Thrombotic microangiopathies are a heterogeneous group of inherited and acquired disorders sharing a common clinical presentation of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. These disorders have been treated with plasma exchange (TPE) based on randomized controlled trials, which found this therapy to be effective in thrombotic thrombocytopenic purpura (TTP). For the remaining disorders, low- to very low-quality evidence exists for the use of TPE. When TPE is applied, the treatment regimen used for TTP is usually applied. There is a need for further evaluation of the role of TPE in the treatment of thrombotic microangiopathies other than TTP.
Key points
- •
Thrombotic microangiopathies (TMA) are inherited and acquired disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage resulting from microvasculature occlusion.
- •
Randomized controlled trials involving plasma exchange (TPE) exist only for thrombotic thrombocytopenic purpura (TTP) with evidence supporting use in other TMA consisting of low- to very low-quality evidence.
- •
The American Society for Apheresis considers TPE ineffective for the treatment of Shiga toxin–mediated TMA, selected complement-mediated TMA, and selected drug-associated TMA.
- •
The usual course of TPE applied to TTP is usually applied to the other TMA.
- •
The usual replacement fluid used in TMA is plasma, with the exception of Streptococcus pneumoniae -associated hemolytic uremic syndrome, where albumin is the suggested replacement fluid.
Introduction
Thrombotic microangiopathies (TMA) are a heterogeneous group of disorders, some inherited and some acquired, that share common clinical features. These features are microangiopathic hemolytic anemia (MAHA) ( Box 1 ), thrombocytopenia, and organ damage due to microvasculature endothelial damage. Although several disorders are considered to be TMA, this review is limited to those for which the use of plasma exchange (TPE) has been described in the medical literature. The disorders discussed are briefly described in Table 1 . Of note, in addition to the traditional names used, Table 1 also provides alternate names, where available, in parentheses as recommended by George and Nester. These suggested alternate names are intended to provide clarity when discussing these disorders by describing the cause of the TMA.
- •
Anemia
- •
Schistocytes
- •
Decreased haptoglobin
- •
Elevated LDH
| Disorder a | Pathophysiology | Patient Population | Signs and Symptoms | ASFA Category | ASFA Recommendation Grade |
|---|---|---|---|---|---|
| TTP (ADAMTS13 deficiency-mediated TMA) | Deficiency of ADAMTS13 activity due to either congenital deficiency or development of inhibitory autoantibodies | Adults or children | MAHA, thrombocytopenia, fever, neurologic symptoms, renal dysfunction | I | 1A |
| Shiga toxin–associated HUS or typical HUS or diarrhea-associated HUS (ST-TMA) | Direct endothelial damage due to toxic effects of Shiga toxin | Predominantly a disease of children <5 y of age | MAHA, thrombocytopenia, renal dysfunction, bloody diarrhea | IV | 1C |
| pHUS | Endothelial damage due to crypt antigen exposure or inhibition of Factor H due to protein damage leading to unregulated complement activation | A disease of children <2 y of age associated predominantly with S pneumoniae pneumonia | MAHA, thrombocytopenia, and acute kidney injury | III | 2C |
| aHUS (complement-mediated TMA) | Endothelial damage due to unregulated complement activation | Adults or children | MAHA, thrombocytopenia, and acute kidney injury | Complement gene Mutations—II Membrane cofactor mutations—IV Factor H autoantibodies—I | Complement gene Mutations—2C Membrane cofactor mutations—1C Factor H autoantibodies—2C |
| HSCT-TMA | Endothelial damage due to infection, chemotherapy, radiation therapy, and/or GVHD | Adults or children | MAHA, thrombocytopenia, renal failure, and neurologic symptoms | III | 2C |
| Renal transplant-associated TMA | Endothelial damage due to calcineurin inhibitors and possibly other transplant-related factors | Renal transplant patients | MAHA, thrombocytopenia, and worsening or delayed graft function | NC | NC |
| Drug-associated TMA (drug-mediated TMA immune reaction or drug-mediated TMA toxic dose-related reaction) | See Table 3 | Adults or children | MAHA, thrombocytopenia, and renal failure | See Table 3 | See Table 3 |
| Malignancy-associated TMA | Coagulation cascade activation due to tumor tissue factor expression | Adults with cancer, predominantly adenocarcinomas | MAHA, thrombocytopenia, bone pain, respiratory symptoms, anorexia, and weight loss | NC | NC |
a Names in parentheses suggested by George and Nester for clarity.
TPE is a medical procedure whereby plasma is removed and replaced with a colloid or a combination of a colloid and crystalloid replacement fluid. The potential mechanisms of actions of TPE are numerous and vary according to the disease entity being considered. In the case of the TMA, possible mechanisms of action include the removal of pathologic antibodies, the removal of abnormal plasma proteins, and the replacement of absent or abnormal plasma proteins. The American Society for Apheresis (ASFA) provides guidance on the use of TPE in the treatment of many, but not all, of the TMA. The role of apheresis therapy in the treatment of a disorder is defined by the ASFA category, with the ASFA recommendation grade providing an indication of the strength of the recommendation to perform the procedure and the quality of the published evidence supporting the treatment. These ASFA categories and the ASFA recommendation grade are defined in Box 2 and Table 2 , respectively, and given for each disorder, where available, in Table 1 . Key considerations in using TPE to treat any disorder are listed in Box 3 and are again described for many of the TMA in the ASFA guidelines. This information is provided in the sections discussing the various TMA.
Strong recommendation: 1
Weak recommendation: 2
High-quality evidence (eg, randomized, double-blinded, controlled trials): A
Moderate-quality evidence (eg, controlled trials): B
Low- or very low-quality evidence (eg, case series or reports, expert opinion): C
| Category | Definition |
|---|---|
| I | Accepted first-line therapy, stand-alone or as an adjunct to other therapies |
| II | Second-line therapy, stand-alone or as an adjunct to other therapies |
| III | Optimum role of apheresis is uncertain, decision-making should be individualized based on each patient’s clinical situation |
| IV | Apheresis therapy ineffective or harmful |
- •
Volume of plasma exchanged
- •
Fluid used to replace the removed plasma
- •
Frequency of treatment
- •
Length of treatment
Introduction
Thrombotic microangiopathies (TMA) are a heterogeneous group of disorders, some inherited and some acquired, that share common clinical features. These features are microangiopathic hemolytic anemia (MAHA) ( Box 1 ), thrombocytopenia, and organ damage due to microvasculature endothelial damage. Although several disorders are considered to be TMA, this review is limited to those for which the use of plasma exchange (TPE) has been described in the medical literature. The disorders discussed are briefly described in Table 1 . Of note, in addition to the traditional names used, Table 1 also provides alternate names, where available, in parentheses as recommended by George and Nester. These suggested alternate names are intended to provide clarity when discussing these disorders by describing the cause of the TMA.
- •
Anemia
- •
Schistocytes
- •
Decreased haptoglobin
- •
Elevated LDH
| Disorder a | Pathophysiology | Patient Population | Signs and Symptoms | ASFA Category | ASFA Recommendation Grade |
|---|---|---|---|---|---|
| TTP (ADAMTS13 deficiency-mediated TMA) | Deficiency of ADAMTS13 activity due to either congenital deficiency or development of inhibitory autoantibodies | Adults or children | MAHA, thrombocytopenia, fever, neurologic symptoms, renal dysfunction | I | 1A |
| Shiga toxin–associated HUS or typical HUS or diarrhea-associated HUS (ST-TMA) | Direct endothelial damage due to toxic effects of Shiga toxin | Predominantly a disease of children <5 y of age | MAHA, thrombocytopenia, renal dysfunction, bloody diarrhea | IV | 1C |
| pHUS | Endothelial damage due to crypt antigen exposure or inhibition of Factor H due to protein damage leading to unregulated complement activation | A disease of children <2 y of age associated predominantly with S pneumoniae pneumonia | MAHA, thrombocytopenia, and acute kidney injury | III | 2C |
| aHUS (complement-mediated TMA) | Endothelial damage due to unregulated complement activation | Adults or children | MAHA, thrombocytopenia, and acute kidney injury | Complement gene Mutations—II Membrane cofactor mutations—IV Factor H autoantibodies—I | Complement gene Mutations—2C Membrane cofactor mutations—1C Factor H autoantibodies—2C |
| HSCT-TMA | Endothelial damage due to infection, chemotherapy, radiation therapy, and/or GVHD | Adults or children | MAHA, thrombocytopenia, renal failure, and neurologic symptoms | III | 2C |
| Renal transplant-associated TMA | Endothelial damage due to calcineurin inhibitors and possibly other transplant-related factors | Renal transplant patients | MAHA, thrombocytopenia, and worsening or delayed graft function | NC | NC |
| Drug-associated TMA (drug-mediated TMA immune reaction or drug-mediated TMA toxic dose-related reaction) | See Table 3 | Adults or children | MAHA, thrombocytopenia, and renal failure | See Table 3 | See Table 3 |
| Malignancy-associated TMA | Coagulation cascade activation due to tumor tissue factor expression | Adults with cancer, predominantly adenocarcinomas | MAHA, thrombocytopenia, bone pain, respiratory symptoms, anorexia, and weight loss | NC | NC |
a Names in parentheses suggested by George and Nester for clarity.
TPE is a medical procedure whereby plasma is removed and replaced with a colloid or a combination of a colloid and crystalloid replacement fluid. The potential mechanisms of actions of TPE are numerous and vary according to the disease entity being considered. In the case of the TMA, possible mechanisms of action include the removal of pathologic antibodies, the removal of abnormal plasma proteins, and the replacement of absent or abnormal plasma proteins. The American Society for Apheresis (ASFA) provides guidance on the use of TPE in the treatment of many, but not all, of the TMA. The role of apheresis therapy in the treatment of a disorder is defined by the ASFA category, with the ASFA recommendation grade providing an indication of the strength of the recommendation to perform the procedure and the quality of the published evidence supporting the treatment. These ASFA categories and the ASFA recommendation grade are defined in Box 2 and Table 2 , respectively, and given for each disorder, where available, in Table 1 . Key considerations in using TPE to treat any disorder are listed in Box 3 and are again described for many of the TMA in the ASFA guidelines. This information is provided in the sections discussing the various TMA.
Strong recommendation: 1
Weak recommendation: 2
High-quality evidence (eg, randomized, double-blinded, controlled trials): A
Moderate-quality evidence (eg, controlled trials): B
Low- or very low-quality evidence (eg, case series or reports, expert opinion): C
| Category | Definition |
|---|---|
| I | Accepted first-line therapy, stand-alone or as an adjunct to other therapies |
| II | Second-line therapy, stand-alone or as an adjunct to other therapies |
| III | Optimum role of apheresis is uncertain, decision-making should be individualized based on each patient’s clinical situation |
| IV | Apheresis therapy ineffective or harmful |
- •
Volume of plasma exchanged
- •
Fluid used to replace the removed plasma
- •
Frequency of treatment
- •
Length of treatment
Thrombotic thrombocytopenic purpura (ADAMTS13 deficiency-mediated thrombotic microangiopathies)
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that carries a high risk of mortality if prompt treatment is not initiated. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a proteolytic enzyme that cleaves ultra-large von Willebrand factor multimers (UvWF) into smaller monomers. Congenital absence of ADAMTS13 or presence of an inhibitor leading to decreased activity level has been established as the underlying pathophysiology of TTP. UvWF circulate in the plasma and bind platelets leading to microthrombi in small blood vessels, resulting in clinical manifestations of TTP including MAHA, thrombocytopenia, renal failure, fever, and neurologic changes. When a patient presents with anemia and thrombocytopenia, an urgent evaluation is warranted to rule out TTP. Peripheral smear suggestive of MAHA and the presence of thrombocytopenia are sufficient indicators to initiate TPE according to current recommendations. Rock and colleagues demonstrated that TPE was superior to plasma infusion in TTP patients in a randomized trial. In cases whereby TPE is not available, plasma infusion should be used because equivalence has been demonstrated when large volumes of plasma are infused. However, these volumes carry a high risk of volume overload, particularly if the patient has developed renal failure from their TTP. ADAMTS13 level and inhibitor level are checked on the pre-TPE blood sample, because levels have important prognostic and diagnostic implications. Patients with undetectable ADAMTS13 levels at the initiation of TPE have a higher survival rate (82%) when compared with patients with detectable levels (46%), and patients with ADAMTS13 activity less than 10% have a higher risk of relapse. During TPE, ADAMTS13 is replaced, whereas inhibitory antibodies and UvWF are removed.
The usual treatment course, as recommended by ASFA, as well as criteria for discontinuing TPE is given in Box 4 . Of note, the disappearance of schistocytes is not a criterion for discontinuation of TPE because their presence or absence is not correlated with relapse. In addition, there is also no evidence supporting the superiority of abruptly discontinuing TPE versus weaning TPE once the criteria outlined in Box 4 have been achieved. TPE replacement fluid used must contain ADAMTS13 and have included fresh frozen plasma (FFP), thawed plasma, methylene blue–photoactivated plasma, solvent detergent-treated plasma, and plasma, cryoprecipitate reduced. del Rio-Garma and colleagues, however, found methylene blue–photoactivated plasma inferior to FFP. Theoretically, solvent detergent-treated plasma and plasma, cryoprecipitate reduced, because of reduced vWF, should offer benefits over FFP. A randomized trial, however, failed to demonstrate a benefit of plasma, cryoprecipitate reduced in patients with TTP at initial presentation.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
