CL- 110

john T. Owings, MD; F. William Blaisdell, MD

Obiectlvez To determine a rational approach to hepa-fin dosing for thromboembolism prophylaxis.

thromboplastin time to 5 seconds above the upper limit ofnom1al); and (3) low-molecular-weight heparin (30 mg sub-cutaneously twice daily without monitoring).

Design: Literature review.Concluslons: Adjusted-dose heparin thromboembo-lism prophylaxis is both the safest and most reliablemethod currently available.

Results: Three commonly used heparin dosing regimenswere identified: (1) standard low-dose heparin (5000 U ad-ministered subcutaneously 2-3 times per dar); (2) adjusted-dose heparin (adequate to eleva te the activated partial Arch Surg. 1996;131:1069-1073

LTHOUGH THE anticoagu-lant heparin was discov-ered by McLean in 19161and subsequently intro-duced into clinical prac-

tice by Murray et al in 1936; the nature of

heparin's actions and appropriate dosage stillremains unclear. Considerable contro-'versy exists regarding the advantages anddisadvantages of the various low-dose regi-mens now being advocated for thrombo-embolism prophylaxis. These include(1) the standard low-dose heparin regi-men, 5000 U of subcutaneous heparin 2 to3 times a daT,i; (2) adjusted-dose heparin,

sufficient subcutaneous or intravenous hep-arin to raise the activated partíal thrombo-plastin time (APTT) 2 to 5 secondsabovenormal5; and (3) low-molecular -weight hep-afÍn, 30 mg subcutaneously twice daily with-out monitoring.6-8 .

BACKGROUND

In 1939, Brinkhous9 demonstrated that the

anticoagulant activity ofheparin wasmark-edly augmented byá plaSma cofuctor. Thiscofactor was llamea aritithrombin 111 byAbildgaardin 1968.10 Jtis now understoodthat heparin,in nomial patients, potenti-ates the antithrombotic effects of antithrom-binllI and that heparin itself is only a weakantithrombin. i,7,Il Although antithrombin

III acts at multiple sites on the clotting cas-cacle, its primary mechanism of action is to

From the Department of

Surge')', UniversityofCalifornia, Davis, MedicalCenter, Sacramento, Calif

THE CONTROVERSY

10 1979, Wessler and Gitel,li experi-enced hematologists, expressed skepti-

neutraliZe activated factor X at the final com-mon pathway of coagulation.12 The re,cog-nition of heparin's ability to potentiate theaction ofantithrombin III suggested thatdoses of heparin lower than those usedtherapeutically might be efIective for throm-boemb6lism prophylaxis in surgical pa-.ti~n~ and carry less risk for hemorrhageth2n theconventional therapeutic doses., The international studies by Kakkar

'etaI4.13 of thromboembolism prophylaxisin hip surgery in 1975 gave credibility tothe use of low-dose heparin prophylaxisin surgical patients. In this series,. a double-blind randomized international trial inwhich more than 4000 patients were stud-ied, a placebo-treated control group wascompared with one in which 5000 Uofheparin was administered subcutane-ously twice daily, starting prior to sur-gery and continuing for 3 days postopera-tively. Sixteen patients in the control groupand 2 in the treated group died of pulmo-nary embolism; 32 patientsin thei controlgroup and 11 in the treátéd groupd~vél-.-.oped clinical evidence of deép .veirithrom-bosis (DVT). The incidencebf bleedingwas the same inboth groups...giVing cred-ibi1.ity to the argument that 10w dosagesof hepann were safe and effective.

cism regarding the universal benefit of low-dose hepa-fin and stated -

Despite conflictlDg claims.Iow-dose heparin regimens are pres-entIy beIieved to be oflimited vaIue in open prostatectomy, andmajar orthopedic procedures. especiaIly in repairs of femoralfractures and reconstrUctiye operations on the hip and knee.lnadequate data are available on prophylaxis for emergency sur-gery or trauma. A low-dose heparin regimen is also consid-ered inadequate forpatients undergoing operation during an

activethrombotic process.

tors for decreased antithrombin III activity to be the sameas those previously published for thromboembolism}2Low antithrombin Illlevels were found to be associatedwith DVT, adult respiratory distress syndrome, and dis-seminated intravascular coagulation. This caused us toconclude that unmonitored thromboembolism prophy-taxis using fue antithrombin III potentiator heparin wouldlikely result in a significant failure rate because those pa-tients for whom prophylaxis was intended lacked ad-equate amounts of antithrombin Ill.

Damus and Wallace23 had noted that antithrombinIlllevels are low in patients with liver disease; sepsis, anddisseminated intravascular coagulation. In an athero-sclerosis risk study of 15800 middle-aged men andwomen, Conlan et ap4 reported that antithrombin Illlev-els were significantly higher in women than in men andin blacks than in whites. Antithrombin IIIlevels de-creased with age in men but increased in age with women.They concluded that antithrombin Illlevels as well asother risk factors must be considered when evaluatingpatients for prophylaxis for arterial thrombosis.

It has become clear that an increased thrombotic ten-dency can be anticipated in patients who have de-creased antithrombin Illlevels. Low levels are seen in sickand injured patients and those with preexisting, ac-quired, or congenital antithrombin III deficiency, as seen

below.Factors Associated With Decreased Levels01 Antithrombin 111

Congeni.tal deliciency

Advanced ageLiver disease

Nephrotic syndrome

SepsisMajor traumaDisseminated intravascular coagulation

L -Asparaginase therapy

All of these patients benefit little or not at all froro stan-

dard low-dose heparin prophylaxis.

ADjUSTED-DOSE HEPARIN

Leyvraz et a15 pointed out that the efficacy of fixed dosesof 5000 U of heparin injected subcutaneously every 8 or12 hours has been disappointing in many clinical set-tings when objective techniques such as phlebographywere used to detect DVT. They noted that individual re~sponses to fixed doses of heparin varied greatly. Theytested the hypothesis that dosage adjustment of subcu-taneous heparin to produce an APTT in the high~normal range might result in greater reduction of post~operative thrombosis than fixed~dose heparin. In 79patients undergoing elective hip arthroplasty, one groupreceived a fixed dose of 3500 U of heparin subcutane~ously every 8 hours for 7 days. Thirty~nine percent of thesepatients developed DVT as diagnosed by venography. Asecond group was given the same initial dose, but the dosewas subsequently adjusted to keep the APTT between 35and36 seconds from the dar of operation to the seventhpostoperative day. These patients needed progressivelymore heparin to maintain the APTT in the prescribed

Hampson et al,15 in 1974, perfonned a prospective pla-cebo-controlled study of the efficacy of standard low-dose heparin for preventing DVT in patients undergo-ing hip replacement. They found that although the meantime to the occurrence of DVT was longer in the pa-tients receiving heparin, there was no significant differ-ence in the incidence between the heparin and controlgroups. The authors observed that previoustrials that con-cluded by the 10th postoperative dar likely missed a sig-nificant numberof thrombi. From this they concludedthat". ..heparin 5000 units three times daily has no ef-fect on the frequency or extent of post-operative

thrombi."15We and others havealso found that low-dose hep-

arin prophylaxis appeared to be inadequate in prevent-ing thrombotic complications in trauma patients and af-ter certain major surgical operations.16,17 Ruii et ap8recently raised a more alanning note~ rhey studied 100consecutive trauma patientS in an unrandomizedfash-ion, 50 of whom receiyed 5000 U of subcutaneous hep-arin every12 hours and the remaining receiving no DVTprophylaxis. Although ihe patients ~reaied with heparinhad more riSk factors10r ~hromboembolism, the resuliswere remarkable..Fo~r~een\28%) of50 patients receiv-ing heparin deve~oped DVT;only 1 (12%) oí. the 59 pa-tients who did not ,receive heparin developed DVT. Theyconcluded ~t patients who were at increased risk ofDVTare better served with either increased doses of heparin

or altemate formsof DVT prophylaxis.Wille-Jorgensen and Ott19 noted that despite pro-

phylaxis W1th low-dose heparin, postoperative throm-boembolism still occurred in 10% of patients undergo-ing abdominal operations. They found by multiple logistic!egression that age, body mass index, preoperative he-moglobin concentration, and colorectal operations con-tributed to the prediction of failure for low-dose hepa-rinprophylaxis and that sex, malignant lesions, previous,thiQmboembolism, hypertension, diabetes mellitus, and, ..'.varicose veins did noto'v.,A. ..¡,;;¡[,T~ereasons for thereported failures of standard low-

,~ .

Miller et al!O in

'.

This finding was confirmed.: al;lwh? pro-

ARCHSURGNOL131, OCT 1996'." '-! -~ '1070,,~,c ,

range. Only 13% of these patients developed veno-graphic evidenc'e of DVT. The bleeding complicationswere identical in the 2 groups. Leyvraz et al subse'.::'quendy advised giving sufficient heparin to raise fue APTT2 to 5 seconds above the upper limit of normal.

Green et ap5 compared adjusted-dose heparin withconventional-dose heparin in patients with spinal cordinjury and found a much lower incidence of DVT in thegroup receiving adjusted-dose heparin. Hirsh,26 in a re-view of the results of studies on low-dose vs adjusted-dose heparin, found a postoperative incidence of DVTfrom 25% to 35% with low-dose and 12% to 15% withadjusted-dose heparin. As a result, adjusted-dose hepa-fin was widely accepted as the most appropriate meansof using heparin for thromboembolism prophylaxis.

single-dose regimen wasdose heparin and dosesprovide equivalent ptotection.8.28

Another theoretical advantage of using low-molecular-weight heparin was the potentiallor áreduced risk for bleeding. Experimentally, the hemor~rhagic effects of standard heparins and low-molecular-weight heparins have been compared in a variety ofanimal models. In most of these studies, standard hep-arin appeared to be associated with ~ore bleeding at anequivalent antithrombotic effect than low:-molecular-weight heparin.ll This, however, has not proved to be thecase clinically, as almost all comparative clinical studieshave showed no difference in the incidence of bleedingbetween patients given standard heparin and low-molecular-weight heparin.28.29,32,34.35 The balance of evi-dence clearly points out that the 2 types of heparin arecomparable in terms of hemorrhagic complications.

The final theoretical advantage of low-molecular-weight heparin prophylaxis was that it was less likely tobe associated with heparin-induced thrombocytope-nia!11.36 Warkentin et ap7 noted that heparin-inducedthrombocytopenia occurred in 9 of332 patients who re-ceived unfractionated heparin and in none of 303 pa-tients receiving low-molecular-weight heparin. Eight ofthe 9 patients with heparin-induced thrombocytopeniahad 1 or more thrombotic events (venous in 7 patientsand arterial in 1 patient) and the incidente of heparin-dependent IgG antibowes washigher among patientswhoreceived unfractionated heparin (7.8%) iban amongpatients who received low-molecular-weightheparin '(2%).Even though ibis difference m~y seem significant,"thecurrent Physicians' Desk Reference;38 suggests that theoccurrence of thrombócytopenia following lhe admin-istrationof low-molecular-weight heparin is 2% vs 3%for unfractionated heparin, a trivial difference. Unfortu-nately, if ~ patienthas been previously sensitized withunfractionated heparin, the low-molecular~weight hepa-rins have an 80% to 100% risk for cross-reactivity}9Because of this, patients with heparin-:induced throm-bocytopenia who require continued anticoagulationshould not be treated with low.;molec~lar-weight hepa-rins. These patients mar be treated with either directthrombin inhibitors or heparinoids (soon to be releasedin the United States).

LOW-MOLECULAR-WEIGHT HEPARIN

CONTROVERSY REGARDING THE V ARIOUSHEPARIN REGIMENS

Because low-molecular-weight heparin offered the prom-ise of being more effective, with prolonged action analess risk for bleedirig and platelet-induced thrombocy-topenia, it has been promoted with enthusiasm. l:Iow-ever. asjust noted, its theoretical benefits have not beenrealized clinically. This drug is expensive because of itscost of purification, and it is still dependent on the pres-

Recently, the literature has been flooded with articles ad-vocating the use oflow-molecular-weight heparin for clot-ting prophylaxis.6-8.27o31 Unfractionated heparin is basi-cally a dirty compound consisting of components withmarked variation in molecular weight. Because the mecha-nism of action of heparin is based on its ability to poten-tiate the activity of antithrombin Ill, the demonstrationthat low-molecular-weight fractions of heparin have amuch higher content of the pentasaccharide segment re-sponsible for this potentiation suggested that this wouldbe an ideal drug for thromboembolism prophylaxis. Asa result, the pharrnaceutical industry, using depolymer-ization, fractionation, and other chemical processes, hassucceeded in developing a number of different low-molecular-weight fractions from parent unfractionatedheparin. As the heparin was broken clown into its low-molecular-weight fractions, however, it lost its ability topro long the APTT .11 This led to the hope that the bleed-ing complications would be lessened while the anti-thrombotic benefit would be retained.

The primary problem with the use oflow-molecular-weight heparin has been an inability to document the ef-fect of a given dose except through measurement of itsex yivo antifactor Xa activity .11.27,32 There are serious ques-tions, however, as to whether this test accurately re-flects the activity of this drug!3 There are 2 primary rea-sons for these questions. First, the relative contributionof antifactor lla and antifactor Xa activity varies be-tween different low-molecular-weight heparin prepara-tions; hence, measuring only the antifactor Xa actiVitymar underestimate the effects of those with a highernonantifactor Xa effect. Second, when an experimentalmodel of thrombosis is used, protection from thrombo-sis with low-molecular-weight heparin continues after theex vivo antifactor Xa activity has decreased. The inabil-ity of most laboratories to monitor low':molecular-weight heparin's effect on a practical basis has restrictedit:5 use primarily to low-dose prophylaxis in the UnitedStates.

Another.theoretical advantage oí low-molecular-weight heparins, in addition to improved antifactor Xaactivity, is their more prolonged duration of action.11.28A reduced binding of low-molecular-weight heparintoplasma proteinsand endothelial cells is thought to con-

~~

*APTT indicates activated partial thromboplastin time.

low molecular component that reaches the circulation;ie, a fraction similar to that found with low-molecular-weight heparin. In theory, increasing the dose of subcu-taneous unfractionated heparin in fue standard-dose hep-arin regimen would provide equivalent results to those

of low-molecular-weight heparin.It can be concluded from a review of the literature

that in most patients the difference between low-molecular-weight heparin and adjusted unfractionatedheparin is minimal. The incidence of complications inboth regimens is small and so far there are no random-ized series that demonstrate a clinically significant dif-ference between fuero. There are theoretical advantagesand disadvantages to each (Tab.e). The primary advan-tages of low-molecular-weight heparins are that the in-cidence of thrombocytopenia is probably slightly lowerthan with adjusted-dose unfractionated heparin and moni-toring is not used. The primary disadvantages are that itis difficult if not impossible to monitor the effect of low-molecular-weight heparin and the drug is still quite ex-

pensive.

CONCLUSIONS

From the standpoint of prophylaxis in normal patientswith normal antithrombin III levels, all heparin regi-mens are probably equally effective.5,39-45 The increasedcost oflow-molecular-weight heparin is balanced by thedecreased need for monitoring. However, patients whoare at the highest risk of clotting or who actually haveongoing low-grade clotting, such as those with majortrauma, sepsis, ischemic tissue, or shock, should be as-sumed tohave low or depleted antithrombin IIIlevels.Under these circumstances, the standard low-dose hep-arin and low-molecular-weight heparin regimens are notonly ineffective but mar actually increase the clotting ten-dency. This is likely because low doses of heparin tendto produce platelet aggregation and in so doing mar in-crease thromboembolic complications.1l,18;34,44 There havebeen studies that show superiority of the low-molecular-weight heparin prophylaxis over the low-dose standardheparin regimens in this high-risk group. 46 However, stud-

ies documenting superiority of the low-molecular-weight regimens to adjusted-dose standard heparintherapy in this group do not yet existo Adjusted-dose stan-dard heparin therapy mar result in more effective pro-phylaxis because as endogenous antithrombin III activ-ity decreases, the heparin dose is increased to maintainan antithrombotic effect. Because it is difficult without

ence of antithrombin 1lI for its activity. Those advocat-ing the use oflow-molecular-weight heparin suggest thatit is more effective than standard low-dose heparin.7.28,30Although low-molecular-weight heparin is expensive, thelack of monitoring results in costs comparable to thoseof an adjusted-dose heparin regimen with daily APTT

monitoring.7A fundamental problem with most of the low-

molecular-weight heparin studies is that they comparedstandard low-dose unfractionated heparin with low-molecular-weight heparin. Leyvraz et a15 in 1983 dem-onstrated the clear superiority of adjusted-dose heparinto standard low-dose heparin. Since the original publi-cation of Leyvraz et al, adjusted-dose heparin has beenthe regimen of choice for thromboembolism prophy-laxis in most centers, including our own.

Kakkar et a135 recently reported a multicenter trialin which low-molecular-weight heparin was comparedwith standard low-dose heparin in more than 3000 pa-tients undergoing majar abdominal surgery. The pur-pose of the study was to evaluate the incidence ofbleed-ing betWeen the 2 groups. Strikingly, the incidence ofDVTand pulmonary embolism was no different between the2 groups. Although there were fewer minar bleedingevents (wound hematomas) in the low-molecular-weight heparin group, there was no difference in the in-cidence of major bleeding events.

Clagett et al34 in their summary of current series pro-vide information on the effectiveness of various regi-mens of thromboembolism prophylaxis. This is one ofthe few articles that compares adjusted-dose heparin withlow-molecular-weight heparin. Their series reviewed com-parative data on adjusted-dose heparin and low-molecular-weight heparin for the preventioR of DVT after electivehip replacement. Their summary found the incidence ofDVT tobe 50% for untreated controls, 34% for low-gose heparin, 16% for low-molecular-weight heparin, and

11% for adjusted-dose heparin.Vsing volunteers, Bendetowicz et ap7 compared

plasma levels 1 to 24 hours after subcutaneous injectionof 50bo IV of unfractionated heparin with 40 mg of low-molecular-weight heparin (n=12 for each type).Levels

and antifactor Xa ac-activities of the materials in-

heparin and.

it is primarily the

ARCH 5URGNOL131. OCT 19961071

~

measuring antithrombin IIIlevels to determine the groupof patients who would benefit from adjusted-dose hep-arin, OUT conclusion is that adjusted-dose heparin shouldremain the prophylactic method of choice.

Reprints: ]ohn T. Owings, MD, Department 01 Surgery,4301 X St, Sacramento, CA 95817-2282.

lation and hepatic lailure coagulopathy. Thromb Res. 1975;6:27-38.24. Conlan MG, Folsom AR, Finch A, et al. Antithrombin 111: associations with age,

race, sex and cardiovascular disease risk lactors. Thromb Haemost. 1994;72:551-556.

25. Green D, lee MY, Ito VV, et al. Fixed- vs adjusted-dose heparin in the pro-phylaxis 01 thromboembolism in spinal cord injury. JAMA. 1988;260:1255-1258.

26. Hirsh J. Heparin. N Engl J Med. 1991 ;324:1565-1574.27. Bendetowicz AV, Beguin S, Caplain H, Hemker HC. Pharmacokinetics and phar-

macodynamics 01 a low molecular weight heparin (enoxaparin) alter subcu-taneous injection: comparison with unlractionated heparin: a three-way cross-ayer study in human volunteers. Thromb Haemost. 1994;71:305-313.

28. Colwell CW Jr, Spiro TE, Trowbridge AA, et al. Use 01 enoxaparin, a low-

molecular-weight heparin, and unfractionated heparinlor the prevention 01 deepvenous thrombosis alter elective hip replacement: a clinical trial comparingefficacy and saletY. J Sane Joint Surg Am. 1994;76:3-14.

29. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight hep-arin compared with continuous intravenous heparin in the treatment of proxi-mal vein thrombosis. N Engl J Med. 1992;326:975-982.

30. Thomas DP. Prevention 01 post-operative thrombosis by low molecular weighthepann in patients undergoing hip replacement. Thromb Haemost. 1992;67:491-493.

31. Turpie AG, levine MN, Hirsh J, et al. A randomized controlled trial 01 a low-

molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in pa-tients undergoing elective hip surgery. N Engl J Med. 1986;315:925-929.

32. Boneu B. low molecular weight heparin therapy: is monitoring needed? ThrombHaemost. 1994;72:330-334.

33. Fareed J, Hoppensteadt D, Walenga JM. low molecular weight heparin in themanagement of thromboticdisorders. In: Fareed J, ed. Low Molecular WeightHeparin in the Prophylaxis and Treatment of Thrombotic Disorders. Chicago,111: loyola UniversitY Press; 1994:233-241.

34. Clagett GP, Anderson FA Jr, levine MN, Salzman EW, Wheeler HB. Prevention01 venous thromboembolism. Chest. 1992;102(suppl):391S-407S.

35. Kakkar W, Cohen AT, Edmonson RA, et al. low molecular weight versus stan-dard heparin lor prevention 01 venous thromboembolism after majar abdomi-nal surgery. Lancet. 1993;341:259-265.

36. Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med.1995;332:1374-1376.

37. Warkentin TE, levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia inpatients treated with low-molecular-weight heparin or unlractionated heparin.N Engl J Med. 1995;332:1330-1335.

38. The Physicians'Desk Reference Guide to Prescription Drugs. 2nd ed. Montvale,NJ: Medical Economics Data; 1994:1853-1854.

39. Greinacher A, Michels 1, Mueller-Eckhardt C. Heparin-associated thrómbocy-topenia: theantibody is not heparin specific. Thromb Haemost. 1992;67:545-549.

40. Collins R, Scrimgeour A, Yusul S, Peto R. Reduction in fatal pulmonary em-bolism and venous thrombosis by perioperative administration 01 subcutane-ous heparin: overview 01 results 01 randomized trials in general, orthopedicand urologic surgery. N Engl J Med. 1988;318:1162-1173.

41. Eriksson BI, Kalebo P, Anthymyr BA, et al. Prevention 01 deep-vein thrombo-sis and pulmQnary embolism alter total hip replacement: comparison 01 low-molecular-weight heparin and unlractionated heparin. J Sane Joint Surg Am.1991;73:484-493.

42. Morris GK, Henry AP, Prestan BJ. Prevention 01 deep-vein thrombosis by low-dose heparin in patients undergoing total hip replacement. Lancet. 1974.2:797-800.

43. Planes A, Vochelle N, Mazas F, et al. Prevention of postoperative venous throm-bosis: a randomized trial comparing unlractionated heparin with low molecu-lar weight heparin in patients undergoing total hip replacement. Thromb Hae-mosto 1988;60:407-410.

44. Taberner DA, Poller l, Thomson JM, lemon G, Weighill FJ. Randomized study01 adjusted versus lixed lowdose heparin prophylaxis 01 deep vein thrombo-sis in hip surgery. Sr J Surg. 1989;76:933-935.

45. Thomas DP, Merton RE. A low molecular weight heparin compared with un-Iractionated heparin. Thromb Res. 1982;28:343-350.

46. Geerts WH, Jay R, Cope K, et al. Thromboprophylaxis after majar trauma: adouble-blind RCT comparing lDH andthe lMWH, enoxaparin. Thromb Hae-mosto 1995;73:973.

1. McLean J. The thromboplastic action of cephalin. Am J Physio/. 1916;41:250-257.

2. Murray oWG, Jaques LB, Perrett TE, Best CH. Heparin and vascular occlusion.Can Med Assoc J. 1936;35:621-622.

3. Kakkar W, Corrigan T, Spindler J, et al. Efficacy of low doses 01 heparin inprevention 01 deep-vein thrombosis after majar surgery: a double-blínd, ran-domized trial. Lancet. 1972;15:101-106.

4. Kakkar W. Prevention of fatal postoperative pulmonary embolism by low dosesof heparin: an international multicentre trial. Lancet. 1975;2:45-51.

5. Leyvraz PF, Richard J, Bachmann F, et al. Adjusted versus fixed-dose subcu-taneous heparin in the prevention of deep-vein thrombosis after total hip re-placement. N Eng/ J Med. 1983;309:954-958.

6. Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosisalter hip replacement: randomized comparison between unlractionated hepa-fin and low molecular weíght heparin. BMJ. 1991;303:543-548.

7. Hirsh J, Levine MN. Low molecular weight heparín. B/ood. 1992;79:1-17.8. Menzin J, Richner R, Huse O, Colditz GA, oster G. Prevention 01 deep-vein

thrombosis following total hip replacement surgery with enoxaparin versus un-fractionated heparin: a pharmacoeconomic evaluation. Ann Pharmacother.1994;28:271-275.

9. Brinkhous KM. The inhibition of blood clotting: an unidentified substance whichacts in conjunction with heparin. Am J Physio/. 1939;125:683-687.

10. Abildgaard U. Highly purifíed antithrombin 3 with heparin colactor activity pre-pared by disc electrophoresis. Scan J C/in Lab /nvest. 1968;21 :89-91.

11. Ofosu FA. Pharmacology 01 unlractionated and low-molecular-weight hepa-rins. In: Bounameaux H, ed. Low-Mo/ecu/ar-Weight Heparins in Prophy/axisand Therapyo{ Thromboembo/ic Diseases. New York, NY: Marcel oekker Inc;1994:1-20.

12. oemers C, Henderson P, Blajchman MA, et al. An antithrombin 111 assay basedon lactar Xa inhibition provides a more reliable test to identiiy congenital an-tithrombin 111 deliciency than an assay based on thrombin ínhibition. ThrombHaemost. 1993;69:231-235.

13. Kakkar W, Corrigan TP, Fossard oP, et al. Prevention 01 fatal postoperativepulmonary embolism by low doses 01 heparin. Lancet. 1977;1:567-569.

14. Wessler S, Gitel SN. Heparin: new concepts relative to clinical use. B/ood. 1979;53:525-544.

15. Hampson WG, Harris FC, Lucas HK, et al. Failure 01 low-dose heparin to pre-vent deep-vein thrombosis after hip replacement arthroplasty. Lancet. 1974;2:795-797.

16. Blaisdell FW. Prevention of deep vein thrombosis. Surgery. 1978;83:243-244.17. Gruber UF, Duckert F, Fridrich R, Torhorst J, Rem J. Prevention 01 postop-

erative thromboembolism by dextran 40, low doses 01 heparin, or xantinol nico-tinate. Lancet. 1977;1:207-210.

18. Ruíz AJ, Hill SL, Berry RE. Heparin, deep venous thrombosis, and trauma pa-tients. AmJSurg.1991;162:159-162.

19. Wille-Jorgensen P, Ott P. Predicting failure of low-dose prophylactic heparinin general surgical procedures. Surg Gyneco/ Dbstet. 1990;171:126-130.

20. Miller RS, Weatherford DA, Stein O, Crane MM, Stein M. Antithrombin 111 andtrauma patients: lactors that determine low levels. J Trauma. 1994;37:442-445.

21. Owings JT, Bagley M, Gosselin R, Romac O, Disbrow E. Effects of critical in-jury on plasma antithrombín actívity: low antithrombin levels are associatedwíth thromboemboi.ic complícations. J Trauma. 1996;41:396-406.

22. GeertsWH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venousthromboembolism after majar trauma. N Eng/ J Med. 1994;331:1601-1606.

23. oamus PS, Wallace GA. Immunologic measurement of antíthrombín 111 hep-afín colactor and alpha 2 macroglobulín in dissemínated intravascular coagu-