Alternatives To Heparin For

Low Molecular Weight Heparins (LMWHS)

A new class of anticoagulants widely used in Europe with few approved in North America. They are fragments of heparin produced by chemical or enzymatic depolymerization of standard heparin.

Unlike standard heparin, LMWHs are unable to bind thrombin (Ila) and anti-thrombin III (ATIII) simultaneously so they cannot accelerate the inactivation of Ila, but do inhibit Xa activity. The anti-Xa/anti-IIa ratio of LMWHs ranges from 2:1-4:1 and are based on in vitro testing that may not reflect in vivo anticoagulant activity.

Largely due to LMWH's inability to bind to plasma proteins or endothelial cells, these molecules have excellent bioavailability, increased biological half life and can be administered 1-2 times per day. Current approved indications are DVT prophylaxis/treatment and hemodialysis.

Monitoring may be difficult as at prophylactic doses there is no effect on standard clotting tests and anti-factor Xa levels do not necessarily correlate with thera-

Table 13.2. Alternative anticoagulants to heparin

Drug

Source

Chemical Structure

Mechanisms of action

Cross-reactivity with heparin antibodies porcine and bovine glycosaminoglycans: inhibits factor Xa mucosa extract; mean MW 4-6.5 kDa > thrombin

Heparinoid

Ancrod synthetic porcine mucosa extract mixture of heparan, dermatan and chondroitin sulfates Malayan pit viper "thrombin like" venom extract enzyme

Argatroban synthetic Hirudin leech salivary gland extract arginine analog 66 amino acid polypeptide inhibits factor Xa > thrombin proteolysis of fibrinogen thrombin active site inhibitor thrombin active site inhibitor yes : 90% yes: 10%

no no

Hirulog Iloprost Aspirin synthetic synthetic synthetic hirudin derived peptide thrombin active site inhibitor prostacyclin analog adenylyl cyclase activator acetylsalicylic acid cyclo-oxygenase inhibitor

LMWH

no no no peutic efficacy. Protamine will neutralize anti-IIa effect (90%) but only 60-70% of Xa activity. Clotting factors are of no use.

There is a > 90% cross reactivity with heparin induced antibody. While there are a number of different manufacturers of LMWHs, there is little evidence that their clinical efficacy is significantly different if dosed appropriately.

A patient for AVR was administered Enoxaparin 20 mg i.v. into the prime, 150 mg postaortic/atrial cannulation and 70 mg i.v. bolus 60 minutes later. CPB was initiated 15 minutes after the 150 mg i.v. bolus and lasted 110 minutes. Factor Xa levels intraoperatively were between 0.84-0.92. Postoperative blood loss totaled 2500 cc and the patient received additional protamine and desmopressin. At re-exploration oozing from the aortic suture line was noted and treated with local Tissel. The patient received a total of 5 units PRBC, 4 units FFP and 7 units platelets.

A patient undergoing a redo MVR was administered Tedelparin. The patient received 10,000 IU Sc q12h preop (Xa levels 0.2-0.4 IU/ml) then 10,000 IU i.v. intraoperatively with an additional 5,000 IU in the prime. The CPB time was 90 minutes and uneventful. The patient received protamine 50 mg i.v. and no blood products.

Danaproid Sodium (Orgaran)

Is a mixture of low molecular weight (6000 daltons) sulfated glycosaminogly-cans derived from porcine intestinal mucosa but devoid of heparin and heparin fragments.

Consists of (a) heparin sulfate with low affinity for ATIII (80%), (b) heparin sulfate with high affinity for ATIII (4%), (c) dermatan sulfate (8-16%) (d) chon-droitin sulfate (< 8.5%).

Acts by inhibiting factor Xa and to a lesser extent IIa (ratio 20:1) using ATIII. There is minimal or no effect on platelets. The elimination T1/2 of anti-Xa activity is 25 h but IIa activity is 7 h. It is predominantly excreted as inactive Xa/ATIII complex by the kidneys and is not removed by dialysis. No simple way to reverse its action except time as it is only partially neutralized by protamine. There is < 10% cross reactivity with heparin induced antibody.

Table 13.3. Commercially available LMWHs (* in Canada)

Generic

Trade

Producer

Antifactor

Mean Saccharide

Plasma

Xa/IIa ratio

MW

units

half life

(range)

(min)

Enoxaparin*

Lovenox

Rhone Poulenc

2.7:1

4500 (3k-8k)

10-27

129-180

Dalteparin*

Fragmin

Kabi Pharm.

2.0:1

5000 (2k-9k)

7-30

119-139

Nadroparin

Fraxiparin

Sanofi-Winthrop

3.2:1

4500 (2k-8k)

7-27

132-162

Tinzaparin*

Logiparin

Novopharm

1.9:1

4500 (3k-6k)

10-20

111

Ardeparin

Normoflo

Wyeth-Ayerst

2.0:1

6000 (2k-15k)

7-50

200

ORG 10172

Lomoparin

Organon***

20:1

6500

1100

*** not LMWH but Danaproid

Dosing recommendations for cardiac surgery are as follows:

1. 125 U/kg iv bolus post thoracotomy

2. 2 U/ml in priming fluid of pump

3. 7 U/kg/hr iv infusion on CPB

4. if clotting noted additional bolus 1250 U

A report on 230 patients treated with Orgaran briefly mentioned 10 patients who underwent ACB. Their regimen included a bolus of 8750 units and adding 7500 U into the pump as well as running an infusion of 1500 U/hr during the CPB run. Antifactor Xa levels were monitored. The only comment is higher then normal bleeding.

A report on 47 patients receiving various dosing regimens showed 45 of 47 successfully completing CPB while 2 were abandoned intraoperatively. Complications included 18 of 45 (40%) patients demonstrating intraoperative clotting requiring additional booster injections of Orgaran, and increased postoperative bleeding which required exploration in 17 of 45 (37%) patients.

Ancrod (Arvin)

Thrombin like enzyme (proteinase) obtained from the venom of the Malayan pit viper that is highly specific for fibrinogen, producing anticoagulation by defibrinogenation. Enzymatically cleaves fibrinogen to split off A fibrinopeptides resulting in small fibrin polymers which are unstable and do not cross link to form thrombin. They are markedly susceptible to digestion by plasmin. It stimulates release of plasminogen activator from endothelium. There are no direct platelet effects but FDP inhibits platelet aggregation.

Require initial loading dose (1-2 U/kg) over 8-12 h followed by maintenance (0.5 -1.0 U/kg/24 h). Rapid defibrinogenation may overwhelm the RES and paradoxically cause a hypercoagulable state.

There is a changing rate of metabolism that depends on removal by the RES. Initially rapid elimination (T1/2 3-5 h for first few hours) but longer T1/2 as concentration decreases (90% of Ancrod is cleared by 4 days). Monitor with fibrinogen levels: therapeutic 0.2-0.7 g/L. Fibrinogen levels usually return to normal within 24 h of stopping drug. Reversal with cryoprecipitate, but long T1/2 of drug.

Ancrod was used in 20 patients for CABG. Patients received an infusion of 8.4 U/hr x 12 h with fibrinogen levels checked q 4 h. Once the target fibrinogen level of 0.4-0.8 g/L was reached the infusion was stopped, if fibrinogen > 0.8 gm/L the infusion was restarted at 2.1 U/h. The average total Ancrod dose requirement was 1.65 ± 0.55 U/kg. Patients had uneventful CPB runs, with an average time of 92 minutes. Perioperative blood loss and blood product requirements were higher compared with a control group of 20 patients.

Though successful, drawbacks exist as ancrod has to be administered over at least 6 h and serial fibrinogen levels followed. The duration of action is difficult to predict and is prolonged in patients with renal dysfunction. Despite an antidote being commercially available, ancrod is not easily reversible though cryoprecipi-tate will increase fibrinogen levels. Postoperative bleeding is likely to be higher and the role of autotransfusion is poorly defined. Finally and most disturbing is

that despite an adequately defibrinogenated patient (level 0.2-0.4 g/L) one patient receiving ancrod at this institution clotted off the pump.

Hirudin

Anticoagulant from medicinal leeches that acts as a direct anti-thrombin. Currently available as recombinant DNA (disulphatohirudins) or synthetic hirudin analog peptides (hirulogs). Unlike heparin, acts by binding tightly to formed thrombin independent of AT III cofactor. Prevents fibrinogen clotting and activation of V, VIII, XIII and platelets thus minimizing further thrombin formation. Renal elimination with short T1/2 therefore no need to reverse. There is no antidote though it is hemofiltered.

Trialled extensively in animal models. One patient for AVR with HIT received a bolus of 0.2 mg/kg followed by an infusion of 0.1 mg/kg to maintain a PTT between 60-80 sec (hirudin level 1-1.5 ug/ml). The patient was bolused 9 mg 10 minutes prior to CPB and 5 mg was added to the prime. Additional boluses were given through the pump run of 83 minutes. Chest tube losses were 240 cc and no thrombotic sequelae were noted.

Selected Readings

1. Chong BM. Annotation: Heparin induced thrombocytopenia. Br J of Hematology 1995; 89:431-439.

2. Slaughter TF, Greenberg CS. Heparin associated thrombocytopenia and thrombosis implications for perioperative management. Anesthesiology 1997; 87(3):667-675.

3. Zulys VJ, Teasdale SJ et al. Ancrod as an alternative to heparin anticoagulation for cardiopulmonary bypass. Anesthesiology 1989; 71(6):870-876.

4. Low molecular weight heparin: Biochemistry, pharmacology, perioperative prophylaxis regimens and guidelines for regional anesthetic management. Anesth Anal 1997; 85:874-885.

5. Magnani, Beijeng et al. Orgaran anticoagulation for cardiopulmonary bypass in patients with HIT. Chapter 31, Anticoagulants for the Cardiovascular Patient, Henley and Belfus (1997).

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