Modelo normativo

There has been very little work published on coagulation abnormalities in vaso-occlusive complications of SCD other than painful crisis and, in particular.

there has been no comprehensive study of how levels of procoagulants and anticoagulants may contribute towards the development of CVD in SCD. The only study in the literature was published while my thesis was underway (Tam, 1997) and was a small pilot study on 9 older children with HbSS (mean age 12.6 years) with a past history of stroke but no recent transfusion. This patient group had significantly lower PC and PS activity levels than a control group of 4 HbSS children without clinical or radiological evidence of stroke. This study is obviously too small to draw any real conclusions from though the authors do suggest that there is a relationship between PC and PS deficiencies and an increased risk of stroke and that it would be of benefit to screen children for deficiency and start them on a transfusion programme before a clinical event occurs.

One of the main aims of this study was to establish whether or not children with known CVD had any significant differences in any of the factors controlling thrombin generation or inhibition compared to those who had normal vasculature. The screening programme to detect asymptomatic CVD with TCD +/- MRI/MRA, which was in place in this clinic, has allowed me to look at this in untransfused patients as all those with symptomatic CVD remained on long-term regular transfusion which potentially could reverse abnormalities present that may have been important in the pathogenesis of the original cerebral event. To analyse my data I divided the non-transfused HbSS children into 3 groups; group A were those who had proven CVD on at least 2 TCD studies with or without MRI/MRA abnormalities but were asymptomatic; group B were those who had been found to have normal cerebral vasculature on such studies and group C were those who had not been screened. I compared groups A and B to each other and to the subgroup of group D - group D(s) who were the 10 transfused children with stroke (table 49).

My results have found no excess risk for thrombosis or stroke as measured by levels of natural anticoagulants, response to APC, and the presence of an antiphospholipid antibody in the children with abnormal cerebral vessels in group A comparing them to group B, suggesting that none of these are important in the pathophysiology of CVD in this disease. Similarly, there were no differences in these parameters between group D(s) and groups A or B except that both A and B had significantly lowered APC resistance ratios compared to group D(s). Therefore the process that occurs to prevent further cerebral events when the %HbS is lowered to less than 20 - 30% during a transfusion programme does not appear to involve reversal of deficiencies in any of the natural anticoagulants but somehow APC resistance, which is probably acquired, reverses. As the ‘standard’ APC resistance ratio is derived from a APTT based assay with and without the addition of APC then any of the parameters that affect the APTT or the action of APC in inhibiting activated FV or activated FVIII can affect this ratio. As I stated in section 6.0.3. I was unable to examine a possible relationship between FVIII levels and APC resistance ratios. FXI and FXII were the only APTT-based factors that were studied and group D(s) did have reduced levels compared to group B but not A and there were no differences for FXII between these 3 groups. More detailed coagulation assays would be required to examine what is responsible for the normalisation of the functional APC resistance in group D(s) compared to groups A and B.

The lack of an association between the development of CVD and deficiency of the natural anticoagulants, response to APC, or the presence of an antiphospholipid antibody is an important negative finding of my study. First of all it refutes completely the results of the small pilot study already mentioned (Tam, 1997) which did find lower levels of PC and PS in children who had had a stroke. Secondly, there is still considerable dispute in the literature as to whether these

thrombophilia conditions are important in the pathogenesis of cerebral arterial thrombosis in children without SCD. All published studies are small and include case reports, which have to be regarded as anecdotal (Nowak Gotti et al. 1996a; Nuss et al. 1995; Gurgey et al. 1996; Olson et al. 1994; Devilat et al. 1993; Nowak GottI et al. 1996b). There are no large controlled studies published to date and the data from this study does not support suggestions that these conditions cause childhood arterial thrombosis. The role of a patent foramen ovale, which has recently been recognised as an important cause of stroke in young adults, deserves evaluation in children with stroke with and without SCD.

The only significant differences between groups A and B in this study were that the children with asymptomatic CVD had lower Hb and higher WBC values than those with normal vasculature. Both of these are known to signify more clinically severe SCD and be related to higher mortality rates and also a higher risk of stroke in other published series (Platt et al. 1994; Balkaran et al. 1992; Ohene Frempong, 1991). It is not clear whether or not a high WBC per se or aberrant WBC-endothelial interactions are important in the initiation of CVD or, conversely, whether a higher WBC is reactive, secondary to intimai hyperplasia and endothelial damage in the cerebral vessels or to sites of chronic infection. One common site for chronic infection in children, particularly those with SCD, is the hypertrophied tonsillar bed and as a causative relationship between obstructive sleep apnoea and stroke has been proposed (Davies et al. 1989; Madderin et al. 1989; Robertson et al. 1988), one hypothesis for the association between a reactive elevation in WBC and the development of CVD is that chronic tonsillar hypertrophy could play an important central role (Ajulo, 1994). One interesting study looking at neutrophils in SCD patients has found increased numbers of circulating activated neutrophils which show increased adherence to vascular endothelium (Fadlon et al. 1998). Further work is obviously required in this field to determine exactly what is the role

and importance of WBC in this disease and whether interactions between WBC and endothelial cells or between WBC and platelets such as WBC-platelet complexes play a role. The importance of tonsillar hypertrophy in the pathogenesis of CVD also needs to be examined as this was not addressed in the recent CSSCD study (Ohene Frempong et al. 1998). However a further finding in my study suggests that even though the group with CVD have a higher WBC than those without, this is not reversed by transfusion as there was no difference in WBC between groups A and D(s). As transfusion is known to prevent clinical recurrence but does not correct the high WBC this is evidence against a prominent role for WBC in CVD.