Saudi Journal of Kidney Diseases and Transplantation

: 2006  |  Volume : 17  |  Issue : 2  |  Page : 235--244

Review of Thrombotic Microangiopathy (TMA), and Post- Renal Transplant TMA

Mohammad Reza Ardalan 
 Assistant Professor of Nephrology, Renal Transplantation Unit, Imam Hospital – Tabriz, Medical University, Tabriz, Iran

Correspondence Address:
Mohammad Reza Ardalan
Assistant professor of nephrology, Renal Transplantation Unit, Imam Hospital – Tabriz Medical University, Tabriz


Thrombotic microangiopathy (TMA) is a rare but devastating disorder; it involves small vessels and is characterized by intravascular thrombi of aggregated platelets leading to thrombocytopenia and variable degrees of organ ischemia and anemia, which is due to erythrocyte fragmentation in microcirculation. Childhood cases with predominant renal involvement are referred as the hemolytic uremic syndrome (HUS), and adults with major central neurological involvement are labeled as thrombotic thrombocytopenia purpura (TTP). Endothelial damage due to toxins and/or lack of defense against complement activation have a central role. Recent discovery of the von Willebrand Factor cleaving protease (ADAMTS 13) has offered new insight into the pathogenesis of TMA. TMA is also a well-recognized serious complication of renal transplantation. Clinical features of intravascular hemolysis are not always found. It may occur as de novo or recurrent and the majority of de novo cases are related to cyclosporin therapy. Viral infections, severe renal ischemia and acute vascular rejection are less frequent causes. Recurrence is negligible in diarrhea-associated HUS in childhood, but non-diarrheal HUS recurs in majority of adults following renal transplantation. Renal transplantation is contraindicated in familial/relapsing recurrent forms of HUS.

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Ardalan MR. Review of Thrombotic Microangiopathy (TMA), and Post- Renal Transplant TMA.Saudi J Kidney Dis Transpl 2006;17:235-244

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Ardalan MR. Review of Thrombotic Microangiopathy (TMA), and Post- Renal Transplant TMA. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2021 Feb 26 ];17:235-244
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Thrombotic Microangiopathy (TMA), is a lesion of arterioles and capillaries and en­compasses syndromes of thrombocytopenia, microangiopathic hemolytic anemia, and variable degrees of organ ischemia and impairment. [1] Thrombocytopenia ( 3 ) occurs in most cases, anemia occurs due to fragmentation of red blood cells (RBC) and mechanical hemolysis during blood flow through arterioles, partially occluded by platelet aggregates [Figure 1]. Organ ischemia is due to platelet aggregation within the micro­circulation. [2],[3] Coomb's test is normal and lactate dehydrogenase (LDH) is extremely elevated; clotting studies are usually but not always normal [except in Pneumococci asso­ciated hemolytic uremic syndrome (HUS)]. [4],[5],[6] Injury to endothelial cells is the most important factor and, depending on whether renal or brain microvasculature involvement is more prominent, two clinical entities of the hemo­lytic uremic syndrome (HUS) or thrombotic thrombocytopenia purpura (TTP) have been described. [1]

 Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenia Purpura

TMA with renal impairment as the pre­dominant feature is referred to as HUS. It is generally associated with shiga toxin and the outcome is usually good in children. [4]

However, renal and neurological sequelae are reported in adults following HUS. Shiga-like toxin (Stx)-producing Escherichia-coli, serotype O157:H7 have been related to large number of diarrhea-associated HUS (D+HUS) cases; to a lesser extent, Stx-producing shigella is also linked to D+HUS. [2] Nuraminidase­associated HUS complicates pneumonia or meningitis caused by Streptococcus pneu­moniae. [1] At least 80% of childhood, but no more than 5% of adult HUS is D+HUS. [7] After exposure to Stx-E coli, 3 to 9% in sporadic cases, and up to 20% in epidemic forms, develop HUS. [2] Larger amount of toxin, treatment with antimicrobial agents, and/or a profound inflammatory response, all favor the onset of full-blown HUS. [8] Toxin-laden neutrophils transmit the Stx to the kidneys where it is delivered to high-affinity glycolipid receptor, globotriacylceramide (Gb3), expressed on glomerular endothelial, tubular and mesangial cells. [2],[9] The prevalence of these receptors in the kidney is the biochemical basis for the preferential renal involvement in HUS. After internalization, this toxin induces endothelial damage (apoptosis, and necrosis), increases adhesion properties and increases von Willebrand Factor (VWF) secretion. [5]

Non-Stx- HUS is less common than Stx­HUS and accounts for only 5-10% of all cases of HUS [Table 1]. [2],[5] Non-Stx-HUS can occur sporadically or in families and most frequently seen in adults. [2],[10] A wide variety of triggering factors have been identified for the sporadic form of D-HUS, including: bacterial and viral infections, pregnancy, sclero­derma, systemic lupus erythematosus (SLE), anti-phospholipid antibody disease and a long list of drugs including mitomycin, cysplatin, bleomycin, gemcitabin, cyclosporin, tacrolimus, OKT3, quinidine, ticlopedin, clopedigrel, INF-alfa, etc. [11] In approximately 50% of sporadic, non-Stx-HUS (idiopathic HUS), no clear triggering factor can be found. [10] Familial forms account for less than 3% of all cases of HUS; both dominant and recessive forms have been reported. [2] The dominant form has an adult onset and carries a poor prognosis, with high incidence of end-stage renal disease (ESRD) occurring in up to 90% of cases. [2] Familial HUS and sporadic non-Stx-HUS may be caused by genetic abnormalities of proteins involved in the regulation of com­plement activation. Low complement C3 levels in this group suggest that this disease could be sustained by over-activity of the alternate complement pathway in microcirculation. [7],[2],[12] Complement regulatory factor H (HFI) normally controls alternate complement acti­vation; membrane co-factor protein (MCP, CD 64) is also a membrane-anchored complement regulator that, by inactivating membrane bound C3b, protects glomerular endothelial cells against C3 activation [Figure 2]. [7] Environ­mental triggers like viruses, bacteria, toxins, drugs, systemic disease and pregnancy, in the absence of HF1 protecting capacity could activate complement and lead to formation of C3b followed by the formation of membrane attack complex (C5b9) and endothelial damage. The binding of factor H with the active complement component of C3b inactivates it (IC3b) and this is facilitated by factor I (FI). The half-life of factor H is about six days and in severe factor H deficiency, its activity is less than 1% of normal. [2],[13],[14] . In those situations, wherein complement over activation and C3b production is beyond the protective capacity of mutated HF1, there is formation of membrane attack complex, endothelial damage, platelet deposition and microvascular thromboses. All above findings support the concept of complement dysregulation in the pathogenesis of some familial-HUS. [7] Lack of protein H inhibitory capacity causes uncontrolled complement activation, low C3 levels and recurrent HUS. [15],[16] This usually develops in families, leads to ESRD and invariably recurs after renal transplantation. [17] There are case reports that combined liver and kidney transplantation improves this deficiency and prevents post- transplantation recurrence. [18],[19]

TTP is known with its pentad of: neurological deficit, renal failure, thrombocytopenia, micro­angiopathic hemolytic anemia and fever. In current clinical practice, thrombocytopenia, peripheral blood schistocytosis and elevated serum LDH are sufficient to suggest it. [4] Like HUS, it is also a disorder of small vessels. Novel insight into its pathophysiology followed the discovery of the VWF-cleaving protease ADAMTS13 (Frulin, Tsai), a member of zinc metaloproteinase (190,000 daltons ) that cleaves ultra large-VWF (ULVWF) soon after secretion from endothelial cells. When it is unfolded in a shear-dependent manner, it binds more platelets and also is cleaved better. [5] [Figure 3] Homozygote or heterozygote mutation of both alleles (9q34) of ADAMTS13, or auto­antibody (IgG) against it have been reported. Sometimes, ULVWF emerging from endo­thelial cells exceeds the enzyme capacity to cleave it (e.g., during pregnancy). [4],[5],[20] Addi­tionally, endothelial cell stimulation by histamine, shiga toxin, tumor necrosing factor-alpha, interleukin (IL)-8 and IL-6 also increase VWF secretion. [4] Interestingly, in chronic thrombo­cytopenic state other than TTP, VWF concen­tration is decreased. [2] ADAMTS13 enzyme activity below [4]

Both congenital and autoantibody induced TTP respond well to plasma exchanges. [7] Plasma exchange is the mainstay of therapy because it first removes the inhibitors and secondly, adds the protease and increases the activity of ADAMTS13. Another promising strategy for disappearance of these anti­ADAMTS13 antibodies is anti-CD 20 (rituximab) that acts on lymphocytes. [20]

We could say that HUS and TTP constitute a single entity, despite dissimilar etiology, acting through the common mechanism of endo­thelial cell damage. [1] As has been reported, some viral agents or hyper-eosinophilic syndrome as a result of microvascular endothelial damage cause TMA. [11] Despite evidence that 70-80% of TTP patients have a decreased VWF-cleaving protease activity. [20] and VWF-cleaving protease activity is normal in HUS, clinical syndrome overlapping occurs. Complement H mutation in familial thrombotic thrombocytopenia purpura and also lack of ADAMTS13 activity in cases of HUS has been reported. [1],[20] . Deficiency of VWF protease activity and complement regulatory protein H have also been found with familial and recurrent forms of TMA. However, it should be noted that most patients with TTP have complete or partial deficiency of ADAMTS13 activity, but complete ADAMTS13 deficiency is very rare in HUS. [20]

 Post-Renal Transplant TMA

Thrombotic microangiopathy (TMA) is a well-recognized and serious complication of renal transplantation. The time from transplant­ation to diagnosis of TMA is variable; it has been reported to be between few days to years after transplantation, suggesting that different mechanisms are involved. [21] TMA may occur de novo in the transplanted kidney without previous history of TMA as a cause of ESRD. Calcineurin inhibitors, humoral (C4b positive) rejection, ischemia, and less frequently viral infections, are all proposed etiological factors.

The clinical presentation of post-transplant­ation TMA is variable; it often manifests clinically as the HUS, with classical findings of renal failure, hemolytic anemia, schiocytes, and thrombocytopenia, with worsening renal function or delayed graft function (DGF). Localized TMA presents with worsening renal function, and DGF, with few or no systemic manifestations, thrombocytopenia and anemia. [6] The proportion of patients with localized TMA has varied widely in different studies and the reported figures range from 10-100% of all cases. [6] Since the clinical features of post-transplant TMA are few, diagnosis of TTP/HUS should be made exclusively on the basis of clinical and pathological findings. [2] At times, renal dysfunction can be the only finding and acute rejection, CsA and tacro­ limus nephrotoxicity, and Cytomegalovirus (CMV) infection could confuse the situation. [7]

The rate of graft loss is strongly influenced by whether the TMA is systemic or renal limited with localized TMA having a better short-term prognosis than systemic TMA. [6] Localized or systemic TMA represent a spectrum of severity of the same disorder; it may initially present as localized but subse­quently progress to systemic disease. [6]

Both CsA and tacrolimus have been asso­ciated with TMA, affecting 3-to14% of patients on CsA and approximately 1% of patients who are given tacrolimus. [7],[21] Cyclosporin has multiple pro-thrombotic effects and has been associated with de novo TMA and recurrent HUS after renal transplantation. In a study, the authors described the course of 26 CsA-associated cases of HUS in 188 consecutive renal transplant recipients; only two of 26 patients had systemic evidence of TMA. Hematological changes can precede or follow the signs of target organ dysfunction. [7] Thus, an acute rise of serum creatinine to 0.5 mg/dl above baseline may be the only clue, [7] this underscores the importance of considering HUS in the differential diagnosis of patients with renal allograft dysfunction even in the absence of systemic symptoms and an allograft biopsy should be performed to confirm it. [7],[22] Because of increased bioavailability and serum peak levels, the frequency of HUS is even higher in patients treated with Neoral. [23]

Vasoconstriction due to a reduction of both prostacyclin synthesis and prostacyclin-to­thromboxane A2 ratio, decreased generation of activated protein C, increased production and release of high-molecular- weight VWF multimer from endothelial cells, endothelial toxicity and its pro-thrombotic and anti­fibrinolytic activity, all enhance leukocyte adhesion to vascular endothelium, [10] and release of thromboplastin from mononuclear cells.

All these factors are proposed mechanism for CsA-induced TMA. [7] Concomitant ischemia­reperfusion and its deleterious effect on endothelium, and higher dosage of CsA further augment the deleterious effects of CsA. [10] Pre-glomerular constricting properties of both CsA and tacrolimus in turn result in increased vascular shear stress, which amplify the micro­angiopathic process. [7] Rarely, OKT3 has been associated with de novo post-transplant TMA, and recently, sirolimus has been implicated as possibly contributing with increased complement activation, thrombin activity, and increased TNF-alfa release being the proposed mechanisms. [24],[25]

Renal ischemia by it self is an initiating event for development of TMA. Prolonged ischemia is a pro-apoptotic factor and endo­thelial cells acquire pro-coagulant properties upon activation of apoptosis. [25] After reper­fusion, contact between apoptotic microvascular endothelial cells and blood constituents, causes activation of platelets and occurrence of TMA alongside with ATN during renal transplant­ation without significant independent association between HLA mismatch and recipient sensitization. [24],[25] Acute vascular rejection that damages the endothelial cells should always be considered in the differential diagnosis of post-transplant TMA, particularity when tubules and interstitial infiltration are accompanied by severe endo-vasculitis affecting entire renal allograft vasculature. [7],[10]

Distinguishing between post-transplant TMA and acute vascular rejection is extremely difficult on clinical grounds; it is confirmed only on renal biopsy. [6] Both cases are associated with acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. [7] TMA is the result of non-inflammatory endo­thelial damage, formation of fibrin and activation of platelets. In acute vascular rejection (AVR), the immune system is activated leading to inflammatory response, activation of the classic complement pathway resulting in production of C4d and antibody against endothelial cells. Thus, staining for C4d may suggest acute vascular rejection more than TMA. [10]

Viruses, particularly CMV infection, influenza A, parvovirus B-19, HIV, and HHV-6, and anti-cardiolipin antibody positivity in a subset of hepatitis C virus are reported as triggers of TMA. [26],[27] Patients with parvo­ virus B-19 infection present with fever, fatigue, arthralgia, aplastic anemia, thrombocytopenia, and deterioration of renal function about 15-20 days after renal transplantation. [28],[29] Parvovirus can infect the endothelial cells through a specific binding to P-antigen on cell surface; similar mechanisms have been involved in the setting of infection with CMV, which is a well known pathogen for endo­thelial cells, increasing expression of adhesion molecules, and interference with metabolism of VWF. [6],[27],[28],[29],[30] Exposure to agents that are toxic to the vascular endothelium, such as viruses, bacteria, immune-complexes, auto-antibodies and cytotoxic drugs, could initiate a local intravascular thrombosis. In normal circum­stances, factor H, by modulating C3bBb activity, effectively limits complement deposition and further extension of thrombosis. However, when factor H is defective, C3bBb-convertase formation and complement deposition may become uncontrolled. [7],[31]

If the cause of ESRD is HUS/TTP, its recurrence is negligible for childhood type D+HUS and outcome after kidney transplant­ation is good with recurrence rate ranging from 0 to 10 %. [2] In adult type non-Stx-HUS, approximately 50% of renal transplanted patients develop recurrence of the disease in the allograft while the recurrence rate is nearly 100% in familial/recurrent forms with the median time to recurrence being 30 days after transplantation. The one-year graft survival is about 80% after childhood, and less than 30%, after adult-onset HUS. [10] Living related transplantation is associated with an increased risk of recurrence, probably suggesting a genetic (familial) predisposition, and the possibility that the donor might have a same factor H abnormality. Treatment with calcineurin inhibitors also increases the risk of recur­rence. [7] Despite intensive therapy, there is no effective treatment for recurrence and graft failure. Recent studies indicate that recurrence rate ranges from 30-100% in patients with factor H abnormality, which is a plasma factor originating predominantly in the liver, and kidney transplant does not correct this defect; [2] thereby, renal transplantation is contraindi­cated in familial/relapsing form and also, it is not a good option for non-Stx-HUS. [7] The risk of recurrence is not simply a function of patient's age, but rather is associated with the type of the HUS. [32] MCP, a membrane bound protein [5] that express on almost all cells, is highly expressed in the kidney and can be found on glomerular endothelial cells by immuno-histochemichal analysis and renal transplantation would reasonably correct this defect, and D+HUS due to this defect does not recur after transplantation. [2] Deficiency in activity of the VWF-cleaving metalo­protease ADAMTS13 is also a cause of post-transplant TMA. [31]


The characteristic histological lesion of TMA consists of arteriolar wall thickening (capillaries and arterioles), swelling and detachment of endothelial cells from the basement membrane (sub-endothelial space widening), accumulation of fluffy amorphous material in the sub-endothelium, ballooning of glomerular lobules, and glomerular ischemia. [7] The constituents of arterial thrombi in TTP and HUS include platelet and VWF initially, and fibrinogen and thrombin at later stages. [2] Sometimes, the histological findings are indistinguishable from malignant hypertension. [1] The different clinical manifestations are related to the distribution of micro-vascular lesion. [9],[28] Thus in HUS, the micro-thrombi are mainly confined to the kidney while TTP mainly involves the brain. [1] An acute vascular rejection or rejection process that damages the endo­thelial cells might culminate to TMA. [10] AVR should always be considered in the differential diagnosis, particular when tubular and inter­stitial infiltration is accompanied by severe endo-vasculitic lesions affecting the entire vasculature. [7] Criteria for pathologic diagnosis of TMA, includes presence of one or more of the following findings:

a) Arteriolar or arterial thrombi

b) Occlusion of glomerular capillaries with amorphous material that correspond to sub-endothelial accumulation of electron lucent deposits.

c) Severe arteriolar or arterial endothelial widening [Figure 4] [6]


Withdrawal of the cause, and treatment of precipitating factors are the most effective approaches. Plasma exchange, as the mainstay therapy for TMA confers its effectiveness by replenishing the missing ADAMTS13 and/or removal of its inhibitors. Genetic and recurrent forms of TMA with factor H deficiency do not respond to plasma exchange. In sporadic cases precipitated by drugs, dis­continuation of the offending agent and plasma exchange usually elevate the ADAMTS13 activity. Interestingly, antimicrobial treatment could worsen the outcome of D+HUS and plasma exchange worsens the nuraminidase­associated HUS. [1],[2] In resistant forms of HUS, removal of the kidney as a major site of augmented shear stress is followed by hematological and clinical remission. [1] Splene­ctomy as a rescue therapy may serve in very selected cases of plasma exchange-resistant HUS, or recurrent TTP. [1] Rituximab is a promising first-line immunosuppressive treat­ment in patients with acute refractory, and severe relapsing, TTP related to anti­ADAMTS13 antibodies. [33] Anti-thrombotic or anti-platelet agents are not helpful.

Treatment strategy in transplantation asso­ciated TMA includes drug withdrawal or dose reduction as first-line therapy for de novo CsA-or tacrolimus-associated TMA; it is effective in fewer than 50% of patients although a higher success rate (84%) has been reported with adjunctive plasma infusion or exchange. [7] Dose reduction, withdrawal, or conversion from one calcinurin inhibitor to another may result in acute rejection. [7] After remission is achieved, patients re-challenged with lower dose of CsA, or tacrolimus, or conversion from one calcineurin inhibitor to another, also are not without risk. Despite having different binding proteins, they have similar toxicities like endothelial injury, increased thromboxane A2 production, and decreased nitric oxide production, all of which are central to the pathogenesis of TMA. [7],[34]

Sirolimus as a macrocyclic lactone has different mechanism and side effects. It does not cause vasoconstriction and nephrotoxicity, and it has got less potential for endothelial toxicity; thus combination of sirolimus, MMF, and corticosteroids appears to be an effective alternative to CsA-based regimen.[34] Sirolimus was associated with a good outcome in 15 patients with CsA or tacrolimus associated HUS. There are case reports that combined liver and kidney transplantation improves this deficiency and prevents post-transplant recurrence.[19],[20]


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