hemostatic abnormalities in total artificial heart patients as detected by specific blood markers

Hemostatic Abnormalities in Total Artificial Heart Patients as Detected by Specific Blood Markers Jeanine M. Walenga, PhD, Debra Hoppensteadt, MS, Jawed Fareed, PhD, and Roque Pifarre, MD Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, Illinois

We retrospectively evaluated the hemostatic system of 13 patients during implantation (2 to 35 days) of the Jarvik 7-70 total artificial heart (TAH). Although all patients were clinically manageable while on the TAH, 5 had excessive generalized bleeding. After the heart transplant procedure, 2 patients had neurological events and 1 patient, thrombosis of the leg. While the patients were supported by the TAH, the routine coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen, factor assays, and platelet count) showed slight abnormalities but no correlation to hemorrhagic or thrombotic events. In contrast, plasma and cellular activation markers, which are highly sensitive and specific for hypercoagulability, fibrinolysis, or platelet activation, revealed activation in all patients. Most striking was the marked activation of the fibrinolytic system ( p < 0.05 to 0.001). Correlations of individual

he use of the total artificial heart (TAH) as a bridge to T transplantation has made possible the survival of patients with end-stage cardiac disease until a donor heart becomes available. The first human implantation was performed in 1969 by Cooley and colleagues [l], and the first successful bridge to heart transplantation was accom- plished by Copeland and associates [2] in 1985.

Beginning in 1988, the Jarvik 7-70 TAH (Symbion, Inc, Salt Lake City, UT) has been used in patients at Loyola University Medical Center with end-stage heart failure as a bridge over time until an appropriate donor human heart becomes available for transplantation. Although these patients and those at other institutions have experienced varying degrees of hemorrhagic complications and occasional thrombotic episodes, the overall successful outcome has highly warranted continued use of the TAH. However, as stated by Joyce and co-workers [3], "although the incidence of transient ischemic attacks and cerebrovascular accidents is much less frequent than initially expected with the permanent use of the TAH, it does continue to be a potential threat during the time of implant ."

To further understand what effect the TAH and its associated surgical intervention have on the hemostatic

Accepted for publication Oct 21, 1991.

Address reprint requests to Dr Walenga, Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153.

patient data compared with the average TAH group response could be made between excessive enhancement of fibrinolysis (increased D-dimer and tissue plasminogen activator and decreased plasminogen activator inhibitor) and bleeding. A hypercoagulable state (increased fibrinogen and thrombin-antithrombin complex and decreased antithrombin I11 and protein C), decreased fibrinolysis (decreased tissue plasminogen activator and D-dimer), activated platelets (increased thromboxane BJ, or combi- nations of these were associated with thrombosis. The hemostatic activation returned to normal 1 day after removal of the TAH. These data suggest that the patient with a TAH requires more sophisticated laboratory monitoring and individualized treatment for excessive fibrinolysis, hypercoagulable state, or platelet activation to avoid thrombotic and hemorrhagic complications.

(Ann Thorac Surg 1992;53:844-50)

system of this patient population, we have undertaken a study to investigate the hemostatic profile of TAH recipients. Because only limited hemostatic data on a few TAH patients are available [3-81, we chose this screening ap- proach to evaluate specific plasma and cellular markers of thrombotic, fibrinolytic, platelet, and endothelial function. The results of these assays were compared with the results of the routinely ordered coagulation tests (prothrombin time [PT], activated partial thromboplastin time [APTT], fibrinogen, and platelet count).

Because of their nature (specificity of origin and sensi- tivity in response to stimuli), alterations in these variables indicate the initial changes that occur at specific biochemical sites associated with activation of the hemostatic system, well before any alteration in the PT, A m , and fibrinogen assays is observed [9-131. It is now possible to detect not only a hypocoagulable state (leading to hemorrhage) but also a hypercoagulable state (leading to thrombosis). In addition, the cause of the disorder can be identified through these plasma markers. For example, a severe hemorrhage can be caused not only by a lack of coagulation factors or loss of platelet function but also by an excess of fibrinolytic activity. Clearly, the treatment in each case would be different. Furthermore, risk factors and the initial phase of activation can be detected rather than only the major changes to which the PT, APTT, and fibrinogen respond. Through the clinical use of these hemostatic markers, a more defined diagnosis and thus a

0 1992 by The Society of Thoracic Surgeons 0003-4975/92/$5.00

Ann Thorac Surg 1992;53:844-50

WALENGA ET AL 845 TAH-INDUCED HEMOSTATIC ABNORMALITIES

Table 1. Summary of Data on Patients Supported With a Total Artificial Heart ~ ~~~~

Days on Admitting Diagnosis

No. Age Patient (Y) Sex TAH Status

1 26 M 10 ICM, CAD, MVI, LVD Died 14 mo after Tx (chronic rejection) 2 52 M 17 Failed Tx Alive 3 42 M 33 ICM, CAD, postcardiotomy CS Died 14 d after Tx (multiple CVAs) 4 64 M 14 DCM, CHF, arrhythmias, Alive

ventricular tachycardia 5 62 M 23 ICM Alive 6 25 M 2 DCM Alive 7 59 M 2 ICM, acute MI Alive 8 25 F 2 Postpartum ICM, cardiac arrest Alive 9 55 M 35 ICM, acute MI, CS Died 4 mo after Tx (CMV, Pneumocystis

pneumonia) 10 18 M 6 Giant cell myocarditis Alive 11 60 F 5 ICM, CAD, CS Died 8.5 mo after Tx (bronchopneumonia

12 16 M 2 DCM, MVI Alive 13 19 M 2 ICM Alive

CAD = coronary artery disease; CHF = congestive heart failure; CMV = cytomegalovirus; CS = cardiogenic shock; CVA = cerebrovascular accident; DCM = dilated cardiomyopathy; ICM = ischemic cardiomyopathy; LVD = left ventricular dysfunction; MI = myocardial infarction; MVI = mitral valve insufficiency; TAH = total artificial heart; Tx = transplantation.

with multiple-organ failure)

more targeted treatment of thrombotic and hemorrhagic disorders of TAH recipients should be possible.

Material and Methods A total of 13 patients (11 male and 2 female) were entered in this study (Table 1) [14]. Patients received the Jarvik 7-70 TAH as a bridge over time until a donor heart became available and was transplanted (range, 2 to 35 days of support; 7 patients I 6 days and 6 patients 2 10 days). The patients ranged in age from 16 to 64 years (mean age, 40 f 18 years; 6 patients < 30 years old and 5 patients 2 55 years old). The clinical diagnoses included cardiomyopathy (11 patients: 8 ischemic and 3 dilated), giant cell myocarditis (1 patient), and failed heart transplant (1 patient). Additional associated complications included cardiogenic shock (3 patients), coronary artery disease (3 patients), acute myocardial infarction (2 patients), mitral valve insufficiency (2 patients), ventricular dysfunction (2 patients), and terminal congestive heart failure (1 patient).

While supported by the TAH, all patients were given intravenous heparin sodium to maintain the activated clotting time at 170 to 200 seconds (normal, 70 to 100 seconds) and dipyridamole (100 mg four times a day).

Blood samples were collected in citrate or EDTA (eth- ylenediaminetetraacetic acid)/indomethacin once daily (early morning draw) from patients while on the TAH. Blood was collected through an indwelling Swan-Ganz catheter. The initial 10 mL of blood was discarded so as not to contaminate the specimen with flush heparin. Blood collection tubes were placed on ice and immediately centrifuged at 2,000 g for 20 minutes at 4°C to obtain cell-free plasma. Aliquots of plasma were immediately frozen (-70°C) for analysis within 3 weeks.

The clinical orders for laboratory evaluation included PT, APTT, fibrinogen, fibridfibrinogen split products, platelet count, complete blood count, and plasma free hemoglobin. Other tests ordered as needed were thrombin time, antithrombin I11 (AT 111), factors VII, IX, and X, and bleeding time.

For this study, several blood variables specific for coagulation and fibrinolytic, platelet, or endothelial activation were measured:

Coagulation System Variables PT* APTT* Fibrinogen* Fibridfibrinogen split products* Factor assays* Thrombin time* Bleeding time* AT I11 Protein C Protein S Thrombin-antithrombin (TAT) complex

D-dimer Fibrinogen degradation products Fibrin degradation products Total degradation products Tissue plasminogen activator (PA) Plasminogen activator inhibitor (PAI) Plasminogen a*- Antiplasmin

Fibrinolytic System Variables

* This is a routine clinical order.

846 WALENGA ET AL TAH-INDUCED HEMOSTATIC ABNORMALITIES

NORMAL

Ann Thorac Surg 1992;53:%50

50.-

Platelet Variables Platelet count* Platelet factor 4 Thromboxane B, (TxB,) 6-Keto prostaglandin F,, (PGF,,)

tPA PA1 PGFl,

Other Complete blood count* Plasma free hemoglobin*

Endothelium Variables

These variables include activators, inhibitors, and by- products of biochemical reactions.

The TAH patient group was compared as a whole with a normal population (apparently healthy, nonsmoking, nonobese, and nonmedicated). Further comparisons were made between the TAH-supported patients with complications (hemorrhagic or thrombotic) and the average TAH group response. Statistical analysis was performed by analysis of variance with significance determined at a p value of less than 0.05. These studies were approved by the Internal Review Board of Loyola University Chicago before their undertaking.

Results While on the TAH, 8 patients (62%) showed no major hemostatic abnormalities, whereas 5 patients (38%) experienced hemorrhagic complications and required an ex- ploratory operation. Because no definite bleeding site was identified at reoperation, the bleeding in these 5 patients was recorded as a generalized coagulation disorder, not a technical problem associated with implantation of the device. These patients received fresh frozen plasma, platelets, cryoprecipitate, or a combination of these.

All patients underwent heart transplantation. After transplantation, 1 patient sustained a massive stroke within 48 hours, 1 patient experienced a transient ischemic attack, and 1 patient had development of venous thrombosis of the leg. The overall long-term survival rate (>1 year after transplantation) of these patients is currently 69% (9/13).

Coagulation System Evaluation For global screening of coagulation function, the PT and APTT assays were performed in patients supported by the TAH. The values for both assays were slightly prolonged above normal. However, there were no changes throughout the TAH period in patients with or without bleeding complications. The PT values ranged from 13.1 to 14.8 seconds (normal, 10 to 12 seconds) and the APTT values, from 34.3 to 50.3 seconds (normal, 32 to 34 seconds).

Assays for factors VII, IX, and X showed little variation during TAH support. Levels were typically 80% to loo%, except in 1 patient with 45% to 65% levels. The level of factor VIII, a reactive protein, on the other hand, was typically elevated (100% to 200%) in all patients with the

* This is a routine clinical order.

TAH. Similarly, fibrinogen values were somewhat elevated compared with normal and actually rose during the days of TAH support from an average of 3.5 g/L (350 mg/dL) to 4.5 g/L (450 mg/dL) ( p < 0.004 versus normal).

Antithrombin I11 is an important inhibitor of activated coagulation factor X and thrombin. Levels of AT I11 were significantly lower than normal, averaging approximately 60% ( p < 0.001) on the first day (Fig 1). A slight increase of 5% to 10% was noted after the first day on the TAH. Protein C, an inhibitor of factors Va and VIIIa, was also significantly lower than normal, ranging from approximately 28% to 40% ( p < 0.001) during the first 2 days on the TAH and remaining low in most patients over the first 10 days (Fig 2). Protein S, the cofactor for protein C activation, was low (33% to 42%; p < 0.001) during the first 2 days of TAH support but increased to nearly normal levels afterward (see Fig 2).

The TAT complex is formed when coagulation is acti-

% NORMAL

"'T A-A PROTEIN C m-¤ PROTEIN S

p NORMAL 100- I RANGE T -

A

* 0 I

1 2 3 4 5 6 7 8 9 1 0 ~ 1 0

TAH DAYS

Fig 2 . Daily morning blood plasma samples, collected during the course of total artificial heart (TAH) support, were analyzed for protein C and protein s, two plasma inhibitors of coagulation. Results represent a mean ? one standard error of the mean. (*p < 0.05 by t test.)

Ann Thorac Surg 1992:5384&50

.r T


OF NORMAL

NGlML 15

10

5

0 1 2 3 4 5 6

* T

TAH DAYS

Fig 3. Daily morning blood plasma samples, collected during the course of total art$cial heart (TAH) support, were analyzed for thrombin-antithrombin complex, a marker of coagulation activation. Results represent a mean 2 one standard error of the mean. (*p < 0.05 by t test.)

vated, and the formed thrombin then binds to circulating AT 111. The TAT complex is thus a marker of a hypercoagulable state. On days 1 through 3 of TAH support, the TAT complex levels were significantly elevated to 6 to 9 ng/mL (normal, 1 to 4 ng/mL) (p < 0.001) (Fig 3). Gradu- ally these levels fell but remained elevated at 4 to 6 ng/mL for up to 10 days on the TAH (p < 0.001).

Fibrinolytic System Evaluation In all TAH patients, levels of fibridfibrinogen split products were highly elevated, indicating coagulation or fibrinolytic activation or both. These blood samples were analyzed by newer, more sensitive assays to determine specifically the extent of fibrinolytic activation. Quantita- tion of the total (fibrin and fibrinogen) degradation products revealed levels of 3 to 7 pg/mL (normal, <0.2 pg/mL) (p < 0.001) during the first 10 days of TAH support (Fig 4).

rGlML

1 2 T

I A d TDP .-8 FbDP e-0 FaDP i

I-

//

* . - 0

UPPER LIMIT -OF NORMAL

1 2 3 4 5 6 7 8 9 l o r 1 0

TAH DAYS

Fig 4. Daily morning blood plasma samples, collected during the course of total artificial heart (TAH) support, were analyzed for fibrin degradation products (FbDP), fibrinogen degradation products (FgDP), and total degradation products (TDP), the sum of the preced- ing two variables. These are markers of fibrinolytic system activation. Results represent a mean * one standard error of the mean. (*p < 0.05 by t test.)

rGlML

9 * "i 1

3 1 UPPER LIMIT

: : : : : : : : : ! I OF NORMAL 1 2 3 4 5 6 7 8 9 10>10

TAH DAYS

Fig 5. Daily morning blood plasma samples, collected during the course of total art$cial heart (TAH) support, were analyzed for D-dimer, a marker of fibrinolytic system activation. Results represent a mean ? one standard error of the mean. (*p < 0.05 by t test.)

The levels of fibrinogen degradation products were only slightly elevated with the TAH, 0.3 to 0.5 pg/mL (normal, (0.2 pg/mL) (p = 0.05) but remained elevated for 10 TAH support days (see Fig 4). The levels of fibrin degradation products, on the other hand, were highly elevated at 2 to 6 pg/mL (normal, < 0.2 pg/mL) (p < 0.001) for all TAH support days (see Fig 4).

D-dimer is currently the most specific blood marker to indicate ongoing fibrinolytic activation. In the TAH patients, markedly elevated levels of D-dimer were measured, 3,000 to more than 5,000 ng/mL (normal, 50 to 300 ng/mL) (p < 0.001), throughout the entire 10 days of TAH support examined (Fig 5).

The major components of the fibrinolytic system are plasminogen, the active enzyme that degrades fibrin, and a2-antiplasmin, an inhibitor of plasminogen. About half of the patients had low levels of plasminogen (40% to 60% of normal; p = 0.03) and a,-antiplasmin (50% to 70% of normal;

0-0 (I 2 ANTI-PLASMIN A-A PLASMINOGEN

% NORMAL

125

100

75

50

1 2 3 4 5 6 7 8 9 10210

TAH DAYS

Fig 6. Daily morning blood plasma samples, collected during the course of total artificial heart (TAH) support, were analyzed for cy2-

antiplasmin, an inhibitor of fibrinolysis, and plasminogen, an activator of fibrinolysis. These are markers of fibrinolytic system activation. Results represent a mean 2 one standard error of the mean. (*p < 0.05 by t test.)


Ann Thorac Surg 1992;53:844-50

p = 0.01). Both variables increased to 90% of normal after 10 days on the TAH (Fig 6).

Levels of tPA, an activator of plasminogen, were significantly elevated in the TAH patients, ranging from 7 to 14 ng/mL (normal, 1.0 to 4.0 ng/mL) (p < 0.001) (Fig 7). Three patients showed excessively high levels of tPA (>15 ng/mL). Levels of PAI, the inhibitor of tPA, generally followed a similar pattern as tPA but did not become as elevated. The PA1 levels ranged from 3 to 9 ng/mL (normal, 1 to 4 ng/mL) (p 5 0.01) (Fig 7). Two patients showed PA1 levels higher than 15 ng/mL. There was more variation in the data for PA1 than for tPA.

Evaluation of Platelets The platelet count was normal but showed a slight de- crease during the first days on the TAH (90 to 200 x 109L [90 to 200 x 103/pl] versus normal, 250 to 350 X 109L [250 to 350 X 103/pL]). A trend showing an increase in platelet count after 7 days of TAH support was observed with platelet counts rising to 200 to 300 X 109/L (200 to 300 x l@/pL). Platelet factor 4 is a substance released from platelets when they are activated. The platelet factor 4 levels were elevated more than tenfold (>lo0 ng/mL) over normal levels (4 to 8 ng/mL). No differences were observed between patients. These levels remained elevated over the first 10 days of TAH support.

Thromboxane B, is a prostaglandin synthesized in the platelet. It is a potent platelet-aggregating agent that is released on platelet activation. The TxB, levels were significantly elevated during the first TAH days, ranging from 400 to 500 pg/mL (normal, 90 to 110 pg/mL) (p < 0.001). These levels fell after 4 days of TAH support to about 300 pg/mL but remained higher than normal (p < 0.001) (Fig 8).

6-Keto prostaglandin F,, (PGF,,) is a prostaglandin synthesized in the vascular endothelium. It is a potent anti-platelet aggregating agent. The levels of PGF,, were markedly elevated in TAH patients immediately postop- eratively but then fell to 150 to 250 pg/mL (normal, 90 to 110 pg/mL) (p < 0.001). This elevated level was not as

nglml 30-1

204 - 15

10

5 UPPER LIMIT

or : : : : : : : : : : 4 -

1 2 3 4 5 6 7 8 9 lor10

TAH DAYS

Fig 7. Daily morning blood plasma samples, collected during the course of total artificial heart (TAH) support, were analyzed for tissue plasminogen activator (t-PA), an activator of fibrinolysis, and plasminogen activator inhibitor (PAI), an inhibitor of fibrinolysis. These are markers of fibrinolytic system activation. Results represent a mean 2 one standard error of the mean. (*p < 0.05 by t test.)

a 100 NORMAL

RANGE

0 0 1 2 3 4 5 6 7 8 9 1 0 > 1 0

TAH DAYS

Fig 8. Daily morning blood plasma samples, collected during the course of total artificial heart (TAH) support, were analyzed for thromboxane B, (TXB,) and 6-keto prostaglandin F,, (PGF,,), markers of platelet activation and inhibition, respectively. Results represent a mean rf: one standard error of the mean. (*p < 0.05 by t test.)

significant as the elevation of TxB,, but it remained elevated for 10 TAH support days (see Fig 8).

Comment In this study of the TAH patient, the possible abnormalities that can occur in the components of the hemostatic system were investigated: the platelets, the fibrinolytic system, the coagulation system, and to some extent the endothelium. The TAH patients were compared as a group during time of support with a normal control group (plasma pool from 5 male and 5 female apparently healthy 25- to 35-year-olds). A surgery control group (ie, patients having completed cardiopulmonary bypass for an elective operation) was not selected for the following reasons: The hemostatic values in the normal population are well established. The typical postoperative response, although investigated in pilot studies, has not been established for all hemostatic variables in all surgical procedures. It is known that changes in some of the hemostatic markers occur with operation [15, 161; however, whether a rela- tionship to a clinical abnormality in the postoperative phase exists has not yet been defined. This study provides information as to the hemostatic changes that occur as part of the TAH experience, ie, the combination of the patient’s disease, operation, use of extracorporeal circulation, catheterization, artificial surface and rheological effects of the TAH, and other medical manipulations (eg, intraaortic balloon pump).

Alterations in hemostatic variables resulting from general surgical manipulation are known to recover to normal levels within 2 days after operation [16]. This pattern was observed for plasminogen and a,-antiplasmin and even more evidently for PA1 and PGF,, in our TAH study. However, the level of the other markers remained consistently elevated with the TAH (up to 35 days postopera- tively) and returned to normal the first day after its removal. This pattern suggests that these hemostatic changes were, in fact, due to the TAH. In general, a hypercoagulable state, platelet activation, and, most crit-

Ann Thorac Surg 1992;5384450


ical, excessive fibrinolytic activation were present in these patients. Perhaps more importantly, however, a change from the average TAH patient response (group mean) could often be associated with excessive bleeding or clotting disorders.

A hypercoagulable state was determined by the increased level of the TAT complex in most patients. The TAT complex forms when thrombin is generated by coagulation activation. With heparin treatment, however, this interaction is modified. Heparin will enhance the binding between thrombin and AT 111 but also attenuate the amount of thrombin generated. Overall, in a well- managed surgical patient there will be a moderate increase in the TAT complex level [17]. On the other hand, lower than expected TAT complex levels could be indica- tive of thrombin or AT I11 consumption.

In 2 patients, a lower than average TAT complex level was observed for several consecutive days. One patient sustained a stroke and the other, a transient ischemic attack after heart transplantation. In 3 other patients, the TAT levels fluctuated between less than the TAH group mean and the TAH group mean levels. Several days after these fluctuations began, the patients experienced episodes of excessive bleeding from the mediastinum, which responded to treatment with fresh frozen plasma and cryoprecipitate. Patients with no hemorrhagic or thrombotic complications had higher than normal, but steady, TAT levels.

Evaluation of the important inhibitors of the coagulation cascade revealed low levels of protein C, low levels of AT 111, and normal levels of protein S in the TAH- supported patients. The low protein C and AT III levels would contribute to the development of a hypercoagulable state. In 1 patient who had a very unstable postoperative course, consistently low protein C levels (30% to 40%) were observed. In addition, 2 patients with consistently higher fibrinogen levels than the TAH group average experienced a thrombotic episode after heart transplantation.

Analysis of the fibrinolytic system with the routine fibridfibrinogen split products assay indicated activation of fibrinolysis in all patients at all times. The total degradation products assay, like the fibridfibrinogen split products assay, measures the breakdown products of fibrin and fibrinogen. Unlike the fibridfibrinogen split products assay, however, the total degradation products assay is quantitative and uses an antibody that recognizes epitopes of earlier generated, smaller particles. D-dimer specifically identifies a breakdown product of cross-linked (polymerized) fibrin. Thus, elevated levels of D-dimer are a clear indication that an organized thrombus had formed, which then underwent lysis (thrombolysis).

Both the D-dimer and total degradation products assays revealed significantly elevated clotting/fibrinolytic activity. Further testing showed that approximately 85% of the total degradation products were derived from the degradation of fibrin, and only 15% were derived from the degradation of fibrinogen. This indicates largely a second- ary, not a primary, fibrinolytic state.

To understand what caused this excessive activation,

several components of the fibrinolytic system were quantitated. Levels of plasminogen and 0,-antiplasmin, the central enzyme and the inhibitor, respectively, of the system, were only decreased during the early days on the TAH but were normal thereafter. On the other hand, the tPA levels were significantly increased throughout all days on the TAH, and PA1 levels were slightly elevated.

Tissue plasminogen activator is the major activator of plasminogen, whereas PA1 is the important inhibitor of tPA. The ratio of tPA to PA1 in the TAH patients was 2.0 or greater for the group mean. Normally the ratio is 1.0 such that a balance is maintained between the two enzy- matic activities. The enhanced level observed in the TAH patient could have been a physiological compensation for the contact (coagulation) and platelet activation stimulated by the artificial surface and rheological effects of the TAH.

In several patients, the enhanced fibrinolysis was associated with bleeding from the mediastinum that was treatable with fresh frozen plasma and cryoprecipitate. Before treatment, these patients had a very elevated tPA level or a lower than TAH group average PA1 level. The effect of this was manifested in D-dimer levels higher than the TAH group average.

Conversely, in general, in the patients who experienced clinical thrombosis, the tPA levels were lower than the TAH group mean, the PA1 levels were higher than the TAH group mean, and the D-dimer levels were lower than the TAH group mean. In addition, the tPA to PA1 ratio was less than 2.0, indicating a lower level of fibrinolytic activity than what was generally observed in the TAH patients. These changes usually preceded the clinical event by several days. One patient had an elevation of fibrinogen degradation products, a finding indicating a primary fibrinolytic state.

To assess platelet activation, TxB, and platelet factor 4, both release products from the platelet, were quantitated. In general, all patients had levels elevated above normal during the entire period of TAH support. However, the patient who experienced a transient ischemic attack had a higher level of TxB,, a very potent platelet-aggregating substance, than the group average. This enhanced activity lasted at least 4 days before the clinical event occurred. Levels of platelet factor 4 were so elevated in all patients that it could not be used as a diagnostic aid. However, its antiheparin activity may have had some clinical significance.

Levels of PGF,,, a natural antagonist of TxB, because it is a potent anti-platelet aggregating substance, rose slightly with the TAH but returned to normal after its removal. This indicates that there was less than normal protection against the high TxB, levels. Although not done in this study, assays for platelet function would have been very interesting to measure.

In hemostasis, the platelet-vascular endothelium interaction is integral to normal function. The endothelium of the TAH patients was greatly stimulated, as suggested by the higher than normal levels of PGF,,, tPA, and PAI, all of which are derived from the vascular endothelium. Thus it appears that all aspects of the hemostatic system were


Ann Thorac Surg 1992;5384450

greatly activated in the TAH-supported patient, but that the natural balance between the components was still maintained, albeit at a higher level. However, in those patients not responding like the average TAH patient, excessive bleeding was observed. In those patients in whom thrombotic complications developed after transplantation, it is likely that the added stress of the second operation [14], coupled with the risk factors described here, set the stage for the development of these complications.

In the TAH patient, the alterations in the IT, APTT, activated clotting time, and thrombin time assays were useful to monitor heparin therapy. The factor assays and platelet count were useful to evaluate the patients for severe deficiencies that could be treated with blood com- ponent therapy. However, these routine assays did not reflect the physiological state of the patient or the efficacy of drug treatment, nor were they able to predict thrombotic or hemorrhagic complications.

The data from this study indicate that patients with a TAH should be evaluated not only by the routine coagulation assays but also by more sensitive plasma markers specific for coagulation (hypercoagulable), fibrinolytic, and platelet activation. In particular, the fibrinogen, protein C, TAT, tPA, PAI, D-dimer, and TxB, assays revealed diagnostically useful information.

We are indebted to Mary Bourassa, BS, MT(ASCP), Rosemary Murphy, BS, and Stephanie Weber, BS, MT(ASCP), for their invaluable technical skills; to the intensive care nursing staff for assistance in blood collection; and to Kathy Grady, RN, MS, and Linda Bartlett, RN, for help in obtaining medical record information. Our gratitude is extended to Maher Istanbouli, CCP, Jamal Sinno, CCP, and their staff for the expert monitoring of the TAH patients. We also express our gratitude to Prof J. W. ten Cate (Academic Medical Center, Amsterdam, the Netherlands) for his expert advice and helpful suggestions in the preparation of the manuscript.

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hemostatic abnormalities in total artificial heart patients as detected by specific blood markers

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