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Management Of Thrombotic Thrombocytopenic Purpura

British Journal of Haematology2000-06-01作者：Gail A. Rock

Thrombotic thrombocytopenic purpura (TTP) is not a common disorder, but the young age, acute onset, fulminant course and sometimes fatal nature of the disease make it remarkable. Although first described by Dr Eli Moschkowitz in 1924, the pathogenesis of the disorder has only recently begun to be truly understood ( Moschkowitz, 1924). Moschkowitz (1924) reported the presentation of a 16-year-old girl with fever, anaemia, central nervous system impairment, renal dysfunction and cardiac failure. The patient died after 2 weeks, with the autopsy showing hyaline thrombi in the terminal arterioles of the majority of organs – a finding considered to be characteristic of the disorder. Over the years, a classical textbook description of a pentad of symptoms for TTP, consisting of microangiopathy, haemolytic anaemia, thrombocytopenia, fluctuating central nervous system abnormalities, fever and renal impairment, has developed. However, it now appears that the classical pentad is infrequently present in the early stages of disease. Only after there is widespread formation of microthrombi and a resultant impact on various organ systems does the full pentad express. In a series of 135 patients that we have recently reported, all patients had schistocytic haemolytic anaemia and thrombocytopenia ( Rock et al, 1998 ). However, only 30 had fever and 86 had neurological abnormalities. Renal impairment was present in 18% of patients. These findings are supported by the literature; a review of published cases by Ridolfi & Bell (1981) reported that 98% of patients had microangiopathic haemolytic anaemia (MHA), 83% thrombocytopenic purpura, 84% neurological symptoms and 76% had renal disease. We have therefore proposed that TTP should be redefined as a syndrome of Coomb’s negative microangiopathic haemolytic anaemia and thrombocytopenia in the absence of other possible causes of these manifestations. In our experience, TTP occurs, for the most part, in previously healthy, relatively young individuals who suffer the sudden onset of a thrombotic disorder in which platelet microaggregates deposit in the arterial microvasculature. In our largest series of patients, 85 were women and 50 were men, with a mean age of 41·7 years (range 18–72) ( Rock et al, 1998 ). Occlusion of small arterioles by platelet plugs containing variable quantities of von Willebrand factor (VWF) characterizes the disease. Electron microscopy has shown the thrombi to be composed of degranulated and altered platelets with little fibrinogen or fibrin ( Asada et al, 1985 ). Although TTP is uncommon, more than 200 cases have been reported each year for the last 5 years to the Canadian Apheresis Group, which captures the data on most TTP patients in the country. This is somewhat higher than the data from a recent US epidemiological study, which indicated an incidence of 3·7 cases per 1 000 000 residents ( Torok et al, 1995 ), but may be reflective of an enhanced awareness of the disorder in Canada because of our several TTP studies and the fact that the incidence of TTP appears to be rising recently. It is possible that the true mortality of the disease is underestimated as the majority of deaths occur within 48 h after presentation ( Brailey et al, 1999 ). Clinical Multiple forms of this syndrome are recognized, ranging from those in which the causative factor has been identified, such as in Shiga toxin-induced TTP/haemolytic uraemic syndrome (HUS), to the more obscure idiopathic forms. Most commonly seen is the acute single-incidence episode which, with appropriate therapy, generally resolves within weeks. Chronic relapsing forms of the disease are also seen. In four such patients, there has been documentation of the presence of unusually large factor VIII multimers in the intervals between relapse ( Moake et al, 1982 ). A juvenile chronic relapsing form has also been seen in which these patients appear to respond to infusion of plasma administered on a periodic schedule established to prevent relapses. Four of these patients have been shown to have a congenital deficiency of a protease which reduces high molecular weight forms of VWF ( Furlan et al, 1998 ). Unfortunately, the initiating agent(s) of most forms of the syndrome is not yet known. Laboratory Generally, the earliest initial presentation is purpura owing to thrombocytopenia. We found that the initial platelet count correlated with mortality: 32% of patients with a platelet count of ≤ 20 × 109/l died compared with 18% with a higher platelet count ( Rock et al, 1998 ). However, others have not found this association ( Brailey et al, 1999 ). Although it is well known that platelet microaggregates are formed, the evidence is variable regarding the activation of platelets in TTP. Several studies have shown an increase in CD62, an activation marker, but other studies have found this not to be the case ( Ahn et al, ). there is a schistocytic anaemia and an It is in et the and the in patients with acute TTP, that the was to of from a of as a of and not the of an increase in and 2 to It is to that this is not a disorder of the formation of platelet or other or of the system are seen and the and fibrinogen are generally not In our 135 patients, the and were in patients ( Rock et al, 1998 ). Although the patients variable in the majority had a of von Willebrand This to the generally that TTP is to form of This fact is supported by evidence and altered of most the finding of of in by TTP plasma ( et al, 1999 ). a of evidence has for an for forms of TTP. The TTP ( et al, 1999 has these which evidence showing the presence of as well as an Willebrand factor Although the initiating of the syndrome is not yet it is that there is a common of disease the presence of of von Willebrand factor in the plasma and on the of the platelets and the formation and of platelet in the microvasculature. A of possible have been considered to for as The presence of platelet In & a from plasma of acute TTP patients. This platelets with a platelet ( et al, ). has a in TTP plasma of the disease ( et al, ). is an that is found in It is to have a in platelet and the for also characteristic on This altered VWF is with platelets and to and has been shown to formation of platelet ( et al, ). von Willebrand VWF is present in plasma 1 and is in platelet to and A series of VWF multimers be on large molecular weight multimers are found in the of and in platelet These but not plasma VWF of platelets high ( et al, ). and of plasma VWF have been reported for patients with TTP. These the in plasma of high molecular weight multimers of a chronic relapsing form of TTP ( Moake et al, 1982 and of the forms of multimers acute or relapsing TTP. VWF is in the pathogenesis of the platelet and as supported by the finding of VWF in the thrombi in TTP. et found that VWF was enhanced in acute TTP, but not to of the of the TTP also found that in and TTP cases there was enhanced of VWF acute disease as by a in the VWF that of VWF occur ( et al, 1999 ). In our of 135 patients with acute TTP ( Rock et al, ), we found VWF to be but with a variable presentation of VWF patients had most had a of multimers or the forms. VWF multimers not with or other and all be for the of multimers which are to this the the and of the VWF multimers are with a of various patients with chronic relapsing disease are seen to have multimers in plasma in or may be to the acute disease. to platelets for was first by which as the patient ( & It was that this from the to or which with platelets and to and has been reported to be in TTP patients ( & as is the with most other in TTP, it has been reported as in others ( et al, ). However, the that to is now well and by thrombocytopenia and the with to platelet to thrombotic and We have found in the of of patients ( et al, ). of a of by and by is a known as and It is in platelets as well as other organs and have been described for a as a with a large of and in ( et al, is to and is not seen in the of large ( et al, ), to the of microthrombi in TTP. We found that these platelets in most cases and that this was enhanced in the presence of The appear to be a of a of from system or in to platelet in these TTP patients. et reported in which also found in TTP patients a and by forms of with the form and an more to the to the This may to the variable seen in We have also found in patients with the and thrombotic but not those with ( Rock et al, ). have also been reported in TTP ( et al, ). & that plasma from patients with TTP of and of platelets in In our experience, the majority of TTP by with ( Rock et al, 1998 ). to and VWF from which platelet such as high or platelet in platelet on it was that patients with TTP have a deficiency of platelet or of a that the formation of this which platelet and ( et al, ). In our ( Rock et al, 1998 ), the of was for the first patients the However, the were variable and it was not considered to this other platelet have been et and Rock et indicated that the of platelet was in patients with TTP. et this to the activation of the It should be that platelets are in with to the these platelets than However, our finding that of VWF multimers from plasma was in of patients with TTP to an in a which is or ( Rock et al, ). This that VWF is to the platelets in TTP has recently been by others ( et al, 1998 ). et also found that episode and TTP patients had platelet in and VWF on platelets the platelet was not in most TTP This that the VWF to the platelets from plasma than from the the platelets are not this appear to that the VWF is from the and to the platelets This of VWF to platelets disease may for of the seen in the plasma for VWF VWF VWF is by as a large of by ( et al, ). it is in the between and by a of and ( et al, ). Furlan et reported that with a relapsing form of TTP had a deficiency of this VWF protease plasma patients had platelet and The of the VWF protease was to be and in these patients. & in and Furlan et in have found that the of plasma VWF is or acute TTP with a to after have an the which appears to for the of the acute disease. Furlan et reported that TTP patients had this was not the case for or and that this may a to between the However, ( et al, 1999 of enhanced of VWF in TTP patients other than forms as in TTP. the it is that the presence of and to as a of in VWF a in the of TTP. In most TTP has an acute onset with initiating However, the majority of cases appear to be with other are well These ( et al, ), ( et al, ), ( and ( and ( et al, ). uraemic syndrome is a disorder with TTP in that is the formation of platelet microthrombi with a haemolytic schistocytic anaemia, but in that the is seen in the with of platelet microthrombi in the TTP and to be the disorder, with initiating but the of formation and of platelet In a association with has been ( et al, ). This is known to have several the of high molecular weight VWF from It as an and there has been relatively little evidence of an in TTP, cases of TTP have been to to ( et al, in association with ( et al, ), TTP has also been seen with and The association between syndrome and is well established ( & In to the microangiopathic haemolytic anaemia, thrombocytopenia and renal which are is commonly seen. The is to be characteristic of this of it from the other TTP is most commonly in by of the are present in the the is In a recent & that the presence of in of cases was an of TTP. However, in our early series of patients with TTP, we found in all patients, it was to to this in the of which are This may not be it is considered that the and therefore the may be in cases of TTP, but that there is a common of formation and with platelet by & is that and may in patients and may the also appear to have a to TTP ( et al, ), the of such as and the is to The by of the is well as is the of a has also been with cases of TTP. in the in the platelet by the of to the to after is to prevent and formation after cardiac ( et al, ). et reported on patients who TTP These patients were years who had for than 1 The by which this syndrome is not known. These have that TTP has been first years on the This is an in that that is to has now of the in the The presence of the in cases of or TTP and the of the syndrome in patients these that an may be TTP has been reported to be common in series ( Torok et al, 1995 ). In our Canadian experience, this is not seen. have been of a between and TTP ( et al, ), and have been to this in of the TTP may also it is more commonly seen in the et reported that women who are or in the make of TTP patients, and that the disease the it to in In our series of patients to our patients were or had with and syndrome may TTP has also been described in association with However, this association is and the may be platelet may be with ( et al, 1998 ). In series of patients with the and we have the presence of to These were not present in other patients that had the but ( Rock et al, ). years, TTP an fatal disorder. than a of a after the disease was first it was that plasma infusion was to the course of a fact that was to the presence of a in plasma that the factor for platelet ( & with plasma infusion to of plasma on the that there be to the of The of which the to plasma it possible to large plasma that a plasma be within a of with of the plasma with appropriate other A review ( & that widespread plasma the mortality was In the Canadian Apheresis reported on the of a in which patients were to plasma with plasma or plasma infusion on of the first of the ( Rock et al, ). The plasma plasma for the first by plasma The infusion patients 30 h each We found that plasma was to plasma infusion in the of TTP, with 1 In the that the of plasma administered in the was than that which was is the of a large of a plasma may have been more by a of this was to the between a factor in the of plasma infusion is the which be by the not the of the of of of the was in the of forms of plasma plasma infusion The fact that was seen with only with for a or altered factor in the Bell et have also reported that plasma with has been most for TTP. data from several studies for the first of the by that this is or than In our study, we the of plasma which is the plasma after and This was first by & and is on the that high molecular weight VWF multimers are in the of the disease. It is that as is relatively in the higher molecular weight multimers of factor VIII this the not to the of forms. A of the VWF in and the from that plasma is shown in The of VWF is in compared with of plasma the we have found an of of VWF in and in This with with from patients the of VWF ( et al, 1998 ). that we have with Dr that the that has described is present in in the as in plasma – it is not in the VWF of and were from to plasma platelet was from and was to the of the Canadian with the for VWF multimers were a and was from were with and with an initial study, patients with TTP who had not to plasma with were with plasma the and in our first patients who the first course plasma with a with patients as an increase in platelet count to than × 109/l and neurological we a count 000 with neurological and 83% of patients 1 previously patients The was the of the first and of the patients were after 1 These were than those reported in our plasma and plasma infusion and than those seen in other TTP patients the but because of the of These data are We have now a of plasma plasma with plasma ( Rock et al, ). In a series of of these patients, we have the of von Willebrand factor and the on and 5 of plasma shown in the of von Willebrand factor were the course of in those patients who The in and in the presence of forms ( with after A by et also compared patient after the of or The was in the that and in the that of these were than those that we in our series but the were the showing the of of VWF in plasma are from patients. VWF and after plasma with or plasma plasma plasma after after after platelet with with In our experience, patients with with evidence of renal have to in the as those with TTP ( Rock et al, ). are studies that have the plasma The of the platelet count is × 109/l for ( The for Apheresis the platelet count is × 109/l and to after of and the is ( et al, ). However, there is of as shown by a recent of 20 in the ( & per of the established a platelet count of × 109/l as a have established a platelet count of × 109/l and a platelet count of 200 × 109/l was as a with of the the to be within the not in This that of the not a for of initial of We have a schedule 2 for and per in The to or other is In our were relatively common the of the first of for patients, the (range patient plasma of the to the of plasma or plasma is the of patients to the plasma from large of plasma per is A relatively plasma which is with a and to has been developed. may have an for in TTP for it has been reported to the high molecular weight forms of VWF ( Moake et al, and may therefore be as the plasma We have recently the from of various as shown in by Dr and found that the higher molecular weight forms of VWF found in plasma are in all VWF in 1 and plasma A platelet A of this is that the does not This such as and A recent of in the was on are to of plasma for is from large plasma and therefore be the are showing of TTP patients with plasma ( Moake et al, ). Although the is present in are to that is to of on of A has to be in such as A with in which the for the of disease is well known. The presence of and in TTP is now well it is to that or of a protease be of A has been reported by et to be in the of TTP patients who had previously been to plasma et have reported in cases of were to from the by & and Furlan et have to on the of the disease and may have impact on described of these have shown the presence in the plasma of an to a which is present in the plasma and is for the of the unusually large molecular weight VWF which platelet of to the and of the with the protease from plasma may the for the of plasma this a which was – because it was most – an of the by which it the recent in the possible may have impact in TTP. This be it is possible to the from plasma and it to these patients. This infusion of of the to the in the as factor VIII is administered to patients with various be to and a of have been in with plasma for the of TTP. these are a of and has also been with to TTP ( et al, ). In our first Canadian study, patients in of the with and We to in with plasma The for this is on the formation of platelet and the that and of platelet be of as the is variable in to platelet activation in TTP. et TTP patients to and with or and and after that the the of in the of acute TTP and that 1 year of to be in relapses. with other in TTP, the of early in the disease or to prevent have been In et patients who had or more of TTP a found that the of acute relapse and the for It should be in that is not a for TTP. there is evidence of an has not shown an to this or in with is to the to on the of an for the a of have been have been Moake et a of of h or appropriate to the of has not been it is to for the of However, as evidence an for the disorder to in is a and has also been to of thrombocytopenia, and ( Ahn et al, ). on the of an disorder in TTP, there is for the of which is to an on the in TTP. & reported that to TTP plasma were by and that the of this is known to platelet which prevent and In to was administered within of ( et al, 1998 ). In a by et patients after to respond to had a of These also found in ( et al, ). the of after for is not known. has also been in TTP, as a and as an in with it is as with other to the to the The recent finding of a weight to the of an for TTP. there has been an in the of the of and there is the of the seen with in and a thrombocytopenia which is known to be by platelet This is by the fact that and have been in TTP in the with variable and in of the fact that more data are to that TTP is an the data not the of In has not seen in the of TTP, it has been and for It may be that not appropriate which are to the or more on the of in TTP is it be to of the of to TTP in a such a an in patients who not respond to plasma that has from the is that there appears to be to platelet in these thrombocytopenic patients on the that the patient is not but that platelets are of the and that of platelets only to formation of more there have been of after platelet ( et al, et al, ). platelets should be to TTP only in patients A of our of patients that of patients have with this variable of years after initial ranging from to years ( et al, 1995 ). et reported a patient with of relapsing TTP in which the last were with containing The initial episode of TTP had to respond to and only after to episode to respond to but with The of in has yet to be Although is infrequently first it has been common in to after in to prevent Several small studies have described patients who have from such an ( & We and others ( & have found for platelet count or the the presence of a protease be to be the of acute TTP a may for relapse and also in the of the of The high of relapse the of and patient awareness of this In our experience, early in these relapsing cases appears to be most and is by a patient who the of In of and therapy, patients not This is most seen with such as in and TTP in which the disease does not respond well to cases of TTP have been by the of A and sometimes with The of TTP with various a for in the of TTP. plasma has also been reported to be in the of TTP ( et al, Rock et al, 1998 ). of the of in TTP and the of to platelets and a should be considered in patients. The data from et this the of TTP a more on is it is that to of patients or all of a of in the of the disease. of are as of the this there is the of an to the in TTP. and of this protease is a of and is to be a of in the of the early in this was the relatively to protease of von Willebrand However, several now have which are to This should of the protease with a to it to the – in the as factor VIII are to factor VIII patients with of a for protease deficiency A that be in a the early and of these patients. This to be to the or the to this of a of von Willebrand factor in the for be It is of that a plasma with be in to the absence of the higher molecular weight forms of von Willebrand factor are of in is to a protease is the of TTP, the the high molecular weight forms of VWF the It should also be as to the in plasma is In the it be to in a plasma is as as or than plasma and the in von Willebrand factor in the plasma have impact on the disease. The first in patient is of the The presentation be considered with on the fact that the of a full pentad of symptoms is not for A full count and should be and and of and fibrinogen TTP is or should be The plasma with or should be with for the first after should be the platelet count has to 000 × 109/l and has for 2 should not be should also be as considered are data that have to in these patients and appear to have the of are well known. In patients, there appears to be of therefore of the or A and should be a and are have to with the fact that has been in the of TTP the is and not yet Only by the true of this disorder be has been but patients to from this acute onset disorder platelet The to and the of the Canadian Apheresis and the Canadian of Apheresis who have patients and data to our TTP also to for this Dr for review and and for This has been supported in a from the

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