PCC)	• PCC 50 IU/kg IV
Rivaroxaban	Direct Xa	• Prothrombin complex concentrate (PCC) • Andexanet alpha	• PCC 50 IU/kg IV • AA low dose: 400 mg IV bolus, 480 mg infusion • AA high dose: 800 mg IV bolus, 960 mg infusion
Apixaban	Direct Xa	• Prothrombin complex concentrate (PCC) • Andexanet alpha	• PCC 50 IU/kg IV • AA 400 mg IV bolus, 480 mg infusion
Edoxaban	Direct Xa	• Prothrombin complex concentrate (PCC) • Andexanet alpha	• PCC 50 IU/kg IV • AA 800 mg IV bolus, 960 mg infusion
Bivalirudin	Direct IIa	• None	—
Lepirudin	Direct IIa	• None	—
Desirudin	Direct IIa	• None	—
Dabigatran	Direct IIa	• Idarucizumab	• Idarucizumab 5 g IV bolus
Warfarin	II; VII; IX; X; protein C; protein S	• Vitamin K • Fresh frozen plasma (FFP) • Prothrombin complex concentrate (PCC)	• Vitamin K IV 1–2 mg or PO 2.5-10 mg q12h • Administer until corrected • PCC 25–50 IU/kg IV

DOAC’s with reversal agents

Dabigatran – reversal agent is Idarucizumab

If specific reversing agents are not available, activated prothrombin complex concentrates can be used for this (as well as FFP)

Dabigatran reversibly binds to thrombin molecules, inactivating them

Apixaban + Rivaroxaban – reversal agent is Andexanet Alfa

If specific reversing agents are not available, four-factor prothrombin complex concentrates can be used for these (as well as FFP)

These are Factor 10a inhibitors

Warfarin – four factor PCC’s first line, then FFP, Vitamin K takes minimum 6 hours

Andexanet

Given while knife to skin and will work for 2 hrs
Binds and sequesters factor Xa