3. La literatura mediúmnica en Brasil y Colombia
3.1 Francisco Cándido Xavier, un médium completo
•Type 3 Type 2B Type 2A
Figure 8.1.
The response o f the BT and the CT pre and post Haemate P in three patietns with type 2A, type 2B and type 3 VWD.8.4. DISCUSSION
The CT as measured by the PFA-100™ were studied in a group o f 53 patients with different types o f VWD. These results confirmed that the PFA-100™ has a higher sensitivity (94%) than the classical BT (58%) in detecting VWD. Thus, by performing the BT alone the diagnosis o f VWD would have been missed in nearly h alf o f these patients (42%). In contrast, by assessment o f the CTs only 6% o f patients with VWD would have been missed.
Simple algorithms for analysis o f the PFA-100™ results have been proposed [Favoloro 1999; Ortel 2000] stating that finding a normal CT can exclude a defect in the primary haemostasis and only an abnormal result should always be confirmed by fiirther tests. However, in this study three patients had normal PFA-100™ testing but they were diagnosed with type 1 VWD based on other criteria as described in Chapter 4. These data add to the difficulties in diagnosing type 1 VWD, especially the mild forms as discussed in detail in Chapter 4, and it also demonstrates that finding o f a normal PFA-100™ cannot on its own exclude a diagnosis o f VWD. If there is a strong clinical suspicion o f VWD then the diagnosis should be fiirther investigated with other tests irrespective o f the PFA-100™ results. Thus, although the CT have a very high predictive value o f VWD it has very little negative predictive value and the decision that a patient is not affected by VWD should not rely on PFA-100™ testing alone.
The available literature also suggests that if only the CT-EPI is prolonged and the CT- ADP is normal, an aspirin effect should be suspected. However, the finding o f a CT-ADP prolongation irrespective o f the CT-EPI (normal or prolonged) indicates a qualitative platelet defect or VWD and platelet aggregation and VWF studies are necessary [Favoloro 1999; Ortel 2000].
In this study both cartridges were found to be equally sensitive to VWD in contrast to other reports where CT-ADP was found to be superior to CT-EPI, with CT-ADP sensitivities varying between 87% (Schlammadinger 2000) to 100% (Fressinaud 1998). However, when the analysis o f the CT was performed on the subtypes o f VWD, only the CT-ADP was significantly different in the various groups, whereas the CT-EPI and the BT were not.
The V W FiAC did not differ between the subtypes o f VWD as the severity o f the disease was very variable in each group. Similarly, the VWF : AC/VWF : Ag ratio was not significantly different between the subtypes, reflecting the small number o f patients analysed in each group and also the use o f the VWFiAC assay instead o f the classical VW FiRiCo assay. However, interestingly, the CT-ADP was significantly longer in patients with type 2A and type 2M as compared to type 1 VWD, reflecting not only the severity o f the disease but also its value as a global test for primary haemostasis in the presence o f qualitative defects in VWF.
Among the variables which can influence the CT analysed in this study, the VWF:AC emerged as the main predictor o f the CT with both cartridges and o f the BT, accounting for about 30 % o f their variation. As a direct consequence, the VWF : AC/VWF : Ag ratio and the type o f VWD also emerged as important variables. The dependency o f the BT on the VWF levels is in contrast to some o f the published studies (Rodeghiero 1992). 14% o f the variation in the CT-ADP and the BT could be accounted for by the type o f VWD (as quantitative or qualitative) which indirectly emphasizes the importance o f other variables which define the type o f VWD, such as the multimeric structure o f VWF and the platelet VWF (Fressinaud 1999, Cattaneo 1999).
In contrast to CT-ADP, the CT-EPI was not influenced by the type o f VWD and the VWF: AC had only a small effect on its variation, suggesting that this cartridge is o f less use in the assessment o f the diagnosis and classification o f VWD.
The platelet count had a borderline significant influence on the CT-ADP cartridge and no effect on the CT-EPI. The haematocrit had no influence on neither the CT or the BT. The lack o f significance o f the platelet count and haematocrit variables is probably due to the small number o f patients who had thrombocytopaenia or low haematocrits and were included in this study.
W ith regard to the blood group, these data demonstrated that in patients with VW D the CT was not affected by the blood group. This is in contrast with a recent report which
found higher CT in normal individuals with blood group O (Lasne, 2000). However, although the plasma VWF are lower in individuals with blood group O, the platelet VWF, which is independent o f the blood group (Rodeghiero 1992), is crucial for establishing and maintaining primary hemostasis as reflected by the BT. Furthermore, this study found that the BT was also independent from the blood group in patients with VWD which confirms (Rodeghiero 1992) but also contradicts some o f the available literature (Caekebeke 1989). As the CT is an in vitro alternative for the BT and the BT is independent o f the blood group, it would be expected that the CT is also independent o f the blood group.
In the second part o f this study the use o f PFA-100™ to monitor treatment was studied. Two patients with type 1 VWD were analysed and th e ^ e r e unresponsive to DDAVP as the VW F levels did not correct at two hours post infusion. Similarly, at two hours post DDAVP infusion, the CTs remained prolonged (>250 sec in one patient and a slight shortening o f the CT without normalisation was observed in the second one) showing that the lack o f correction o f the CTs reflected the poor response to DDAVP.
Fressinaud at al. reported a correction o f the CT at 30 minutes post DDAVP infusion in all their patients who responded to DDAVP. However, at three hours post DDAVP infusion the CT were mildly prolonged or had returned to baseline levels [Fressinaud 1999]. These workers defined as a good response to DDAVP i f a full correction o f the CT was achieved at 30 min post infusion [Fressinaud 1999]. However, the correction o f
the CT was a short lasting effect and if the response to DDAVP was defined as the correction o f the CT at three hours post infusion, the majority o f their patients would have been considered unresponsive. Testing the CT at longer intervals post DDAVP infusion is probably more appropriate especially when the CT is used to monitor treatment in patients with VWD receiving DDAVP.
The response to DDAVP was assessed in one patient with type 2M VWD with the R611H mutation (previously described in Chapter 6) who was unresponsive to DDAVP as defined by low VWF levels ( < 5 0 lU/dl) and very prolonged CT at two hours post DDAVP. It has been suggested that among patients with type 2M the response to DDAVP may vary according to the genetic defect [Fressinaud 1999]. In contrast to the findings in this patient, other investigators have reported a good response to DDAVP with normalisation o f the CT in patients with type 2M VWD and the R611H mutation [Fressinaud 1999].
The fourth patient who received DDAVP had type 2A VWD with the R834C mutation, which belongs to group 2 mutations where there is increased proteolysis o f VWF (Lyons 1992). This patient (patient LC who is described in detail in Chapter 7) was found to be responsive to DDAVP as the VWF levels did correct at two hours post DDAVP but the CT remained unchanged post DDAVP.
The response to DDAVP by monitoring the CT was studied in four patients. A good correlation was found between the response to DDAVP and the correction o f the CT in two patients with type 1 and one patient with type 2M VWD and no correlation was found in the patient with type 2A VWD. As the number o f patients analysed here is small, no conclusion can be drawn on the value o f the CT in monitoring treatment with DDAVP. However, it appears that at least in type 2 VWD the response to DDAVP may depend on the underlyirr 3 genetic mutafion and this hypothesis merits further investigations.
The CT was also used to monitor the response to treatment with clotting factor concentrates (CFCs) in three patients with VWD. It was observed that the CT did not correct after the administration o f Haemate P despite the normalisation o f plasma F V ni/V W F levels. In contrast to the CT, the BT shortened without normalisation in two patients at two hours post Haemate P. In explanation to the inability o f the CT to reflect the response to CFCs, two main factors should be considered. Firstly, although the plasm a VWF levels were corrected, the infusion o f concentrate did not correct the platelet VWF, which is essential for the formation o f the platelet plug [Mannucci 1995] and an important determinant o f the CT [Fressinaud 1999]. The three patients who received an infusion o f Haemate P m ay have underlying quantitative and /or qualitative abnormalities in the platelet VWF (with the additional contribution o f thrombocytopaenia in the type 2B patient). The multimeric content o f these concentrates may be another contributing factor to the lack o f correction o f the CT after administration o f CFCs. The PFA-100™ is sensitive to the high molecular weight forms o f the multimers [Fressinaud 1999], which