Infectious Purpura Fulminans: Caution Needed in the Use of Protein C

We welcome the comments of Dr Finn and colleagues and believe they have raised a number of interesting points. Firstly, the assertion that a placebo-controlled randomized trial is required prior to the introduction of novel therapies has its merits and supporters in the context of protein C (PC) replacement in severe purpura fulminans associated with meningococcaemia. The major concern we have with this argument is that it presupposes that the rapid severe depletion of PC that is seen in patients with purpura fulminans secondary to meningococcaemia is not playing a pivotal role in the pathophysiology of the widespread microvascular thromboses that is the hallmark of this disease. Also, we know that PC deficiency is a well-recognized cause of purpura fulminans and that PC replacement therapy has been shown to reverse this condition in other situations (Dreyfus et al, 1991). Secondly, the reference by Finn et al to be potential hazards associated with the use of aspirin and heparin in ischaemic stroke may not be entirely appropriate. We believe that the conceptual difference between heparin and protein C replacement in purpura fulminans and anti-platelet therapy plus heparin in ischaemic stroke, together with the differences in the pathophysiology of these two conditions, invalidates any meaningful comparison. However, although the potential risks of haemorrhagic complications with the use of heparin and protein C are low, we do advocate aggressive coagulation support with particular reference to platelet count and fibrinogen level, as outlined in the Annotation (Smith & White, 1999). Thirdly, Finn et al state that there is insufficient data on PC kinetics to design a study on PC replacement therapy in meningococcaemia. This is not correct. We have considerable data on the kinetics of PC replacement in this condition. A loading dose of 100 iu/kg followed by 10 iu/kg/h, with subsequent dose adjustments according to the level of circulating protein C as measured by a clotting and or chromogenic assay, is a highly reliable regimen for maintaining protein C in the normal range. Finally, the use of activated protein C (APC) may be more complicated than PC replacement. At present there is insufficient data on the failure of mechanisms responsible for PC activation in meningococcaemia to justify the use of APC in meningococcaemia, given the increased potential for haemorrhagic complications with this therapy. We know that PC is severely reduced in meningococcaemia associated with purpura fulminans and is predictive of morbidity and mortality in this condition. We also know that PC deficiency causes purpura fulminans. Therefore, given our current state of knowledge, we believe that the primary aim should be to normalize circulating PC levels with PC replacement therapy. We thank Finn et al for their comments. We do accept that some physicians will require a randomized trial prior to the use of PC replacement therapy and this is clearly stated in the Annotation. We welcome the development of a United Kingdom ‘network’ to coordinate trials in meningococcaemia and we would certainly make our data available to this group.