Systemic Hematologic Status Following Intraventricular rt-PA for Intraventricular Hemorrhage

Abstract

Background and Purpose

This is the first prospective evaluation of changes in systemic hematologic status following administration of intraventricular rt-PA in patients with intraventricular hemorrhage.

Methods

Laboratory data from subjects enrolled in the Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Trials were analyzed. We analyzed pre/post rt-PA dosing coagulation parameters. Longer-term changes in hematologic status were studied in subjects that received study agent after blood clot in the 3^rd/4^th ventricles had resolved radiologically.

Results

Plasma fibrinogen increased significantly in both treatment groups. Dosing did not have a significant impact on any systemic coagulation parameters in either treatment group.

Conclusions

Intraventricular rt-PA is unlikely to impact systemic coagulation or compound the effects of systemic anticoagulation for DVT prophylaxis.

Introduction

Thrombolytic treatment of intraventricular hemorrhage (IVH) with low dose intraventricular rt-PA¹ has shown significant improvement in 30-day survival. Intravenous rt-PA produces a transient systemic hypocoagulable state.² Administering intraventricular thrombolytics to hypertensive IVH patients could contribute to a systemic coagulopathy and increase risk for both intra and extra-cranial bleeding. We performed a retrospective analysis of data from a large placebo-controlled multisite trial to assess the impact of intraventricular rt-PA on systemic coagulation.

Methods

The CLEAR IVH Trial study procedures have been published previously.³ We investigated changes in PT, PTT, platelets, plasma plasminogen, and plasma fibrinogen in patients who had blood coagulation data both prior to and within 36 hours after the first dose of study agent. To explore longer term effects of rt-PA when dosing may have systemic effects after restoration of normal CSF resorption, we studied a smaller subgroup that received study agent after blood clot in the 3^rd/4^th ventricles had resolved in whom an additional lab draw was performed within 24 hours after a dose was administered following clot resolution in the 3^rd/4^th ventricles. Adverse events were recorded prospectively.

Rt-PA and placebo groups were compared for demographic and clinical characteristics using chi-square analysis, t-test, and the Kruskal-Wallis one-way analysis of variance as appropriate. Regression analyses were used to compare treatment and placebo groups adjusting for baseline coagulation parameters, baseline IVH volume and gender. All results are presented as mean±standard deviation. P-values less than 0.05 were considered significant.

Results

Laboratory data were available for 78 of 100 enrolled subjects. Demographic and clinical characteristics are shown in Table 1. Coagulation data was similar in both treatment groups at baseline and during dosing (Table 2). Percent increase in plasma fibrinogen was statistically associated with time relative to first dose, but there was no statistically significant difference between placebo and rt-PA groups (P<0.01, Figure 1).

Table 1.

Patient Demographics

	Coagulation Post First Dose(s)			Coagulation Around Ventricle Clearing
Characteristic	rt-PA (n=57)(%)	Placebo (n=21)(%)	P Value	rt-PA (n=20)(%)	Placebo (n=7)(%)	P Value
Age (yr)	54±11	56±7	0.43	53.6±11	54.7±5	0.85
Gender
Male	36 (63.16)	7 (33.33)	0.02	14 (70.00)	3 (42.9)	0.20
Female	21 (36.84)	14 (66.67)		6 (30.00)	4 (57.1)
Race
African-American	32 (56.14)	9 (42.86)		11(55.0)	5 (71.4)
White	13 (22.81)	7 (33.33)	0.33	4 (20.0)	2 (28.6)	0.54
Asian	6 (10.53)	1 (4.76)		3 (15.0)	0 (0.00)
Hispanic	4 (7.02)	4 (19.05)		2 (10.0)	0 (0.00)
Other	2 (3.51)	0 (0.00)		0 (0.00)	0 (0.00)
Diagnostic CTIVH Volume (mL)	46.0±33	50.8±36	0.53	45.5±23	52.3±39	0.96
Diagnostic CT ICH Volume (mL)	9.9±9	12.7±13	0.81	12.3±10	12.6±17	0.45
Hypertension	46 (80.70)	18 (85.71)	0.61	17 (85.0)	7 (100.0)	0.28
Prior Antiplatelet Use	5 (8.77)	4 (19.05)	0.21	1 (5.0)	0 (00.0)	0.55
Total rt-PA Administered	3.1±2.0	0	<0.00	8.33±6.9	0	<0.00
Prior to Lab Draw (mg)			1			1
Time From First Dose to Lab Draw (Hours)	14.74±8.85	11.95±7.35	0.20
Time From Last Prior Dose to Lab Draw (Hours)	7.57±4.74	5.51±5.18	0.44
Time From Ventricle Clearing to Dose (Hours)				5.34±4.4	8.87±5.5	0.14
Time From Ventricle Clearing Dose to Lab Draw (Hours)				10.20±6.7	5.27±3.15	0.10
Time From First Dose to 3rd/4th Ventricle Clearing (Days)				2.74±1.1	7.04±3.5	0.03

Table 2.

Baseline and Post-First Dose Coagulation Parameters

	Baseline		Post First Dose		% Δ in Coagulation Parameter
Coagulation Parameter	rt-PA	Placebo	rt-PA	Placebo		rt-PA			Placebo
	Mean±SD (n)	Mean±SD (n)	Mean±SD	Mean±SD	Mean±SD	Median	Range	Mean±SD	Median	Range
Platelet Count (plt/mm3)	236±61 (56)	238±65 (21)	211±59	204±62	−9.81±14.6	−12.4	−48.6–31.2	−14.42±13.1	−13.13	−43.3–11.3
PTT (Seconds)	29.4±4.2 (57)	28.8±6.0 (18)	30.0±4.2	29.0±5.9	2.16±8.0	0	−12.4–41.5	0.81±2.6	0	0–10.5
PT (Seconds)	13.0±2.0 (52)	12.6±1.7 (20)	13.2±2.0	12.7±1.6	0.95±3.4	0	−6.76–13.1	0.54±2.4	0	−2.04–10.7
Fibrinogen (mg/dL)	461±140 (43)	448±92 (16)	508±150	478±103	12.37±22.14	2.38	−33.7–97.24	7.24±12.	2.79	−6.82–39.7
Plasminoge n (%)	103±15 (34)	108±17 (12)	103±17	107±18	0.27±8.14	0	−25.56–18.0	−0.46±8.60	0	−11.11–21.3

Figure 1.

Percent change in plasma fibrinogen concentration from baseline shown by locally weighted scatterplot smoothing.

Demographic and coagulation data were similar in both treatment groups in the 27 subjects who had laboratory data after clearance of 3^rd/4^th ventricles (Table 1) (please see http://stroke.ahajournals.org), except for time from administration of the first dose to clot resolution in the 3^rd/4^th ventricles. After re-matching the placebo group to the rt-PA group using the time of clearance of the rt-PA group to account for time related change, there were no significant differences between the two groups' coagulation parameters.

Deep venous thrombosis (DVT) occurred in 2.5% of rt-PA and 4.5% of placebo patients. One patient had a myocardial infarction. Symptomatic brain bleeding occurred in eight rt-PA and one placebo subject. Coagulation data were similar between subjects who had symptomatic brain bleeding and those who did not. The only non-CNS bleeding event reported (GI hemorrhage) was in the placebo group. None of 29 subjects who received subcutaneous heparin or coumadin during intraventricular rt-PA dosing experienced systemic bleeding.

Discussion

In contrast to intravenous thrombolytic administration, patients were exposed to significantly lower doses of intraventricular rt-PA (maximum of 3.0 mg q12h for up to 13 days). Our findings show that administration of low-dose intraventricular rt- PA does not significantly change systemic hematologic status in patients with IVH either before or after radiographic clearance of the 3^rd/4^th ventricles.

Following administration of 100 mg intravenous rt-PA, there is a decrease (16–36%) in circulating fibrinogen.⁴ We observed a mean increase in fibrinogen in both groups after the first dose and after ventricle clearance, which we attribute to an acute phase hematologic response to intracranial hemorrhage.⁵

Systemic hematologic status is an important consideration in the treatment of hemorrhagic stroke, as hemorrhagic stroke is an independent risk factor for DVT.⁶ The rate of DVT and pulmonary embolism among all rt-PA subjects in the CLEAR IVH trial is consistent with other studies,^1,7 suggesting clinically that intraventriclar rt-PA does not initiate systemic fibrinolysis, and would be unlikely to compound the effects of systemic low dose anticoagulation for DVT prophylaxis. The effect of local factors on brain bleeding such as extent of tissue trauma and timing of local t-PA delivery in relation to hemostasis would benefit from further investigation.