Use of a Heparinoid in Patients with Hemorrhwc Stroke and

Thromboembolic Disease H. Ten Cate, MC,” C. P. Henny, MC,” H. R. Buller, MD, PhD,” J. W. Ten Cate, MD, PhD,”

and H. N. Magnani, MB, BS, MSc, PhD?

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A new heparinoid, Org 10172, was given to five patients with hemorrhagic stroke with thromboembolic complications. Treatment did not cause progression of cerebral bleeding, and thrombotic processes were inhibited. No side effects were encountered.

Ten Cate H , Henny CP, Uiiller HR, Ten Cate JW, Magnani HN: Use of a heparinoid in patients wit-h hemorrhagic stroke and thromboembolic disease. Ann Neurol 15:268-270, 1084

Deep venous thrombosis is a frequent (33 to 7557 incidence) and serious complication of acute stroke { 111. Although heparin is the drug of choice for the treatment of deep venous thrombosis, its use is limited because of the involved bleeding risk, which has been estimated to vary between 1 and 33% [ 5 ] . In patients with hemorrhagic stroke the use of anticoagulants is limited because of an often assumed but unproved risk of rebleeding [l]. Although heparin used for the pre- vention of deep venous thrombosis in patients with nonhemorrhagic stroke has been shown to be effective [2, 71, its application in those with hemorrhagic lesions is generally not accepted.

Certain recently developed heparin fractions and heparinoids that may be effective antithrombotic agents lack the main side effect of heparin, i.e., bleed- ing. We report our experience with five patients with hemorrhagic stroke in whom a heparinoid was used as the antithrombotic agent.

Materials and Methods The heparinoid Org 10172 (batch K, Organon, International BV, Oss, The Netherlands) is derived from porcine intestinal mucosa. It has a mean molecular weight of 6,500 and a specific activity of 8.0 anti-Xa units per milligram.

The anticoagulant activity of this compound is character- ized by a specific anti-Xa activity in plasma, mediated through antirhrombin 111, and a concurrent negligible effect on gen- eral clotting. For the monitoring of the heparinoid’s activity, an automated amidolytic anti-Xa assay was used. In this assay a rest sample is diluted with purified antithrombin I I I and activated factor X. After incubation, chromogenic substrate S-2222 (Kabi Vitrum. Amsterdam) is added. The residual

factor Xa splits a paranitroaniline group from the substrate, which causes a yellow color to appear in the test cuvet. Color intensity is quantitated spectrophotometrically, and the activ- ity of the heparinoid present in the test sample can be read from a calibration curve [lo}.

All patients suffered cerebral hemorrhage and concurrent deep venous or cardiac thrombosis. Standard anticoagulants were considered to be contraindicated. A standard dose regi- men consisted of a loading dose of 200 mg of Org 10172 administered intravenously, followed by continuous intrave- nous infusion of 20 mg per hour by means of an infusion pump. The dosage was further adjusted o n the basis of the results of the anti-Xa assay; plasma anti-Xa levels between 0.4 and 0.8 Uiml were considered “therapeutic” on the basis of animal experiments. Prior to discontinuation of heparinoid therapy, treatment with oral anticoagulants (OACs) was initi- ated and adjusted to a therapeutic level ( 5 to 10”/r), as dete:r- mined by findings of the thrombotest.

The major variables evaluated in this study were anti- thrombotic effect (as verified by either phlebography or echocardiography) and bleeding; the latter was evaluated by:

1. daily assessment of the neurological siatus of the patierit by the attending physician

2. repeated cerebral CT scanning 3. hemoglobin level determination 4. evaluation for hematuria

Case Reports Patient 1 A 61-year-old man was admitted to the hospital with a right- sided hemiparesis and aphasia. A computed tomographic (CT) scan revealed an intracerebral hematoma in the left hemisphere (deep temporoparietal; maximal size, 4.5 x 2

From the “Deparrment ot Hematology, Division of Hemostasis and Received Fcb 14, 1983, and in revised form June 28 and Julv 2 Thrombosis, University Hospital “\7irilhelmina Gasthuis,” 2e Hel- merssrraar 106, 1054 CN Amsterdam, and the tMedical Research and Development l in i t . Organon, Oss, The Netherlands.

Accepted for publication July 3 1, 1983.

Address reprint requesrs tO H, Ten

268

Steadystate Plasma Anti-Xu Values Obtained During Treatment of Five Patients with 0r.g 101 72”

Patient No.

Value 1 2 3 4 5

Mean 0.96 0.63 Range 0.85-1.09 0.45-0.82 Pretreatment value 0.02 0.01

”All values are expressed as units per milliliter.

cm). Two weeks later the patient developed clinical signs of thrombosis in the right leg. Phlebography revealed proximal deep venous thrombosis with a floating tail. Heparinoid ther- apy was instituted the next day. The patient’s neurological condition improved, and thrombotic symptoms diminished. No symptoms suggestive of pulmonary emboiism were en- countered. Phlebography after two weeks of therapy re- vealed regression of the thrombus tail. A CT scan at the same time showed disappearance of the cerebral hematoma. OAC treatment was initiated, and two weeks later the patient was discharged in good condition.

Patient 2 A 65-year-old man receiving long-term OAC therapy for peripheral vascular disease had an acute right-sided hemi- plegia. A C T scan indicated a large hematoma within the left basal hemisphere (basal ganglia; maximum diameter, 1.5 cm). OAC therapy was stopped. Three weeks later the patient developed clinical symptoms of thrombosis in the right leg; phlebography revealed a proximal deep venous thrombosis. The next day heparinoid therapy was initiated. The patient was treated for six weeks continuously, after which a CT scan showed disappearance of the hematoma and medication was changed to OACs. Phlebography revealed no further propa- gation of the deep venous thrombosis. The patient was dis- charged in stable condition.

Patient 3 A 74-year-old woman with a history of epilepsy, angina pec- toris, and paralysis of the right leg was admitted to the hos- pital with a ieft hemiparesis. Just prior to admission, she had developed symptoms of thrombosis in the right leg and had been treated with OACs. Upon admission of the patient CT scan showed a small, oblong hemorrhagic area in the right basal ganglia; OAC therapy was discontinued. Phlebography showed a large proximal deep venous thrombosis in the right leg, and heparinoid treatment was started. Subsequently, the patient developed status epilepticus, coma, and unexplained fall of 2.5 mmoVL in hemoglobin level; a CT scan, however, showed no increase in the hemorrhagic area, and heparinoid treatment was continued for two weeks. The patient later died of recurrent status epilepticus.

Patient 4 A 75-year-old man receiving OACs was hospitalized with a ieft-sided hemiparesis. C T scanning showed a right parietal hematoma with a maximum diameter of 3 cm. One week later the patient developed thrombosis in the left leg confirmed by phlebography. Treatment with heparinoid was started and continued for two weeks. The cerebral hematoma

0.72 0.64 0.63 0.50-0.89 0.47-0.82 0.59-O.80 0.05 0.00 0.0 1

resorbed normally, and after two weeks only slight edema could be detected on CT scan. Phlebography showed stabili- zation of the deep venous thrombosis. Heparinoid therapy was stopped, and two weeks later the patient was discharged in good condition.

Patient 5 A 57-year-old man was admitted to the hospital with acute right-sided hemiparesis and aphasia. He had had an an- teroseptal myocardial infarction the day before admission. Echocardiography revealed a thrombus within the left ven- tricular apex. A CT scan showed a large (4 x 5 cm) hemor- rhagic infarct related to the left middle cerebral artery. Heparinoid infusion was started and continued for two weeks, during which time the patient experienced no further embolic events. Echocardiography then showed complete resolution of the thrombus.

Laboratory Evaluation Prior to and during heparinoid therapy, biochemical, hematological, and coagulation profiles were deter- mined, including bleeding time, thrombocyte count, prothrombin time, kaolin cephalin clotting time, and thrombin time. Antithrombin 111, factors I1 and X, plasminogen, and cy2-antiplasmin also were monitored. No values of any of the evaluated variables exceeded normal ranges. No abnormalities in liver and kidney functions were noted. Plasma anti-Xa activities, deter- mined at a steady-state level, are given in the Table. Slight dosage adjustment within the therapeutic range was necessary to reach a steady-state level.

Discussion Although heparin is the drug of choice for the treat- ment of acute deep venous thrombosis, its use may be dangerous in the presence of cerebral hemorrhage or hemorrhagic infarct. The alternative-no treatment of the deep venous thrombosis-is hardly acceptable. Kucera [6} reported a 10% mortahy from pulmonary embolism in patients with proximal deep venous thrombosis. The heparinoid Org 10172, which in animal experiments showed antithrombotic activity without a tendency tu induce bleeding {Sl, offers new opportunities in the treatment of high-risk patients 131. The beneficial effect of the heparinoid may be the re- sult of the absence of a platelet binding site, which IS a part of the heparin molecule 14, 91.

Ten Cate et al: Heparinoid in Hemorrhagic Stroke 269

In our five patients the effectiveness of therapy was evaluated by phlebography or echocardiography. No propagation of thrombosis was noted, and a gradual shrinkage of the hemorrhagic area was observed during therapy. No hemorrhagic complications were noted. Although a drop in hemoglobin level in one patient suggested blood loss, no primary bleeding site could be detected.

Our experience in five patients suggests that the heparinoid Org 10172 may he a potentially safe and effective antithrombotic agent. Randomized, blind studies are required to test the validity of the present results.

The nursing staff and the attending physicians of the Department of Neurology (Prof Dr H. van Crevel, head) are gratefully acknowl- edged for their support. Thanks are due to Prof Dr H. van Crevel and Dr L. Zegerius of the Department of Neurology for valuable comments, and to Mrs Joke van der Hall for typing the manuscript.

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270 Annals of Neurology Vol 15 No 3 March 1984