Summary of the differential diagnosis and treatment of thrombotic microangiopathies
| Condition . | Comments . | Summary of treatment . |
|---|---|---|
| TTP | Diagnosis confirmed by severe ADAMTS13 deficiency | PEX, immune suppression including rituximab (or CD20 monoclonal antibody therapy) |
| Immune mediated | Presence of antibodies to ADAMTS13 | Newer therapies under investigation include nanobodies and recombinant protein |
| Secondary to an underlying precipitant | Antibody mediated, but precipitating event identified on investigation | Congenital TTP requires replacement of missing enzyme, eg, with plasma infusion |
| Congenital TTP | Typically in pregnancy, but infection/neonatal period may be associated with younger diagnoses | In secondary TTP, requires treatment of underlying condition as well as TTP therapy |
| HUS | Diagnosis of exclusion Genetic analysis may confirm complement mutations | STEC/IA-HUS: confirm by serology/PCR |
| Complement mediated | Exclude STEC- and non-STEC-causing HUS presenting up to 7 days following hemorrhagic colitis, confirm by serology/PCR but also pneumococcus, HIV and viral associated | Pneumococcus: supportive treatment including antibiotics and washed blood products |
| Infection associated | Cobalamin C (Cbl-C) deficiency is a rare cause in neonates/childhood associated with | B12 and folic acid for Cbl-C deficiency |
| Secondary HUS | Eculizumab for CM-HUS | |
| DIC | Thrombocytopenia is often the initial feature Coagulation abnormalities are variable, but associated low fibrinogen suggests severity | Treat underlying precipitant Supportive blood products for active bleeding (anticoagulation if thrombosis) |
| Sepsis; malignancy; trauma; hematological disorders, eg, acute myeloid leukemia; obstetric complications | ||
| B12 deficiency | Anemia, reticulocytosis, and thrombocytopenia, but typical MAHA features not present | Careful review of blood film |
| Vitamin B12 replacement | ||
| Cancer | TMA maybe the initial feature of a cancer presentation or in relation to drugs required to treat active cancer | No role for PEX |
| May represent bone involvement | Treat underlying disease | |
| Usually adenocarcinomas or hematological malignancies | No contraindication to platelet transfusions in thrombocytopenia | |
| TA-TMA | Results from endothelia cell damage, from underlying conditioning therapies, immunosuppressives, or complications relating to the transplant, eg, graft-versus-host disease | No role for PEX |
| Symptomatic therapy | ||
| Reduce or stop offending drugs | ||
| Question role for complement inhibitor therapy | ||
| DA-TMA | A number of drugs very rarely associated with antibody-mediated TTP | No proven role for PEX, unless antibody-mediated ADAMTS13 deficiency confirmed |
| Chemotherapy and newer specific treatments, eg, vascular endothelial growth factor inhibitors, associated with an HUS-type picture | Question role for complement inhibitor therapy | |
| Underlying pathophysiology may be varied | ||
| Autoimmune disease/vasculitis | A variety of autoimmune/vasculitic conditions may present as a trigger to TTP/HUS or may have MAHAT features, but with normal ADAMTS13 levels | PEX if associated with low (<10%) ADAMTS13 activity levels |
| Relevant immunology investigations +/− biopsy will confirm | Immunosuppressive therapy depending on results of further investigations | |
| Question role of complement inhibitor therapy, eg, in anti-phospholipid syndrome | ||
| Infections | May precipitate TTP or HUS | Supportive care |
| Viral-, bacterial-, or atypical/fungal-associated damage to endothelia cells | Treat underlying infection following confirmation by serology, culture, or PCR | |
| Malignant hypertension | May be primary or in association with a specific disorder, eg, IgA nephropathy | Symptomatic treatment |
| Cannot reliably differentiate from CM-HUS, especially if normal renal size on radiological examination and no chronic features of high blood pressure, eg, on ophthalmic examination | If pathogenesis is unclear, consider a trial of complement inhibitor therapy | |
| Renal biopsy if possible to help differentiate | ||
| Pregnancy | ||
| TMA precipitated by pregnancy | TTP or CM-HUS | PEX and complement inhibitor therapy if CM-HUS |
| Pregnancy-associated TMA | PET/HELLP: delivery usually helps resolution, but with progressive symptoms/worsening laboratory parameters, consider TTP or HUS | Control blood pressure, deliver baby if severe |
| Condition . | Comments . | Summary of treatment . |
|---|---|---|
| TTP | Diagnosis confirmed by severe ADAMTS13 deficiency | PEX, immune suppression including rituximab (or CD20 monoclonal antibody therapy) |
| Immune mediated | Presence of antibodies to ADAMTS13 | Newer therapies under investigation include nanobodies and recombinant protein |
| Secondary to an underlying precipitant | Antibody mediated, but precipitating event identified on investigation | Congenital TTP requires replacement of missing enzyme, eg, with plasma infusion |
| Congenital TTP | Typically in pregnancy, but infection/neonatal period may be associated with younger diagnoses | In secondary TTP, requires treatment of underlying condition as well as TTP therapy |
| HUS | Diagnosis of exclusion Genetic analysis may confirm complement mutations | STEC/IA-HUS: confirm by serology/PCR |
| Complement mediated | Exclude STEC- and non-STEC-causing HUS presenting up to 7 days following hemorrhagic colitis, confirm by serology/PCR but also pneumococcus, HIV and viral associated | Pneumococcus: supportive treatment including antibiotics and washed blood products |
| Infection associated | Cobalamin C (Cbl-C) deficiency is a rare cause in neonates/childhood associated with | B12 and folic acid for Cbl-C deficiency |
| Secondary HUS | Eculizumab for CM-HUS | |
| DIC | Thrombocytopenia is often the initial feature Coagulation abnormalities are variable, but associated low fibrinogen suggests severity | Treat underlying precipitant Supportive blood products for active bleeding (anticoagulation if thrombosis) |
| Sepsis; malignancy; trauma; hematological disorders, eg, acute myeloid leukemia; obstetric complications | ||
| B12 deficiency | Anemia, reticulocytosis, and thrombocytopenia, but typical MAHA features not present | Careful review of blood film |
| Vitamin B12 replacement | ||
| Cancer | TMA maybe the initial feature of a cancer presentation or in relation to drugs required to treat active cancer | No role for PEX |
| May represent bone involvement | Treat underlying disease | |
| Usually adenocarcinomas or hematological malignancies | No contraindication to platelet transfusions in thrombocytopenia | |
| TA-TMA | Results from endothelia cell damage, from underlying conditioning therapies, immunosuppressives, or complications relating to the transplant, eg, graft-versus-host disease | No role for PEX |
| Symptomatic therapy | ||
| Reduce or stop offending drugs | ||
| Question role for complement inhibitor therapy | ||
| DA-TMA | A number of drugs very rarely associated with antibody-mediated TTP | No proven role for PEX, unless antibody-mediated ADAMTS13 deficiency confirmed |
| Chemotherapy and newer specific treatments, eg, vascular endothelial growth factor inhibitors, associated with an HUS-type picture | Question role for complement inhibitor therapy | |
| Underlying pathophysiology may be varied | ||
| Autoimmune disease/vasculitis | A variety of autoimmune/vasculitic conditions may present as a trigger to TTP/HUS or may have MAHAT features, but with normal ADAMTS13 levels | PEX if associated with low (<10%) ADAMTS13 activity levels |
| Relevant immunology investigations +/− biopsy will confirm | Immunosuppressive therapy depending on results of further investigations | |
| Question role of complement inhibitor therapy, eg, in anti-phospholipid syndrome | ||
| Infections | May precipitate TTP or HUS | Supportive care |
| Viral-, bacterial-, or atypical/fungal-associated damage to endothelia cells | Treat underlying infection following confirmation by serology, culture, or PCR | |
| Malignant hypertension | May be primary or in association with a specific disorder, eg, IgA nephropathy | Symptomatic treatment |
| Cannot reliably differentiate from CM-HUS, especially if normal renal size on radiological examination and no chronic features of high blood pressure, eg, on ophthalmic examination | If pathogenesis is unclear, consider a trial of complement inhibitor therapy | |
| Renal biopsy if possible to help differentiate | ||
| Pregnancy | ||
| TMA precipitated by pregnancy | TTP or CM-HUS | PEX and complement inhibitor therapy if CM-HUS |
| Pregnancy-associated TMA | PET/HELLP: delivery usually helps resolution, but with progressive symptoms/worsening laboratory parameters, consider TTP or HUS | Control blood pressure, deliver baby if severe |