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2316 Part XII: Hemostasis and Thrombosis Chapter 135: Fibrinolysis and Thrombolysis 2317

than 5 percent of stroke patients currently receive t-PA treatment, indi- Anticoagulation is useful to prevent thrombus extension, while throm-
cating the need for focused community educational efforts. 366–368 Ran- bolytic therapy or surgery can restore perfusion.
domized studies with rt-PA have shown that intravenous thrombolytic Early approaches to acute peripheral arterial occlusion involved
therapy can be safely extended to 4.5 hours after symptom onset in streptokinase. Several small studies demonstrated reperfusion in
selected patients, whereas streptokinase was associated with an unac- approximately 40 percent of patients, with greatest success when occlu-
ceptably high rate of intracranial hemorrhage. 344,345,347 In addition, intra- sions were recent; bleeding complications occurred in up to one-third
382
cranial hemorrhage can be reduced by identifying patients at greatest of subjects. Following the report in 1974 by Dotter of successful
381
risk using MRI diffusion–perfusion mismatch to identify reversible thrombolysis in peripheral arterial occlusion using locally administered
ischemia. 346,369–371 The combination of potent antiplatelet therapy using thrombolysis, practice moved progressively to the nearly exclusive use
a glycoprotein IIb/IIIa antagonist with a lower dose of a thrombolytic of local intraarterially administered treatment. Advantages include
agent may improve results. 372–377 delivery of a high concentration of drug directly to the site of throm-
In summary, current recommendations limit thrombolytic therapy bosis, the ability to follow the course of treatment using the treatment
for stroke to patients presenting within 3 hours of symptom onset. 378–380 catheter, and identification of local vascular lesions requiring endovas-
The approved therapy is with 0.9 mg/kg (maximum: 90 mg) of t-PA cular or surgical treatment after recanalization.
administered intravenously with 10 percent as an initial bolus and the Treatment involves arterial access from a remote site followed by
remainder infused over 60 minutes. The best results are obtained in fluoroscopic guidance of the catheter to administer drug directly into
patients who meet strict eligibility requirements (Table 135–6). Patients the thrombus. Therapy is delivered by continuous infusion over hours
should be closely monitored for bleeding complications, especially to days and requires close monitoring and a large dose of thrombolytic
intracranial hemorrhage, and careful attention should be paid to blood agent. Successful reperfusion occurs in approximately three-quarters
384
pressure and other comorbidities. of cases. Ouriel and colleagues reported that thrombolytic therapy
383
resulted in a 70 percent recanalization rate, and a frequency of limb
PERIPHERAL VASCULAR DISEASE salvage that mirrored that of operative intervention. There was, how-
Acute peripheral arterial occlusion presents with the sudden onset of ever, a survival advantage in patients receiving primary thrombolytic
new, severe leg symptoms or acute worsening of chronic ischemia, and therapy resulting primarily from a decrease in the occurrence of in-
often involves embolic or thrombotic occlusion of leg arteries. The goals hospital complications. The Surgery versus Thrombolysis for Ischemia
of treatment are to preserve limb function through restoration of flow. of the Lower Extremity (STILE) trial, which compared the optimal sur-
gical procedure to catheter directed thrombolysis with either t-PA or
urokinase, was terminated prematurely because of ongoing or recurrent
TABLE 135–6. Guidelines for Tissue-Type Plasminogen ischemia at 30 days in surgically treated patients. More than half of
385
Activator Therapy in Stroke patients receiving thrombolysis had a decrease in the magnitude of the
Eligibility surgical procedure eventually required, with significant reductions in
Time from symptom onset to therapy ≤3 hours the 1-year rate of major amputation. In addition, there was no difference
Results from European Cooperative Acute Stroke Study (ECASS) in outcome with t-PA versus urokinase.
The Thrombolysis or Peripheral Arterial Surgery (TOPAS) I study
III trial suggest treatment within 4.5 h of onset is beneficial compared recombinant urokinase or surgery for initial therapy of acute
Exclusions lower-extremity ischemia of less than 14 days duration. The 1-year
386
Prior intracranial hemorrhage mortality and amputation-free survival were similar in the urokinase
Major surgery within 14 days and surgery groups. There was a significant reduction in the frequency
Gastrointestinal or urinary tract bleeding with 21 days and magnitude of surgical interventions eventually required in patients
Arterial puncture in noncompressible site randomized to initial thrombolysis. The larger TOPAS II study showed
387
Recent lumbar puncture recanalization in 80 percent of patients who received urokinase.
Amputation-free survival at 1 year was not significantly different
Intracranial surgery, serious head trauma, or prior stroke within between the surgical and thrombolysis groups, 70 percent and 65 per-
3 months cent, respectively. Major hemorrhagic complications were significantly
Minor neurologic deficit more frequent with urokinase (13 percent) compared to 6 percent with
Seizure at time of stroke onset surgery (p = 0.005).
Clinical findings of subarachnoid hemorrhage In other studies, reteplase appears to be equally effective as t-PA or
Active bleeding urokinase with comparable recanalization rates, and clinical outcomes
388,389
Persistent systolic blood pressure (BP) >185 and/or diastolic BP and bleeding complications. Prourokinase also gave similar overall
results to urokinase in a phase II study. In an open-label trial, staph-
390
>110 or requiring aggressive treatment ylokinase, a highly fibrin-specific Plg activator, resulted in revascular-
Arteriovenous malformation or aneurysm ization in 83 percent of subjects with occluded arteries. Occasional
391
Evidence of hemorrhage on computed tomography scan allergic reactions occurred, and severe bleeding complications were
Platelets <100,000/μL comparable to those with other agents. The addition of abciximab, a
International normalized ratio >1.5 on warfarin glycoprotein IIb/IIIa, inhibitor, to urokinase resulted in more rapid clot
392
Elevated partial thromboplastin time on heparin like lysis in a randomized study, and good results were also reported
393
Blood glucose <40 or >400 mg/dL with reteplase and abciximab. Intraoperative thrombolysis during
thromboembolectomy has been used successfully to improve clear-
ECASS III additionally excluded patients >80 years old, patients ance of distal thromboemboli with or without adjunctive mechanical
with a combination of previous stroke and diabetes mellitus, thrombectomy. 394–398
and patients with an National Institutes of Health Stroke Scale Thrombolysis should be viewed as one part of a combined, com-
score of >25.
prehensive management approach to peripheral arterial occlusion.

Kaushansky_chapter 135_p2303-2326.indd 2316 9/18/15 5:13 PM