Total hip or knee replacement, DVT prophylaxis

Unfractionated heparin

Complete anticoagulation during cardiopulmonary bypass

Low-Dose SC heparin

Low molecular weight heparin (LMWH)

Oral anticoagulants (warfarin)

Antiplatelets medications

Effect of herbal therapies on coagulation

References

Regional Anesthesia in the anticoagulated patient

The American Society of Regional Anesthesia (ASRA) developed the 2^nd consensus statement on this topic in April 2002, which was published 2003. The statement focuses on anticoagulation and neuraxial blocks (spinal and epidural). The risk following plexus and peripheral techniques remains undefined.

Epidural hematoma is defined as a rare but potentially catastrophic complication of spinal or epidural anesthesia. Although, it can happen spontaneously, its incidence dramatically increased in the US after the introduction of low molecular weight heparin.

The following is a summary of pharmacological anticoagulation options for DVT prophylaxis and treatment, as well as treatment for acute coronary syndromes, according to the 2^nd consensus statement:

Total hip or knee replacement, DVT prophylaxis

Unfractionated heparin: 3,500 U SC q8 hours, started 2h prior to surgery. After surgery, dose adjusted to maintain the aPTT within the upper normal range.

Low molecular weight heparin:

Ardeparin sodium (Normiflow^®): 50 U/kg SC q 12h, started 12-24h after surgery

Dalteparin sodium (Fragmin^®): 5,000 U SC qd, started 12h before surgery, or

2,500 U SC 7h after surgery,

then 5,000 U SC qd

Danaparoid sodium (Orgaran^®): 750 U SC q 12h, started 2h before surgery

Enoxaparin sodium (Lovenox^®): 30 mg SC q 12h, started 12-24h after surgery, or

40 mg SC qd, started 10-12h before surgery

Tinzaparin (Innohep^®): 75U/kg SC qd, started 10-12h before surgery

Warfarin sodium: 5 m orally, started the night before, or

immediately after surgery.

Adjusted to prolong the INR = 2.0-3.0

General surgery, DVT prophylaxis

Unfractionated heparin: 5,000 U SC q8-12h, started 2h before surgery

Low molecular weight heparin:

Dalteparin sodium (Fragmin^®): 2,500 U SC qd, stated 1-2h before surgery

Enoxaparin sodium (Lovenox^®): 40 mg SC qd, started 2h before surgery

Acute Coronary Syndrome and DVT therapy

Enoxaparin sodium (Lovenox^®): 1 mg/kg SC q12h, (outpatient DVT and non q-wave MI)

1 mg/kg SC q12h, or 1.5 mg/kg SC qd (inpatient treatment of DVT or PE)

Dalteparin sodium (Fragmin^®): 120 U/kg q12h or 200 U/kg qd (non q-wave MI)

Tinzaparin (Innohep^®): 175 U/kg qd

The following is a summary of the 2002 ASRA guidelines adapted with permission from Neal JM: Neural Blockade and Anticoagulation. In: Regional Anesthesia, The Requisites in Anesthesiology. Rathmell J, Neal J, Viscomi C (eds). Philadelphia, Elsevier Mosby, 2004

Anticoagulant	ASRA guideline	Catheter removal	Evidence strength
LMWH	Single preop dose: Delay block 10-12 h. Postop single daily dosing: Delay block 6-8 h. Postop twice daily dosing: Delay block 24 h	Single daily dosing: Remove 10-12 h after last dose; Wait ≥ 2 h before next dose Twice daily dosing: Remove ≥ 2 h before first dose.	Pharmacokinetic data Large series of case reports
Standard heparin	SQ 5,000 U/first dose: Delay heparin for 1-2 h after block. IV/first dose: Delay 1 h after block. IV/continuous: discontinue 2-4 h. Check aPTT prior to block.	Discontinue heparin for 2-4 h Check aPTT prior to removal.	Pharmacokinetic data Prospective and retrospective case surveys and case reports
Warfarin	New dose: check INR if 1^st dose given >24 h before or if 2^nd dose given. Chronic use: discontinue for 4-5 days. Check INR	If used for > 36 h, remove with INR <1.5	Case series and case reports
Aspirin/NSAIDs/COX-2 inhibitors	No issues if patient is not taking other anticoagulants	No issues	Retrospective case surveys
Other antiplatelet agents	Discontinue for: Ticlopidine (Ticlid): 14 days Clopidogrel (Plavix): 7 days Eptifibatide/tirofiban: 8 hrs Abciximab: 48 hrs	No recommendation	Pharmacokinetic data
Thrombolytics/ Fibrinolytics	Avoid a block within 10 days of drug administration. Avoid giving the drugs for 10 days after the block. If block was received around the time drug given, check neurological status ≤ 2 h	No recommendation	Surgical recommendation
Fondaparinux (Arixtra)	Do not combine with neuraxial anesthesia	No recommendation	No data
Herbal supplements	No specific concerns	No issues	No data

I encourage you to read the 2002 consensus statement as published in Regional Anesthesia and Pain Medicine in May-June 2003. Some highlights are:

Fibrinolytic and thrombolytic therapy: plasmin originates from plasminogen and dissolves intravascular clots. Exogenous plasminogen activators, such as streptokinase and urokinase dissolve thrombus and affect circulating plasminogen. Endogenous t-PA formulations (alteplase and tenecteplase) are more fibrin-selective and have less effect on plasminogen. While the plasma half-life of thrombolytic drugs is only hours, it can take days for the thrombolytic effect to resolve; fibrinogen and plasminogen are maximally depressed at 5 hours after this therapy and remain significantly depressed at 27 hours. Contraindications to thrombolytic therapy include surgery or puncture of non-compressible vessels within 10 days.

Recommendation:

Patients on fibrinolytic and thrombolytic drugs should not receive spinal or epidural procedures. Data are not available to recommend a precise number of days. Ten days has been the usual recommendation.

Unfractionated heparin: the major anticoagulant effect of heparin is due to binding with antithrombin (AT). This effect leads to inactivation of thrombin (factor IIa), factor Xa, and factor IXa. Intravenous injection results in immediate anticoagulant activity, whereas SC injection results in a 1 to 2 hour delay. The anticoagulant effect of heparin is typically monitored with aPTT. Administration of a small dose (5,000 U) SC heparin for prophylaxis of DVT generally does not prolong the aPTT, and is typically not monitored. It can result in unpredictable 10-fold variability and therapeutic blood concentrations in some patients within 2 hours after administration.

Intraoperative systemic heparinization: usually IV injection of 5 to 10,000 U.

Recommendation:

· Performance of neuraxial procedure at least 1 hour prior to administration of heparin.

· Bloody or difficult placement may increase risk, but there are no data to support mandatory cancellation of a case. Communication with the surgeon plus risk-benefit decision about proceeding is warranted.

· Heparinization into the postoperative may be continued and the risk of bleeding may be increased and so is the risk of spinal hematomas in the presence of a catheter (increased risk at removal).

· Indwelling neuraxial catheters should be removed 2 to 4 hours after the last heparin dose. Evaluation of the patient’s coagulation status should be assessed before manipulation. Re heparinization should occur not before 1 hour after catheter removal

· Avoid neuraxial block in patients with other coagulopathies.

· Monitor the patient postoperatively for at least 12 hours

Complete anticoagulation during cardiopulmonary bypass: To date there are no cases of spinal hematomas associated with cardiopulmonary bypass. A review has recommended the following precautions:

· Avoid neuraxial blocks in patients with known coagulopathy of any cause

· Delay surgery for 24 hours in the event of a traumatic tap.

· Perform procedure at least 1 hour prior to systemic heparinization.

· Tightly control heparin doses and reversal doses to shortest duration compatible with desired effect

· Remove epidural catheter when normal coagulation is restored

· Closely monitor patients postoperatively for signs and symptoms of spinal hematomas.

Low-Dose SC heparin: commonly used for DVT prophylaxis in general and urologic surgery. A dose of 5,000 U of heparin every 12 hours has been used effectively. There is often no detectable change in aPTT. Small percentage of patients (2-4%) may become therapeutically anticoagulated during SC heparin therapy. There is extensive experience in the US and Europe without complications. There are only 4 case reports of neuraxial hematomas in concomitance to the use of SC heparin.

Recommendation:

· Performance of neuraxial block before the injection of SC heparin may be preferable, although

· There does not appear to be an increased risk of bleeding in the presence of SC heparin. The risk may be increased in debilitated patients after prolonged therapy.

Low molecular weight heparin (LMWH): The biochemical and pharmacological properties of LMWH differ from those of unfractionated heparin. Most relevant are: no measured effect on anti-Xa level, prolonged half-life and non-reversibility with protamine. Since the introduction of LMWH in the United States in 1993 over 40 spinal hematomas were reported in association with its use over a 5-year period. This is in contrast with the European experience of only 13 spinal hematomas reported over a decade of extensive use. It should be noted that European dosing of LMWH is once daily, with the first dose administered 10 to 12 hours preoperatively.

Recommendation:

· On patients receiving preoperative LMWH needle placement should occur at least 12 hr after last dose or 24 hr with higher doses

· Avoid neuraxial blocks in those patients receiving a dose of LMWH 2 hr preoperatively because needle placement would occur at peak anticoagulant activity.

· First dose of postoperative LMWH should be administered no earlier than 24 hr after the neuraxial procedure.

· Catheters should be removed prior to initiation of LMWH and first dose administered 2 hr after catheter removal

· If patient has been receiving a single daily dose catheter can be safely maintained. However it should be removed a minimum of 12 hr after the last dose and the subsequent dose a minimum of 2 hr after catheter removal.

6. Oral anticoagulants (warfarin): They interfere with the synthesis of vitamin K-dependent clotting factors: II (thrombin), VII, IX, X. The effects of warfarin are not apparent until a significant amount of biologically inactive factors are accumulated and is dependent on factor half-life:

· Factor VII: 6 to 8 hr

· Factor IX: 24 hr

· Factor X: 25 to 60 hr

· Factor 2: 50 to 80 hr

Factor activity level of 40% for each factor is adequate for normal hemostasis.

The PT and INR are most sensitive to the activities of factors VII and X and are relatively insensitive to factor II.

Because factor VII has a short half-life prolongation of PT and INR may occur in 24 to 36 hr. Prolongation of the INR (More than 1.2) occurs when factor VII is down to 55% of baseline, while an INR of 1.5 is associated with factor VII activity of 40%. Thus an INR of more than 1.5 should be associated with normal hemostasis.

Upon discontinuation of warfarin factor VII activity will rapidly increase and the INR will decrease. However factor II and X recover much more slowly, thus hemostasis may not be adequate even though the INR is 1.4 or less. Adequate levels of all vitamin K-dependent factors are typically present when the INR is less than 1.2.

In emergency situations the effect of warfarin can be reversed by vitamin K injection and/or transfusion of fresh frozen plasma.

Recommendation:

· Do not perform neuraxial blocks on patients who have been on chronic warfarin therapy.

· Caution should be exercised when patients have had their warfarin discontinued prior to surgery. Ideally 4 or 5 days should elapse and PT and INR should be measured prior to any neuraxial block. Remember that early after warfarin discontinuation the PT/INR reflects predominantly factor VII levels while the rest of factors activity is still inadequate. Wait until PT and INR are normal.

· Concurrent use of medications that affect other components of the clotting mechanism may increase the risk of bleeding and do so without affecting PT/INR (aspirin and other NSAIDs, ticlopidine and clopidogrel).

· Patients receiving one initial dose more than 24 hr prior to block should have PT/INR checked before proceeding.

· As thromboprophylaxis with warfarin is initiated with a catheter in place during low dose warfarin therapy, PT/INR should be checked daily and before catheter removal. The INR prior to removal should be less than 1.5.

· Continue neurological exams at least 24 hr after removal.

7. Antiplatelets medications: include:

· NSAIDs (aspirin, ibuprofen, others)

· Thienopyridine derivatives like ticlopidine (Ticlid) and clopidogrel (Plavix)

· Platelet GP IIb/IIIa receptor antagonists (abciximab, eptifibatide and tirofiban).

- NSAIDs inhibit platelet cyclooxygenase (COX) and prevent the synthesis of thromboxane A2. COX exists in 2 forms; COX-1 regulates constitutive mechanisms, while COX-2 mediates pain and inflammation (no effect on platelets). Platelet function is affected for the life of the platelet following aspirin; other nonsteroidals (naproxen, ibuprofen) have a short-term effect (3 days).

- COX-2 inhibitors like celecoxib (Celebrex) and rofecoxib (Vioxx) are anti-inflammatory agents that affect COX-2 an enzyme not present in platelets, and thus do not cause platelet dysfunction.

- The thienopyridine derivatives have antiplatelet effect from inhibition of ADP-induced platelet aggregation. These agents are used in the prevention of cerebrovascular thromboembolic events. Labeling recommends, “if a patient is to undergo elective surgery, and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days and ticlopidine 10-14 days prior to surgery.”

- Platelet GP IIb/IIIa receptor antagonists inhibit platelet aggregation by interfering with platelet-fibrinogen and platelet-von Willebrand factor binding. Time to normal platelet aggregation ranges from 8 hr (eptifibatide, tirofiban) to 24 to 48 hr (abciximab). Labeling precautions recommend that puncture of non-compressible sites and “epidural” be avoided.

Recommendation:

· Difficult to generalize because these drugs have different effects

· There is no accepted test to guide antiplatelet therapy.

· NSAIDs: their use alone does not seem to create a level of risk that will interfere with the performance of neuroaxial blocks.

At this time there is no specific concern as to the timing of single-shot or catheter techniques or the timing of catheter removal in conjunction with NSAIDs.

· Thyenopyridine derivatives: risk unknown. Follow labeling precautions: clopidogrel (Plavix) 7days and ticlopidine (Ticlid) 14 days.

· GP IIb/IIIa antagonists: risk unknown. Follow label precautions: 48 hr for abciximab and 4-8 hr for eptifibatide and tirofiban

· The concurrent use of other medications affecting clotting may increase the risk of bleeding complications.

8. Effect of herbal therapies on coagulation: The use of herbal medications is widespread in surgical patients.

· Garlic: inhibits platelet aggregation in a dose dependent fashion. Its effect appears to be irreversible and may potentiate the effect of other platelet inhibitors. There is one case of epidural hematoma in an octogenarian that was attributed to heavy garlic use.

· Ginkgo: Appears to inhibit platelet-activating factor (PAF). Four cases of spontaneous intracranial bleeding have been associated with ginkgo use.

· Ginseng: inhibit platelet aggregation in vitro and prolongs Thrombin time and activated partial thromboplastin time in rats. These findings need to be confirmed in humans. On the other hand it was associated to a significant decrease in warfarin anticoagulation in 1 reported case.

Recommendation:

· Herbal drugs by themselves appear to represent no added significant risk for spinal hematomas in neuraxial blocks.

· Mandatory discontinuation or cancellation of surgery is not supported by available data.

· Concurrent use of other medications affecting clotting may increase the risk of bleeding.

· No specific concern about timing of neuraxial catheter removal.

New Anticoagulants (Direct Thrombin Inhibitors and Fondaparinux), from ASRA website (January 2006):

New antithrombotic drugs which target various steps in the hemostatic system, are continually under development. The most extensively studied are antagonists of specific platelet receptors and direct thrombin inhibitors. Many of these agents have prolonged half-lives and are difficult to reverse without administration of blood components.

Thrombin inhibitors

Recombinant hirudin derivatives, including desirudin, lepirudin, and bivalirudin inhibit both free and clot-bound thrombin. Argatroban, an L-arginine derivative, has a similar mechanism of action. Although there are no case reports of spinal hematoma related to neuraxial anesthesia among patients who have received a thrombin inhibitor, spontaneous intracranial bleeding has been reported. Due to the lack of information available, no statement regarding risk assessment and patient management can be made. Identification of interventional cardiac and surgical risk factors associated with bleeding following invasive procedures may be helpful.

Fondaparinux

Fondaparinux produces its antithrombotic effect through factor Xa inhibition. The FDA released fondaparinux with a black box warning similar to that of the LMWHs and heparinoids. The actual risk of spinal hematoma with fondaparinux is unknown. Consensus statements are based on the sustained and irreversible antithrombotic effect, early postoperative dosing, and the spinal hematoma reported during initial clinical trials. Close monitoring of the surgical literature for risk factors associated with surgical bleeding may be helpful in risk assessment and patient management. Until further clinical experience is available, performance of neuraxial techniques should occur under conditions utilized in clinical trials (single needle pass, atraumatic needle placement, avoidance of indwelling neuraxial catheters). If this is not feasible, an alternate method of prophylaxis should be considered.

References

Neal JM: Neural Blockade and Anticoagulation. In: Regional Anesthesia, The Requisites in Anesthesiology. Rathmell J, Neal J, Viscomi C (eds). Philadelphia, Elsevier Mosby, 2004, pp 151-156
Bergqvist D, Wu CL, Neal JM. Anticoagulation and Neuraxial Regional Anesthesia: Perspectives. [Editorial] Reg Anesth Pain Med 2003; 28: 163-166
Horlocker tt, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: Defining the risks (The Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med, 2003; 28: 172-197