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Keywords:

  • TTP;
  • ADAMTS 13 activity;
  • treatment with plasma exchange;
  • Rituximab

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Thrombotic microangiopathies are a relatively rare group of congenital and inherited disorders caused by defects in processing the ultra large forms of von Willibrand factor which pathologically give rise to platelet rich microthrombi in the micro arterial circulation leading to end organ damage particularly in the brain, heart and kidneys. Identification of the ADAMTS 13 gene has led to the definition of congenital deficiency of its activity or failure of activity due to the development of an inhibitory IgG antibody. The idiopathic autoimmune form of the disease is the most common. There are various subgroups of acquired TTP associated with HIV infection, pregnancy, pancreatitis, associated with bone marrow transplantation, various disseminated malignancies and certain drugs, particularly Clopidogrel. Diagnostic assays are now becoming widely available to identify ADAMTS 13 activity and also acquired antibodies to the enzyme. Mainline treatment is associated with daily plasma exchange with associated other immunosuppressant treatments particularly steroids and recently the use of Rituximab, a monoclonal anti-CD20 antibody. Despite improvement in treatment modalities there is still significant mortality of 10–20%, particularly if there is a delay in initiating plasma exchange. Relapse also occurs in 20–50% of patients although this may be improved by Rituximab therapy.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Thrombotic Thrombocytopenic Purpura (TTP) was first described in the literature in 1924, by Moschcowitz, presenting in a 16-year-old girl with fever, haemolytic anaemia, paralysis, coma and death. TTP was defined by the pentad of fever, thrombocytopenia, microangiopathic haemolytic anaemia (MAHA), renal dysfunction and neurological symptoms. The pathological hallmark was platelet-rich microthrombi in the small vessels of multiple organ. Relapsing episodes of thrombocytopenia, responding to plasma infusion in a child and adult became known as the Upshaw-Shulman syndrome, represents what we now know as congenital TTP.

The discovery of ultra large von Willibrand factor multimers (ULVWFMs) in four patients with chronic relapsing TTP (Moake et al., 1982), suggested a deficiency of VWF ‘polymerase’. The proteolytically active enzyme in the plasma of patients that cleaved VWF at the tyrosine 1605-methionine 1606 bond was defined (Furlan, Robles & Lamie, 1996; Tsai, 1996) in patients with congenital TTP (Furlan et al., 1997) and acquired TTP with IgG autoantibody inhibitors (Furlan et al., 1998a; Tsai & Lian, 1998). In 2001, VWF cleaving protease was identified as ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif), a member of the ADAMTS family of metalloproteases, with the gene located on chromosome 9q34 (Fujikawa et al., 2001; Levy et al., 2001; Zheng et al., 2001). ADAMTS 13 is 37 kb, comprises 29 exons. It is secreted and synthesized primarily in the hepatic stellate cells.

Pathogenesis of TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

VWF appears to be the key factor implicated in the pathogenesis of TTP. VWF, a plasma glycoprotein, is the primary adhesive link between platelets and the subendothelium and is synthesized by endothelial cells and megakaryocytes. VWF unfolds under conditions of high shear stress, allowing rapid proteolysis by ADAMTS 13 into smaller fragments of VWF. Under physiological conditions, the large VWFMs released by endothelium, induce platelet aggregation only in areas of high shear stress, such as arterioles and capillaries. Normally, this only occurs for a brief time as VWF is rapidly broken down by ADAMTS 13. However, in congenital deficiency or failure of ADAMTS 13 to act because of an inhibitory antibody, there is excessive platelet aggregation.

The catalytic or substrate recognition sites of ADAMTS 13 are thought to be in the cysteine rich/spacer domain. The structure/function of ADAMTS 13 has become clearer but the regulation of this protease is unknown. The roles of each domain of ADAMTS 13 have been investigated. Truncation to remove the spacer domain abolishes ADAMTS 13 activity, indicating its role in mediating VWF-ADAMTS 13 interaction. The binding affinity for VWF declines by threefold if the Complement C1r/C1s, Uegf, Bmp1 (CUB) domains are removed, but increases twofold if the 8th thrombospondin TSP-1 is also deleted.

Severe deficiency of ADAMTS 13 activity appears specific for congenital or acquired idiopathic TTP (Furlan et al., 1998a,b; Tsai & Lian, 1998). Results regarding the specificity of severe ADAMTS 13 deficiency in distinguishing acute TTP from haemolytic uraemic syndrome (HUS), suggest severe deficiency is about 90% specific and sensitive for TTP (Peyvandi et al., 2004; Zheng et al., 2004).

Reductions in ADAMTS 13 have been documented physiologically (in pregnancy associated with increased substrate-VWF) and pathologically in sepsis associated with enzyme consumption (Scully et al., 2008a) and factors such as ADAMTS 13 transcription is less responsive to inflammatory markers. The ADAMTS 13 deficiency and the increased VWF adhesion activity may be clinically significant as they are associated with the clinical prognosis in sepsis and other medical conditions.

Experiments in ADAMTS 13 deficient mice who were either partially or completely deficient in VWF, VWF deficiency abrogates the ADAMTS 13 deficient prothrombotic state, suggesting that VWF is the only relevant substrate under these conditions. Inducing an endotoxaemic state in the mice (using shigatoxin), there was complete protection from thrombocytopenia in the VWF absent, ADAMTS 13−/− mice, whereas in ADAMTS 13+/+ mice with normal VWF, TTP could be triggered. With an established model of endotoxaemia and gram-negative sepsis, thrombocytopenia or mortality was not affected by either VWF or ADAMTS 13 deficiency, suggesting an alternative mechanism for the thrombocytopenia. Therefore, there is an interplay of genetic and environmental factors, predisposing patients to TTP but also the risk of relapse/recurrent episodes.

Diagnosis of TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Diagnosis of TTP required thrombocytopenia, MAHA and pathognomonic characteristic microthrombi composed mainly of platelet aggregates throughout the body, which may lead to specific organ symptomatology. This will increase the differential diagnosis (Table 1) and a level of clinical suspicion is required.

Table 1.   Differential diagnosis of thrombocytopenia and MAHA
  1. MAHA, microangiopathic haemolytic anaemia; CMV, cytomegalovirus; HSV, herpes simplex virus.

Autoimmune haemolysis/Evans syndrome
Disseminated Intravascular coagulation
Pregnancy [Eclampsia, Haemolysis, elevated liver enzymes and low platelets (HELLP)]
Drugs (Calcineurin inhibitors)
Malignant hypertension
Infections, typically viral (CMV, Adenovirus, HSV) or severe bacterial (meningococcus, pneumococcus), fungal
Catastrophic antiphospholipid syndrome
Autoimmune disease (Lupus nephritis, acute scleroderma)
Vasculitis
Haemolytic uraemic syndrome
Malignancy

Thrombocytopenia is a result of platelet consumption in the microcirculation and MAHA because of mechanical fragmentation of erythrocytes during flow through partially occluded high shear microvessels. Elevated lactate dehydrogenase (LDH) and low haptoglobin levels are markers of haemolysis. LDH may be greater than the degree of haemolysis and probably reflects cell breakdown because of microvascular thrombosis. Reticulocyte counts are raised and anaemia, because of haemolysis, may be exacerbated without folic acid replacement. The Direct Coombs test is negative and a baseline clotting screen (prothrombin time, activated partial thromoplastin time and fibrinogen) is typically normal. Virology screen pre-treatment is necessary to exclude human immunodeficiency virus (HIV)-associated TTP and in view of the volumes of plasma, to exclude, albeit very rare, viral transmission (Table 2).

Table 2.   Routine laboratory testing for patients with a diagnosis of TTP
Recommended diagnostic laboratory investigations at presentation of TTP
  1. TTP, thrombotic thrombocytopenia; ANA, anti-nuclear antibodies; RF, rheumatoid factor; LA, lupus anticoagulant; ACLA, anti-cardiolipin antibody

Full blood count and blood film
Reticulocyte count
Clotting screen including fibrinogen and d-dimers
Urea and electrolytes
Liver function tests
Calcium levels
Lactate dehydrogenase
Urinalysis
Direct antiglobulin test
Hepatitis A/B/C and HIV testing
Pregnancy test (in women of child bearing age)
Blood Group
Auto-antibody screen (ANA/RF/LA/ACLA)
ADAMTS 13 assay

The median platelet count is between 10 and 30 × 109/l at presentation, with approximately half having platelet counts <150 × 109/l after 7 days of treatment. Median haemoglobin levels were 8.7 g/dl, LDH −1750 IU/l and bilirubin levels were raised in 70% on admission. Creatinine levels, which varied at presentation (49–526 μmol/l), the median was not significantly different from the normal range (96 μmol/l, normal range <92 μmol/l) (Scully et al., 2008b).

Clinical presentation

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

TTP is more common in women, can present at any age, but typically in the 3rd/4th decades. Afro-Caribbean and Caucasian ethnicity are most common and obesity (body mass index > 30) (Vesely et al., 2004) appears to be a risk factor. Mortality remains between 10% and 20% (Vesely et al., 2004; Scully et al., 2008b). In the SE England registry mortality was 8.5%, primarily in women, half within 24 h of presentation (Scully et al., 2008b). The median number of plasma exchange (PEX) to remission is 10–15 for an acute episode (Scully et al., 2008b). The risk of relapse is between 30% and 50% (Terrell et al., 2005).

Presentation includes symptoms of thrombocytopenia and features of nervous system involvement, (confusion, headache, paresis, aphasia, dysarthria, visual problems, encephalopathy or coma) in 70–80% of cases. At least 10% of all cases presented in a coma (Scully et al., 2008b). Fever is present in about a quarter of patients. Renal involvement with proteinuria and microhaematuria occurs in approximately 40% of patients, but severe renal insufficiency requiring haemodialysis is rare and more indicative of atypical HUS (aHUS). Cardiac disease at presentation is more common than previously described. Conduction defects and arrhythmias may be an acute cause of mortality, associated with microvascular thrombosis affecting arterioles supplying the sinoatrial node. Symptomatic heart failure is increased in patients who have been given a recent platelet transfusion. Indeed, measurement of troponin T levels, raised in 50% of acute TTP cases and specifically in idiopathic TTP, has highlighted that cardiac involvement is probably underestimated. The lesions formed during acute TTP are dynamic in their development and resolution and do not usually cause complete vessel occlusions. The microvascular thrombosis is widespread and multi-organ. The presence of clinical symptoms suggests the critical need for treatment.

Subgroups of TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Congenital TTP, associated with mutations in the ADAMTS 13 gene, may be homozygous, compound heterozygous or heterozygous with Single Polymorphisms, affecting ADAMTS 13 production and/or secretion. Acquired idiopathic TTP, with no obvious precipitating cause, is in the majority of cases associated with antibody, usually IgG or inhibitory activity against ADAMTS 13 (Scully et al., 2007). In both of these subgroups, ADAMTS 13 activity is severely reduced, typically <5%, at the initial presentation of acute TTP. Secondary TTP cases have by definition a defined precipitating cause. The ADAMTS 13 activity within this group is variable. For example, HIV, pregnancy and some drug-induced TTP cases in many cases has low ADAMTS 13 activity (<5%) and may have a positive anti-ADAMTS 13 IgG antibody. However, pancreatitis-associated TTP have activity levels mid range (approximately 30–40%). Bone marrow transplant is no longer recognized as causing TTP but rather transplant-associated microangiopathy (TAM) (Table 3). The idiopathic group had more severe neurological disease and all the coma cases were from the idiopathic group with antibody positive disease (Scully et al., 2008b).

Table 3.   Classification of the subtypes of TTP
  1. TTP, thrombotic thrombocytopenia; ADAMTS 13, a disintegrin and metalloprotease with thrombospondin type 1 motif.

  2. BMT have been redefined as ‘transplant’ associated microangiopathy.

Congenital TTP<5% of all casesADAMTS 13 <5%, no inhibitor. Confirmed by mutational analysis of ADAMTS 13May present at birth, in childhood or adulthood (usually in pregnancy in females)
Acquired idiopathic TTPApproximately 80% of all casesNo specific underlying cause, but may be triggered by e.g. infection, anaesthetics. ADAMTS 13 activity <5% at presentation (may be higher with relapse), positive inhibitor or IgG 
Secondary TTP10–15% of all casesVariable ADAMTS 13 activity and antibody levelsBecause of: pregnancy; HIV; drugs, such as quinine, CSA; pancreatitis; autoimmune disease (malignancy)

Acute idiopathic TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

In patients with idiopathic TTP, the number that have severe ADAMTS 13 deficiency has varied, but this in part reflects the assay methodology and inclusion criteria, such as HUS patients, who typically have normal or marginally reduced ADAMTS 13 activity. Those with antibody positive disease are more likely to have refractory disease, delayed response to treatment acutely and early death.

HIV-associated TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

TTP may be the initial presenting feature of HIV disease. HIV-associated TTP therefore, does not appear to be primarily autoimmune in nature, but may be due to a direct action of HIV on endothelium, resulting in reduced ADAMTS 13 production. After recovery from TTP sustained remission is maintained in those continuing with HAART; stopping HAART results in acute TTP relapse (Miller et al., 2005). This observation may imply that HIV has a causal role in this condition. ADAMTS 13 measurements may have a predictive role on the severity and outcome of HIV-associated TTP. Those with severe ADAMTS 13 deficiency (<5%) had fewer AIDS-related complications and higher CD4+ T cell counts, compared to HIV-TTP with ADAMTS 13 >5%, who had an increased mortality (Malak et al., 2008). There is normalization in ADAMTS 13 activity, as the CD4 count recovered and HIV viral load fell (Miller et al., 2005), after treatment with HAART and PEX. As in Idiopathic Thrombocytopaenic Purpura, there does, in some patients, appear to be an immune component, with positive IgG antibodies to ADAMTS 13. Generally, these patients still respond to HAART and PEX, but occasionally, further therapy is required, e.g. with Rituximab. Steroids can be given in HIV-positive TTP patients without a significant increase in atypical infections.

Pregnancy-associated TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

The risk of pregnancy as a precipitating cause of acute TTP accounts for approximately 10–25% of all cases of TTP in women. Forty-five per cent of all cases of TTP occur in women of childbearing age. There is also the risk of relapse of TTP during subsequent pregnancies and other pregnancy-related thrombotic microangiopathies, such as pre-eclampsia (PET)/ HELLP (haemolysis, elevated liver enzymes, low platelets) and HUS may further complicate the diagnosis of TTP (Table 4). In healthy women, there is a physiological reduction in ADAMTS 13 activity after the first trimester (weeks 12–16) up until the end of the postnatal period when the levels normalize to pre-pregnancy levels (Sanchez-Luceros et al., 2004). There was a significant correlation between higher VWF:Ag levels and lower ADAMTS 13 activity.

Table 4.   Typical features in pregnancy-associated microangiopathies
 MAHAThrombocytopeniaCoagulopathyHBPAbdominal symptomsRenal impairmentNeurological symptoms
  1. PET, pre-eclampsia; HELLP, haemolysis, elevated liver enzymes and low platelets; TTP, thrombotic thrombocytopenia; HUS, haemolytic uraemic syndrome; AFLP, acute fatty liver of pregnancy; SLE, systemic lupus erythematoisis; APL syndrome, antiphospholipid syndrome (catastrophic); HBP, high blood pressure.

PET++±+++±±++
HELLP++±+++++±
TTP+++++±++++++
HUS+++±++++++±
AFLP±+++++++±
SLE++±+±+++
APL syndrome+++±++++++

Women presenting with TTP during pregnancy appear to fall into two groups; late onset adult congenital TTP and acquired, antibody-mediated TTP. Congenital TTP may first present during pregnancy and there is a very high risk of relapse in subsequent pregnancies. Diagnosis is confirmed in patients with ADAMTS 13 activity <5%, no evidence of an inhibitor and confirmation by mutational analysis of the ADAMTS 13 gene. There is a high neonatal mortality (50%) and morbidity (46% of the remaining live births were premature). There was only one normal pregnancy and delivery in which plasma infusions had started from 8 weeks gestation (Fujimura et al., 2008).

In women with acquired TTP, normal levels of ADAMTS 13 pre-pregnancy/onset of pregnancy were associated with a lower likelihood of relapse (Scully et al., 2006).

Drug-associated TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

TTP in association with drugs accounts for <15% of all TTP cases (Vesely et al., 2004; Zheng et al., 2004; Scully et al., 2008b). The estimated incidence of ticlodipine-associated TTP is 1one per 1600–5000 patients treated whilst that following clopidogrel is 1.5–5.8 per million treated, which is similar to the reported incidence of TTP. Antibody inhibitors to VWF-cleaving protease have been identified in both drugs Plasmapheresis is effective treatment with reported survival rates of 76–91% and is superior to plasma infusion. Quinine causes an antibody mediated idiosyncratic disorder, typically in females and in the largest series that were treated with PEX and withdrawal of the drug, mortality was 21%.

Pancreatitis-associated TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Patients, initially presenting with acute pancreatitis, acute TTP was diagnosed days after resolution of pancreatitis. The ADAMTS 13 activity was only moderately reduced and did not correlate with the severity of TTP or pancreatitis (McDonald et al., 2008). All patients received PEX and steroids did not result in exacerbation of pancreatitis.

Bone marrow transplant associated microangiopathy

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

The Thrombotic Associated Microangiopathy (TAM) results from endothelial toxicity associated with chemotherapy, infections, immunosuppressives and Graft versus Host Disease. Despite some features in common, TAM has important differences from de novo TTP-absence of ADAMTS 13 deficiency, a different spectrum of clinical symptoms, poor response to PEX and lack of evidence of systemic microthrombi formation. ADAMTS 13 has not been found to be markedly reduced (Peyvandi et al., 2006).

Malignancy-associated thrombotic microangiopathy

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Thrombotic Micro Angiopathy has been reported in a variety of malignancies, but especially, adenocarcinomas, involving the stomach, breast and lung. Presentation is either at early stage of the disease or with terminal disseminated disease. ADAMTS 13 activity is not been severely reduced and treatment of the underlying cancer is the mainstay of therapy. While PEX has not been of benefit, Protein A immunoabsorption has had positive responses in some cases of malignancy associated TMA.

Assays

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Antibodies to ADAMTS 13 can be demonstrated in up to 90% of cases of acquired TTP associated with ADAMTS 13 activity levels <5% (Peyvandi et al., 2004; Rieger et al., 2005). Such antibodies appear to reduce circulating functional enzyme levels. Most autoantibodies are inhibitory and therefore can be detected and titrated in vitro using classical mixing studies (Furlan et al., 1998a; Tsai & Lian, 1998; Peyvandi et al., 2004). The use of recombinant ADAMTS 13 in a simplified enzyme-linked immunosorbent assay allows the rapid identification of autoantibodies, primarily IgG (Scheiflinger et al., 2003).

Treatment of TTP

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Plasma

Acute TTP had a mortality of 90% before the advent of PEX (Rock et al., 1991). Although mortality has improved it remains unacceptably high at 15–20%, often related to a delay in diagnosis or access to appropriate therapy. Morbidity is less well documented, but may also be high, as a result of microvascular thrombotic complications and the effect of therapy, including apheresis procedures.

Corticosteroids

Steroids are still widely used in the treatment of acute TTP, despite little evidence documenting their efficacy. In combination with PEX as initial treatment of TTP, addition of methylprednisolone 2 mg/kg/day to daily PEX resulted in a complete remission rate of 76%. With the demonstration of a functional deficiency of ADAMTS 13 and in the majority of acquired cases, an inhibitor, primarily IgG antibodies, the use of steroids in patients is appropriate.

Rituximab

Rituximab (Mabthera®; Roche Pharmaceuticals, Bastle, Switzerland), is a monoclonal anti-CD 20 antibody which specifically depletes B cells. Two prospective studies have successfully and safely used Rituximab, as second line therapy in patients with acute TTP who fail to respond to standard daily PEX and methylprednisolone and in patients with relapsed acute idiopathic TTP who have previously demonstrated antibody to ADAMTS 13 (Fakhouri et al., 2005; Scully et al., 2007). Treatment was associated with prompt clinical remission before completion of the four weekly infusions and normalization of routine laboratory parameters. Rituximab was associated with normalization of ADAMTS 13 activity in most cases, and often in patients who had recurrent acute TTP episodes and with undetectable ADAMTS 13 activity before the use of Rituximab (Scully et al., 2007). Rituximab was associated with complete remission within a median of 11 days of initiation of therapy (Scully et al., 2007; Jasti et al., 2008). Rituximab has been used electively to prevent relapses (Fakhouri et al., 2005; Scully et al., 2007). Unexpectedly, the risk of relapse appears to be considerably reduced. Comparison of patients who have received Rituximab in relapsed or refractory disease, compared with those who have received conventional therapy, the Rituximab group had a significantly longer median progression free survival (45.8 vs. 0.9 months, P = 0.0025) (Heidel et al., 2007). There are reports of infectious complications, but often there is associated steroid use and there is no evidence that Rituximab increases infection risk.

Other therapies

Vincristine in refractory TTP cases, increased platelet counts and increased ADAMTS 13 activity. However, there is a risk of inducing peripheral neuropathy. Both daily dosing and pulsed cyclophosphamide therapy have been used successfully although reported numbers are extremely low. However, the combination with steroids often has an unexpected infectious profile, as documented in other autoimmune conditions.

Clinical and haematological response uniformly occurred 7–14 days after initiating Ciclosporin treatment. However, relapses are documented after cessation of therapy (Levy et al., 2001). A trial of PEX and steroids or cyclosporin (CSA), at a dose of 2–3 mg/kg twice a day, 18 patients received CSA, remission occurred in 89%, 14% relapsed while on CSA and there was a 33% relapse after stopping 6 months of treatment. Steroids (1 mg/kg/day) (n = 12) with PEX in acute TTP, 83% achieved remission, but 60% suffered an exacerbation (within 30 days) and needed more PEX than the CSA group (Cataland et al., 2007a,b).

A 78% response rate at 6 months was achieved when aspirin and dipyridamole were administered in conjunction with PEX (Rock et al., 1991). In a prospective randomized trial designed to address the effect of the addition of aspirin and dipyridamole to standard treatment (PEX and steroids), a similar overall response was obtained in both groups.

Supportive therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Red cell transfusion is required for rapid haemolysis and 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 contra-indicated unless there is life-threatening haemorrhage as they have been temporally associated with disease exacerbation. 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 PEX or precipitate early relapse. Thromboprophylaxis, with low molecular weight heparin, should be considered in patients once platelet count >50 × 109/l. Compression elasticated stockings should also be used from admission.

Refractory disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Despite the improvement in survival, there remains a subgroup with a slow or incomplete response to PEX ± steroids. Refractory disease has been arbitrarily defined as persistent thrombocytopenia (platelet count <150 × 109/l) or LDH elevation after a total of seven daily PEX procedures. Refractory disease may be redefined as progression of clinical symptoms and/or platelet count <150 × 109/l. Treatment of this group of patients is difficult and typically associated with acquired antibody mediated disease. Increasing the intensity of exchanges and addition of further steroids have provided some benefit. As discussed, remission can be achieved in refractory TTP using Rituximab or CSA, but the latter may relapse subsequently on stopping this treatment.

Relapse

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References

Subsequent relapse remains problematic and occurs in 20–50% of cases. All patients should be aware of the possibility of relapse and advised to report early if symptoms suggestive of relapse develop. Patients with ADAMTS 13 activity <10% or an inhibitor or an anti-ADAMTS 13 antibody had a threefold increase in relapse over 1 year (Peyvandi et al., 2008).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis of TTP
  5. Diagnosis of TTP
  6. Clinical presentation
  7. Subgroups of TTP
  8. Acute idiopathic TTP
  9. HIV-associated TTP
  10. Pregnancy-associated TTP
  11. Drug-associated TTP
  12. Pancreatitis-associated TTP
  13. Bone marrow transplant associated microangiopathy
  14. Malignancy-associated thrombotic microangiopathy
  15. Assays
  16. Treatment of TTP
  17. Supportive therapy
  18. Refractory disease
  19. Relapse
  20. References
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