Coagulopathy Yasuto

in Chronic

KAWAKAMI,

Takaho

Subdural

TANIMOTO

and

Hematoma Yutaka

SHIMAMURA

Department of Neurological Surgery, Kobe West Municipal Hospital, Kobe

Abstract Coagulation

factors

hematoma. reduction tion

of XII.

antithrombin disorder caused

were

studied

in

30 fluids

aspirated

Factor

VIII

III were

and

IX inhibitors

decreased

and

were

not

present

fibrinopeptide

A was

causing these abnormal data spontaneously. the marked reduction of factor VIII, therefore

were affected extrinsic

from

25 patients

with

chronic

subdural

Compared with the normal range for plasma, the hematoma fluids demonstrated a marked in factors II, V, VII, VIII, and X, moderate reduction of factors IX and XI, and slight reduc

differently.

clotting

The

pathway

results

show

in hematoma,

excessive suggesting

or negligible. markedly

The decrease the intrinsic

activation

Activated

increased.

C and a basic

in activated protein C possibly and extrinsic clotting pathways

of coagulation,

its importance

protein

No case had

in the growth

predominantly via the of chronic

subdural

hematoma. Key words: activated

chronic protein

subdural

C,

hematoma,

antithrombin

III,

coagulopathy, fibrinopeptide

Introduction

chronic

Chronic subdural hematoma (SDH) is frequently associated with increased fibrinolytic activity which destabilizes hemostatic clotting resulting in recurrent hemorrhage from the hematoma capsule. 4,''8'2"4 However, coagulation in chronic SDH has been little studied. Labadie and Glover9) suspected coagulation mechanisms were important in chronic SDH growth as the subdural fluids from two patients demon strated accelerated intrinsic clotting. Kawakami et al.'s recently reported marked reductions of factors II, V, VII and X, and antithrombin III, and an in crease in fibrinopeptide A (FPA) in hematomas compared with venous blood in 19 patients. These results strongly suggest that coagulation is exces sively activated in chronic SDH. Coagulation initially proceeds by two separate pathways, the intrinsic and extrinsic systems, which converge by activating the final common pathway causing fibrin formation. The intrinsic system is initiated when blood contacts any surface except normal endothelial and blood cells. The extrinsic sys tem is initiated when tissue thromboplastin activates factor VII. The activities of these clotting pathways were evaluated in 30 hematoma fluids from 25 Received

March

6, 1990;

Accepted

June

11, 1990

extrinsic

clotting

SDH

patients.

system,

A

Materials

and

Methods

Twenty-nine chronic SDH patients were admitted to our hospital from May 1985 to July 1989. Four pa tients were excluded from the present coagulation study. One patient had a thoracoabdominal aortic aneurysm associated with diabetes and chronic renal failure which required dialysis 3 times a week. One patient was receiving chemotherapeutic agents for ovarian carcinoma when the chronic SDH was diagnosed. Two patients had acute blood clots or hygroma in the subdural space. The 25 patients were aged from 47 to 88 years (mean 68 years), including 19 males and six females, and presented with 12 right and 18 left hematomas. They had no signs and symptoms of hemorrhagic or gastrointestinal disorders or history of vitamin K related drugs. There were no significant abnor malities in serum glutamic oxaloacetic and pyruvic transaminases, lactate dehydrogenase, bilirubin, alkaline phosphatase, amylase, blood urea nitrogen, creatinine, red blood cell count, hematocrit, and hemoglobin concentrations. The bleeding and clot ting times were within normal limits. Three patients (Cases 1, 4, and 19) developed a recurrence and two patients (Cases 2 and 7) had bilateral hematomas.

The coagulation study investigated 30 hematoma fluids. Chronic SDH was aspirated under local anesthesia through a burr hole in the ipsilateral frontal region. About 10 ml of hematoma was removed through the outer hematoma membrane. Hematoma fluid samples in plastic tubes were centrifuged, then imme diately frozen and stored at -70°C until analysis. All clotting factors were assessed by the chromogenic substrate method." Factors II, V, VII, and X were evaluated by photometric prothrombin time assay and factors VIII, IX, XI, and XII by photometric activated partial thromboplastin time (APTT) assay. Factor VIII and IX inhibitors were measured by APTT assay using the Bethesda unit method.' Acti vated protein C was measured by the APTT clotting time method"' and antithrombin III by the synthetic chromogenic substrate method."' FPA was mea

Table

I

Coagulation

study

in 25 cases

with

chronic

subdural

sured

by radioimmunoassay.

"'

Results Table I summarizes the clinical results for all labo ratory tests. The hematoma volume ranged from 20 to 250 ml (mean 117 ml). Factors II, V, VII, VIII, and IX were measured in all 30 hematoma fluids and factors X, XI, and XII were measured in 29 (Fig. 1). Compared with the normal range for plasma: factor II in the hematomas was increased in one, normal in two, and decreased in 27; factor V was in creased in one, normal in one, and decreased in 28; factor VII was normal in four and decreased in 26; factor VIII was normal in two and decreased in 28, and was less than 1 % in 10 hematomas. Factor IX was increased in two, normal in nine, and decreased in 19; factor X was normal in two and decreased in

hematoma

Fig. 1

27; factor XI was increased in one, normal in 11, and decreased in 17; factor XII was increased in four, normal in 21, and decreased in four. Factor VIII and IX inhibitors, activated protein C, antithrombin III, and FPA were measured in all hematomas. The lower limits in measurement of activated protein C and antithrombin III were 10% and 25%, respectively and the upper limit of FPA was 50 ng/ml. Factor VIII inhibitor was not present in 18, 1 BU/ml in nine, and 2 BU/ml in three, and factor IX inhibitor was not present in 25 and 1 BU/ ml in five. Activated protein C was normal in three and decreased in 27, and less than 10% in four. Antithrombin III was decreased in all hematomas and was less than 25% in seven. FPA was increased in all hematomas and was more than 50 ng/ml in 20. Discussion Following injury to blood vessels, platelets begin to accumulate at the damaged area to form the primary hemostatic plug. Plasma coagulation proteins are then activated to initiate secondary hemostasis which proceeds by two separate clotting systems.',') The ex trinsic clotting system requires factor VII, and the in

Clotting factor (factors II, V, VII-IX: n = 30, X-XII: n = 29), activated protein C (n = 30), antithrombin III (n = 30), and fibrinopeptide A (n = 30) levels in chronic subdural hema toma fluid. Shaded area represents normal range for plasma. Broken line indicates lower or upper limit in measurement.

trinsic clotting system involves factors VIII, IX, XI, and XII. Alternatively, the complex of factor VII, calcium, and tissue thromboplastin released from the extrinsic clotting system can also activate factor IX of the intrinsic clotting system. The final common pathway converts factor II to thrombin in the presence of factor V, calcium, phospholipid, and factor Xa. Factor VIII and IX inhibitors are systemic antibodies that specifically neutralize factors VIII and IX, respectively. Regulatory mechanisms prevent extension of the hemostatic plug beyond the injury site. Activated protein C and antithrombin III are the most important inhibitors in plasma. Activated protein C inactivates factors Va and VIIIa and antithrombin III probably causes neutralization of factor Xa, which controls the major amplification step for thrombin formation in both the extrinsic and intrinsic clotting systems. Thrombin cleaves the amino termini of the fibrinogen Acx chains releasing 2 moles of FPA which is rapidly cleared from system ic blood. Therefore, the plasma FPA level closely reflects the actual rate of FPA release. Fibrinogen is generally present in excess in blood, so that the FPA release rate essentially depends on effective thrombin activity.

Our 25 cases demonstrated no basic disorder which might cause decreased clotting factor, acti vated protein C, or antithrombin III, and increased FPA levels. When regulating mechanisms function normally, only a small quantity of each factor is converted to the active form. Therefore, the marked reduction in antithrombin III and insignificant amounts of factor VIII and IX inhibitors in the hematomas strongly suggest that the decreased levels of clotting factors were caused by rapid consumption reflecting excessive coagulation. As a result, excess thrombin was formed resulting in the marked in crease in FPA levels in the hematomas. The marked reduction in levels of factor VII as well as factors II, V, and X is due to excessive activation of both the extrinsic clotting system and the common final path way. In contrast, the intrinsic clotting factors did not demonstrate a uniform pattern: marked reduction in factor VIII, moderate reduction in factor IX and XI, and slight reduction in factor XII. The lower level of activated protein C caused depressed inactivation of both factors Va and VIIIa and accelerated conver sion of factors V and VIII to the active form resulting in excessive consumption. Therefore, less in trinsic clotting factors than extrinsic clotting factor VII were used. These results demonstrate that the excessive activa tion of coagulation in hematoma was predominantly via the extrinsic clotting system. However, the similar pattern of reduction in factors IX and XI sug gests that activation of factor IX by the complex of factor VII, calcium, and tissue thromboplastin via the extrinsic clotting system was not significant. Many histological investigations of the hematoma membrane have demonstrated the considerable pro liferation potential and fragility of the numerous macrocapillaries and capillaries."' Hematological studies of hematoma fluid have shown evidence of hyperfibrinolysis. Therefore, recurrent hemorrhage from the hematoma capsule caused by defective clot formation is considered the basis of chronic SDH growth. However, it is quite conceivable that ex cessive activation of coagulation, predominantly via the extrinsic clotting system, is also important. Coagulation is initiated by tissue thromboplastin release from injured capillary endothelial cells of the hematoma capsule. Excessive activation occurs because activated protein C and antithrombin III levels are depressed in hematomas, although the cause remains unknown. The a2-plasmin inhibitor level, the most important plasmin inhibitor in plasma, is also depressed in hematoma fluids. 12,11, Therefore, regulatory mechanisms for both coagula tion and fibrinolysis are depressed in hematomas.

Our results strongly suggest that excessive activation of both coagulation and fibrinolysis are important in the progressive enlargement of chronic SDH.

Acknowledgments We are grateful to Mr. S. Saiki, Special Reference Laboratories, Tokyo, for laboratory tests, Mr. Y. Sato, Sankyo Co., Ltd., Tokyo, for references, and Mr. K. Yamaguchi, Tanabe Seiyaku Co., Ltd., Osaka, for illustrations.

References 1)

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Dati F, Barthels M, Conard J, Flückiger J, Girolami A, Hänseler E, Huber J, Keller F, Kolde HJ, Müller Berghaus G, Samama M, Thiel W: Multicenter evaluation of a chromogenic substrate method for photometric determination of prothrombin time. Thromb Haemost 58: 856-865, 1987 Handin RI: Bleeding and thrombosis, in Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS (eds): Harrison's Principles of Internal Medicine, ed 11. New York, McGraw-Hill, 1987, pp 266-272 Hibino S: Hematology. Tokyo, Maruzen, 1985, pp 1502-1564 (in Japanese) Ito H, Komai T, Yamamoto S: Fibrin and fibrinogen degradation products in chronic subdural hematoma. Neurol Med Chir (Tokyo) 15[Part I]: 51-55, 1975 Ito H, Komai T, Yamamoto S: Fibrinolytic enzyme in the lining walls of chronic subdural hematoma. J Neurosurg 48: 197-200, 1978 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, van Eys J: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 34: 869-872, 1975 Kawakami Y, Chikama M, Tamiya T, Shimamura Y: Coagulation and fibrinolysis in chronic subdural hematoma. Neurosurgery 25: 25-29, 1989 Komai T, Ito H, Yamashima T, Yamamoto S: Etiology of chronic subdural hematoma. Role of local hyperfibrinolysis. Neurol Med Chir (Tokyo) 17[Part II]: 499-505, 1977 (in Japanese) Labadie EL, Glover D: Local alterations of hemo static-fibrinolytic mechanisms in reforming subdural hematomas. Neurology (Minneap) 25: 669-675, 1975 Martinoli JL, Stocker K: Fast functional protein C assay using Protac. A novel protein C activator. Thromb Res 43: 253-264, 1986 Nossel HL, Younger LIZ, Wilner GD, Procupez T, Canfield RE, Butler VP Jr: Radioimmunoassay of human fibrinopeptide A. Proc Natl Acad Sci USA 68: 2350-2353, 1971 Saito K, Ito H, Hasegawa T, Yamamoto S: Plasmin

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Scully MF, Kakkar VV: Methods for semi micro or automated determination of thrombin, antithrom bin, and heparin cofactor using the substrate, H-D - Phe-Pip-Arg-p-nitroanilide⋅2HCl. Clin Chim Acta 79: 595-602, 1977 14) Weir B, Gordon P: Factors affecting coagulation. Fibrinolysis in chronic subdural fluid collections. J Neurosurg 58: 242-245, 1983

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Yamashima T, Yamamoto S: How do vessels pro liferate in the capsule of a chronic subdural hema toma? Neurosurgery 15: 672-678, 1984

13)

Address

reprint

ment

Hospital, Japan.

requests

of Neurological 2-4

to: Y. Kawakami, Surgery,

Ichiban-cho,

Kobe

M.D., West

Nagata-ku,

Depart Municipal

Kobe

653,

Coagulopathy in chronic subdural hematoma.

Coagulation factors were studied in 30 fluids aspirated from 25 patients with chronic subdural hematoma. Compared with the normal range for plasma, th...
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