4. Drugs Affecting Coagulation

Answer 1

The process of coagulation ends with a haemostatic plug that forms following platelet activation

subsequently reinforced by fibrin
This final step involves the conversion of soluble fibrinogen to insoluble strands of fibrin

reaction catalysed by thrombin.

Thrombin (factor IIa) is one of several important serine proteases
that are present in the coagulation cascade,

and is formed from prothrombin (factor II) in the presence of activated factor X

Both coagulation pathways activate factor X, which,
as Xa (the suffix ‘a’ denotes ‘active’), converts prothrombin to thrombin.

Question 2

The newer model of coagulation

Answer 2

The newer model of coagulation suggests

that thrombin is generated initially by the extrinsic pathway

in a process that involves the activation
of factors IX and X by a tissue factor-factor VIIa
->forms in response to damaged vascular endothelium.

Factor Xa binds with prothrombin (factor II) to form thrombin (factor IIa).

Thrombin + positive feedback = thrombin activates factors V and VIII
activate factor IX (to IXa) and X (to Xa) with the generation of more thrombin (IIa).

Enzyme complexes, such as prothrombinase
further activate platelets and accelerate continued thrombin formation

factor XIII (fibrin stabilizing factor) links fibrin polymers via covalent
bonds, while thrombin itself activates an inhibitor of fibrinolysis.

Question 3

EX + In

Answer 3

the two classically described pathways are the
‘intrinsic’, or contact, pathway, all of whose components are present within blood,

and the ‘extrinsic’ pathway, in which some components are found outside blood.

The intrinsic system is triggered by contact with exposed
collagen in endothelium, and the extrinsic system is activated by the release of tissue
thromboplastin.

he pathways converge on the activation of factor X. The protein
coagulation factors are present in blood as inactive precursors, which are then
activated by proteolysis, particularly of serine moieties. The cascade is amplified,
with each step producing greater quantities of activated clotting factors than the one
preceding it. The process in health is held in check by antithrombin III, which
neutralizes all the serine proteases involved in the cascade.

Question 4

Drugs Affecting Coagulation

Warfarin

Answer 4

warfarin is a competitive inhibitor of vitamin K reductase, and so prevents
the regeneration of the reduced active form and the addition of the essential carboxyl
moiety to the four coagulation factors

coumarins

The elimination half-life
of factor VII is only 6 hours, whereas that of factor II is 60 hours (the t½ of factors IX
and X are 24 and 40 hours, respectively). The effect of warfarin on the prothrombin
time (or international normalized ratio, [INR]) starts at 12–16 hours and lasts for
4–5 days

is metabolized by the hepatic mixed function oxidase P450 system, and
there are a number of drugs which can interfere with its metabolism

potentiated by agents that inhibit hepatic drug metabolism
- cimetidine, metronidazole and amiodarone

attenuated by dietary
vitamin K and by drugs such as barbiturates and carbamazepine which induce
hepatic cytochrome P450.

Question 5

Heparins

Answer 5

Heparins:

heparin is not a single homogenous substance. Heparins are a family of
sulphated glycosaminoglycans

Heparin fragments, low-molecula rweight heparins (LMWHs), are much more commonly used than unfractionated preparations.

Heparins inhibit coagulation by potentiating the action of antithrombin III (ATIII).

ATIII inactivates thrombin and other serine proteases by binding to
the active serine site and so inhibits factors II, IX, X, XI and XII

The larger molecules of unfractionated heparin bind both to the enzyme
and to the inhibitor, but the smaller LMWHs such as tinzaparin, dalteparin and
enoxaparin increase the action of ATIII only on factor Xa.

The in vitro effect of
unfractionated heparin is measured by the APTT, which is not prolonged by
LMWHs.)

Question 6

Antiplatelet Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs)

Answer 6

Aspirin (acetyl salicylic acid) is the original example of this class of drug.

Aspirin and the non-selective COX inhibitors such as diclofenac and ibuprofen inactivate the enzyme cyclo-oxygenase (COX) by binding to COX-1

Aspirin binds irreversibly; the others exhibit competitive antagonism which is reversible.

Platelet synthesis of thromboxane (TXA2), which promotes platelet aggregation,
then falls.

TXA2 also reduces the synthesis of prostaglandin PGI2 (also known as epoprostenol or prostacyclin) in vascular endothelium.
This substance inhibits platelet aggregation

The persistent inhibition of platelet aggregation results from the fact
that vascular endothelium is able to synthesize new PGI2,

whereas platelets are unable to produce new TXA2

Question 7

Clopidogrel.

Answer 7

Clopidogrel.

This is a thienopyridine which binds covalently to the P2Y12 ADP
receptor on platelet cell membranes,

induces a conformational change which renders
it inactive and thereby prevents receptor-mediated platelet aggregation

Receptor blockade inhibits fibrin cross-linking by preventing activation of the glycoprotein IIb/IIIa pathway.

Clopidogrel acts within 2 hours of oral
administration, and its irreversible effects last for the lifetime of the platelet (usually
7–10 days).

Question 8

Ticagrelor

Answer 8

Ticagrelor. This is a nucleoside analogue which also blocks the P2Y12 ADP receptor
but at a site separate from that of ADP agonism.

Unlike clopidogrel therefore it is a
reversible allosteric antagonist.

Question 9

Aspirin

Answer 9

Aspirin (acetyl salicylic acid).

The effect of aspirin is dose-dependent.

At the commonly prescribed low dose of 75 mg daily,
the drug acetylates serine residues
on COX-1 in a reaction that is irreversible.

This inhibition blocks the generation by
platelets of thromboxane A2 with a consequent reduction in thrombocyte aggregation
and a prolongation of bleeding time.

650 mg daily,
aspirin also blocks COX-2, which thereby mediates its anti-inflammatory, antipyretic
and analgesic effects.

Question 10

Abciximab.

Answer 10

Abciximab.
This is a monoclonal antibody and specific GPIIb/IIa receptor antagonist

which inhibits all pathways of platelet activation.

It is given by infusion and has a long duration of action,

which means that platelet function will not be restored until
at least 12 hours after discontinuing the infusion. It provokes an antibody response
so repeated administration is not possible.

Question 11

Direct oral anticoagulants (DOACs):

Answer 11

does not depend on other proteins but rather target a specific molecule.

Compared with warfarin, the DOACs have a more rapid onset and
offset of action with more predictable anticoagulation profiles. There are two main
classes of DOAC: activated thrombin inhibitors and activated factor X inhibitors

Question 12

Direct Thrombin Inhibitors: (Anti-Activated Factor II Inhibitors, Anti-FIIa)

Answer 12

Dabigatran.

This a direct thrombin inhibitor whose effects peaks at 2–3 hours with
an elimination half-life of 12–14 hours. It is unusual in that it has a specific reversal
agent in the form of idarucizimab,

which is a monoclonal antibody that restores coagulation to normal within minutes.

Bivalirudin. This is an analogue of hirudin (a natural anticoagulant peptide found in
the salivary glands of leeches). Bivalirudin is a synthetic 20 residue peptide which is
an irreversible thrombin inhibitor. It is an intravenous preparation

Question 13

Activated Factor X Inhibitors (Anti-FXa)

Answer 13

Rivaroxaban, apixaban.
These are examples of orally active direct factor Xa inhibitors.

The peak effect of
rivaroxaban is at 4 hours,
and as factor Xa activity takes
24 hours to normalize, the drug can be given once daily.

Apixaban has a similarly selective,
reversible direct action on factor Xa
but needs twice daily dosing.

Question 14

Fondaparinux

Answer 14

Fondaparinux.

This is a synthetic pentasaccharide that is chemically similar to
heparins and which binds to the same high-affinity binding sites on antithrombin
III (ATIII) to potentiate its effect on activated factor X.

The drug is given subcutaneously.

Question 15

Approach to a Surgical Patient Who Is Receiving Anticoagulants

Warfarin

Answer 15

this will need to be adapted according to the specific
clinical situation, but before elective surgery

warfarin is usually stopped 4–5 days preoperatively.

If the INR remains unacceptably high, then the patient should be
given vitamin K (1.0 mg intravenously) and fresh frozen plasma (FFP; 15 ml kg−1).

After minor surgery, the warfarin can be resumed on the first postoperative day.

After major surgery, anticoagulation should be maintained by heparin infusion
(typically at a rate of 1,000–2,000 units h−1) or by subcutaneous low-molecularweight
heparin (LMWH).

If necessary, the actions of heparin can be reversed by protamine (1 mg for every 100 units of heparin), whose positive charge neutralizes the negatively charged heparin.

Question 16

Vitamin k

Answer 16

Vitamin K:
clotting factors II, VII, IX and X are glycoproteins which contain glutamic acid.

Reduced vitamin K (named from the German word ‘Koagulation’) acts as
an essential co-factor in this hepatic γ-carboxylation reaction, during which vitamin
K is oxidized from the reduced active hydroquinone form to the inactive 2,3-epoxide.
In the presence of vitamin K reductase, this process is then reversed.

Question 17

Bridging

Answer 17

70-year-old man requires inguinal hernia repair. He is on
long-term warfarin for atrial fibrillation with an INR of 2.8. Plan: aim for an INR
<2.0. Stop warfarin without substituting another anticoagulant and restart normal
dose after surgery. There is no need for bridging anti-coagulation in these patients.

Sample scenario (2): a 65-year-old man requires colonic resection. After mechanical
mitral valve replacement, his INR has been kept between 3.0 and 4.0. Plan: stop
warfarin early enough to allow the INR to fall below 2.0, and follow one of two main
options. (1) Heparin: infuse intravenous heparin to maintain activated partial
thromboplastin time (APTT) at 1.5–2.5, stop 2 hours prior to surgery and then
restart 6 hours postoperatively. Restart warfarin as soon as oral intake is restored
(2)
LMWH: for example, tinzaparin 100 units kg−1 daily, increasing to 175 units kg−1
postoperatively

Question 18

surgery is urgent

Answer 18

If surgery is urgent, then a high INR should be reduced by FFP and
vitamin K and possibly by prothrombin complex concentrate (PCC). Restart warfarin
as soon as oral intake is restored.

Question 19

FFP and PCC

Answer 19

FFP and PCC.

FFP does not contain sufficient quantities of the
vitamin K–dependent clotting factors
for complete reversal of warfarin-induced bleeding,

although it does reduce the INR.

Prothrombin complex concentrate (PCC, Beriplex)
contains factors II, VII, IX and X and in a dose of 25–50 units kg−1

will correct such acquired coagulation factor deficiencies within 1 hour. A single treatment for a 70 kg patient costs around £550

Question 20

Surgery:

Answer 20

Surgery:
neurosurgery requires normal coagulation;

cataract surgery may be performed safely with an INR of up to 2.5.

Some surgeons will sometimes undertake
emergency procedures such as hemiarthroplasty in patients whose INR is similarly
high.

They do so because clinical experience suggests that, contrary to expectation,
blood loss under these circumstances is not excessive. Many surgeons would be
prepared to perform routine surgery such as day-case arthroscopy on a patient with
an INR of 2.0.

Question 21

Spinals, Epidurals and Antithrombotic Drug Treatment

Answer 21

Incidence. The third National Audit Project (NAP) of the Royal College of Anaesthetists
(Br J Anaesth 2009, 102: 179–90), which examined major complications of
neuraxial blockade, identified eight cases of vertebral canal haematoma, all of which
were associated with epidural analgesia. Seven out of those eight had received
antithrombotic drugs. NAP 3 estimated an incidence of permanent harm of 1 in
20,000 epidurals and 1 in 140,000 subarachnoid (spinal) blocks.

Question 22

‘Safe’ intervals

Heparins

Clopi
Aspirin

Warfarin

Answer 22

UFH 4hours if prophylacis - check aptt

LMWHs (prophylactic) 12 hr 2–4 hr

LMWHs (treatment) 24 hr 2–4 hr

Clopidogrel 7 days No delay needed

Aspirin None No delay needed

Coumarins (e.g. warfarin) INR <1.4 No delay needed

Question 23

DOAC

Answer 23

Rivaroxaban 24 hr 2–4 hr

Apixaban 24h wait 2-4h

Dabigatran - prev C/I AoA 96-120h

Fondaparinux 36 hr 6–12 hr

Ticagrelor 72 hr No delay needed

Bivalirudin 10 hr 2–4 hr

Question 24

Vascular surgery.

Answer 24

Vascular surgery. One special circumstance is in vascular surgery during which
some anaesthetists are nervous about siting an epidural catheter in patients who may
receive large doses of intravenous unfractionated heparin intraoperatively. There is
no prospective evidence which attests to the safety of this practice, but observational
studies in large numbers of patients (3,000) have found no increased incidence of
epidural haematoma formation.

Question 25

Aspirin and clopidogrel.

Answer 25

Aspirin and clopidogrel. Both drugs have an irreversible action of platelet function
so it seems curious that a 7-day interval is recommended between the administration
of clopidogrel and neuraxial block, whereas no interval at all is mandated for aspirin.
The reasons are unclear but are likely to be the result of several large studies, such as
the CLASP study which suggests that aspirin is safe in this regard

Clopidogrel in a dose of 75 mg daily shows between 40% and 60% inhibition at
steady state, but the data sheet makes no mention of contraindications to neuraxial
blockade. It is, however, a more potent inhibitor of platelet function than aspirin, and
the prohibition seems to be based on the pharmacokinetics of the drug together with
the fact that there are no studies as yet which support its safety in the context of
neuraxial anaesthesia

Question 26

Regional anaesthesia.

Answer 26

Regional anaesthesia. There are no firm recommendations published in respect of
regional blockade and concurrent antithrombotic treatment, mainly because of the
heterogeneity of blocks that are performed. Each must be considered on an individual
risk/benefit basis. Most major nerve plexuses are in relatively close association
with major vessels such as the femoral, popliteal, subclavian or axillary arteries. The
routine use of ultrasound however, makes inadvertent vascular puncture a rare event,
and the consequences are likely to be much less severe than haemorrhage into the
vertebral canal.

Question 27

BJA Ed Key points

Answer 27

Vertebral canal haematoma is a rare, potentially devastating complication of neuraxial anaesthesia. The risk is higher in patients who are anticoagulated.
*
Major bleeding in peripheral nerve blocks can also have serious sequelae.

These guidelines and a recent expert consensus opinion describe the principles underlying risk/benefit decisions in peripheral nerve blocks in anticoagulated patients.
*
Separate guidance exists for patients with acute hip fractures, patients who are pregnant, and patients with chronic pain.

Question 28

Hip #

Answer 28

recognised that 30–40% of patients with hip fractures take anticoagulant medications, VCH is an extremely rare complication and that the elevated risk in a patient who is anticoagulated is unquantifiable but likely small

For those taking DOACs, it suggests waiting for at least two drug half-lives before proceeding with surgery. Accordingly, spinal anaesthesia is acceptable 24 h after the last ingested dose of a Xa inhibitor (e.g. apixaban and rivaroxaban), provided that the measured creatinine clearance is >30 ml min−

dabigatran, the guidance recommends that the patient should be listed for surgery on the afternoon of the day after the last ingested dose. Thrombin time should be measured at 0800 on the day of surgery, and, if normal, it is acceptable to proceed to surgery under spinal anaesthesia or GA. If thrombin time is prolonged, the guideline recommends contacting haematology and considering reversal with idarucizumab

Question 29

Venous Thromboembolism (VTE) Prophylaxis

Answer 29

Risk factors for VTE: the long list
includes age (exponential increase);

pregnancy (which as a hypercoagulable state increases risk 5);

obesity (3 increase in risk if BMI exceeds 30);

previous positive history;

congenital thrombophilic states such as protein C deficiency,
or factor V Leiden;

thrombotic states such as

malignancy (7 increase) and heart failure;
immobility (hence the importance of thromboprophylaxis
in critical care); and hormone therapy, including HRT, the oral contraceptive
and oestrogen-receptor antagonists such as tamoxifen.

Trauma surgery, and lower limb and pelvic surgery also increase risk.

Question 30

Prevention

Answer 30

Prevention: these conditions should be tailored to likely risk to include early
mobilization, hydration (to minimize haemoconcentration and improve blood
rheology), graduated elastic compression stockings, intermittent pneumatic
compression devices and pharmacological intervention, usually in the form of
low-molecular-weight or unfractionated heparins