Hematologic Interventions for Acute Central Nervous System Disease

Introduction

Acute central nervous system (CNS) diseases are notable for two critical features. The first, and perhaps most obvious, is that these are diseases that are life threatening and likely to cause major permanent neurologic disability. In short, the consequences of these diseases can be devastating to patients and their families. The second critical feature of acute CNS disease is the remarkable time sensitivity of most treatment interventions. The window of opportunity to intervene and attenuate brain injury is often measured in minutes. Recognition of the acuity of these diseases is critical to the way one approaches consultative decision making. The most common acute CNS diseases relevant to the consulting hematologist are ischemic stroke and intracranial hemorrhage. In the setting of ischemic stroke, common questions relate to the choice and timing of early antithrombotic therapy, and management of bleeding complications from these therapies. For intracerebral hemorrhage (ICH), pertinent management issues center on agents to achieve hemostasis and diagnostic issues related to the role of potential hemorrhagic abnormalities contributing to ICH. The goal of this chapter is to provide a general background on the state of current therapeutics relevant to hemostasis and thrombosis in acute CNS disease, and to address more specifically common scenarios for which hematologic consultation might be sought.

Acute Ischemic Stroke

Thrombolytic and antithrombotic therapies play a major role in the acute treatment of patients with ischemic stroke. The major goals of thrombolytic therapy are to achieve recanalization of occluded cerebral vessels, to restore cerebral perfusion, and to salvage potentially viable neuronal tissue. Antithrombotic therapy is used to prevent recurrent or progressive arterial thrombosis, to stabilize potentially active embolic sources, and possibly to augment the body's own intrinsic thrombolytic mechanisms. Antithrombotic agents are also used to mitigate against the high incidence of venous thromboembolism characteristic of neurologically impaired patients. Both strategies carry with them a risk of bleeding, which is higher in stroke patients than in patients with other types of diseases for which these therapies are indicated.

Antithrombotic Therapy

Antiplatelet Agents

Two large randomized controlled trials have proven the benefit of aspirin in acute ischemic stroke (AIS). The International Stroke Trial (IST) enrolled 19,435 patients and demonstrated that aspirin 300 mg daily started within 48 hours of stroke onset significantly reduced the risk of recurrent ischemic stroke from 3.9% to 2.8% ( P < .05) without causing a significant increase in the rate of ICH (0.8% vs. 0.9%, not significant [NS]). At 6 months, the percentage of aspirin-treated patients who were dead or dependent was also lower (62.2% vs. 63.5%, P = .07, a difference of 13 per 1000). The Chinese Acute Stroke Trial (CAST) enrolled 21,106 patients and demonstrated that aspirin 160 mg daily started within 48 hours of stroke onset reduced the risk of recurrent ischemic stroke from 2.1% to 1.6% ( P = .01) and mortality from 3.9% to 3.3% ( P = .04). There was a small, nonsignificant increased risk of hemorrhagic stroke in patients who received aspirin (1.1% vs. 0.9%, NS). The proportion of patients dead or dependent was reduced from 31.6% to 30.5% ( P = .08), comparable to the results seen in IST.

Clinical trials have evaluated several alternative antiplatelet treatment strategies in select stroke patients. The CHANCE and SOCRATES trials both enrolled patients with minor stroke or transient ischemic attack and started treatment within 24 hours of onset. The CHANCE trial, conducted entirely in China, enrolled 5170 patients and compared dual antiplatelet therapy with aspirin and clopidogrel for 21 days followed by clopidogrel alone from day 22 to day 90 to aspirin monotherapy for 90 days. A significant reduction in recurrent stroke was seen with dual antiplatelet therapy (8.2% vs. 11.7%, hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57 to 0.81; P < .001), with no significant difference in bleeding between the two groups. The SOCRATES trial enrolled 13,199 patients and compared 90 days of ticagrelor to aspirin, demonstrating a nonsignificant reduction in recurrent vascular events in the ticagrelor group (6.7% vs. 7.5%, HR 0.89; 95% CI, 0.78 to 1.01; P = .07), with no significant difference in bleeding.

The EARLY trial evaluated aspirin plus extended-release dipyridamole initiated within 24 hours of stroke onset to the same regimen initiated after 7 days of aspirin monotherapy. The composite outcome of recurrent vascular events and major bleeding complications within 90 days was nonsignificantly lower with early initiation of aspirin plus extended-release dipyridamole (10% vs. 15%, P = .20). Notably, there was no significant difference in bleeding risk between the two regimens. The intravenous GPIIb/IIIa inhibitor abciximab was tested in 808 patients with acute stroke within 5 hours of onset. No benefit was found, and the rate of symptomatic ICH was substantially higher with abciximab (5.5% vs. 0.5%, P = .002).

Anticoagulant Agents

There have been a number of large randomized, controlled trials testing early anticoagulation with parenteral unfractionated heparin (UFH) or low-molecular-weight heparins (LMWHs). Overall, these trials, which have enrolled thousands of patients, have shown no significant benefit to early parenteral anticoagulation in patients with ischemic stroke. In the largest trial of acute anticoagulation (the IST), the rate of recurrent ischemic stroke at 2 weeks was significantly reduced in the patients allocated heparin (2.9% vs. 3.8%), but the rate of ICH was increased equivalently (1.2% vs. 0.4%), and there was no difference in number of dead or dependent patients at 6 months (62.9% for either group). Treatment with heparin resulted in a 9 per 1000 excess of transfusion or fatal extracranial bleeding.

There are only very limited data on alternative anticoagulants. Argatroban, an intravenously (IV) administered direct thrombin inhibitor (DTI) approved for use as an anticoagulant in patients with heparin-induced thrombocytopenia, has undergone preliminary testing in patients with acute stroke. In an initial multicenter pilot trial, 119 patients were randomized to either argatroban or placebo. Treatment was started relatively late, with approximately half the patients treated more than 48 hours after symptom onset. Clinical outcome was assessed with a nonstandard rating of global improvement. At 1 month, 54% of the patients treated with argatroban were noted to have significant improvement compared with 24% of the placebo group ( P < .01). There was no excess of ICH in the argatroban group. In a subsequent, multicenter randomized trial involving 176 patients randomized to receive IV argatroban (high or low dose) or placebo within 12 hours of stroke symptom onset, there were no differences in clinical outcome among the treatment allocation groups. Symptomatic ICH occurred in 3 of 59 (5.1%) patients given high-dose argatroban, 2 of 58 (3.4%) given low dose, and 0 of 54 (0%) given placebo. These apparent differences among groups were not statistically significant ( P = .18). Based on these results, argatroban cannot be recommended for routine use in patients with AIS. However, this drug may have a role in stroke patients who also suffer from heparin-induced thrombocytopenia.

Bleeding Risk Associated With Parenteral Anticoagulation

Therapeutic full-dose parenteral anticoagulation results in an incremental increased risk of symptomatic ICH of 1% to 4% over the risk with placebo or aspirin. The risk of hemorrhage appears higher in patients with earlier initiation of anticoagulation after stroke. For example, in the TAIST trial, the rate of symptomatic ICH was 4.8% in patients with initiation of full-dose tinzaparin within 12 hours of symptoms onset, and 0.3% in those patients with therapy started greater than 24 hours after symptom onset, compared with an overall rate of symptomatic ICH in the group allocated aspirin of 0.2%. In a trial of dose-adjusted IV heparin started within 3 hours of symptom onset, symptomatic ICH occurred in 6.2% of patients treated with anticoagulation compared with 1.4% receiving placebo. Risk also appears higher in those with larger infarctions.

Effect in Subgroups

Stroke is a heterogeneous disease process, with multiple distinct mechanisms leading to cerebral infarction, and thus it is plausible that there may be a differential response to specific therapies based on the underlying stroke mechanism.

Large Vessel Atherosclerotic Stenosis/Occlusion

Several randomized trials have provided data on the potential benefit of acute anticoagulation in the subgroup of patients with large vessel atherosclerotic disease (LVD). Post hoc analysis of the TOAST trial suggested a therapeutic benefit of danaparoid in patients with internal carotid artery stenosis or occlusion. In this subgroup a favorable outcome was seen at 3 months in 68.3% of the danaparoid-treated patients compared with 53.2% of those receiving placebo ( P = .02). No benefit was seen in patients with stroke due to other mechanisms. In contrast, the TAIST trial did not find evidence of benefit in the subgroup of patients with stroke due to large artery disease. In the FISS-tris study, there was a suggestion of benefit of the LMWH nadroparin compared with aspirin in the 353 patients with large vessel disease (complete or near-complete recovery in 54% with LMWH vs. 44% with aspirin, odds ratio [OR] 1.55, 95% CI 1.02 to 2.35). In contrast, in the 245 patients enrolled who did not have large vessel disease, the opposite was found (complete or near-complete recovery in 51% with LMWH vs. 66% with aspirin, OR 0.54, 95% CI 0.32 to 0.91). Given the limitations of post hoc subgroup analysis, the potential benefit of anticoagulation in this setting remains controversial; however, its use in patients with large vessel stenosis, particularly those with minor stroke or TIA, is relatively common in current clinical practice.

Cardioembolism

The use of acute anticoagulation in patients with cardioembolic stroke is intuitively appealing given the proven benefit of long-term oral anticoagulation in reducing recurrent stroke risk in this population. However, data from clinical trials fairly clearly establish that this intuitive assumption is incorrect. The prototypical cardioembolic stroke mechanism is atrial fibrillation. In the Heparin in Acute Embolic Stroke Trial (HAEST), 449 patients with AIS and atrial fibrillation were randomized to receive either the LMWH dalteparin or aspirin within 30 hours of stroke onset. HAEST is unique among trials of acute anticoagulation in that a population of patients with a homogenous stroke mechanism (atrial fibrillation) was studied. During the initial 2 weeks following randomization, recurrent ischemic stroke was nonsignificantly higher in the dalteparin group (OR 1.13; 95% CI 0.57 to 2.24), as was the percentage of patients with symptomatic ICH (2.7 vs. 1.8%). There was no significant difference in long-term functional outcome between the groups. Subgroup analysis of more than 3000 patients with atrial fibrillation in the IST trial also showed no benefit for heparin, and other trials have had concordant results. In summary, there is no indication for acute parenteral anticoagulation in patients with atrial fibrillation and AIS. The most probable explanation for these findings is that the risk of early recurrent stroke is relatively low in most patients with atrial fibrillation, but the risk of ICH is increased with acute anticoagulant therapy. In clinical practice, oral anticoagulation with warfarin is generally started when the patient is clinically stable and able to swallow or when definitive enteral access has been obtained in those with severe swallowing dysfunction. For patients with very large infarctions, warfarin may be delayed for 1 to 2 weeks after the stroke. There is considerable uncertainty about when to start the new-generation direct oral anticoagulants (dabigatran, rivaroxaban, apixaban), which have a relatively immediate onset of anticoagulant effect. Preliminary observational data suggest that starting these drugs within the first few days after minor stroke is safe; it seems reasonable to delay administration for 1 to 2 weeks in patients with larger infarctions.

Hypercoagulable States

There are extremely limited data on the acute treatment of patients with stroke due to hypercoagulable states. A decision about use of parenteral anticoagulation must take into consideration the perceived short-term risk of recurrence balanced against the risk of causing ICH in the individual patient. Most inherited hypercoagulable states likely have a relatively low short-term risk of recurrence, and therefore acute anticoagulation may not be indicated. In contrast, some acquired hypercoagulable states, such as heparin-induced thrombocytopenia, catastrophic antiphospholipid antibody syndrome, or hypercoagulability associated with most adenocarcinomas, may have extremely high short-term risk of stroke recurrence, justifying early parenteral anticoagulation.

Thrombolytic Therapy

The approval of IV administration of recombinant tissue plasminogen activator (tPA) for treatment of stroke in 1995 revolutionized acute stroke care. In the pivotal NINDS tPA trial, treatment with IV tPA within 3 hours of symptom onset resulted in substantially increased odds of a favorable outcome at 3 months (OR 1.7; 95% CI 1.2 to 2.6). Treatment with tPA was associated with a substantial increase in the risk of symptomatic intracranial hemorrhage (6.4% vs. 0.6%, P < .001). It is important to note that the primary outcome measure (favorable outcome at 3 months) in the NINDS trial incorporates within it the adverse clinical consequences of the complication of ICH; this has sometime been the source of confusion in interpretation of the study. Overall, the treatment effect of thrombolysis seen in the NINDS trial was large. For every 100 patients treated with tPA, approximately 12 additional patients will recover with no or minimal disability compared with those treated with placebo, and approximately 30 will have some reduction in disability as a result of treatment. Subsequently, tPA has been shown to be beneficial when administered between 3 and 4.5 hours after symptom onset, although the absolute benefit is lower than when administered earlier. The marked time dependence of tPA on outcome after ischemic stroke has been verified in pooled analysis of multiple clinical trials. This has important implications for organization of emergency stroke care at the systems level. Additional studies have demonstrated the benefit of tPA extends to a broad population of patients with AIS, specifically including the very elderly (older than 80 years).

The alternative IV thrombolytic agents streptokinase, urokinase, and desmoteplase have either been tested in only a limited fashion in the stroke population or have not shown clear evidence of benefit. These agents cannot be recommended for routine clinical use in stroke patients at this time. Tenecteplase has been compared directly with tPA in AIS and appears to be equivalent to tPA in efficacy and safety; it may represent a reasonable alternative agent, although to date use in stroke remains rare.

Careful patient selection is a critical aspect of thrombolytic therapy for stroke. A standard management protocol and set of inclusion and exclusion criteria derived from the NINDS trial have been widely adopted ( Tables 38.1 and 38.2 ). All patients considered for tPA must have a head computed tomography (CT) that shows no evidence of hemorrhage. The most important additional criterion relevant to the hematologist relates to exclusion criteria based on abnormal baseline hemostatic studies. Patients with a platelet count less than 100,000/µL are excluded from treatment due to a theoretical increased risk of bleeding. However, in patients without any clinical history to suggest thrombocytopenia, this finding is extremely uncommon, and many experts believe thrombolytic therapy should not be delayed to wait for a platelet count unless there is reason to suspect thrombocytopenia. If there is no history of anticoagulant use, it is not necessary to obtain a prothrombin time (PT) and/or partial thromboplastin time (PTT) prior to treatment. However, therapeutic anticoagulation is considered a contraindication to tPA for ischemic stroke. Current guidelines specify that, for patients taking warfarin, the international normalized ratio (INR) must be 1.7 or less and, for patients who have received heparin, the PTT must be within the normal range. Reversal of warfarin effect using prothrombin complex concentrates (PCCs) prior to thrombolysis is theoretically possible and has been anecdotally reported; however, the safety and efficacy of this approach remains unknown. One limited study in rats suggested that this might allow successful thrombolysis with a bleeding risk similar to nonanticoagulated animals. An emerging challenge to decision-making in AIS is how to assess the anticoagulant state of patients otherwise eligible for tPA but who are taking newer oral anticoagulants, for which rapidly available laboratory tests to assess the anticoagulant effect are either unavailable or for which interpretation is not well defined (see later).

TABLE 38.1

Criteria for Selecting Patients With Acute Ischemic Stroke for Thrombolytic Therapy With Tissue Plasminogen Activator

Presence of a significant neurologic deficit
No signs of rapid dramatic neurology recovery
Symptoms not suggestive of subarachnoid hemorrhage
Onset of symptoms <4.5 h before beginning treatment ^a
No head trauma or prior stroke in previous 3 months
No myocardial infarction in the previous 3 months
No gastrointestinal or urinary tract hemorrhage in previous 21 days
No major surgery in the previous 14 days
No arterial puncture at a noncompressible site in the previous 7 days
No recent lumbar puncture
No history of previous intracranial hemorrhage
Blood pressure ≤185 mm Hg systolic and ≤110 mm Hg diastolic
No evidence of active bleeding or major trauma on examination
Not taking warfarin or, if on warfarin, INR ≤1.7
If receiving heparin in previous 48 h, PTT must be in normal range
Platelet count ≥100,000/µL
Blood glucose concentration >50 mg/dL
No seizure at onset of symptoms (unless neuroimaging confirms stroke)
CT does not show evidence of severe hypodensity or mass effect (relative contraindication)
CT does not show evidence of hemorrhage

CT, Computed tomography; INR, international normalized ratio; PTT, partial thromboplastin time.

a For patients treated between 3 and 4.5 hours after symptom onset, caution should be exercised in the following groups of patients: (1) patients older than 80 years, (2) those taking warfarin regardless of INR, (3) those with a baseline NIH Stroke Scale score greater than 25, and (4) those with a history of both prior stroke and diabetes. These patients were excluded from ECASS-III, so the relative efficacy and safety of rt-PA in these groups is uncertain.

TABLE 38.2

Protocol for Administration and Management of Patients Treated With Tissue Plasminogen Activator

The dose of tPA is 0.9 mg/kg (maximum dose 90 mg) infused over 60 min with 10% of the dose given as a bolus over 1 minute.
Patient should be admitted to an intensive care or stroke unit for monitoring.
Neurologic assessments and blood pressure measurements should be performed every 15 min during the first 2 h after starting the infusion, then every 30 min for the next 6 h, then hourly until 24 h after treatment.
If the patient develops severe headache, acute hypertension, nausea or vomiting, or neurologic deterioration, the tPA infusion should be stopped and an emergent CT scan obtained.
Blood pressure should be kept at or less than 180/105 for 24 h after tPA infusion has started
A follow-up CT scan should be obtained at 24 h to assess for hemorrhage before starting antithrombotic therapy

CT, Computed tomography; tPA, tissue plasminogen activator.

The most important complication of thrombolysis is symptomatic intracranial hemorrhage. This occurred in 6.4% of patients treated with IV tPA in the NINDS trial. Similar rates of hemorrhage have been seen in other studies. Situations that have been associated with a greater risk of bleeding are increasing stroke severity, hypodensity on CT scan (indicating areas of already evolving infarction), baseline use of antiplatelet therapy, and hyperglycemia. Use of tPA in patients on warfarin with subtherapeutic INR (1.7 or less) does not appear to be associated with an increased risk of hemorrhage. It is important to recognize that not all hemorrhage after thrombolytic therapy for ischemic stroke is due to the thrombolytic agent itself; reperfusion injury may cause hemorrhage in the absence of thrombolytic agents.

A standardized management protocol for patients with symptomatic ICH post-tPA was used in the NINDS trial and is widely used in clinical practice. This protocol recommends measurement of PT/PTT and fibrinogen, and transfusion of 6 to 8 units of platelets and 6 to 8 units of cryoprecipitate as a source of fibrinogen. Other strategies used at some centers include additionally administering fresh frozen plasma (FFP) or thawed plasma (particularly if the latter is immediately available for administration while awaiting cryoprecipitate), administering cryoprecipitate guided by fibrinogen levels (e.g., to maintain fibrinogen >100 mg/dL), or use of antifibrinolytic agents (such as aminocaproic acid) or recombinant factor VIIa (rFVIIa). Given the relative rarity of post-tPA ICH, there are no formal data on the relative efficacy of these different measures. One small study did document that, despite reversal strategies, 4 of 10 patients with post-tPA ICH had continued hemorrhage expansion.

Mechanical Thrombectomy

Catheter-based intervention to mechanically remove thrombi from occluded large cerebral arteries (mechanical thrombectomy) is now a proven strategy to improve outcome in patients with AIS associated with a large artery occlusion. This procedure typically involves using either a stent retriever, which is inserted into the clot then removed, or an aspiration catheter to suction clot out of the vessel. At least five trials, performed between 2010 and 2014, each demonstrated substantial benefit to this intervention. A pooled analysis of these trials including 1287 patients showed that intervention improved the number of patients who recovered to functional independence from 26.5% to 46.0% (OR 2.4, 95% CI 1.9 to 3.0, P < .0001). Most of the patients included in these trials were also treated with IV tPA. Importantly, mechanical thrombectomy appears to be reasonably safe even in patients on therapeutic anticoagulation who are excluded from IV tPA.

Consultation Strategies

Hematologic consultation regarding AIS therapy is most often related to selecting a treatment strategy for patients who have post-thrombolytic hemorrhage. In these patients, hemorrhage expansion likely occurs extremely rapidly, such that there is a brief window in which intervention may be able to arrest bleeding. An obvious complicating factor is that hemostatic agents, which are associated with an increased risk of arterial thrombosis, may be particularly hazardous in the setting of a patient with an acute vascular occlusion causing ischemic stroke. At our center, we treat patients with symptomatic post-tPA ICH with two doses of platelets and 10 units of cryoprecipitate; we administer thawed plasma if it is available immediately while awaiting the other blood products. We do not use antifibrinolytic drugs or rFVIIa due to concerns about the risk of further worsening arterial thrombosis and do not routinely monitor fibrinogen levels in these patients.

With the introduction of direct oral anticoagulants (DOACs), hematologists may also be consulted regarding whether a patient taking one of these agents could be considered for treatment with IV tPA. Standard consensus guidelines specify that patients taking warfarin with an INR greater than 1.7 are ineligible for IV tPA. At present, there are no corresponding guidelines for patients taking the newer DOAC drugs (dabigatran, rivaroxaban, apixaban). A reasonable approach is to attempt to estimate, at least qualitatively, whether a significant anticoagulant effect is present in the individual patient. If there is a reliable history of recent dosing of a new DOAC within a time frame in which significant anticoagulation would be expected, then tPA should not be used. Unfortunately, in clinical practice it is often difficult if not impossible to obtain a rapid, reliable history of compliance with and timing of oral anticoagulant intake in the acute stroke patient. In the case of dabigatran, decisions about treatment might be based on the results of the PTT or thrombin time. For the most part, patients thought to be taking dabigatran but who have a normal PTT are unlikely to have significant anticoagulation, and it may be reasonable to treat such patients with tPA (at present, this is the practice at our institution). Because the thrombin time appears more sensitive to the anticoagulant effect of dabigatran, a more conservative approach is to exclude patients from tPA if thrombin time is prolonged, assuming this is available with the rapid turnaround necessary to be useful in decision making for thrombolytic therapy. For rivaroxaban, a similar strategy using the PT may be reasonable (i.e., if the PT is normal, treatment with tPA is allowed), although different thromboplastin reagents used to determine PT may give variable results, and unlike with warfarin variation is not corrected by using INR. There are limited data with apixaban or other DOACs on which to base a recommendation.

Cerebral Venous Thrombosis

Cerebral venous thrombosis (CVT) is a relatively rare disease process, which can present abruptly with either brain ischemia or hemorrhage, or more insidiously causing increased intracranial pressure (ICP) due to obstructed venous drainage (see Chapter 17 ). Occasionally, patients will have slowly progressive venous ischemia or a combination of venous ischemia and hemorrhage. Hemorrhage in the setting of CVT is due to venous obstruction causing impaired outflow and thus differs markedly from arterial hemorrhage, with important therapeutic implications.

The mainstay of treatment for acute CVT is parenteral anticoagulation. Given the relative rarity of CVT, this recommendation is based on limited data. There have been only two small randomized, controlled trials evaluating acute parenteral anticoagulation in CVT, both of which suggested benefit. The first evaluated dose-adjusted IV heparin following a heparin bolus of 3000 units. The trial was stopped early after enrollment of only 20 of the planned 60 patients based on a substantial benefit favoring heparin. In the 10 patients in the heparin group, 8 had complete recovery and 2 mild deficits at 3 months, whereas of the 10 patients in the placebo group, only 1 had complete recovery, 6 had minor deficits, and 3 died ( P < .01). The second trial compared subcutaneous nadroparin (180 anti–factor Xa units per kg daily divided in two doses) to placebo in 59 patients with acute CVT. At 3-month follow-up, fewer patients in the nadroparin group had poor outcome (13% vs. 21%, absolute treatment difference favoring nadroparin −7%, 95% CI −26% to 12%); however, the results did not reach statistical significance. An important consideration in CVT is whether to use anticoagulation in the presence of intracerebral bleeding. Given the pathophysiologic basis of venous hemorrhage, there is a theoretical rationale for continuing anticoagulation. In the previously mentioned study of nadroparin, there were 29 patients with venous hemorrhage evenly distributed between the two groups and there was no evidence of hemorrhage expansion or new hemorrhage in the group treated with anticoagulation. An additional retrospective study of IV heparin in 43 patients with CVT and hemorrhage also demonstrated safety and potential efficacy of anticoagulation in this setting. Based on these considerations, most experts recommend anticoagulation for CVT even in the presence of hemorrhage.

Thrombolytic therapy using direct catheter-based infusion of thrombolytic agent into the occluded venous sinuses or mechanical catheter-based thrombectomy of venous clot is used in some patients with CVT, particularly those who progress despite therapeutic anticoagulation. Data on the clinical benefit of these procedures are limited.

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