Fixed combinations of low-molecular weight or unfractionated heparin plus dihydroergotamine in the prevention of postoperative deep vein thrombosis

Fixed Combinations of Low-Molecular Weight or Unfractionated Heparin Plus Dihydroergotamine in the Prevention of Postoperative Deep Vein Thrombosis Vqay V Kakkar, FRCSE, FRCS, Mark D Stringer, MRCP, FRCS, Anthony R Hedges, FRCSE, FRCS, Christopher J Parker, FRCS, Dieter Welzel, MD, Valerie P Ward, BA, Ruth M Sanderson, BSC, Derek Cooper, PhD, Savitri Kakkar, MB, BS, London England A prospective, double-bhnd, randomized, controlled clmlcal trud compared the efficacy and safety of flxed combmatlons of low-molecular weight heparm or standard unfractlonated heparm plus d&ydroergotamme mesylate m the preventlon of deep vem thrombosu m high-nsk patients undergomg elective maJor abdommal surgery. Two hundred patients, with a mean age of 66.6 years and almost half with mahgnancy, were allocated to receive elther 5,000 IU unfractlonated heparm plus 0.5 mg tiydroergotamme mesylate twice dady or 1,500 IU low-molecular we&t heparin plus 0 5 mg &hydroergotamme mesylate once dally together with one placebo mjectlon per day. Treatment was commenced 2 hours preoperatlvely and contmued for at least 7 days The mcldence of deep vem tbromboss, determmed by radlolabelled flbrmogen uptake and phlebography, was 11 percent in the unfractlonated heparm plus dlhydroergotamme mesylate group and 11.4 percent m the low-molecular weight heparm and dlhydroergotamme mesylate group. Nelther these figures nor those for major proximal thrombl proved slgmfuzmtly Mferent Of the four parameters used to assess hemorrhaec comphcatlons, only the decrease m postoperatlve hemoglobm levels m the low-molecular weqght and dlhydroergotamme mesylate group reached statlstlcal sqmf~cance. These results mdlcate that once-dally prophylaxis with a combmatlon of low-molecular weight heparm and dlhydroergotamme 1ssafe, effectlve, and convement m high-nsk patients undergoing major abdommal surgery

From the Thrombosis Research and Computer Units, Km& College School of Medlcme and Dentlstrv. Denmark Hill. London. Eneland Supported m part by Medtcal Re&arch Councd Program &ant&i/ 756 and grants from the Thrombow Research Trust, London, England Requests for reprmts should be addressed to &Jay V Kakkar, FRCSE, Thrombosu Research Unit, Kmg’s College Hospital, Denmark Hdl, London, SE5 8RX, England

eep vem thrombosis 1sa frequent postoperative comD plication m patients over the age of 40 undergomg major elective surgery When no specific prophylactic measures are used, it 1s estimated that the mcldence of deep vem thrombosis ranges from 25 to 50 percent m the various studies reported m the literature [I-31 It 1shlgher m older patients, particularly those over the age of 60 years, who have malignant neoplasms and who undergo surgical procedures of several hours duration [4-61 Pulmonary embolism is its most feared comphcatlon The incidence of fatal embohsm m these particularly high-risk patients approaches 1 percent [7] Changes m blood coagulation and stasis m the deep veins of the lower hmbs are both considered to be lmportant factors m the pathogenesls of deep van thrombosis Low-dose heparm prophylaxis reduces not only the madence of deep vem thrombosis but also that of fatal pulmonary embolism [ 71 Methods to mmlmlze venous stasis perloperatlvely have also independently proved to be beneficial [8] It 1s therefore loglcal to propose that prophylaxis might be even better usmg methods that antagonize both of these factors together rather than counteracting either factor alone Dlhydroergotamme mesylate 1sa hydrogenated ergot preparation that causes vasoconstnctlon by a direct effect on vascular smooth muscle In low doses (0 5 mg), it exerts a preferential vasoconstrlctlve effect on veins and venules, with mmlmal effects on arteries and arterioles, thereby counteracting venous stasis and accelerating venous return from the legs [9-121 Several chmcal trials using a fixed combmatlon of heparm and dlhydroergotamme mesylate have shown a significantly greater reduction m deep vem thrombosis detected by the radlolabelled fibrinogen uptake test than the same amounts of heparm given alone [ 13-191 However, this advantage has not been totally consistent for patients undergoing major abdommal surgery and it may be that high-risk patients, particularly those more than 60 years of age with mahgnancy, benefit most from this combmation [13] Recent studies have also demonstrated that a single dally uqectlon of low-molecular weight heparm IS as effective as twice dally standard unfractlonated heparm m preventing postoperative deep vem thrombosis [20-221 One such preparation of low-molecular weight heparm 1s produced by Sandoz AG (Nurnberg, West Germany) by a chemical crackmg process under acldlc condltlons The mean molecular weight of this preparation 1s approxlmately 8,000 daltons In vitro assays reveal an anti-Xa-

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to-activated partial thromboplastm time ratio of 4 2 1 Thus, 1,500 umts of low-molecular weight heparm provides a slrmlar anti-Xa activity to 5,000 units of standard unfractlonated heparm In addition, because of a longer blologlc half-hfe, low-molecular weight heparm can be given once dally by inJectIon, rather than two or three times a day as with unfractlonated heparm The purpose of this study was to determme whether a fixed combmatlon of low-molecular weight heparm and dlhydroergotamme mesylate given once dally IS equally safe and efficacious m the prevention of deep vem thrombosis after major elective abdominal surgery m high-risk patients as a twice-dally regimen usmg a fixed combmatlon of unfractlonated heparm and dlhydroergotamme mesylate PATIENTS AND METHODS

scribed previously [24] Each patient received 100 &I of iodine-125 fibrmogen the day before surgery, and then legs were scanned using a counter ratemeter (model M5310E, J & P Engmeermg, Reading, England) Deep vem thrombosis was diagnosed S the counts increased by 20 percent or more at the same site or compared with adjacent sites on the same or opposite leg and if this difference persisted or mcreased m the subsequent 24 hours If the patient had consistently increased counts, ascending phlebograms were performed The technique of phlebography has been previously described, but we now use Iohexol (Ommpaque@ contauung 240 mg lodine/ml) as the contrast medium [25] The frequency of chmcally suspected pulmonary embolism was recorded together with any confirmatory evldence from ventllatlon-perfusion lung scannmg [26] The pathologist recorded the disease or condltlon directly leadmg to death and any other significant conditions contrlbutmg to death Details of the locatlon of pulmonary emboh were recorded (that IS, whether the embolus was present m the pulmonary trunk, mam pulmonary artery, or lobar or segmental arteries) The leg veins were exammed for deep vem thrombosis, and if thrombl were present, then location was documented Any excessive operative blood loss was recorded by the surgeon Surgical wounds and subcutaneous mJectlon sites were examined regularly for hematoma formation In addition, the preoperative hemoglobm concentration and the hemoglobm level 1 week after surgery, together with any intervening blood transfusion requirements, were noted In the evaluation of safety data, an analysis of vanante was carried out on the variables studied using a statlstlcal package (Social Science AMDAHL 47O/V8, Uruverslty of London) Contmuous variables were compared usmg the Student t test and categoric variables usmg the chl-square test Where the data were not normally dlstnbuted, contmuous variables were analyzed usmg the Mann-Whitney U test For the assessment of efficacy, frequency data were analyzed usmg the chlsquare test with Yates’ correction

Two hundred consecutrve patients 40 years of age or older admltted for major electrve abdommal surgery were investigated Patients havmg emergency surgery and those receiving anticoagulant therapy before admlsslon to the hospital were not included Wmlarly, patients with a hemorrhagic or vasospastlc dlathesls and those with severe coronary artery disease were excluded Previous eplsodes of deep vem thrombosis or pulmonary embolism, obesity, the presence or absence of varicose veins or mahgnant disease, and other risk factors likely to influence the incidence of thrombosis were recorded for each patient on a proforma deslgned to facilitate computer analySIS The reason for the mvestlgatlons was explained to each patlent and their consent obtained before entry mto the study The study was a prospective, double-blind, random~zed, controlled trial Patients fulfilling the study entry cnterla were randomly allocated to receive a fixed comblnation of either 5,000 IU unfractlonated heparm and 0 5 mg dlhydroergotamme mesylate twice dally or 1,500 IU low-molecular weight heparm and 0 5 mg dlhydroergotamme mesylate once dally Patients m the latter group also received a dally placebo mJectlon of a pharmacologically inert substance Two hundred boxes, each containing 21 ampules, were prepared The ampules m each box contained either a fixed combmatlon of unfractlonated heparm and dlhydroergotamme mesylate or low-molecular weight heparm and dlhydroergotamme mesylate and a placebo solution of gelatin with the same consistency The ampules were marked with different color labels mdlcatmg preoperative, morning, and evemng mJectlons The boxes were numbered m random order, and one was provided for each patient on entry to the trial The first inJection, which contained either low-molecular weight or unfractlonated heparm, was admuustered 2 hours preoperatlvely Subsequent mJectlons usmg a standard technique were given every 12 hours for at least 7 postoperative days [23] After the 10th postoperatlve day, if the patient was still immobde, prophylaxis was continued usmg standard unfractlonated heparm Deep vein thrombosis was detected by the radlolabelled tibrmogen uptake test using the technique de-

Two hundred patrents between 40 and 89 years of age were admltted to the trial One patlent was withdrawn because the contents of one box of drugs were damaged during treatment An additIona 20 patients were not included m the analysis of results due to msufficlent data, mainly because of early hospital discharge (12 patients), 6 patients died lmmedlately postoperatively (2 from myocardlal mfarctlon, 3 from carcmomatosls, and 1 from acute pancreatltls), 1 patient had minor surgery only, and 1 patient’s operation was cancelled after a preoperative prophylactic mjectlon Of the remaining 179 patients, 9 1 received the combination of unfractlonated heparm and dlhydroergotamme mesylate (Group A) and 88 received low-molecular weight heparm and dlhydroergotamme mesylate (Group B) The two groups were well matched in terms of sex ratlo, operations performed, and other factors that could predispose to the development of post-

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TABLE I Group Data, Frequency ot Risk Factors, and Incldencw ot Deep Vein Thrombosis and Pulmonary Embolism’ Variable No of patients Male female

Age Wr. mean f SD) <40 40-49 50-59 60-69 70-79 >60 Werght (kg, mean f SD), n-167 <40

Overall

Group At

179 (21) 76(11) 3(10) 665f 106 0 15

91 (IO) 39(7) 52(4) 65 86 f 10 1 0 7

31 50 67 16 644%

17 (2) 28 (2) 32 (4) 7 (2) 63 44 f 14 1

(4) (5) (9) (3) 133 4

40-59 60-79 80-99 Prevrous history Deep vest thrombosrs Pulmonary emboksm Myocardial infarction Lower limb fracture

61 (3) 77 (IO) 25 (7)

Varicose veins Varicose ulcers *fignancY

44 (4) 10 (2) 87 (13)

8 3 9 t

(0) (0) (0) (0)

Croup Bt 00 (II) 37(4) 51(6) 6747 f 11 0 8 14 22 35 9 654f

(2) (3) (5) (1) 125

2

2

34 (1) 37 (4) 12 (5)

27 (2) 40 (6) 13 (2)

5 0 5 0

3 3 4 1

21 (2) 4 (0) 38 (6)

23 (2) 6 (2) 49 (7)

* Values In parentheses indrcate number of patrents who developed venous thrombosmbollsm(20 isotoprcdeep vern thrombrsnd 1 addltlonslpulmonsry embolism) + Croup grven unfractionsted heparrn t (iroup given low-molecular werght heparrn

operative deep vem thrombosis (Tables I and II) In Group A, the mean patient age was 65 9 f 10 1 years, the mean interval between hospital admission and operation was 9 9 f 13 2 days, and 38 of 91 patients (42 percent) were undergoing surgery for malignancy In Group B, the mean age was 67 5 f 11 years, the mean mterval before operation was 7 8 f 10 3 days, and 49 of 88 patients (56 percent) had surgery for malignant conditions Thus, both groups comprised a major proportlon of particularly high-risk patients The mean duration of prophylaxq radlolsotope scanning, and postoperative hospltahzatlon periods were slmllar m Groups A and B with no statlstlcally significant differences (Table III) Isotopic deep van thrombl were detected m 20 patients (11 2 percent) 10 Group A patients and 10 Group B patients In one patient m the latter group, the scan was positive for only 48 hours, normahzmg thereafter, and a venogram was not obtained Postoperative deep vem thrombosis was demonstrated on ascending venography m 18 patients Thirteen thrombl were confined to the calf vems, two extended mto the proximal veins, and the remammg three thromh were dlscontmuous, mvolvmg both the tibia1 and femoral or lhac vessels (Table III) Four of the patients m Group B developed deep vein thrombosis after the study drug had been discontinued, m three cases prematurely Of the latter, prophylactic heparm was stopped due to excessive bleedmg m two patients The difference m the frequency of venous thromboembolism m the two groups was not statlstlcally sigmficant Furthermore, if the frequency of major thrombl was THE AMERICAN

considered (tibia1 vein thrombus more than 10 cm or any proximal deep vem thrombus except an isolated femoral vem cusp thrombus), there was again no significant dlfference, there being seven major thrombl m Group A and five m Group B A pulmonary embolism occurred m two patients In one, this was detected at autopsy, after death from bronchopneumoma, m the other patient, clinical symptoms developed 18 days after total gastrectomy with Roux loop reconstruction and repair of a dlaphragmatlc defect Perfusion defects on lung scanning were consistent with the TABLE II Operatlons Performed’ Operation (n = 179) Thoracoabdominal gastric 8 esophageal procedure Total 8 part&l gastrectomy Gastric drainage Cholecystectomy Dther biliary operation Laparotomy Total (L partfal colectomy Anterior resectron Abdominoperineal resection Fcrmatlon of colostomy Closure of colostomy Small bowel resection Other

Overall

Croup A

Croup B

8 (2)

3 (1)

5 (1)

t7 (2) 9 (0) 30 (3) 13 (1) 10 (2) 22 (3) 10 (3) 13 (3) 4 (0) 9 (1) 1 (0) 33 (1)

7 (0) 4 (0) 19 (2) 6 (0) 5 (0) 8 (1) 3 (1) 7 (3) 1 (0) 7 (1) 0 21 (1)

10 (2) 5 (0) 11 (1) 7 (1) 5 (2) 14 (2) 7 (2) 6 (0) 3 (0) 2 (0) 1 (0) 12 (0)

* Values In parentheses rndrcate number of patrents who developed venous thrornboembolism

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TABLE III Incidence of Deep Venous Thrombosis and Safety Crlterla Overall Patient details (n = 179) Preoperative hosprtalizabon (d) Heparlnlzation period (d) Duratlon of lodtne-125 scannmg (d) Postoperahve hospdakzahon (d) Deep vern thrombosis (n = 18)’ Below knee I0 cm Above & below knee continuous Above 8 below knee, discontinuous 9afety criteria (n = 179) Operative blood loss (ml) Blood transfused (ml) Hemorrhagic

Group A

99f 87fI7 104f4 15 7 f

89fI19

aaf

18

109f45 165f 126 6 7 (1) 2 3 (I)

125

3 3 (I) 1 3 (1)

741 f 783 564 f 906

complicatrons~

132

738 f 500 f

9 (3)

3 (I)

875 833

Group B

78f 103 88f 19 114f49 I7 4 f I2 a 3 4 1 0 745 f 633 f

666 976

6 (2)

Values rn parentheses Indrcate patrents with brlateral deep vein thrombr I Values in parentheses rndlcate patrents wrth wound hematomss l

diagnosis of pulmonary embolism After receiving full therapeutic doses of heparm, the patient made an uneventful recovery These two patients m whom pulmonary embolism was diagnosed were both m Group B Nme of the 179 patients died during the postoperative follow-up period An autopsy was performed on SIXof these patients, but three who died on the 22nd, 27th, and 53rd postoperative days were not examined because their relatives refused permission One patient who died from bronchopneumoma was found at autopsy to have a small pulmonary embolus m a segmental pulmonary artery, but this was not considered to be the primary cause of death by the pathologist Details of mtraoperatlve blood loss and blood transfusion requirements are shown m Table III Preoperative and postoperative hemoglobm levels were 13 2 f 1 9 g/d1 and 13 1 f 1 9 g/dl, respectively, for Group A and 13 f 2 1 g/d1 and 12 5 f 1 5 g/dl, respectively, for Group B Only the decrease m the postoperative hemoglobm level m Group B was statlstlcally significant (p
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COMMENTS Several large prospective, randomized chmcal trials have previously established the efficacy and safety of dlhydroergotamme mesylate plus unfractlonated heparm m the prevention of deep vem thrombosis m patients undergoing major abdominal and orthopedic operations [13,16,17] However, the most effective prophylactic regimen reported to date for patients undergoing major general surgical procedures has been low-molecular weight heparm alone In the study of Kakkar and Murray [2Zj, there were fewer particularly high-risk patients (that is, over 60 years of age with mahgnancy) than m our trial using additional dlhydroergotamme mesylate, and thus a direct comparison 1sdifficult The aim of our study was to compare the safety and efficacy of a fixed combination of 1,500 IU of low-molecular weight hepann and 0 5 mg of dlhydroergotamme mesylate given once dally, with a fixed combmatlon of 5,000 IU of unfractlonated heparm and 0 5 mg of dlhydroergotamme mesylate given twice dally m this same sltuatlon Conclusions are limited because of the relatively small number of patients m this study with a relatively high event rate of 11 2 percent However, the results mdlcate that there was no slgmficant difference between the two prophylactic regimens as there were no significant group differences m either the incidence of thromboembohc disease, or hemorrhagic comphcatlons attributable to the study drug Isotopic deep vem thrombl were detected m 20 patients, 10 m each group, and m 18 of these, thrombl were confirmed by ascending venography Our previous studies on the natural history of postoperative venous thrombosis have shown that major pulmonary emboh only occur when thrombl are located m major veins above the knee [28] In the present study, 13 thrombl were confined to the calf, 2 extended to the proximal lhofemoral vans, and the remammg 3 were dlscontmuous, mvolvmg both the tlblal and femoral or iliac veins When the frequency of major thrombl was considered, there was again no significant difference between the two treatment groups Several criteria were used to assess the safety of the

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two fixed combmatlons These included assessment of mtraoperatlve blood loss, blood transfusion requirements, postoperative drainage of blood collected m Redlvac bottles, and a decrease m hemoglobm levels 1 week after surgery Total mtraoperatlve blood loss was SubJectively considered to be excessive m six patients receiving unfractlonated heparm and dlhydroergotamme mesylate compared with one receiving low-molecular weight heparm and dlhydroergotamme mesylate, but this difference was not statlstlcally significant Only 3 of 179 patients mcluded m this trial (1 77 percent) developed wound hematomas, none of which required drainage In the group of patients receiving unfractlonated heparm and dlhydroergotamme mesylate, mean hemoglobm levels remained the same, but m those recelvmg low-molecular weight heparm and dlhydroergotamme mesylate, the levels decreased slgmficantly by 0 5 g/d1 None of the hemorrhagIC comphcatlons proved serious,, and of the four assessments made, only one revealed a significant difference between the two treatment groups With regard to the potential lschemlc comphcatlons of dlhydroergotamme that have been rarely reported prevlously, we did not observe any similar adverse effects [I61 From our previous studies mvolvmg patients with atherosclerotic occlusive arterial disease, this potential problem did not emerge as a significant risk [27] We have concluded that vasospasm after dlhydroergotamme mesylate admmlstratlon 1svery rare and should not deter the clmlclan from the therapeutic benefits, unless the patlent suffers profound hypotenslon or myocardlal ischemla, m which case the drug should be dlscontmued Why, therefore, should 1,500 IU of low-molecular weight heparm appear to be as effective as 10,000 IU of commercially available unfractlonated heparm when used m combination with dlhydroergotamme mesylate for deep vem thrombosis prophylaxis? Results from several m vitro and m vlvo studies help to answer this critical question Recent studies have shown that heparm fractions of different molecular weights and with high affinity for antlthrombm III (heparm cofactor) differ m then ability to potentlate the mhlbltlon of activated clotting factors [29-311 Inactlvatlon of factor Xa, factor XIIa, and kalhkrern was potentlated by low-molecular weight heparm fractions that had almost no effect on the mhlbltlon of thrombm or factors IXa and XIa [32] This suggests that the antlthrombotlc properties of low-molecular weight heparm may be related to its ablhty to potentlate mactlvatlon of serme protemases m the earliest stages of the coagulation cascade [ 191 In addition. there 1s a well documented increase m whole-blood vlscoslty, partlcularly at low shear rates, during the postoperative period, and prospective studies have demonstrated a direct correlatlon between increased whole-blood vlscoslty and deep van thrombosis [33-351 Heparm reduces this vlscoslty which 1s one of the suggested mechanisms for Its deep vem thrombosis prophylactic action [36] The effects of unfractlonated and low-molecular weight heparm on whole-blood vlscoslty have been compared [21] At two shear rates (0 7 s-l and 2 4 s-l), the vlscoslty was significantly reduced 120 minutes after unfractlonated heparm

(p
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1970, 1 540-2 amme and noradrenahne on resistance, exchange and capltance 25 Kakkar VV The problem of thrombosis m the deep veins of the functions m the penpheral clrculatlon Chn Scl 1970,39 183-201 legs Ann R Co11Surg Engl 1969, 45 257-76 10 Lange E, Echt M Comparative studies on drugs which increase venous tone usmg noradrenaline, ethyladnanol, dlhydroergotamme 26 Wagner HN Jr The use of radlolsotope techniques for the and horse chestnut extract Fortschr Med 1972, 90 1161-4 evaluation of patients with pulmonary disease Am Rev Reap DIS 1976, 113 203-17 11 Fehx R, Rouwen B The vasoactlvlty of dlhydroergotamme Phleobographlc mvestlgatlon Fortschr Med 1972, 90 757-60 27 Kakkar VV Ergotlsm and heparm-dlhydrcergotamme Lancet 12 Kakkar VV, Welzel D, Murray WJG, Malone P, Jones D 1982, 2 96-7 Possible mechanisms of the synergistic effect of hepann dlhydroer28 Kakkar VV, Howe CT, Franc C, et al Natural history of postoperative deep vem thrombosis Lancet 1969, 2 230-3 gotamme (suppl) Am J Surg 1985, 150(4A) 33-8 13 Kakkar VV, Stamatalus JD, Bentley PG, Lawrence D, de Haas 29 Andersson W, Barrowchffe TW, Holmer E, et al AntlcoaguHA, Ward V Prophylaxis of post-operative deep vem thrombosis lant properties of heparm fractionated by affinity chromatography Synergistic effect of hepann and dlhydrcergotamme JAMA 1979, on matnx-bound antlthrombm III and by gel filtration Thromb 241 39-42 Res 1976, 9 575-83 14 Koppenhagen K, Wlechmann A, Zuhlke HV et al Lelstungsfa30 Laurent TC, Tengblad A, Thunberg L, Hook M, Ludahl U hlgkelt und nslko der thrombcembohe prophylaxe m der chlrurgle The molecular weight dependence of the antlcoagulant actlvlty of Em verglelchende untersuchung von hepann-dlhydergot und low- heparm Bmchem J 1978, 175 691-701 dose heparm Theraplewoche 1979, 29 5920-62 31 Lane DA, MacGregor IR, Mlchalsla R, Kakkar VV Antlco15 Butterman G, Haluszczynsla I, Thelsmger W, Pabst HW agulant actlvltles of four unfractlonated and fractionated heparms Post-operative thrombeomebohe-prophylaxe mlt redzlerten low- Throm Res 1978, 12 257-71 dose heparm-ante1 und dlhydroergotamm m fixer kombmatlon 32 Holmer E, Kurachl K, S&ierstrom G The molecular weight Munch Med Wochenschr 1981, 123 1213-6 dependency of the rate enhancing effect of hepann on the mhlbltlon 16 A multlcentre trial Dlhydroergotamme-heparm prophylaxis of of thrombm, Factor Xa, Factor XIa, Factor XIIa and kalhkrem by postoperative deep vem thrombosis JAMA 1984, 257 2960-6 antlthrombm Bmchem J 1981, 193 395-400 17 Kakkar VV, Fok JP, Murray WJG, et al Heparm and dlhydro33 Dormandy JA Chmcal significance of blood viscosity Ann R ergotamme prophylaxis against thromboembohsm after hip arthroCo11Surg Engl 1970, 47 211-28 plasty J Bone Joint Surg 1985, 67 538-42 34 Dormandy JA, Edelman JB High blood vlscoslty an aetlologl18 Hohl M, Luscher P, Annahelm M, Frldrlch R, Gruber UF cal factor m venous thrombosis Br J Surg 1973, 60 187-90 Dlhydroergotamme and heparm or hepann alone for the prevention 35 Humphreys MV, Walker A, Charlesworth D Altered vlscoslty of postoperative thrombosis m gynaecology Arch Gynecol 1980, and yield stress m patients with abdommal mahgnancy relatlonshlp 230 15-9 to deep vein thrombosis Br J Surg 1976, 63 559-61 19 Breddm K, Hormg R, Koppenhagen K Prevention postopera36 Erdl A, Kakkar VV, Thomas DP, Lane DA Effect of low-dose tive thrombotische komphcatlonen mlt hepann und dlhydroergotasubcutaneous hepann on whole-blood vlscoslty Lancet 1976, 2 mm Dtsch Med Wochenschr 1983, 8 98-102 342-4 20 Kakkar VV, Djazaeri B, Fok J, et al Low molecular weight 37 Chem S, Usaml S, Dellenbade RJ, Gregerson MI Shear dehepann and prevention of postoperative deep vem thrombosis Br pendent interaction of plasma protems with erythrocytes m blood Med J 1982, 284 375-9 rheology Am J Physlol 1970,219 143-53 2 1 Kakkar VV, Murray WJG Efficacy and safety of low-molecu38 Mehssarl E, Scully MF, Paes T, Kakkar VV The influence of lar weight heparm (CY216) m preventing postoperative venous LMW hepann on the coagulation and fibrmolytrc response to surthromboembohsm a co-operative study Br J Surg 1985,72 786gery Thromb Res 1985, 37 115-26 91 39 Tobelem G, Mohho P, Dunn F, et al Enhancement of fibrmoly22 Bergqvlst D, Burmark US, Frlsell J, et al Prospective doubleSISm patients with recurrent thromboembohsm and defective reblind comparison between Fragmm and conventional low-dose hep sponse to venous stasis by a low molecular weight heparm (abstr) ann thromboprophylactlc effect and bleeding complications HaePresented at the 7th Intematlonal Congress on Rbrmolysls, Venumostasls 1986, 16 11-8 zla, March 27-30, 1984 Haemostasls 1984, 14 220 23 Griffith JG, Boggs RB Long term heparm therapy Am J 4Q Sasahara AA, Kappenhagen K, Hanng R, Welzel D, Wolf H Card101 1964, 39 14-20 Low molecular weight hepann plus dlhydroergotamme for prophy24 Kakkar VV, Nlcolaldes AN, Renney JTG, Friend JR, Clarke laxis of postoperatIve deep vem thrombosis Br J Surg 1986, 73 MA ~2SI-fibnnogen test adapted for routme screening Lancet 697-700

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