Bleeding after liver biopsy does not correlate with indices of peripheral coagulation

Bleeding After Liver Biopsy Does Not Correlate with Indices of Peripheral

Coagulation KLAUS EWE, MD

Contraindications for percutaneous liver biopsy are often derived arbitrarily from coagulation status of peripheral blood, but no objective data are available on the duration of bleeding from the site o f liver biopsy. "Liver bleeding time" (LBT) was measured after liver biopsy had been performed at laparoscopy in 200 consecutive patients using a 1.8- mm-diameter Menghini needle. LBT was then analyzed in relation to prothrombin time, platelet count, whole blood clot time, length of biopsy cylinder, and liver histopathology. There was no correlation among any of these variables. The average LBT was 4 min 37 sec +- 3 min 48 sec (so). In 10 patients LBT was prolonged over 12 min (X + 2 SD), but their clotting indices were not different from those of other patients. Bleeding could be stopped easily by compression if necessary. This lack of correlation may be explained by the high concentration of clotting factors in hepatic parenchyma and by mechanical compression of the needle track by the elastic tissue in the liver. It is concluded that indices of coagulation in the peripheral blood used in this study are unreliable guides of the risk of bleeding after liver biopsy and, hence, are o f l imited value in determining contraindications to this procedure.

Indications for liver biopsy are many; and the ease of performance, infrequent complications, and diagnostic importance have led to its widespread appli- cation. Contraindications are few, the most fre- quent being that a bleeding diathesis is suspected. However, this contraindication is assessed arbitrarily from indices of clotting in peripheral blood, and no measurements are available of the actual bleeding time from the site of liver biopsy.

Recommendations for acceptable limits of coagulation status for liver biopsy vary widely. Standard textbooks require that the prothrombin time not be prolonged more than 3 sec and that the platelet count be above 80,000/mm 3 (1, 2); another authority suggests a prothrombin time of more than 50% and

Manuscript received March 17, 1980; revised manuscript received July 22, 1980; accepted July 24, 1980.

From the Medical Clinic, Mainz, West Germany. Address for reprint requests: Professor Klaus Ewe, I. Medical

Clinic, Langenbeckstr. l, 6500 Mainz, West Germany.

a platelet count above 100,000/mm 3 (3), and a fourth (4) states that "on occasion the procedure may be carried out safely with a prothrombin level of 40%." However, most clotting factors are produced in the liver and decreased prothrombin activity and platelet counts are common in cirrhosis. In fact, dis- orders of clotting should be expected in many clini- cal situations where liver biopsy is an important diagnostic procedure.

Personal observations during laparoscopy have indicated that bleeding from the liver is not prolonged in patients with long prothrombin times and thrombocytopenia. This prospective study exam- ined "liver bleeding time" in relation to peripheral clotting factors, length of the biopsy cylinder, and hepatic histopathology.

MATERIALS AND METHODS

Patients. Two hundred consecutive patients were stud- ied at laparoscopy, at which time liver biopsy was per-

388 Digestive Diseases and Sciences, Vol. 26, No. 5 (May 1981) 0163-2116/81/0500-0388503.00/1 �9 1981 Digestive Disease Systems, Inc.

BLEEDING A F T E R LIVER BIOPSY AND PERIPHERAL CLOTTING

formed. During this time, no patients were excluded on the grounds of abnormal clotting indices. The only contraindication for biopsy at the time of laparoscopy was if severe obstructive jaundice was suspected on the basis of the appearance of the liver and bilirubin levels above 10 mg/100 ml. There were 67 women and 133 men with an average age of 50.3 years (range 21-82 years).

The h i s t o l o g i c a l d i agnoses were : n o r m a l or minor changes, 38; fatty liver, 58; acute hepatitis, 6; chronic persistent hepatitis, 3; chronic active hepatitis, 21; cirrhosis, 57; metastatic carcinoma, 8; and others, 9.

The last group of nine cases consisted of cholangitis in 5, amyloidosis in l , hemochromatosis in 1, and gran- ulomatous hepatitis in 2. Among the fatty liver group most cases were chronic alcoholics with various degrees of fibrosis but no cirrhosis.

Laboratory Tests. Human thromboplastin containing calcium was used for a one-stage prothrombin time deter- mination (Thromborel, Behring Institute, Marburg, West Germany). Results were expressed as percentage prothrombin activity, the lower range of normal being 70%. Standard curves were drawn for each new batch of thromboplastin. Roughly, a drop of 10% corresponds to a 1-sec prolongation of prothrombin time, 13.5 -+ 2.5 sec corresponding to 100%.

The normal range of thrombocytes (Thrombocounter, Coulter Electronic Co.) was 150,000-300,000/mm 3.

In order to evaluate the entire intrinsic coagulation system in a single, simple test, the whole blood clot time was selected despite its obvious crudity. Ten ml of venous blood were placed into a plastic tube which was closed and tilted every 30 sec. Complete clotting occurs normal- ly in 6-12 min.

Not all tests were available at the time of laparoscopy in all patients. Therefore the numbers of patients available for correlation with liver bleeding time were slightly

less than 200 for each index (178 for prothrombin time, 174 for platelet count, 171 for the whole blood clot time).

Liver Bleeding Time (LBT). LBT was defined as the time elapsing between the moment of the biopsy and the termination of hemorrhage, as determined by irrigation of the liver surface. After the biopsy, a thin needle was in- serted through the abdominal wall using the puncture of the Menghini needle. Saline (154 mM NaC1) was then dripped on the liver surface, inferior to the puncture site, at the rate of 20-30 drops/min. Initially, saline was flushed down the surface of the liver by the blood, but when bleeding stopped, the saline washing over the liver surface remained clear. The time required for the saline to become clear was called the liver bleeding time.

In three patients, the puncture site was compressed by a probe because bleeding lasted longer than 15 min and in a fourth case because very minor bleeding was still pres- ent at 30 min.

Laparoscopy and Biopsy. Laparoscopy was performed using a cold light source (R. Wolf Co., Knittlingen, West Germany). Biopsy was performed with a Menghini needle having an outer diameter of 1.8 mm. Biopsies were taken usually from the right lobe of the liver, and the left lobe was used only when biopsy from the right lobe was not possible for technical reasons. In five cases, two biopsies were taken. The length of the biopsy cylinder was imme- diately measured or, if fragmented, estimated.

Statistical Methods. Correlation coefficients were determined for LBT vs prothrombin time, thrombocyte count, whole blood clot time, and length of the biopsy cylinder. Multiple correlation coefficients were calculated by a stepwise procedure using LBT as the dependent variable and the other indices as independent variables. A BMDP/ 2 program was used for these calculations. Correlations were performed separately for the different diagnostic groups as well as for the total group of observations.

Liver Bleeding Time (min)

12

10-

8- 0411 0

: I �9 18"

" �9 " " "oo !0 " �9 % , . 6 - . . : . " --:!:

eo ~176 | * ~ 4 ' 3 7 " - . . . . . . . . . . . . . . . . . % ' - i . . . . . . -~ - ~ i - -- - -~- - * - ,~ - - -- - - q - - --

4 - $ eO �9 �9 � 9 1 4 9 o e �9 �9 et=e ~ �9 �9 e % t l . . . . . " . q

" �9 o~ o ~ 0 | ~ I �9 : 00 . . . . , . : . - . ' ~ 2- �9 �9 0 5

�9 �9 ~176 eo �9

�9 eo �9 �9 I e e �9

I : r-- * /o ,b 2b 3'o 4b ~b 6b ro 8'0 9'o loo

Prothrombin Time (Quick) Fig 1. Correlation of liver bleeding time and prothrombin time (' = min; " = sec). Horizontal line: average LBT; vertical line: lower limit of normal (70%).

Digestive Diseases and Sciences, Vol. 26, No. 5 (May 1981) 389

EWE

Liver Bleeding Time ( min )

30' ,18' lS' ]

�9 �9 ]

I I

1 0 o o ] - �9 �9 80 I l l �9

8 ~ �9 o~ ~ �9 �9

�9 o~ o � 9 0 �9 �9 �9 6 �9 �9 6 �9 �9 �9

s_ ~ �9 �9 �9 . o i 4 3 7 " t . . . . " - e t ' r e - - - - - 'v I " "o- - - ~ - e - �9 . . . . . . . . t . . . . . . . . . . 1 - -

4 t � 9 1 4 9 � 9 �9 I � 9 1 4 9 � 9 1 4 9 " � 9 �9 �9 �9 ~ o � 9 � 9 �9 o � 9 �9 �9 �9 l ,, _,..._,,,''L,_ ,, 00. �9 �9

/ �9 �9 . . . . . o3 '-

l . . . . k . . . . , , , " , ~ )_ I ' l b o " 2 6 0 ' - 3 o o 4 0 o s o � 9 l / r a m 3

T h r o m b o c y t r C o u n t x l 0 3

Fig 2. Correlation of liver bleeding time and thrombocyte count (' = min;" = sec). Horizontal line: average LBT, vertical line: lower limit of normal (150,000/mm3).

Comparisons between different groups of liver diseases as diagnosed by biopsy were performed for LBT and coagulation indices. A one-way analysis of variance with subsequent testing of all pairwise differences using the method of Schaffee was employed for these calculations. In cases where two biopsies had been obtained, the average of the two LBTs is reported. The individual LBTs of these cases were: 3 and 1; 5 and 3.5; 8.5 and 3.5; 0 and 1; 1 and 4.5; 2.5 and 2.5 min. Patients in whom compression was applied were excluded from this last analysis.

RESULTS

There was no correlation of statistical significance be tween L B T and any of the indices o f coagulation, underlying liver disease , or the length o f the biopsy cylinder.

LBT and Clotting Parameters. The mean and SEM of L B T of all cases was 4 min 37 sec -+ 16 sec. Cor-

re lat ion analyses be tween coagulat ion tests and

Liver

8

6 �84

i 4~37 " - 4

2

BLeeding T ime ( min )

i i 29' 18'

10

�9 o � 9 �9 � 9 �9 �9 �9 �9 *

15' 30'

27 'D , -~

3 0 '

_ s o _ | | 8 �9 �9 ~ e �9 - ' - - z . - % ~ : - . . - - . . - - ~ - - - - - - q - - - 1 . . . . . . . . . %,~.k -

:......,::.,.i : �9 . _ _ .;. ... , ' , ' . , . . ' 3 ~

o o ~ �9 �9 �9 I �9

�9 I

WhoLe B lood Ctot Time Fig 3. Cor re l a t ion o f l ive r b leed ing t ime an d wh o le b lood clot t ime ( ' = min; " =

sec). Horizontal line: average LBT; vertical line: upper limit of normal (12 min).

390 Digestive Diseases and Sciences, Vol. 26, No. 5 (May 1981)

BLEEDING AFTER LIVER BIOPSY AND PERIPHERAL CLOTTING

TABLE 1. CORRELATION OF L B T WITH THE FIVE MOST ABNORMAL VALUES OF DIFFERENT CLOTTING INDICES

Other indices Most abnormal

values LBT Thrombocytes Whole blood Prothrombin time (%) (rain) (per mm ~) clot time (min)

11 4 11 4 24 7 30 5 33 11.5

Thrombocy tes

77,000 7 280,000 25

- - 10 137,000 3 127,000 8

Pro thrombin Whole blood t ime clot t ime

30,000 6 64 31,000 4 69 6-~5 34,000 0.5* 83 35,000 3. 34 6 36,000 1.5 93 9

Whole blood clot t ime

Pro thrombin t ime Thrombocy te s

30 3.5 49 105,000 30 7 55 201,000 27 6.0* 40 78,000 25 4 11 280,000 21 1 43 635,000

*Average f rom two biopsies.

LBT are shown in Figures 1-3. Normal LBT was found when the clotting indices were highly abnormal, such as prothrombi n times of 11%, platelet counts of 30,000/mm ~, and whole blood clot time of 30 min. The five lowest values of single clotting indices and the corresponding LBT are listed in Table 1. On the other hand, LBT was considerably prolonged in some cases with normal clotting values.

Since it is possible that a combination of abnormal indices might be more important, multiple correlation coefficient analysis was performed. No sta- tistically significant correlation with LBT was found in these cases either. This was even true among cir- rhotics, who were characterized by a high incidence of pathological values.

LBT and Length of Cylinder. There was no correlation between the LBT and the length of the biopsy cylinder (Figure 4), and almost no bleeding oc- curred after retrieval of the largest cylinder (4.75 c m ) .

LBT and Liver Histology. No difference of statistical significance was seen in the LBT of various liver diseases (Figure 5), Patients with chronic active hepatitis and metastases did not bleed longer than patients with normal or nearly normal hepatic histology. Mean bleeding time was slightly longer in

the patients with fatty liver and cirrhosis, but there was a wide variation within these groups.

Prolonged or Heavy Bleeding. In 10 cases bleeding lasted longer than 12 min (X --+ 2 so) (Table 2). It stopped spontaneouslyin six. Compression was applied in four; three were bleeding profusely. In the other, blood was still oozing from the biopsy site after 30 min. Bleeding was stopped easily in all cases within a few minutes. Coagulation studies were within the range of other cases with the same conditions, and there was no evident explanation for the prolonged bleeding in individual case~.

DISCUSSION

Severe bleeding after percutaneous liver biopsy is rare, In an early survey of the literature by Terry (5) in 1952, 11 deaths from hemorrhage after biopsy wit h the Vim-Si lverman needle were repor ted among 10,600 cases, all in patients witha "hopeless prognosis."

In 1964 Thaler (6) reported on 20,382 Menghini biopsies in a survey from multiple centers. There was one death from hepatic hemorrhage and nine cases with major intraabdominal bleeding: six received transfusions, three had to be operated. In a similar survey Of 79,381 patients, Lindner (7) reported six deaths from hepatic hemorrhage, and 50

Liver Bleeding Time (rain)

3 0 '

14

12- �9

10-

e � 9 �9 8-

6- �9 ~ I. �9 * � 9 ~" S �9

rx 4 '37"1L -- -- ,r- t _~_ _~. . _ _~._~_ _ _ 2 _ _ _ 4 4 �9 " L I : " �9 a.

2 "

I i a a ~ 2 4

Length of Biopsy Cytinder(cm) Fig 4. Correlat ion of liver bleeding t ime and length of biopsy cylinder (' = min; " - sec). Horizontal line: average LBT; vertical line: average length of biopsy cylinder (2.1 crr0.


LBT {min)

6

3

2

I I

38 22

. d

t~ L L

58 57

I

d=

(.9

Fig 5. Liver bleeding time and histopathology (N = number of patients).

additional patients had substantial intraabdominal bleeding: 26 required transfusion and 4 laparotomy. A wide range of opinions was offered by those sur- veyed. Some indicated that patients were not biopsied if prothrombin levels were below 65% and platelet counts below 60,000/mm 3. Others accepted values as low as 30% and 30,000/mm 3, respectively.

Although the percentage of severe hepatic hemorrhage after biopsy was very low in both studies (0.5 and 0.7%, respectively), the exact risk of bleeding after biopsy cannot precisely be determined because accepted limits of coagulation status varied considerably and patients with severe clotting dis- turbances are not in general biopsied. However, two studies from France suggest that biopsy can be safely performed even in patients with fulminant hepatitis in spite of severely deranged clotting mechanisms (8, 9).

In principal one would expect prolonged bleeding from a vascular organ like the liver in patients with

E W E

abnormal clotting. Several factors may be important.

In vivo clotting mechanisms may remain suffi- ciently intact despite significant abnormalities as measured in vitro. Thus, the coagulation status as measured in the peripheral blood does not necessar- ily reflect that in the area of the puncture site in the liver. Local clotting factors of liver origin may be important, such as the presence of tissue throm- bokinase released after cell injury.

A second factor may relate to the fact that local tissue elastic forces may serve to compress the puncture channel and thus occlude it. The fact that the biopsy cylinder length did not relate to the liver bleeding time may be consistent with this idea. Dammermann et al (10) found slightly longer liver bleeding times following biopsy with a 1.8-mm needle compared to a needle of 1.2 mm diameter in patients with cirrhosis. This effect was not apparent in patients with other liver diseases, and this was attributed to the reduction in elastic forces in the cirrhotic liver. In our series, in cirrhosis and fatty liver mostly with various degrees of fibrosis, bleeding was also slightly longer than in the cases with little or no pathological findings. However, this difference did not reach statistical significance.

Finally, there is undoubtedly a random element in that rarely a puncture will be directed through a me- dium sized or large vessel, in which case clotting and compression factors will be relatively unimpor- tant.

The results of these studies cannot be applied without reservation to the conditions of "blind" percutaneous liver biopsy. The possibility of de- layed bleeding could not be assessed, the number of cases was small, and more detailed and sophisti-

TABLE 2. P A T I E N T S W I T H PROLONGED B L E E D I N G T I M E (>12 MIN)*

LBT Prothrombin Thrombocytes Whole blood (rain) t ime (%) (per mm ~) clot time (min) Diagnosis

12 -- 78,000 12 Primary biliary cirrhosis 15 52 53,000 17 Active alcoholic cirrhosis 18 100 108,000 4.5 Acute hepatitis with cholestasis 30 46 125,000 12 Active alcoholic cirrhosis

12 51 62,000 5 Active cirrhosis 12.5 77 89,000 8.5 Fatty liver 13 42 135,000 8 No significant findings 13.5 73 99,000 -- Fatty liver (alcoholic) 14 74 71,000 16 No significant findings 29 -- -- 32 Fatty liver (alcoholic)

*In the first 4 cases compression was applied, in the latter 6 bleeding stopped spontaneously.

392 Digestive Diseases and Sciences, Vol. 26, No. 5 (May 1981)

BLEEDING AFTER LIVER BIOPSY AND PERIPHERAL CLOTTING

cated studies of clotting mechanisms, such as studies of platelet function, assays of specific coagulation, and fibrinolytic factors and inhibitors, were not performed. However, our patients were gener- ally representative of a sick hospital population and included several with prothrombin activity as low as 10% of normal and platelets as few as 30,000/ mm 3. Therefore it may be concluded from this study that the peripheral coagulation status, as ascer- tained in this study, is an unreliable guide for the evaluation of the risk of bleeding after liver biopsy and, hence, of limited value in determining the contraindications for this procedure. Consequently, the question arises: should the peripheral coagulation status prior to "blind" liver biopsy be abandoned? Our results and those of the French authors (8, 9) tend to point in this direction as far as the bleeding from the liver is concerned, with all the reservations mentioned above. However, it should be kept in mind that the biopsy needle has to pass the abdominal wall before it enters the liver and coagulation conditions here may be and probably are different from those of the liver. This imposes an additional risk of bleeding in disturbed clotting and is an argu- ment for still performing a peripheral clotting status before liver biopsy.

If in doubt as to whether biopsy can be performed because of severe coagulation abnormalities, lap- aroscopic liver biopsy should be preferred to blind biopsy because bleeding can be controlled by compression if necessary.

ACKNOWLEDGMENTS

Drs. U. Baas, V. Eckardt, K. H. Holtermfiller, R. Wa- nitschke, Th. Weihrauch, H. Weis (Mainz), J. Nord (Tampa, Florida) participated in the laparoscopies.

REFERENCES 1. Isselbacher KJ, LaMont JT: Diagnostic procedures in liver

diseases. In Principles of Internal Medicine, TR Harrison (ed). New York, McGraw-Hill, 1977, pp 1580-1584

2. Sherlock S: Diseases of the Liver and Biliary System, 5th ed. Oxford, Blackwell Scientific, 1975

3. Menghini G, Ghergo GF: needle biopsy of the liver. In Gas- troenterology, Vol llI. HL Bockus (ed). Philadelphia, W. B. Saunders, 1976, pp 88-112

4. Edmondson HA, SchiffL: Needle biopsy of the liver. In Dis- eases of the Liver, 4th ed, L Schiff(ed). Philadelphia, J. B. Lippincott 1975, pp 247-263

5. Terry R: Risks of Needle biopsy of the liver. Br Med J 1:1102-1105, 1952

6. Thaler H: Uber Vorteil und Risiko der Leberbiopsiemethode nach Menghini. Wien Med Wochenschr 76:533-538, 1964

7. Lindner H: Grenzen und Gefahren der perkutanen Leber- biopsie mit der Menghininadel. Dtsch Med Wochenschr 92:1751-1757, 1967

8. Paliord P, Patricot F, Grimond JA: Les alterations histologi- ques des hepatites grave et leur evolution. A propos de 45 observations suivies par biopsies. Ann Gastroenterol Hepat 8:133-150, 1972

9. Scotto J, Opolon P, Eteve J, Vergoz D, Thomas M, Caroli J: Liver biopsy and prognosis in acute liver failure. Gut 14:927-933, 1973

10. Dammermann R, Budweg A, Garbe W, Gestefeld K, Grote W, Seevers HH: AbhS.ngigkeit der Nachblutung nach Leber- biopsien yon dem Nadelkaliber. In Fortschritte gastroenter- ologische Endoskopie, H Henning (ed). Baden-Baden, Witzstrock Verlag, 1978, pp 131-132


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Bleeding after liver biopsy does not correlate with indices of peripheral coagulation