Abstract

Thrombotic thrombocytopenic purpura (TTP) was first described by Moschowitz (1924). The classic pentad of diagnostic features has been recognized for many years. However, several other syndromes are also characterized by similar features. These include haemolytic uraemic syndrome (HUS), eclampsia and the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). The concept has arisen that they might represent an overlapping spectrum of disease, although with varying pathophysiological features (see Table I). The recent characterization of a novel von Willebrand factor (VWF)-cleaving metalloprotease activity (Furlan et al, 1996; Tsai, 1996) and its deficiency or inhibition in some forms of microangiopathic haemolysis (Furlan et al, 1997, 1998; Tsai & Lian, 1998) has led to speculation that a pathogenic mechanism for individual patients can be defined more readily and appropriate treatment introduced more rapidly. However, there is still considerable confusion, a lack of properly conducted randomized clinical trials and poor co-ordination of clinical data. This is, in part, because these patients present to a range of specialists including haematologists, obstetricians, nephrologists and infectious disease physicians. These guidelines attempt to define the various clinical subtypes, specify the recognized diagnostic features and look critically at management options. It is acknowledged that there is a lack of evidence from well-conducted studies on which to support some of the recommendations made. Thrombotic thrombocytopenic purpura (TTP) is rare. The reported incidence is 3·7 per million (Torok et al, 1995). However, its prompt recognition and treatment is vital, as delays in initiating treatment have been shown to adversely affect outcome (Pereira et al, 1995). TTP is a clinical diagnosis. It is characterized by the classic pentad of thrombocytopenia, microangiopathic haemolytic anaemia, fluctuating neurological signs, renal impairment and fever, often with insidious onset. Neurological impairment has multiple manifestations including headache, bizarre behaviour, transient sensorimotor deficits (TIAs), seizure and coma. Presence of coma at presentation is a poor prognostic indicator (Pereira et al, 1995; Sarode et al, 1997). Additional complications may be seen: gastrointestinal ischaemia (manifest as abdominal pain) and serous retinal detachment are recognized associations. However, up to 35% of TTP patients do not have neurological symptoms or signs at presentation (Rock et al, 1991). As the triad of acute renal insufficiency, MAHA and thrombocytopenia defines HUS, diagnostic uncertainty may arise. Moreover, fever and renal impairment are present in only a minority of patients (Rock et al, 1991, 1998). In practice, therefore, a diagnosis of TTP may be made in the presence of a microangiopathic haemolytic anaemia and thrombocytopenia in the absence of any other identifiable cause. A number of different clinical variants of TTP have been documented. Clinical subtype may influence management and those recognized are listed in Table II. The predominant histological abnormality found in TTP is the formation of platelet microvascular thrombi. The renal and cerebral circulations are primarily affected, thus accounting for the clinical features of the disease. Excessive platelet aggregation occurs when platelet-rich plasma (PRP) from patients with congenital TTP is exposed to shear stress (Moake et al, 1994). This is mediated by ultra-large VWF multimers (ULVWF) (Moake et al, 1994; Karpman et al, 1997). ULVWF are not a normal constituent of circulating plasma. Instead, VWF circulates as smaller multimeric forms resulting from proteolytic degradation of ULVWF. VWF fragments with mobility corresponding to 189, 176 and 140 kDa are consistently detected in normal plasma in addition to the predominant 225 kDa subunit (Zimmerman et al, 1986; Tsai et al, 1991). These originate as a consequence of cleavage of a single peptide bond between residues Tyr-842 and Met-843 of the mature subunit (Dent et al, 1991). Identical fragments may be generated in vivo by a novel metalloproteinase activity (Furlan et al, 1996; Tsai, 1996). The protease has recently been characterized as a new member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin type-I motif) family, ADAMTS13 (Fujikawa et al, 2001; Gerritsen et al, 2001; Levy et al, 2001). Deficiency of this VWF-cleaving protease (VWF-CP) activity has been associated with acquired and congenital TTP. While all cases of idiopathic TTP have, to date, been associated with severe protease deficiency, secondary TTP may occur in the context of normal protease activity (Veyradier et al, 2001). In a series of 111 patients with thrombotic microangiopathies of whom 66 manifested with TTP (25 idiopathic and 41 secondary) and 45 with HUS, protease deficiency had a sensitivity of 89% and specificity of 91% for TTP. Initial reports suggested that idiopathic TTP is secondary to an inhibitory auto-antibody of IgG subtype (Furlan et al, 1998; Tsai & Lian, 1998), but in the above series, a protease inhibitor was identified in only 14 patients (56%). While congenital TTP appears secondary to a constitutional deficiency (Furlan et al, 1997, 1998), presentation may be delayed until adulthood (Lämmle et al, 2001). Cirrhosis (Mannucci et al, 2001), uraemia (Mannucci et al, 2001), acute inflammation (Mannucci et al, 2001), disseminated intravascular coagulation (DIC) (Loof et al, 2001) and malignancy (Oleksowicz et al, 1999) have now also been associated with reduced VWF-CP activity. Thus, although sensitive, reduced VWF-CP activity is not specific for TTP. Moreover, this model fails to explain the anatomical distribution of thrombi. The endothelium is a heterogeneous organ and is subject to regulation by multiple factors, including cytokines (Drake et al, 1993), microenvironment (Aird et al, 1997) and shear stress (White & Fujiwara, 1986). Alterations in any one of these parameters could influence either VWF-CP activity per se or the susceptibility of VWF to proteolysis. TTP is often characterized by severe thrombocytopenia, which may be useful in its differentiation from HUS. However, in one series, although the mean platelet count was lower in TTP than HUS (18 × 109/l vs 36 × 109/l), there was a wide range and considerable overlap (Vesely et al, 2000). Severe thrombocytopenia at diagnosis (platelet count 50 × 109/l) (Grade C, level IV). Supportive therapy. Red cell transfusion is an essential component of treatment. However, there is no single reliable parameter to guide the need for red cell transfusion. Identical survival rates resulted when a transfusion was given based on a haemoglobin threshold of 7 g/dl rather than 10 g/dl in euvolaemic critically ill patients (Hebert et al, 1999). As TTP may be complicated by rapid haemolysis and cardiac insufficiency secondary to myocardial microvascular thrombi, a patient should be transfused according to critical clinical evaluation after due consideration of the risks and benefits of transfusion. All patients should receive folic acid supplementation. Platelet transfusions are contraindicated unless there is life-threatening haemorrhage as they have been temporally associated with disease exacerbation (Harkness et al, 1981; Gordon et al, 1987). Some centres advocate the use of prophylactic phenytoin in an attempt to minimize secondary seizures. However, neurological features are completely absent in 35% of patients and seizures only occur in a minority of the remaining patients (Rock et al, 1991). Secondary rather than primary prophylaxis of seizures with phenytoin would, therefore, seem appropriate. Although fever is one of the defining features of TTP, an underlying infection should be sought actively; if untreated, occult infection may prevent response to plasma exchange or precipitate early relapse. Hepatitis B vaccination should be given to all patients and can be safely administered using a platelet threshold of 50 × 109/l. Recommendation. Red cell transfusion should be administered according to clinical need (Grade B, level III). Folate supplementation is required in all patients. Platelet transfusions are contraindicated in TTP unless there is life-threatening haemorrhage. Hepatitis B vaccination is recommended in all patients (Grade C, level IV). Despite the improvement in survival, there remains a subgroup with a slow or incomplete response to plasma exchange ± steroids. Refractory disease may be defined as persistent thrombocytopenia (platelet count < 150 × 109/l) or LDH elevation after a total of seven daily plasma exchange procedures. Treatment of this group of patients is difficult and a wide range of additional approaches has been used. Unfortunately randomized clinical trials have not been performed because of the rarity and heterogeneity of this condition. Manipulation of plasma exchange. There are reports documenting responses to plasma exchange in refractory cases of TTP following the substitution of either cryosupernatant (Molinari et al, 1993) or S/D plasma (Harrison et al, 1996) for FFP. Like cryosupernatant, S/D plasma lacks the largest plasma VWF multimers and this may be of importance. If, therefore, there is a suboptimal response to plasma exchange after 7 d or rapid clinical deterioration despite daily plasma exchange, an alternative replacement fluid should be substituted. While methylene blue (MB)-treated fresh-frozen plasma has been used in the management of TTP (Martinez et al, 2000), clinical experience is extremely limited at present and, unlike S/D plasma, VWF multimeric structure is not modified. Whether MB cryosupernatant has a role in the management of TTP will require further clinical experience. Intensification of plasma exchange has also been used in cases of refractory TTP with the introduction of either 12 h or double-volume plasma volume exchanges. At present, this approach is empirical. Recommendation. In the presence of refractory disease an alternative plasma product lacking high-molecular-weight VWF multimeric forms, cryosupernatant or S/D plasma should be used for plasma exchange (Grade C, level IV). Intensification of plasma exchange procedures should also be considered in life-threatening cases (Grade C, level IV). Vincristine. Although vincristine is often used in the treatment of refractory TTP, published literature supporting its efficacy comprises only case reports or small retrospective studies. Nevertheless, these suggest that the administration of vincristine in refractory TTP may be temporally associated with platelet recovery (Welborn et al, 1990; O'Connor et al, 1992; Bobbio-Pallavicini et al, 1994). A role for the early administration of vincristine (within 3 d of presentation) has also been advocated following a small retrospective study (Mazzei et al, 1998). However, such practice would carry a risk of inducing neuropathy without proof of clinical benefit. Until this finding can be corroborated by larger controlled trials, vincristine should be reserved for refractory cases. A number of dosage regimens have been employed with no clear advantage for any single one. A schedule of 1 mg repeated every 3 to 4 d for a total of four doses is popular as it may limit toxicity while retaining efficacy. Higher dose regimens have, however, been used apparently successfully. The mechanism of action of vincristine remains unclear. Recommendation. Vincristine 1 mg repeated every 3 to 4 d for a total of four doses is recommended in refractory TTP (Grade C, level IV). Cyclophosphamide. Cyclosphosphamide has also been advocated for the treatment of TTP, particularly those in patients who experience recurrent relapses (severe intermittent TTP) (Bird et al, 1990; Udvardy & Rak, 1990; Strutz et al, 1998). Both daily dosing and pulsed therapy have been used successfully, although reported numbers are extremely low. Cyclophosphamide is known to be a potent immunosuppressant and this is thought to underlie its efficacy. Cyclosporine. Although cyclosporine is associated with an increased risk of post-bone marrow transplant microangiopathy, there are reports of its successful application to the treatment of refractory (Hand et al, 1998), severe intermittent (Pasquale et al, 1998) and post-autologous bone marrow transplantation (BMT) TTP (Van Ojik et al, 1997). This is consistent with the current autoimmune model of TTP and cyclosporine's immunosuppressive action. While spontaneous resolution cannot be excluded in these patients, clinical and haematological response uniformly occurred 7 to 14 d after initiating treatment. Cyclosporine may, therefore, prove to be a useful therapeutic modality in these difficult patients. However, much remains unanswered. The optimal duration of treatment is unknown, with relapses documented after cessation of therapy (Hand et al, 1998; Pasquale et al, 1998). The optimal target therapeutic range is also unknown: trough serum levels of 200–300 µg/l have been used. The potential toxicity of this drug must also be considered. Recommendation. Intensive immunosuppression using either cyclophosphamide or cyclosporine is indicated in severe refractory or recurrent TTP (Grade C, level IV). The advent of VWF-CP assays is now beginning to confirm the clinical suspicion that TTP currently represents a heterogeneous group of conditions. It has long been recognized that plasma exchange is rarely effective in the treatment of BMT-associated TTP, suggesting that an alternative pathological process might be involved. This theory is supported by the recent finding that VWF-CP activity was normal in seven and only moderately reduced in one of eight patients with BMT-associated TTP (van der Plas et al, 1999). Effective treatment for this group of patients is, however, lacking. Resolution of autologous BMT-associated TTP has been reported following initiation of cyclosporine (Van Ojik et al, 1997), although paradoxically cyclosporine therapy is a recognized risk factor, along with total body irradiation, for allogeneic BMT-associated TTP. In the latter setting, cyclosporine should be stopped. Whether protein-A column immunoabsorption might be useful in such patients is unclear. Certainly this technique has been successfully employed in the treatment of malignancy-associated TTP in which plasma exchange is often found to be ineffective. In one small retrospective series, it was found to be of benefit in seven of 10 patients who had been unresponsive to plasma exchange (Gaddis et al, 1997). Recommendation. Malignancy and BMT-associated TTP are often refractory to plasma exchange. Protein-A column immunoabsorption may be considered (Grade C, level IV). Although remission is now attained in over 80% patients, subsequent relapse remains problematic. Data from the Canadian Apheresis Group estimate that over a 10-year follow-up period up to 36% of TTP patients relapse. Relapse has occurred up to 8 years after the index event (Shumak et al, 1995). All patients should be aware of the possibility of relapse and advised to report early if symptoms suggestive of relapse develop. At present, it is impossible to identify those patients at greatest risk, although the presence of ULVWF during periods of remission is associated with intermittent disease (Moake & McPherson, 1989). There is no consensus whether there is any effective intervention that might reduce this risk. Splenectomy has been advocated as a means of reducing the relapse rate. One small retrospective study including six patients showed encouraging results with relapse rates falling from 2·3 ± 2·0 to 0·1 ± 0·1 events per year when the operation was performed during haematological remission (Crowther et al, 1996). However, acute exacerbations of TTP have occurred post-operati