Page 187 - 2019_08-Haematologica-web

Underlying pathologies in pediatric stroke
Table 2. Univariable analysis: association between prothrombotic risk factors and a second stroke. A single prothrombotic disorder was detected in 269 children.
Risk factor
Fasting Lp(a) >30 mg/dL
Fibrinogen
Fasting homocysteine Antithrombin-deficiency Protein C deficiency Protein S deficiency Factor 5 at rs6025 Factor 2 at rs1799963
Combined defects
AIS: arterial ischemic stroke; Lp: lipoprotein
AIS first onset: numbers with abnormal test /numbers tested (%)
AIS recurrence: numbers with abnormal test /numbers tested (%)
Chi-squared P-value
115/580 (19.8)
43/787 (5.5) 16/708 (2.3) 23/750 (3.1) 26/778 (3.3) 28/708 (4.0) 71/726 (9.8) 21/631 (3.3) 88/848 (10.4)
23/115 (20.0) 0.04
13/43 (30.2) 0.04 7/16 (43.8) 0.01 7/23 (30.4) 0.15 5/26 (19.2) 0.9 7/28 (28.0) 0.2 8/71 (11.3) 0.17 3/21 (15.0) 0.84
23/88 (26.1) 0.04
Table 3. Risk contribution to a second arterial ischemic stroke adjust- ed for age at onset, gender and study center (Cox proportional hazards model).
Reference: no thrombophilia
cant association was found between recurrent AIS and the remaining stroke subgroups: cardiac stroke (HR 1.15, 95% CI: 0.7-2.0; P=0.61); non-vascular/non-cardiac/non-idio- pathic (HR 1.01, 95% CI: 0.5-2.0; P=0.95).
Prothrombotic risk factors
Results derived from univariable analyses are shown in Table 2. A single prothrombotic disorder was detected in 269 children, whereas more than one prothrombotic risk factor was diagnosed in 88 cases. Heterozygous antithrom- bin deficiency, high lipoprotein (a) [Lp(a)], high fibrinogen, high fasting homocysteine and the presence of more than one prothrombotic disorder were associated with recur- rence. Of the 7/23 patients with heterozygous antithrom- bin deficiency who experienced a recurrent stroke, none was on unfractionated heparin or vitamin K antagonist treatment: four were prescribed acetylsalicylic acid at the time of recurrence, one patient was on low molecular weight heparin, while two subjects were taking no pro- phylaxis immediately prior to the recurrent stroke (non- compliance was not excluded). In six of 23 (26%) patients with combined defects and a second stroke, the factor 5 mutation at rs6025 was involved. Interestingly, however, the factor 2 mutation at rs1799963 did not play a role in children with combined defects.
Examination of the roles of different stroke subtypes and prothrombotic risk factors, using multivariable Cox proportional hazards regression of variables with a P- value ≤0.15 in the univariable analyses, adjusted for age, gender and study center, demonstrated that the presence of vasculopathy (HR 2.5), antithrombin deficiency (HR 3.9), elevated Lp(a) (HR 2.3) and the presence of more than one prothrombotic risk factor (HR 1.9) were independent- ly associated with an increased risk of recurrent stroke (Table 3). The time to recurrence, i.e. recurrence-free sur- vival comparing pediatric AIS patients with elevated Lp(a) to those with normal Lp(a) levels is illustrated in Figure 3 (log rank P-value <0.039). Recurrence rates calculated per 100 person-years were 10 (95% CI: 3-24) for antithrombin deficiency, yearly incidence rate 0.1%, 6 (95% CI: 4-9) for elevated Lp(a), yearly incidence rate 0.13%, and 13 (95% CI: 7-20) for the presence of more than one prothrombotic risk factor, yearly incidence rate 0.13%. Exposure time of the children was 2437 years for those with antithrombin
Risk factor
Vascular stroke
Cardiac stroke
Non-vascular, non-cardiac non-cryptogenic
Fasting Lp(a) >30 mg/dL
Fibrinogen
Fasting homocysteine
Heterozygous antithrombin-deficiency Protein C deficiency
Protein S deficiency Factor 5 at rs6025 Factor 2 at rs1799963
Combined prothrombotic risk factors
AIS: arterial ischemic stroke; Lp: lipoprotein
2.3 0.9 3.6 3.9 1.3 2.2 0.7 1.8 1.9
Hazard ratio
Stroke subtypes
Reference: cryptogenic stroke
2.5
1.15 1.01
Thrombophilia
95% confidence interval
1.92-3.5
0.7-2.0 0.5-2.0
1.3-4.1 0.3-2.8 0.8-15.8 1.4-10.9 0.3-5.5 0.5-9.8 0.23-1.91 0.4-7.8 1.12-3.2
Reference: no thrombophilia
deficiency, 1938 years for those with elevated Lp(a) and 2887 years for patients with more than one prothrombitic risk factor. Kaplan-Meier survival curves for children with multiple thrombophilic factors and for those with normal thrombophilic status are illustrated in Online Supplementary Figure S1.
Based on data from the Caucasian pediatric population, the number-needed-to-screen to detect one patient with elevated Lp(a) was 10 and that to detect children with more than one prothrombotic abnormality was 20.
Discussion
In our study cohort of 894 Canadian, English and German
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