1:Réanimation polyvalente , Hôpital Delafontaine, St Denis
2 Réanimation médicale, Hôpital St Louis, Paris
E-mail :Christophe.adrie@outcomerea.org
Since its first description, in 1925, thrombotic microangiopathies (TMA) have lead to one of the most exciting fields and ongoing research in order to elucidate the pathophysiologic mechanisms responsible for this disorder. We did not intend to go through all the different aspects of this very complex disease. We shall review some of the classic clinical knowledge and more recent breakthrough in the understanding of the mechanism and still very controversial treatment.
TMA: recent advances in pathophysiology:
Plasma administration: infusion or exchange?:
TMA and anti infectious therapy.
Platelet transfusions?: The term thrombotic microangiopathy (TMA) encompasses the spectrum of classical thrombotic thrombocytopenic purpura (TTP) described first by Moschowitz [1] and hemolytic uremic syndrome (HUS) described three decades later by Gasser et al [2]. Both share the same histologic lesion, widening of the subendothelial space and microvascular thrombosis, and a similar pathophysiologic process, leading to thrombocytopenia and hemolytic anemia through platelet consumption and erythrocyte disruption in the injured microvasculature [3, 4]. The diagnosis classically relies on the pentad of symptoms: hemolytic anemia with presence of schistocytes and negative Coombs test, thrombocytopenia, fever, central nervous systems abnormalities and renal dysfunction.
Because they share the same histologic lesion, HUS and TTP are now believed to be a variable expression of the same disease called TMA [3]. The different clinical manifestations of HUS and TTP are essentially related to the different distribution of the vascular process. Therefore, in children with glomerular and preglomerular vascular involvement, the dominant clinical manifestations are the consequence of renal dysfunction. In adults, the microangiopathic process electively affects the brain with neurologic symptoms dominating the clinical picture. However, wide differences still remain between the two classic different clinical expressions with numerous overlapping ones
(table 1)
Table 1. Classic clinical aspects differentiating HUS and TTP.
This table represents the main differences between the two usual expressions of thrombotic microangiopathies. Because of the similarities, the HUS and TTP have been recognized as a single entity. This explains the often overlapping and indistinguishable clinical presentation.
Thombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) : a single entity? Thrombotic microangiopathy (TMA).
| Hemolytic-Uremic syndrome | Thrombotic Thrombocytopenic Purpura | ||
| Main organ dysfunction | Renal dysfunction | CNS abnormalities | |
| Spontaneous Outcome | Favorable | Mortality rate >90% | |
| Plasmapheresis | ? | ++++ | |
| Causes | Mainly enteropathogenic Escherichia coli (serotype O157/H7 ++) | Idiopathic Related to HIV, connective diseases, cancer, etc | |
| Age | Children | Adults | |
| Antibiotic | - | +++ | |
| Von Willebrand factor-cleaving protease activity | Normal | Decreased | |
| Factor H | Decreased in some patients | Normal ? | |
Several classifications have been proposed to identify subsets of patients with TMA with similar clinical characteristics. For instance, Drummond [5] and then Remuzzi [3] tried to propose a more complete classification as follows; i) infantile and childhood TMA, ii) hereditary and recurrent TMA, iii) postinfectious TMA, iv) TMA accompanying systemic diseases and finally, v) those associated with pregnancy, or with the use of drugs such as oral contraceptives, cyclosporine A, or antineoplasic drugs etc.
Different triggering factors may be involved such as bacterial viral infection, pregnancy, drug therapy, chemotherapy and bone marrow transplantation. This probably induced endothelial damage which is thought to be the initial step. Unusual large molecular weight multimers vonWillebrand factor (vWf) are normally found in the Weibel-Palade bodies of endothelial cells and in platelet alpha granules. These multimer, but not the normal plasma vWf forms, can induce aggregation of platelets under high shear stress. Systemic endothelial-cell injury may lead to excessive release of these unusual large polymers of vWf that cannot be processed to smaller form by a specific enzyme [6] [7] (figure 1). By consequence, they can be measured in plasma of patient during remission phase and absent during acute or relapse probably because of its "consumption" by the shear stress-induced platelet aggregation [8]. Recently, Furlan et al [9] showed that non familial TTP is due to the presence of an inhibitor of vWf-cleaving factor whereas the familial form seems to be caused by a constitutional deficiency of the protease. This appeared be related to the presence of inhibitory IgG antibodies [10]. Interestingly, the vWf-cleaving factor activity was found normal in non familial HUS [9].
Others autoantibodies have already been associated with TTP such as antiplatelet antibodies, anti CD16 which is a membrane polypeptide and expressed in platelets as well as many other cells [11], and antiendothelial cell antibodies [12]. Immune injury to vascular endothelial cells could expose thrombogenic subendothelial surfaces, induce apoptosis [13] and finally release vWf from intracellular store which could potentiate platelet agglutination through some secondary interaction, such as high share rate or platelet antibodies. All together, these autoantibodies suggest a dysregulation of the immune system and represent the substratum for the use of immune modulatory approaches of this disease. Two distinct verotoxins, verotoxin-1 and -2, also known as shiga-like toxins because of their close homology with the toxin produced by Shigella dysenteriae (serotype 1), cause the human disease. These are closely related exotoxins encoded in the DNA of bacteriophages and incorporated into the genome of a restricted number of Escherichia coli serotypes. Verotoxin is formed by a biologically active subunit A, and a number of B subunits by which the toxin binds to specific glycolipid receptors. The distribution of verotoxin receptors may determine the localization of microvascular lesions [14].
Transient hypocomplementemia with evidence of alternative pathway activation has been reported in typical, diarrhea-associated cases of HUS where the etiology is likely to have been verocytotoxin-producing Escherichia coli [15]. Usually the reduction in plasma concentration is mild and reversible. By contrast, a few cases demonstrate persistently low complement C3 and in some of these, there is low plasma concentration of the complement regulator, factor H. Investigation of these patients, linkage analysis in familial HUS, and more recently reports of mutations in the factor H gene in sporadic cases together indicate an important association between factor H and a clinically recognizable subgroup of HUS [16]. This factor represents the most abundant complement regulator in plasma. It also operates attached to the host surfaces including endothelium. It accelerates the decay of C3bBb, the C3 convertase of the alternative pathway, and with factor I as a cofactor it cleaves and inactivates C3b. Thus, factor H with other complement regulators located on host cells or in the soluble phase prevents indiscriminate complement activation. Certain pathogens have evolved with the ability to bind factor H and thereby subvert complement attack [16]. .
We recently studied a series of 30 patients requiring an admission in ICU [17] (Saint Louis Hospital). There were 19 males and 11 females with a SAPS II [18] and LOD [19] scores of 37.3±18.7 and 6.8±0.7, respectively. TMA was related to HIV infection in 9 cases, systemic lupus erythematosus in 8 cases, 2 were idiopathic, seven were related to drug intake, transplantation, or pregnancy. In 8 cases, an acute infection disease was the only cause found. Moreover, an acute infection episode was diagnosed in twelve patients who had already another underlying disease known to be related to TMA. Thus, acute infectious diseases, suspected or documented, appear to act as a trigger of TMA whether or not there was another underlying association.
The description of the organ failure according to the LOD definition is represented in table 2.
Table 2. Organ failure at admission as described in the LOD score [19]. We defined four groups depending on the associated condition: HIV (Human Immunodeficiency Virus) disease, SLE (Systemic Lupus Erythematosus), Infection (when only an acute infection was diagnosed), and others (miscellaneous such as drugs, malignant diseases, post-partum or idiopathic).
| Organ failure | Infection ( n=7) | HIV disease ( n=9) | SLE ( n=6) | others ( n=8) | total ( n=30) | |
| Cardiovascular | 0 | 1 | 0 | 1 | 2 | |
| Renal | 4 | 5 | 0 | 2 | 11 | |
| Neurologic | 5 | 6 | 2 | 2 | 15 | |
| Hepatic | 1 | 3 | 0 | 0 | 4 | |
| Hematological | 5 | 6 | 4 | 6 | 21 | |
| Pulmonary | 1 | 0 | 0 | 2 | 3 | |
Plasma infusion has been described as a very efficient way to treat TTP since 1977 [21]. Concomitantly, Bukowsky et al [22] showed that plasmapheresis was also an efficient means of plasma administration. Up to 1987, both routes of plasma administration were considered to be equivalent allowing complete remission in 60 to 80% of the cases [23]. Subsequently, Rock et al [24] in a randomized study showed that patient given plasma infusion alone had a lower response at nine days and a higher mortality at six months as compared to the patients with plasma exchange therapy (37 vs. 21%, respectively). However there was a marked disparity in the volume of plasma delivered, being three times higher in the group plasma exchange (with particularly low volume administered in the group plasma infusion: 30ml/kg for the first day and then 20 ml/kg/d).
In contrast, retrospective studies showed that when matching volumes were delivered, the outcome was similar [25] [17]. Indeed, several other groups also believe that high doses of plasma infusion are a safe, readily available, and reasonable alternative to expensive and time-consuming plasma exchange, particularly in TMA induced by Escherichia coli 0157:H7 [4, 26, 27]. The fact that benefit is seen with plasma infusion only argues for a missing or altered factor in circulation [7].
There are no scientific studies that have precisely determined the optimal plasma exchange schedule and duration of plasma administration which remain empirical. Plasma administration either by infusion or exchange represent the cornerstone in the adult with HUS form and in patients with all ages with TTP [28] [29] but its usefulness remains controversial in the children HUS form [3].
Since the first reports of HUS associated with bacteria of the family Enterobacteriaceae such as Escherichia coli (Serotype O157:H7) and Shigella dysenteriae (Serotype 1) [30-32], a large number of other infectious agents have been recognized as to induce TMA [17]. Furthermore, non-bacterial agents such as herpesvirus [33, 34], HIV [35] or other viruses [36], and fungal agents [37] have also been associated with TMA. Clearly, a large variety of non specific infectious agents, besides verotoxin-secreting Enterobacteriaceae, may play a key role in triggering TMA and inducing relapse or refractoriness [17, 38]. This supports active anti infectious treatment against the responsible infection. However, this may not always be the case. Recently, Wong et al. [39] showed that antibiotic treatment of children with Escherichia coli O157:H7 increases the risk of the HUS probably by causing Shiga toxin release from the injured bacteria in the intestine, making the toxin more available for absorption. Therefore the use of antibiotic should be strongly discouraged in children with gastrointestinal infections until the results of stool culture are available. In the same line, despite the absence of an association between treatment and antimotility drugs or opioid narcotics and the risk of the hemolytic-uremic syndrome in this study [39], these drugs should be avoided in children with diarrhea, because of their reported association with complications of Escherichia coli O157:H7 infection and with the prolongation of symptoms [40-42].
Although Bell et al. [28], in a retrospective study, found that steroids alone may be beneficial in TTP patients, it must be emphasized that only non severe patients were managed with steroids alone (i.e., patients that did not show evidence of neurological involvement). Whether they may be of some benefit in addition to plasma therapy remain hypothetical [7]. An appropriate randomized study to assess the role of steroids has not been carried out (especially in association with plasma administration). However, as evidence supporting an immune-mediated basis for the disorder continue to accumulate, steroid therapy increases in acceptance, at least in non-septic patients.
Platelet transfusions may be dangerous in patients with TMA. Patients have been observed to have abrupt, striking deterioration after platelet transfusion, consistent with the exacerbation of thromboses [43] [44]. However, the severity of the disease at presentation has not been compared between patients receiving or not platelet transfusion and it is likely that platelet transfusions were administered to the more severely ill patients. Thus it was not clear whether the platelet transfusion was directly responsible for the unfavorable outcome. Moreover, the dose of plasma administered during plasma exchange were not specified. Other teams reported no observed adverse effect following platelet transfusions when they are required for an invasive procedure [45] [46]. However, until such a procedure will be validated on a larger series of patients, the use of platelet should be avoided and be restricted to patients presenting a refractory life threatening thrombocytopenia and/or requiring surgery or any kind of invasive procedure [45].
These drugs have been extensively used in the treatment of TMA. The rationale for this is based on the formation of platelet aggregates and the consideration that inhibition and down-regulation of platelet responses would be of benefit, although the literature is variable with regard to demonstrating platelet activation in TMA [7]. There is no clear evidence for recommending their use in TMA [46].
In this mini review, we intended to give a little glimpse of the recent advances in these fields and to apprehend some controversies of this rare but interesting disease which may require ICU admission. Plasma administration either by infusion or exchange remains the cornerstone of the treatment of this disease. However much progress remains to be made to better understand the pathophysiology of this disease.
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