SIGNIFICANCE OF ANTITHROMBIN III MEASUREMENT IN PATIENTS ADMITTED TO AN INTENSIVE CARE UNIT

GUALTIERO PALARETI -::, LAURA MINELLI -:>, CRISTINA LEGNANI ::, OTTAVIO BOGG1AN ~:, ANNA SARA CORTICELLI ::"::', SERGIO COCCHERI ~:-

Ospedale Policlinico S. Orsola, Bologna

Servizio di Angiologia e Malattie della Coagulazione ~

Servixio di Terapza Intensiva ~*

Marked alterations in blood coagulation and fibrinolysis are very often found in intensive care patients, induced either by the underlying diseases or by complications that frequently take place under these conditions, such as acute or chronic disseminated intravascular coagulation (DIC), thromboembo- lism and /o r bleeding.

The aims of our study were to critically investigate ill patients admitted to an intensive care unit (ICU), in order to find any early sign of DIC or other hemostatic disturbances and secondly to evaluate the significance of blood clotting tests, particularly the measurement of antithrombin III (ATIII) activity in the follow-up and clinical prognosis of these patients.

MATERIALS AND METHODS

We have studied the blood coagulation pattern of a series o~" 32 severely ill patients (age 46.9 _+ 22.8) consecutively admitted to our ICU for a 60-day period. Diagnoses upon admission were: various postoperative complications (13 patients); multiple and severe trauma (5 patients); sepsis, respiratory failure (3 patients each); coma, severe poisoning (2 patients each); myocardial infarc- tion, acute stroke, liver failure, burns (one patient each). All patients were ex- amined upon admission (blood testing 1, BT1) and survivors were reexam- ined on average after 4 days (blood testing 2, BT2).

The percentage of the ICU fatal cases was 43.7% (14 patients, age 63.7 ___ 7.6), while the survival rate was 56.3% (18 patients, age 39.9 + 22.1, p < 0.001). Six surviving patients were dismissed and 9 patients died in the ICU within three days of admission. Thus, the blood testing 2 was performed only

Key words. Antilhrombin ti1; Blood clotti~tg le.~t~; Disseminated intrava.~cular coagMatiwt; Intensive care.

La Ricevca Clin. Lab. l-l, 527, 1984.

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ANTITHROMBIN llI IN INTENSIVE CARE

on 17 patients, of whom 12 survived and 5 subsequently died; 30 healthy subjects were also studied as a control group.

The following blood clotting tests were carried out: - prothrombin time (PT): Thromborel ~ reagent (Behring Institute); - a c t i v a t e d partial thromboplastin time (APTT): Pathrorntin | reagent

(Behring Institute) ; - fibrinogen: fibrinogen reagent [Boehringer Biochemia Robin (BBR)]; - antithrombin III: a. activity (ATIII-Ch) was measured using the chromo-

genie assay new antithrombin III (BBR); b. protein (ATIII-Imm) was measured using Nor-Partigen | (Behring Institute);

- flbrinogen degradation products (FDP): were measured using the SPLI- Prest test (BBR);

- fibrin monomer (FM) complexes: were detected using the FM-test (BBR); - platelet count.

RESULTS

Results (mean • SD) of the blood clotting tests upon admission of patients and their statistical significance are reported in tab. 1. When compared with the control group, the group of patients showed lower prothrombin activity (p < 0.001), higher fibrinogen level (p < 0.001), lower ATIII protein (p < 0.001) and ATIII activity (p < 0.001); FDP and FM complexes were frequently present. Patients who subsequently died had, in comparison with survivors, lower

survivors Lttal cases tests {no. = 18) (rio. = 14)

PT (%) 74 • 24

APTT (sec)

tibrinoo en (rag%)

ATIII-Ch (%)

ATIIl-lmm (mg%)

FDP (no. of" cases, >_ 10 big/•

FM (no. of positive cases)

}latelets x 1,000

COlltro] all 32 patients group

65 • 2-t 95 • 9.5

p < {}.001

40.9 • 13.8 38.2 • 3.2

359 • 177 220 • 32

p<0,O01

68 + 99 107 • 11

p<0 .001

99 _ 2.4 _, .6 + 5.7 27.2 •

p<0 .001

23 (71.9%)

15 (40.6%)

19,5 +- 133

37.2 • 10.6

401 • 182

52 • 16

p<O.Ol

45.7 • 16,3

304 ~ 160

218

0

0

• 62

78 • 16 53

p < 0 . 0 0 5

25.6 • 4.3 16.2 _+ 5.3

p < 0 . 0 0 1

i0 (55%) 13 (92.8%)

5 (27 %) I 0 (71%)

232 • 157 144 • 65

T a b . 1 - Resu l t s o f b l o o d c l o t t i n g tests u p o n patients" a d m i s s i o n c o m p a r e d w i t h t h o s e o f fl~e c o n t r o l g r o u p a n d s e p a r a t e l y reported for surviving patients and fatal cases. T h e s tat i s t ica l s i g n i f i c a n c e wa s calculatt~d by n'~e;tns o[" the Sittd{wtt's t' test.

528

G. P A L A R E T I e t al.

prothrombin activity (p<0.01), ATIII protein (p<0.001) and ATIII activity (p < 0.005); FDP were present in almost all cases and FM complexes were also very frequently present. An association of ATIII activity lower than 60%, FDP higher than 40 b~g/ml and positive FM test was found in 6 cases, who subse- quently all died.

When the results of BT2 were compared with those of BT1, an increase in ATIII-Ch levels was found only in the patients who finally survived (11/12 cases), but not in the fatal cases. In fact, the mean of the differences in ATIII-Ch levels, calculated in each patient between BT2 and BT1, was +15.6% in surviv- ing patients and -1.9% in the fatal cases (p < 0.05). No other test showed the same prognostic implication.

DISCUSSION

This study demonstrates that blood clotting patterns are very often alter- ed in severely ill patients admitted to an ICU. The most important feature observed was the frequent presence of signs of intravascular disseminated coagulation: reduced ATIII levels and prothrombin activity; presence of fibrin monomer complexes and FDP.

The age of patients and blood clotting tests performed upon patients' admission showed a prognostic value. In fact, patients who died in the ICU were older than the survivors and their ATIII protein and activity levels were markedly reduced, together with lower prothrombin activity and a more clear presence of fibrin monomers and FDP. A fatal clinical outcome could always be predicted when a very low ATIII activity was associated with high FDP levels and presence of fibrin monomer complexes.

In the second blood clotting study almost all patients who survived showed an increase in ATIII-Ch values in comparison with basal values. This test was the only one showing a significantly different trend between patients who recovered and those who subsequently died.

Our results are in line with previous works that tbund reduced ATIII activity levels in patients with severe and critical acute conditions. Bm~ et al. ~ studied 38 patients who had acute or chronic DIC and found an early and significant decrease in ATIII levels that improved during therapy, thus reflecting a cessa- tion of consumption phenomena. SCmPeER et al. 7 studied patients in surgical intensive care and found significantly lower ATIII levels in those with a com- plicated postoperative course, as compared with those without complications. ATIII activity normalized in patients who recovered, but remained low in patients who did not recover. Similar results were obtained by KIERULF et al. s in patients with multiple trauma and by AASEN et al, ~ in patients with acute pancreatitis.

Our study on patients in an ICU confirms that monitoring ATIII activity may serve as a useful diagnostic and prognostic tool regardless of the admission diagnoses and gives correct information about the efficacy of the therapy. In fact, it is well known that the effect of heparin, widely used for the therapy of DIC, is dependent on the ATIII activity :.~ When the latter is reduced, as often occurs in cases of DIC, the efficacy of heparin therapy is also reducedq For this reason measurement of ATIII activity should always be carried out, in principle, before heparin administration.

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ANTITHROMBIN Ill IN INTENSIVE CARE

Fast and accura t e d e t e r m i n a t i o n o f ATIII activity in these condi t ions can be ach ieved by the c h r o m o g e n i c pep t ide subs t ra te assays. T h e s e tests are una f f ec t ed by the possible p r e s e n c e o f FDP a n d / o r h e p a r i n in the s amp le and, f u r t h e r m o r e , they a re easy to p e r f o r m and can be a u t o m a t e d .

In conclus ion, we sugges t to r e p e a t e d l y inves t iga te the b l o o d coagu la t ion p a t t e r n in critically ill pa t ients a d m i t t e d to an ICU, and in pa r t i cu la r to closely m o n i t o r ATIII activity as a useful d iagnost ic , t he rapeu t i c and p r o g n o s t i c tool in these condi t ions .

REFERENCES

1. AASEN A. O., KIERULE P., RUUD T. E., GODAL H. C., AUNE S.: Studies on pathological p la sma proteolysis in patients with acute pancreatitis. A preliminary report - Acta chir. scan& 509 (Suppl.), 83, 1982.

2. BARROWCLIFFE T. W., jOHNSON E. A., THOMAS D.: A n t i t h r o m b i n IlI and h e p a r i n - Brit. reed. Bull. 34, 143, 1978.

3. BICK L. R., BICK M. D., FEKETE L. F.: A n t i t h r o m b i n IlI pa t t e rns in d i s s e m i n a t e d in t ravascu la r coagulation - Amer. J. clin. Pathol. 73, 577, 1980.

4. BLAUHUT B., NECEK S., KRAMER ['~., VINAZZER H., BERGMANN }-t.." Activity Of" antithrombin tit and effect ofheparin on coagulation in shock - Thrombos. Res. 19, 775, 1980.

5. KIERULF P., AASEN A. O., AUNE S., GODAL H. C., RUUD T. E., VAACEJ.: C h r o m o g e n i c pept ide substrate assays in patients with multiple trauma -Acta chir. scan& 509 (Suppl.), 83, 1982.

6. ROSENBERG R. D.: Action and interactions of antithrombin and heparin - New Engt. J. Med. 292, 146, 1961.

7. SCHWPER H. G., ROSS j,, MEULEN F., TEM CATE J. W.: Antithrombin III deficiency in surgical intensive care patients, In: SCHIPPER H. G. (Ed.): Antithrombin III and human antithrombin II1 concentration. Clinical and experimental studies. Rodopi Publ., Amsterdam, 1980; p. 48.

Requests for reprints should be addressed to"

SERGIO COCCHER~ Servizio di Angiologia

e Malattie della Coagulazione Ospedale Policlinico S. Orsola

Via G. Mas~arenti 9, 40138 Bologna - Italia

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