Effect of cardiac operation on platelets

J

THORAC CARDIOVASC SURG

92:434-441, 1986

Effect of cardiac operation on platelets The effect of extracorporeal circulation on platelet count and size (mean platelet volume) was studied in 65 patients (nine bleeders and 56 nonbleeders). In addition to the above, in 26 of the patients platelet

aggregation response to adenosine diphospbate, collagen, and ristocetin was measured. Platelet counts dropped postoperatively both in the bleeder and in the nonbleeder groups. The difference between them was not significant However, the bleeders bad a significantly lower mean platelet volume (7.7 ± 0.84 versus8.68 ± 1.1 8) and lower volume percentage of platelets in whole blood (0.075% ± 0.02% versus 0.116% ± 0.04%) (p < 0.05) than the nonbleeders. None of the bleeders bad a volume percentage of platelets in whole blood higher than 0.095%. AU 20 patients studied for platelet functions bad an abnormal postoperative aggregation response to adenosine diphospbate, collagen, and ristocetin. Three patterm of disturbed response to ristocetin were observed: grade I, delayed onset (14 patients); grade II, incompleteaggregation (five patients); and grade m, total lack of aggregation (one patient). AU patients with delayed-onset responseto ristocetin bad a normal bleeding time, whereas the six patients with grade II and m responses bad prolonged bleeding times and three of them bad clinically significant bleeding. Factor VIII procoagulantactivity,factor VIII-related antigen,factor VIII-ristocetin cofactor, and factor VIII two-dimensional electrophoresis were found normal, which suggests that the von Willebrand-Iike reaction to ristocetin observed in this study was caused by a defect in platelet membrane rather than by factor VIII changes.

Rephael Mohr, M.D., Michael Golan, M.D., Uri Martinowitz, M.D., Esther Rosner, M.D., Daniel A. Goor, M.D., and Bracha Ramot, M.D., Tel Hashomer, Israel

cardi~c

h e major known causes of bleeding after operations are inadequate surgical hemostasis (surgical bleeding),1 a decrease in plasma coagulation factors," 3 thrombocytopenia and platelet dysfunction,' and incomplete heparin neutralization.v' It is common to observea postoperative bleeding tendency, despite adequate hemostasis, normal activated clotting time (ACT), and normal clotting profile. In some centers the therapeutic approach to bleeding in patients with normal ACT is routine administration of platelets.' This approach is based on the rationale that the major hemostatic defects after cardiac operations in patients with a normal ACT are related to platelet dysfunction.':" From The Department of Thoracic and Cardiovascular Surgery (Drs. Mohr, Golan, and Goor) and The Department of Hematology (Drs. Martinowitz, Rosner, and Ramot), The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Received for publication Aug. 5, 1985. Accepted for publication Dec. 3, 1985. Address for reprints: Daniel A. Goor, M.D., Professor of Surgery, Director, Department of Thoracic and Cardiovascular Surgery, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.

434

In this study we attempted to elucidate the relationship between clinically significant bleeding and platelet functions. Patients and methods Sixty-five patients who underwent cardiac operations were studied for postoperative bleeding tendency. There were 50 male and 15 females patients aged between 4 and 72 years (mean 52.5 ± 15). Forty-nine had coronary artery bypass, 12 valve replacement, three repairs of congenital malformations, and one underwent a combined coronary bypass and valve replacement. Patients in whom reoperations and emergency procedures were performed were excluded from the study, as were patients who had been receiving anticoagulants or antiplatelet medications, such as dipyridamole or aspirin-containing drugs during the 2 weeks precedingtheir admission for operation. All patients underwent elective cardiac operations in which cardiopulmonary bypass was used for at least 30 minutes. They were rewarmed to 34 C before discontinuation of cardiopulmonary bypass. Heparin reversal (pork heparin Leo, Leo Pharmaceutical Products, Ballerup, Denmark) by protamine 0

Volume 92 Number 3, Part 1 September, 1986

Effect of cardiac operation on platelets

435

Table Il, Preoperative platelet count, MPV, * and

Table I. Operative data and preoperative

bleeding time of groups A and B

hematologic findings Mean ± SEM

Range

117.8 ± 40 50.5 ± 17

31-210 15-99

22.6 ± 4

19-30

Bypass time (min) Aortic cross-clamping time (min) Lowest temperature (0e) Preoperative bleeding time (min) Preoperative platelet count (XlO'/L)

4

± I

197

± 62

Legend: SEM, Standard error of the mean.

sulfate (Eli Lilly and Company, Indianapolis, Ind.) was monitored by ACT. 3 All pump blood was returned to the patient (through the aortic cannula or intravenously via infusion bags). Relevant preoperative laboratory data and further operative details are shown in Table I. The patients were divided into Group A, bleeders, and Group B, nonbleeders. The first group consisted of nine patients in whom closure of the sternum had to be delayed for at least 40 minutes because of bleeding despite good hemostasis and normal ACT. In addition to the pump blood, these patients received at least 1 unit of banked blood while the chest was still open. Group B consisted of 56 patients who did not have significant postoperative bleeding and did not require the infusion of banked blood in the operating room. None of the 65 patients had to be returned to the operating room because of excessive mediastinal bleeding. The following preoperative and postoperative hematologic parameters were studied in all patients: bleeding time, prothrombin time, partial thromboplastin time, clot retraction, platelet count, and mean platelet volume (MPV). Assays were done before administration of heparin (preoperative), 10 to 15 minutes after the appearance of clots after protamine was administered, and 1, 2, and 24 hours postoperatively. The tests were performed 30 minutes after the blood withdrawal. Platelet count, MPV, and the volume percentage of platelets in whole blood (plateletcrit-PCT) were measured with a Coulter-Counter-S-Plus II counter. Several additional tests were performed on 20 unselected patients: Platelet aggregations were determined by the method of Born and Cross" on a Chrono-Log aggregometer. The aggregation agents used were adenosinediphosphate (ADP, final concentration 3 ~mol/L), collagen (Ethicon, Inc., Somerville, N. J.; final concentration 0.02 mg/ml), and ristocetin (1.2 mg/rnl). All aggregations were performed on platelet-rich plasma

Group A (Nonbleeders) Platelet count (XlO'/L) MPV (ft) Bleeding time (min)

Significance

199 ± 74t 8.16 ± 1.2

4±1

8.91 ± 1.2 4± I

NS NS

*MPY expressesthe average volume of an individual platelet and is calculated electronically by the Counter-S}, by the integration of platelet pulse heights over a period of 3 seconds. tData are shown as mean ± standard error of the mean. :j:Not significant (t test).

with a platelet count higher than 190 X 109/ L. Plateletrich plasma was prepared by centrifuging citrated blood (3.2%) at 1,200 rpm for 10 minutes. The normal slope of aggregation was 45 degrees or higher and normal aggregation percent was above 50% to 60%. (The range of normal slope and percent aggregation was determined in our laboratory on 50 normal control subjects and exactly fitted the specifications given by Chrono-Log Corporation in their manual of operating instructions). Factor VIII procoagulant activity was assayed by the one-stage method. Factor VIII-ristocetin cofactor was assayed by the method of Weiss and associates." Factor VIII-related antigen was determined according to the method of Laurell." Factor VIII two-dimensional cross electrophoresis was performed. 23 Platelet aggregation tests were studied before administration of heparin and 1, 2, and 24 hours after cardiopulmonary bypass. Student's t test was used for statistical analysis.

Results There was no statistically significant difference in preoperative platelet count and MPV between the two groups (Table 11). All patients had a normal preoperative bleeding time. Postoperatively there was a drop in platelet count from the mean preoperative count of 190 X 109/L to 114 X 109/L in group A and 98 X 109/L in Group B (p = NS) (Fig. 1, Table III). However, MPV was 8.68 ± 1.1 and 7.7 ± 0.84 fl in Groups A and B, and PCT was 0.116% ± 0.04% and 0.075% ± 0.02% in Groups A and B, both being significantly lower in the group of bleeders (p < 0.05) (Table III, Fig. 2). No patients in the bleeder group had a PCT level higher than 0.095% (Fig. 2). The aggregation tests (adenosine diphosphate, 3

The Journal of

Thoracic and Cardiovascular

43 6 Mohr et al.

PLATELETS X

Surgery

I I I

10'!L

PLATELET COUNT

Table m. Postoperative platelet count, MPV, and peT

MEAN PU\TELET VOLUME lMPV)

Platelet count (XIO'/L) MPV (f1) PCP (%)

200

Group A (nonbleeders)

Group B (bleeders)

Significance

114 ± 40

99 ± 20

NS

8.68 ± 1.1 0.116 ± 0.04

7.7 ± 0.84 0.075 ± 0.02

p <0.05

p <0.05

'Volume percentage of platelets in whole blood.

150

Table IV 100

Normal level Bleeders Nonbleeders p Value

50

PRE BYPASS

POST 1 2 BYPASS TI ME AFTER BYPASS (HOURS)

24

Fig. 1. Effect of cardiopulmonary bypass on platelet count and mean platelet volume (MPV).

collagen, 0.02 mgjml; and ristocetin, 1.2 mgjml) were normal preoperatively in the 20 patients studied (Figs. 3, 4, and 5A) but abnormal postoperatively (Figs. 3 to 5) (Table IV). Of significance were the findings of three postoperative patterns of aggregation responses to ristocetin. 1. Delayed response (between 35 and 75 seconds) (grade I dysfunction). In these patients, after the aggregation commenced, it progressed and terminated normally (Fig. 5A). None of these patients had a bleeding tendency, and they all had a normal bleeding time. 2. Incomplete response (grade II dysfunction). An incomplete response was characterized by a poor progression of the aggregation (slope near 0 degrees) and a low percent of aggregation (Fig. 5, B). All five patients of this group showed prolonged bleeding time (above 7 minutes, Fig. 6), and clinically, two of them were bleeders. 3. No response (grade III dysfunction). In one patient there was no aggregation response to ristocetin (Fig. 5, C, Fig. 6). This patient was a heavy bleeder. In addition to the disturbed aggregation response to ristocetin, the three patients who bled also had platelet counts below 100 X 109jL (Fig. 7). Concerning factor VIII functions, there was no significant difference between plasma level of factor ~moljL;

VIlI:C (%)

VlIlR:Ag (%)

VlIlRRCo (%)

60-180 >100 >100 NS

60-200 136 ± 24 162 ± 17 NS

50-150 138 ± 38 115 ± 18.5 NS

Legend: VllI:C, Factor VllI procoagulant activity. VllIR:Ag, Factor VllIrelated antigen. VllIR:RCo, Factor Vlfl-ristocetin cofactor activity.

VIII procoagulant activity (VIII:e), factor VIII-related antigen, and factor VIII-ristocetin cofactor activity in the bleeding and nonbleeding patients. Results of factor VIII two-dimensional electrophoresis performed in the bleeding patients were found to be within normal limits.

Discussion In this post-cardiopulmonary bypass study, three types of changes in platelets were observed: a decrease in platelet count, a decrease in platelet size, and a disturbance in aggregation response to ristocetin. As observed by others, 15, 19, 24 cardiopulmonary bypass caused a drop in platelet count to 60% to 70% of the preoperative values (corrected for hematocrit) (Fig. 1). This decrease lasted for about 1 hour, and approximately 2 hours later the platelet number spontaneously rose to 80% to 90% of the preoperative value. There was a similar decrease in the platelet count in nonbleeders and bleeders. The mechanism of reduction of platelet count has been described elsewhere.25 The present report also confirms previous observations that extracorporeal circulation does not cause a reduction of MPV. 26 However, a subgroup of patients who bled postoperatively did have a significantly lower MPV and PCT. This decrease in MPV was not observed in patients who did not bleed postoperatively. The reduced MPV observed in the group of bleeders is probably due to aggregate formation" and elimination of the young and large platelets by the filters of

Volume 92 Number 3, Part 1

Effect of cardiac operation on platelets

September, 1986

peT (%)

TIME (MIN)

• •

0,18

437

0.16 0.14 0,12

•

0.10

:.

3

-

••

.: • •• • •

0.08

0.06 0,04

2

••

AGGREGATION - 44% SLOPE -

1.3

•

0.02

o

I

NON-BLEEDERS

BLEEDERS

Fig. 2. Immediate postbypass volume percentage of platelets in whole blood (peT) in the groups of bleeders versus nonbleeders.

10

20

30

40

50

60

70

00

90

100

Fig. 4. Effect of extracorporeal circulation of aggregation response to collagen (0.02 mg/rnl),

TIM!' (MIN)

fliSTOCETlN POSTOPEl'.ATfVE

(DELAYED RESPONSE) AGGREGATION -

SLOPE -

55%

0.8

RISTQCETlN PREOPERATIVE

AGGREGATION -

2

SLOPE -

DP POSTOPERATIVE AGGREGATION

1

SLOPE -

ADP PREOPERATIVE

32%

AGGREGATION

1.2

SLOPE -

85%

1.4

......,..~--r--,--...------.--,...--r--r---, %

o

W

W

~

~

~

~

ro

00

~

90%

1. 7

~

Fig. 3. Effect of extracorporeal circulation on aggregation response to adenosine triphosphate (ADP) (3 ~mol/L).

extracorporeal circulation. Young platelets are larger and function better than the smaller and older platelets." The selective elimination of young platelets can explain the bleeding tendency. No patients in the bleeder group had a PeT level higher than 0.1%, and

10

20

30

40

50

60

70

80

90

100

Fig. SA. Effect of extracorporeal circulation on aggregation response to ristocetin (1.2 mg/rnl). Delayed response (grade I dysfunction).

this number can serve as a good criterion for the need for platelet transfusion after operation. Hence, despite the fact that platelet count was similar in the bleeder and nonbleeder groups, it was the reduced MPV and PeT that apparently made the difference. The second important observation was related to platelet dysfunction, as was evidenced by the disturbed

The Journal of Thoracic and Cardiovascular Surgery

43 8 Mohr et al.

TIME (MIN) TIME (MIN) RISTOCETIN (CONTROL)

RISTOCETIN

6

AGGREGATION

(I NCOMPLETE RESFONSE)

2 AGGREGATION -

5

SLOPE -

85X

1. 6

SLOPE -

32%

0.2

4

3 RISTOCETIN (TEST) NO RESPONSE

2

2

1

RISTOCETIN (TEST) NO RESPONSE

00

10

20

30

40

50

80

70

60

100

90

CD o

20

10

30

40

50

60

80

70

90 100

Fig. 5. Coot'd. B. Incomplete response (grade II dysfunction). C. No response (grade III dysfunction). C DELAYED RESPONSE BLEEDING TII1E (MIN)

16

oNO RESPONSE • INCOMPLETE RESPONSE

JJf..

12

•

'f" BLEEDER

PLATELETS X

~BLEEDER

10' /L

•

•

200

8

•

150

7

o

0

n

o

0

•

••

•

• • • • 100 • 90 +-------------------

n

4 C

•

•

50

1020304050600

•

• •

C

o

NON-BLEEDER

•

250

•

•

D

o

90

100

RISTOCETIN AGGREGATION (X)

Fig. 6. The relation between ristocetin aggregation, bleeding time, and bleeding tendency after cardiac operations.

o

10

20

30

40

50

60

RISTOCETIN AGGREGATION

70

80

90

100

(Xl

Fig. 7. The relation of platelet count and ristocetin aggregation to bleeding tendency after cardiac operations.

Volume 92 Number 3, Part 1 September, 1986

aggregation tests. Activation of platelets by the surface of the tubing of extracorporeal circulation resulted in release of numerous substances, including beta thromboglobulin and platelet factor 4 from alpha granules. The depleted alpha granule content probably interferes with the ability of the platelets to aggregate." Another mechanism of aggregation disturbance is by increase in plasma concentration of the released platelet-inhibiting agents, such as prostaglandin, prostacyclin, and adenosine triphosphate. 28. 29 The dysfunction of the platelets is displayed by the reduced sensitivity of aggregating agents, such as adenosine triphosphate, collagen, and ristocetin. 14, 28 In the present study the only aggregation disturbance that appeared to be of clinical importance was related to ristocetin. Three grades of disturbed response to ristocetin were observed: In grade I, the mildest form, there was a delayed response, namely, a delay of 35 to 75 seconds from introduction of ristocetin until the beginning of aggregation, which thereafter progressed to normal levels. In grade II, defined as incomplete response, the rate of aggregation progression was slow and aggregation reached lower than normal levels (average 20% ± 7.5%). In grade III, the most severe form, no platelet aggregation appeared in response to ristocetin. A good correlation was found between bleeding tendency and the ristocetin response: Of the 20 patients studied, 14 had grade I ristocetin response and none of them had a bleeding tendency. The remaining six with grade II or III ristocetin responses had prolonged bleeding times. Three among them bled (two had a grade II response and one, grade III). The disturbed ristocetin response is similar to that found in von Willebrand's disease.v-" However, in contrast to the typical response observed in von Willebrand's disease, wherein the in vitro addition of cryoprecipitate to the platelets of patients corrects the disturbed aggregation, after cardiac operations cryoprecipitate improved but did not correct the disturbed response to ristocetin. In the present study the tests of factor VIII activity, factor VIII-related antigen, factor VIII-ristpcetin cofactor, and two-dimensional electrophoresis of factor VIII were normal. Several recently published studies stressed the importance of factor VIII/von Willebrand on platelet adhesion and aggregation, especially in situations with high shear rates and long perfusion times.31,32 It was also demonstrated that much of the platelet-endothelium interaction depends on specific von Willebrand/factor VIII receptor molecules on the plate-

Effect of cardiac operation on platelets 4 3 9

let membrane." The findings of our study suggest that, unlike in von Willebrand's disease, extracorporeal circulation causes a temporary damage or blockade of the receptor site to factor VIII/von Willebrand on the platelet membrane. The importance of the receptors on the platelet membrane was shown in other studies: Musial and associates" showed loss of fibrinogen receptors from the platelet surface during simulated extracorporeal circulation. The use of drugs that act on factor VIII receptor on the platelet membrane improved postbypass platelet function and decreased bleeding." In a recently published study, Addonizio and coworkers" demonstrated functional and morphologic damage to platelet membrane caused by the synthetic surface of the extracorporeal circuit. This damage was prevented by using a stable prostacyclin derivative

(Iloprost)." Another commonly used explanation for the disturbed aggregation observed after cardiopulmonary bypass is related to the disturbed prostacyclin-thromboxane equilibrium.Y":" On the basis of this theory, clinical trials using agents such as prostacyclin and prostaglandin during cardiac operations have been conducted. 19, 39-41 These short-acting prostaglandins indeed prevented platelet aggregation during the operation and have improved the postoperative platelet number and activity. REFERENCES

2 3

4

5

6

7

Bachman F, McKenna R, Cole ER, Najafi H: The hemostatic mechanisms after open heart surgery, J THORAC CARDIOVASC SURG 70:76-82, 1975 Trimble AS, Herst R, Grady M, Crookston JH: Blood loss in open heart surgery. Arch Surg 93:323-326, 1966 Esposito RA, Culliford AT, Calvin SB, Thomas SJ, Lackner H, Spencer FC: The role of the activated clotting time in heparin administration and neutralization for cardiopulmonary bypass. J THORAC CARDIOVASC SURG 85:174-185,1983 McKenna R, Bachmann F, Whittaker BS, Gilson JR, Weinberg MJR: The hemostatic mechanism after openheart surgery. II. J THORAC CARDIOVASC SURG 70:298308, 1975 Verska 11: Control of heparinization by activated clotting time during bypass with improved postoperative hemostasis. Ann Thorac Surg 24: 170-173, 1977 Andersen MN, Hambracus G: Physiologic and biochemical responses to prolonged extracorporeal circulation. Experimental studies during four-hour perfusion. Ann Surg 153:592-598, 1961 Peterson KA, Dewanjee MK, Kaye MP: Fate of indium Ill-labeled platelets during cardiopulmonary bypass per-

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22

Mohr et al.

formed with membrane and bubble oxygenators. J THaRAC CARDIOVASC SURG 84:39-43, 1982 Olinger GN, Hussey CV, Olive JA, Malik MI: Cardiopulmonary bypass for patients with previously documented heparin-induced platelet aggregation. J THORAC CARDIaVASC SURG 87:673-677, 1984 Plachetka JQ, Salomon NW, Larson DF, Copeland JG: Platelet loss during experimental cardiopulmonary bypass and its prevention with prostacyclin. Ann Thorac Surg 30:58-63, 1980 Hennessy VL Jr, Hicks RE, Niewiarowski S, Edmunds LH Jr, Colman RW: Function of human platelets during extracorporeal circulation. Am J PhysioI232:H622-H628, 1977 Edmunds LH Jr, Saxena NC, Hillyer P, Wilson TJ: Relationship between platelet count and cardiotomy suction return. Ann Thorac Surg 25:306-310, 1978 Harker LA, Malpass TW, Branson HE, Hessel EA II, Slighter SJ: Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass. Acquired transient platelet dysfunction associated with selective alpha granule release. Blood 56:824-834, 1980 Friedenberg WR, Myers WO, Plotka ED, Beathard IN, Kummer DJ, Gatlin PF, Stoiber DL, Ray JF III, Sautter RD: Platelet dysfunction associated with cardiopulmonary bypass. Ann Thorac Surg 25:298-305, 1978 Beurling-Harburg C, Galvan CA: Acquired decrease in platelet secretory ADP associated with increased postoperative bleeding in post-cardiopulmonary bypass patients and in patients with severe valvular heart disease. Blood 52:13-23, 1978 Edmunds LH Jr, Ellison N, Colman RW, Niewiarowski S, Rao AK, Addonizio VP Jr, Stephenson LW, Edie RN: Platelet function during cardiac operation. Comparison of membrane and bubble oxygenators. J THORAC CARDIaVASC SURG 83:805-812, 1982 Slichter SJ, Harker LA: Thrombocytopenia. Mechanisms and management of defects in platelet production. Clin Hematol 7:523-539, 1978 Bick RL: Alterations of hemostasis associated with cardiopulmonary bypass. Pathophysiology, prevention, diagnosis and management. Semin Thromb Hemost 3:59-82, 1976 Thomas R, Hessel EA II, Harker LA, Sands MP, Dillard DH: Platelet function during and after deep surface hypothermia. J Surg Res 31:314-318, 1981 Radegran K, Aren C, Teger-Nilsson AC: Prostacyclin infusion during extracorporeal circulation for coronary bypass. J THORAC CARDIOVASC SURG 83:205-211, 1982 Born GVR, Cross MJ: The aggregation of blood platelets. J PhysioI168:178-195, 1963 Weiss HJ, Hoyer LW, Rickles FR, Varma A, Rogers J: Quantitative assay of a plasma factor deficient in von Willebrand's disease that is necessary for platelet aggregation. Relationship to factor VIII precoagulant activity and antigen content. J Clin Invest 52:2708-2716, 1973 Laurell CB: Electroimmunoassay. Scand J Clin Lab Invest 124:Suppl 21-37, 1972

The Journal of Thoracic and Cardiovascular Surgery

23 Laurell CB: Antigen-antibody crossed electrophoresis. Anal Biochem 10:358-361, 1965 24 Addonizio VP Jr, Smith JB, Guiod LR, Strauss JF III, Colman RW, Edmunds LH Jr: The relationship between thromboxane synthesis and platelet protein release during simulated extracorporeal circulation. Blood 54:371-376, 1979 25 Ware JA, Scott MA, Horak JK, Solis RT: Platelet aggregation during and after cardiopulmonary bypass. Effect of two different cardiotomy filters. Ann Thorac Surg 34:204-206, 1982 26 Laufer N, Merin G, Grover NB, Pessachowicz B, Borman JB: The influence of cardiopulmonary bypass on the size of human platelets. J THORAC CARDIOVASC SURG 70:727731, 1975 27 Eldor A, Avitzour M, Or R, Hanna R, Penchas S: Prediction of haemorrhagic diathesis in thrombocytopenia by mean platelet volume. Br Medical J 285:397-400, 1982 28 Addonizio VP Jr, Macarak EJ, Niewiarowski S, Colman RW, Edmunds LH Jr: Preservation of human platelets with prostaglandin E, during in vitro cardiopulmonary bypass. eirc Res 44:350-357, 1979 29 Holme S, Holmsen H: ADP-induced refractory state of platelets in vitro. Scand J Haematol 15:96, 1975 30 Miller JL, Castella A: Platelet-type von Willebrand's disease. Characterization of a new bleeding disorder. Blood 60:790-793, 1982 31 Gralnick HR, Williams SB, Coller BS: Asialo von Willebrand factor interactions with platelets. Interdependence of glycoproteins Ib and lIb/IlIa for binding and aggregation. J Clin Invest 75: 19-25, 1985 32 Houdijk WPM, Sakariassen KS, Nievelstein PFEM, Sixma JJ: Role of factor VIII-von Willebrand factor and fibronectin in the interaction of platelets in flowing blood with monomeric and fibrillar human collagen types I and III. J Clin Invest 75:531-540, 1985 33 Ruggeri ZM, Zimmerman TS: Platelets and von Willebrand disease. Semin Hematol 22:203-218, 1985 34 Musial J, Niewiarowski S, Hershock D, Mormelli TA, Colman RW, Edmunds LH Jr: Loss of fibrinogen receptors from the platelet surface during simulated extracorporeal circulation. J Lab Clin Med 105:514-522, 1985 35 Czer L, Bateman T, Gray R, Raymond M, Chaux A, Matloff J, Stewart M: Prospective trial of DDAVP in treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass. Circulation 72:Suppl 3:519, 1985 36 Addonizio VP Jr, Fisher CA, Jenkin BK, Strauss JF III, Musial JF, Edmunds LH Jr: Iloprost (ZK36374), a stable analogue of prostacyclin, preserves platelets during simulated extracorporeal circulation. J THORAC CARDIOVASC SURG 89:926-933, 1985 37 Walker 10, Davidson JF, Faichney A, Wheatley DJ, Davidson KG: A double-blind study of prostacyclin in cardiopulmonary bypass surgery. Br J Haematol 49:415423, 1981 38 Faichney A, Davidson KG, Wheatley DJ, Davidson JF,

Volume 92 Number 3, Part 1 September, 1986

Walker 10: Prostacyclin in cardiopulmonary bypass operations. J THORAC CARDIOVASC SURG 84:601-608, 1982 39 Longmore DB, Hoyle PM, Gregory A, Bennett JG, Smith MA, Osivand T, Jones W A: Prostacyelin administration during cardiopulmonary bypass in man. Lancet 1:800803, 1981 40 Malpass TW, Amory OW, Harker LA, Ivey TO, Williams DB: The effect of prostacyelin infusion on platelet

Effect of cardiac operation on platelets 44 1

hemostatic function in patients undergoing cardiopulmonary bypass. J THORAC CARDIOVASC SURG 87:550-555, 1984 41 Coppe D, Sobel M, Seamans L, Levine F, Salzman E: Preservation of platelet function and number by prostacyelin during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 81:274-278, 1981

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