|Year : 2003 | Volume
| Issue : 3 | Page : 342-350
|Molecular Basis of Familial Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome
Jessica Caprioli1, Simona Brioschi1, Giuseppe Remuzzi2
1 Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò,Villa Camozzi-Ranica, Italy
2 Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò,Villa Camozzi-Ranica; Division of Nephrology and Dialysis, Ospedali Riuniti di Bergamo, Bergamo, Italy
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|How to cite this article:|
Caprioli J, Brioschi S, Remuzzi G. Molecular Basis of Familial Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome. Saudi J Kidney Dis Transpl 2003;14:342-50
The term thrombotic microangiopathy (TMA), first introduced by Symmers in 1952,  defines a lesion of vessel wall thickening (mainly arterioles or capillaries) with swelling or detachment of the endothelial cell from the basement membrane, accumulation of fluffy material in the sub-endothelial space, intra-luminal platelet thrombosis and partial or complete obstruction of the vessel lumina.  This lesion is common to various diseases.  Laboratory features of thrombocytopenia and hemolytic anemia are almost invariably present in patients with TMA lesions and reflect consumption and disruption of platelets and erythrocytes in the microvasculature. Additional clinical signs depend on the diverse distribution of the microvascular lesions and the consequent organ dysfunction. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable, but somehow clinically different entities have been described. They have been uniformly referred to, in the last few decades, as Thrombotic Thrombocytopenic Purpura (TTP) or as Hemolytic Uremic Syndrome (HUS).
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Caprioli J, Brioschi S, Remuzzi G. Molecular Basis of Familial Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2021 Jun 22];14:342-50. Available from: https://www.sjkdt.org/text.asp?2003/14/3/342/33013
In the majority of cases, toxins, auto-antibodies, pregnancy, systemic diseases and drugs, have been associated with TMA. Rare forms exist that often occur in families and frequently relapse even after complete recovery of the presenting episode. Depending on the involved defect and on the age of onset of the disease, these forms may present with the clinical features of TTP or HUS or both in different members of the same family or in different episodes in the same patient. Death, end-stage renal disease (ESRD) and permanent neurological sequelae are the final outcome in the majority of cases.  Therapy seldom achieves persistent remission of the disease.
Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thrombo-resistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand Factor (vWF) release and fragmentation and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the vWF pathway and of the complement system may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms.
| Abnormal von Willebrand Factor Release and Processing|| |
In normal individuals, vWF is formed as large multimers [ultra large (UL) multimers] due to the polymerization in endothelial cells and megakaryocytes of a native subunit with apparent molecular mass of 225 kDa, and is stored as such in Weibel-Palade bodies and platelet granules. UL multimers do not normally circulate, since they are rapidly reduced into smaller multimers soon after their secretion by cleavage at position 842 Tyr-843 Met of the mature subunit. A major contribution to the understanding of vWF processing has been recently provided by Furlan et al , and Tsai  who purified and haracterized a plasma metalloprotease that physiologically cleaves ultra large vWF multimers. The protease, of approximately 175 kDa, needs bivalent cations for its activation, is inhibited by calcium-chelating agents and is activated only in conditions of low ionic strength or high shear stress. In vivo evidence that proteolytic cleavage is involved in the modification of plasma multimers after secretion has been provided by studies showing that circulating vWF multimers are heterogeneous oligomers of a native 225 kDa subunit and of proteolytic fragments with apparent molecular masses of 189, 176 and 140 kDa.  In patients with TTP and HUS, in contrast to healthy subjects, UL multimers similar to the ones stored in endothelial cells and platelets, were occasionally detected in plasma.  The presence, in patients with TTP and HUS of circulating UL multimers, which in vitro are capable of supporting platelet aggregation more efficiently than normal multimers, was taken as evidence for their pathogenic role in microvascular thrombi. 
In patients with TTP and HUS who recovered after a single episode, UL multimers were found almost exclusively in the acute phase but no longer in remission suggesting a massive release from storage sites of acutely injured endothelial cells which possibly overwhelmed transiently the plasma proteolytic capacity.  By contrast, those cases who had a tendency to recur had circulating UL multimers both in the acute and consistently in the remission phase of the disease, which was initially taken as evidence of a state of persistent endothelial perturbation.  The hypothesis that circulating UL vWF multimers may reflect a condition of endothelial perturbation has been recently challenged by findings that circulating UL multimers in chronic relapsing TTP were associated with a reduced or totally absent activity of the above vWF-cleaving protease that normally cleaves vWF multimers to smaller molecular forms. In two large studies , vWF cleaving protease deficiency was described in patients with different forms of TTP. In familial forms, the deficiency is probably inherited as an autosomal recessive trait. Consistent with this possibility, complete deficiency of vWF-cleaving protease activity was found in two brothers with chronic relapsing TTP, whereas their parents had about half normal protease activity.  Of interest, in both patients with constitutional protease deficiency, disease remission achieved by plasma therapy was concurrent with an almost full recovery of the vWF-cleaving protease activity. Both patients achieved a long lasting remission, although protease activity decreased to less than 20% over 20 days after plasma therapy withdrawal.
The gene, ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin Type 1 repeat), encoding the protease, has been recently identified and cloned. , In families with history of TTP, sequence analysis of patients' DNA identified 12 mutations in the ADAMTS13 gene.  Two of these mutations, a 26 bp deletion in exon 19 and a single T insertion in exon 27, result in frameshifts. A single splice mutation was identified in exon 13; it activates a cryptic donor splice site, resulting in a 23-codon insertion. The remaining nine mutations determine nonconservative amino acid substitutions. Affected individuals within families were either homozygous for the same mutation or compound heterozygous for two different mutations, confirming that the disease was inherited as a recessive trait.
Moreover, in a large study on 83 children with thrombocytopenic and/or hemolytic episodes, Schneppenheim et al reported eight novel mutations in seven TTP patients characterized by vWF-cleaving protease deficiency and lack of acquired inhibitors. Among the molecular defects identified, five were truncating mutations and three were missense mutations. Only one patient was homozygous, whereas the remaining ones were compound heterozygous for two mutations each.  Levy and Kokame , identified also eight single nucleotide polymorphisms (SNPs) associated with amino acid substitution. At present, only one of these SNPs (P475S) has been demonstrated to be associated with reduction in vWF-cleaving protease activity; the functional importance of the remaining SNPs, if any, remains to be uncovered.
In non-familial cases the protease deficiency appears to be the consequence of a specific autoantibody that develops transiently and tends to disappear during remission.  In a patient with recurrent episodes of TTP who was shown to have an acquired inhibitor of the vWF-cleaving protease,  splenectomy, performed one year after the first TTP event, resulted in disappearance of the autoantibody and normalization of the protease activity, platelet count and hemoglobin levels. 
At variance with TTP, in the above studies no deficiency was found in patients with familial or sporadic forms of HUS  which was taken to suggest that presence or absence of this activity were enough to classify patients as having TTP or HUS.
However, a substantial proportion of adult cases with TTP, ranging from 30  to 38%  in two different series, have normal ADAMTS13 levels. On the other hand, undetectable ADAMTS13 activity was found in two adult patients with the familial form of HUS,  in four adults with secondary forms of HUS  and in one adult woman with post-diarrheal HUS.  One may also say that cases with ADAMTS13 deficiency reported as HUS should have been called TTP instead. However, complete deficiency of ADAMTS13 activity was also found in few children with Shigatoxin-HUS: one was reported by Veyradier et al  and another by Hunt et al.  Deschenes  reported the case of a child with relapsing hereditary HUS and neonatal onset, who developed chronic renal failure at 10 years. ADAMTS13 assay showed a complete deficiency of the protease activity in the plasma of this patient in the absence of any detectable inhibitor. Additional children with recurrent HUS with a neonatal onset and complete ADAMTS13 deficiency have been recently described: three were reported by us  and six by Agnes Veyradier and colleagues.  Two independent Japanese groups described three  and two  children with complete ADAMTS13 deficiency suffering from repeated episodes of bleeding associated with chronic thrombocytopenia and microangiopathic hemolytic anemia with neonatal onset and frequent relapses. Mutations in ADAMTS13 gene were found in two of the above patients.  These data indicate that the issue is still controversial and the distinction between TTP and HUS is complicated.
A constant finding in the acute phase of different forms of TTP and HUS is an increase of low molecular weight (Lmw), and decrease of high molecular weight (Hmw) multimers, that would reflect an enhanced proteolytic fragmentation of the molecule. , Also, the observation that vWF undergoes excessive fragmentation in the acute phase of these diseases is remarkably consistent with previous findings of a relative decrease in the native 225 kDa vWF subunit, that only occurs in the acute phase, accompanied by a relative increase of fragments that can only derive from the cleavage of the native subunit.  Native 225 kDa subunit was also decreased in its relative amount in vWF immunopurified and reduced from plasma of both recurrent and familial cases, which can be taken as an additional evidence of enhanced vWF fragmentation.
vWF susceptibility to fragmentation increases in response to rising levels of shear stress,  that induces protein unfolding and makes vWF proteolytic cleavage sites more accessible to specific plasma protease(s). It is therefore speculated that enhanced shear stress in the severely narrowed damaged microvessels accounts for the abnormal vWF fragmentation observed during the acute phase of TTP and HUS. Evidence of increased capacity of fragmented vWF to bind receptors on activated platelets would suggest that shear stress-induced vWF fragmentation may contribute to maintain and further spread microvascular thrombosis. The above interpretation is supported by data that in severe forms of HUS that are resistant to plasma therapy, removal of the kidneys, a major site of vascular bed occlusion and augmented shear stress, was followed by hematologic and clinical remission associated with restoring of the vWF fragmentation pathway to normal.  Consistent with this possibility, in patients with recurrent and sporadic TTP and HUS, increased vWF fragmentation normalized after resolution of the microangiophatic process.
| Congenital Complement Abnormalities|| |
Reduced serum levels of the third component (C3) of the complement system, have been reported since 1974  in both sporadic and familial forms of HUS.  A study from our group revealed that in a large series of familial cases, as compared to controls, levels of circulating C3 were extremely low.  Reduced C3 levels in cases and case-relatives, but not in controls and control-relatives would further indicate that the defect clusters in families. Evidence that low C3 concentration was strongly associated with the disease even more convincingly suggested the possibility of a tight (possibly causal) relationship between decreased C3 and disease manifestation.  On the other hand, in the above series, low C3 levels could not depend on consumption in a still ongoing microangiopathic process, since no patient at the time of the study had any sign of acute disease, and only two had moderately increased LDH levels. 
Two complement pathways can generate C3 activating enzymes: the classical convertase generated by the sequential reaction of C1, C4 and C2, and the alternative pathway convertase. Activation of classical and alternative complement pathway, possibly triggered by circulating immune complexes and damaged erythrocytes respectively, is well documented in acute HUS,  but consistently subsides with remission of the disease. On the contrary, in cases of familial TTP and HUS serum C3 levels were consistently and remarkably depressed in cases as compared to controls, even during remission of the disease.  Even more interestingly, low C3 levels were also found in the relatives of the patients, who had never suffered from TTP or HUS in the past and had no sign of the disease at the time of the study.  Further more, both in cases or in case-relatives, depressed C3 values did not parallel similar changes in C4 levels. These data definitely ruled out the possibility that classical pathway activation accounted for hypocomplementemia in this series.  An inherited defect in C3 synthesis has been suggested to account for decreased C3 serum concentration,  but much more convincing data are now available that low C3 in HUS may derive from either lack or altered function of factor H, a regulatory protein that inhibits the complement activation through the alternative pathway. 
A persistent reduction in C3 levels was found with very low levels of factor H  in one patient with HUS as well as his healthy brother. The finding that the parents, who were first cousins, had half-normal levels of factor H, convincingly indicated that the defect was inherited. Similar findings were then reported in another family. The association between inherited factor H deficiency and low C3 levels was investigated in a large series of families with history of TTP and HUS.  By radial immunodiffusion and Western-blot analysis, two affected subjects of one family were identified, who had very low circulating factor H levels, and moderately low levels were found in two healthy relatives. In these patients, cofactor activity of factor H, measured as the capacity to degrade C3b, was also reduced. In the other families, serum factor H concentration was normal,  although finding normal serum levels does not necessarily exclude an underlying biochemical abnormality in circulating factor H. In this regard, in another family, the two affected members and the healthy father who had normal serum concentrations of factor H by radial immunodiffusion, showed on Western blot additional bands of higher molecular weight that were not found in any control subject . The bands might represent dimeric forms of factor H. At variance, no differences were found in serum levels and patterns of FHL-1 and FHR proteins.  Similar results were obtained in another series of patients with HUS. 
The consistent association found in families between factor H abnormalities and low C3 levels supports the hypothesis that low C3, in the setting of familial TTP and HUS, may depend on a genetic deficiency of factor H.
A report on three large families with HUS  documented that an area on chromosome 1q, where factor H is mapped, segregates with HUS. All subjects in the three families had normal serum factor H levels; however, affected members and obligate carriers within one family were found, by mutation analysis, to have a heterozygous point mutation in factor H, consisting in a C to G transversion causing an arginine to glycine change in Short Consensus Repeat (SCR) 20.  This mutation is likely to alter structure and hence function of factor H protein without modifying its circulating levels. The same authors also described a nonsense mutation, located in SCR1 of factor H gene, in a sporadic case with late onset.  In a large series of patients, four new heterozygous mutations in factor H gene were found.  Three of the mutations were observed in families with dominant transmission, the fourth was found in a sporadic case who experienced disease recurrence on the renal allograft. Another mutation had been described in a family with HUS with a recessive mode of inheritance and severely depressed factor H levels.  In this family an A to T transversion and a 24 bp-deletion were present in homozygosity in affected members and in heterozygosity in the healthy carriers. Altogether, the available data provide compelling molecular evidence that genetic alterations in factor H are involved in both autosomal dominant and recessive HUS.
Caballero et al. performed a mutational screening of factor H gene in 13 Spanish patients. One of these was found to carry a deletion in SCR1 which produces a null allele and results in plasma levels of factor H that are 50% of normal; four missense mutations were also identified which result in alteration of amino acid residues; one of these mutations lies in SCR16 and the other three in SCR20.  In another study, a screening of factor H gene was undertaken in 50 HUS patients. Two familial and three sporadic patients showed alterations in the gene: six missense mutations and a single-base pair deletion causing a frameshift were identified. All these alterations clustered in SCR18-20. '
Till now, about 20 mutations have been found in factor H gene. ,,,, The majority of point mutations are missense mutations leading to a single amino acid change in SCR20, the most carboxy-terminal individually folded domain of factor H. , The resulting mutant proteins are functionally inactive since they have lost ability to bind either sialic acid molecules on endothelial cells or C3 or both, 40 but are normally translated and secreted, ,, which accounts for the normal plasma concentrations of factor H as measured by commonly used laboratory assays. This point is important for clinicians. Since not all patients with heterozygous mutations have a persistent reduction in complement C3, the diagnosis of factor H-associated HUS cannot be dismissed just because concentrations of C3 and factor H are normal.
Heterozygous mutations are associated with incomplete penetrance of the disease as documented by a number of healthy carriers described within families. ,, Heterozygous factor H mutations were also reported in patients with sporadic or recurrent HUS with no familial history; in some of these patients analysis of DNA parental samples revealed that the mutation had been inherited from an unaffected parent. ,, Thus, in a proportion of patients who present with sporadic or recurrent HUS, there is an underlying genetic predisposition and this may have implications for other family members. It is possible that the genetic change is a predisposing factor and that an environmental insult then precipitates the disorder, but it is also possible that polymorphisms in other genes may concur to determine the HUS phenotype.
In support for a role of factor H deficiency in the pathogenesis of HUS, is the complement dependence of some models of glomerular thrombosis, such as the generalized Shwartzman reaction in rabbits and various immune-mediated models accelerated by lipopolysaccharide. However, the observation that factor H deficient individuals occasionally have long remissions or do not present until late in life suggests that a second hit is needed, at least in the heterozygous form. Preceding infection is commonly reported, but specific trigger factors remain unknown.  Upon insult (e.g. during infection and/or inflammation), the release of inflammatory mediators causes endothelial damage and promotes the activation and tissue deposition of the C3 convertase of the alternative pathway of complement. Whereas in healthy individuals such activation would be contained by the immediate binding of factor H to damaged endothelium and subendothelium, in patients carrying factor H mutations sub-optimal factor H function is unable to efficiently restrict the activation of the alternative pathway of complement, allowing the propagation of vascular injury and expression of the disease.
Conceivably, the mutations described above in ADAMTS13 and Factor H genes account for just a minority of genetic forms of TTP and HUS. However, genetic counselling is of paramount importance. In cases with recognized genetic mutations, antenatal diagnosis by amniocentesis or chorionic villus biopsy is possible and the carrier state can be identified. Moreover, those new insights into the comprehension of the molecular basis of familial TTP and HUS open new therapeutic possibilities, such as combined liver-kidney transplantation  or protein replacement with recombinant ADAMTS13 or Factor H.
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