Thrombotic microangiopathy (TMA)
Synonyms
Thrombotic thrombocytopenic purpura (TTP); hemolytic uremic syndrome (HUS)
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Related conditions
Renal failure
Drug toxicity
1. Description of the problem
Thrombotic microangiopathy (TMA) after allogeneic SCT can result from many causes, including the use of calcineurin inhibitors (CNI) (most common), high-dose chemotherapy or radiation, or infections. The clinical spectrum for the TMA varies from biochemical evidence of intravascular hemolysis, hemolytic uremic syndrome (which results primarily in renal failure) and fulminant TTP with multi-system involvement, which is frequently fatal.
TMA results in occlusion of the vasculature by platelet aggregates, leading to mechanical shear and red cell fragmentation and hemolysis. This occlusion leads to tissue ischemia and organ damage. The hallmarks of these syndromes are visual and biochemical evidence of hemolysis with schistocytes on a blood smear, and an elevated and rising LDH with a low haptoglobin.
Clinical features
HUS: Presents with evidence of intravascular hemolysis, thrombocytopenia, and organ damage restricted to the kidney with renal failure. Schistocytes are noted on the peripheral blood smear, the LDH and indirect bilirubin are elevated due to red blood cell hemolysis and tissue ischemia, and the haptoglobin is typically low.
TTP: Presents with evidence of intravascular hemolysis, thrombocytopenia, with ischemic damage that can occur in any organ. Schistocytes are noted on the peripheral blood smear, the LDH and indirect bilirubin are elevated due to red blood cell hemolysis and tissue ischemia, and the haptoglobin is low. Clinically, the classic pentad of findings in TTP includes microangiopathic hemolytic anemia, thrombocytopenia, fever, renal dysfunction, and neurologic abnormalities. Most patients, however, will not have all of these abnormalities. Patients may experience fevers, severe hypertension, progressive renal failure, transaminase elevation, pancreatitis with abdominal pain, respiratory or cardiac symptoms, neurologic symptoms such as headaches, confusion, and ultimately seizures and coma.
Key management points
TMA related to CNI (cyclosporine, tacrolimus): TMA related to CNI is often associated with high levels but can occur soon after initiation of these drugs even with normal levels. CNI should be discontinued once a diagnosis is made. Substituting corticosteroids or other agents for GVHD prevention and treatment is reasonable. It is not known if corticosteroids will have a benefit in treating TMA. Once the signs and symptoms resolve, it is occasionally possible to start an alternative calcineurin inhibitor maintaining adequate levels without recurrent TMA. However, this must be done with extreme caution.
TMA related to conditioning therapy: This is a rare complication often difficult to diagnose resulting from vascular damage from high-dose radiation or chemotherapy. The course is often progressive with no specific therapy. Transfusion support and managing organ toxicity with meticulous supportive care is imperative.
TMA related to infection: TMA related to systemic infection such as CMV is possible. CMV in particular can damage endothelial cells. Management is primarily viral-specific therapy.
TMA/TTP: Fulminant TTP resulting in multi-organ failure from any cause is difficult to treat after allogeneic stem cell transplantation. Maximizing treatment for underlying processes such as infections, GVHD, and other causes is necessary. Patients are treated similar to patients with TTP in other clinical situations with plasma exchange, though this approach is somewhat controversial as reported response rates are low.
2. Emergency Management
1. Discontinue calcineurin inhibitors for patients receiving them.
2. Control hypertension.
3. Treat any underlying infection, GVHD, or other medical problem as appropriate.
4. Avoid nephrotoxic and hepatotoxic agents.
5. Consider plasma exchange for patients with multi-organ involvement.
3. Diagnosis
A diagnosis of TMA is often difficult to make after transplant given that these patients may have many complications mimicking TMA. Different diagnostic criteria have been developed but generally include most of the following:
1. Visual evidence of intravascular hemolysis with >/= 2 schistocytes per high-power field or > 4% schistocytes in the blood with no other obvious cause of hemolysis (i.e., Coombs test negative)
2. New or worsening thrombocytopenia
3. Increasing and elevated LDH
4. Decreased hemoglobin or platelets, or an increase in transfusion requirements
5. Decrease in serum haptoglobin
6. Increased indirect bilirubin
7. Concurrent renal and/or neurologic abnormalities with no other obvious explanation
The diagnosis is often difficult to make and hard to distinguish from other entities. The patient who has evidence of intravascular hemolysis (schistocytes, rising LDH, elevated indirect bilirubin, low haptoglobin) with renal failure, severe hypertension, neurologic symptoms, or other organ damage should be suspected of having TMA and treated accordingly.
Differential diagnosis
Ruling out other causes is critical to making a diagnosis of TMA.
Anemia and thrombocytopenia are common after allogeneic stem cell transplantation. This may be chemotherapy-related, due to bleeding, related to infection, caused by myelosuppression from drug therapy, immune-mediated, or many other causes.
Renal failure is common after allogeneic stem cell transplantation associated with drug toxicity (in particular CNI), infection, volume depletion, and other causes. A direct relationship to TMA is often difficult to identify.
Fevers are common with TTP but are quite common from many causes in transplant patients. Detailed investigations for infectious sources are necessary.
Neurologic complications after allogeneic stem cell transplantation may be due to drug toxicity (such as CNI and posterior reversible leukoencephalopathy syndrome [PRES]), infection, hypertension, bleeding, or other complications.
Confirmatory tests
Review of the peripheral blood smear and biochemical testing for LDH and haptoglobin are necessary. In classic TTP very low levels of ADAMTS-13 protein are thought to be the major etiology in TTP; however, after allogeneic stem cell transplantation ADAMTS-13 levels are often decreased but not extremely low. Therefore ADAMTS-13 testing may not be useful.
4. Specific Treatment
1. Discontinue CNI for patients receiving them.
2. Control hypertension.
3. Treat any underlying infection, GVHD, or other medical problem as appropriate.
4. Avoid nephrotoxic and hepatotoxic agents.
5. Consider plasma exchange for patients with multi-organ involvement.
Daily plasmapheresis and plasma exchange should be considered until it is clear the patient is not responding to therapy. Most patients respond within several days.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
Most patients respond within several days. Thrombocytopenia and anemia (or transfusion requirements) are often improved. The LDH decreases and the haptoglobin increases. For patients with normal bone marrow function, a reticulocyte count should be elevated during intravascular hemolysis.
Alternative diagnoses
There is no absolute diagnostic test for TMA. One should always consider alternative diagnoses, particularly when patients are not responding after several days.
Patients with TMA related to CNI should respond to withdrawal of CNI within several days.
Patients with TTP should respond to plasma exchange within a few days if they are going to respond.
Patients with TMA related to CMV should improve with adequate treatment of infection.
Follow-up
The patient should receive routine appropriate follow-up with daily blood counts, transfusion support, treatment of underlying contributing disorders, and avoidance of CNI if appropriate.
Pathophysiology
TMA after allogeneic stem cell transplant is a heterogeneous group of disorders ranging from HUS to fulminant TTP. Unlike classic TTP that is associated with low levels of ADAMTS-13 protein (leading to spontaneous platelet aggregation), the patient with post-transplant TMA usually has reduced but not extremely low levels of ADAMTS-13. The unifying cause of post-transplant TMA, regardless of specific etiology, is endothelial damage. This may be caused by medications such as calcineurin inhibitors, high-dose radiation with the conditioning therapy, infection, or GVHD. The endothelial damage promotes platelet aggregation, leading to vascular occlusion and mechanical red blood cell hemolysis. The resulting tissue ischemia results in organ damage.
The mechanism of HUS/TTP associated with calcineurin inhibitors is felt to be due to increased production of thromboxane A2 and decreased production of PGI2 combined with direct toxicity to the endothelium. Sirolimus is felt to potentiate these effects when used in combination with a calcineurin inhibitor. This leads to a procoagulant state on the endothelium and secondary microangiopathy.
Epidemiology
The incidence of post-transplant TMA varies widely between 0% to 90%. This wide variation is in part related to difficulty in making the diagnosis and the unclear definition of these syndromes. A practical estimate is that approximately 8% of transplant patients experience post-transplant TMA.
Risk factors for TMA have included older age, advanced disease, use of an unrelated donor, high-dose radiation as part of the conditioning therapy, use of calcineurin inhibitors, infections (particularly CMV and possibly HHV6) and GVHD.
Prognosis
Patients with HUS often improve when the offending agent, such as calcineurin inhibitors, is discontinued.
Patients with TTP have a poor prognosis and a lower response rate to interventions such as plasma exchange compared to other patients with TTP. While mortality estimates are difficult given the lack of definitive diagnostic criteria, the median mortality has been estimated at approximately 6-75% within 3 months of the diagnosis.
Special considerations for nursing and allied health professionals.
Careful management to avoid nephrotoxins and hepatotoxins is critical.
What's the evidence?
George, JN, Li, X, McMinn, JR, Terrell, DR, Vesely, SK, Selby, GB. “Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma”. Transfusion.. vol. 44. 2004. pp. 294-304. This is one of the most comprehensive reviews on all published series of HUS or TTP after allogeneic stem cell transplantation up to 2004.
Ho, V, Cutler, C, Carter, S. “Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus summary: Thrombotic microangiopathy after hematopoietic stem cell transplantation”. Biol Blood Marrow Transplant.. vol. 11. 2005. pp. 571-575.. This provides an up-to-date summary on the features and therapy for post-transplant microangiopathy and suggests an updated definition for a diagnosis of thrombotic microangiopathy after transplant.
Batts, E, Lazarus, H. “Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting?”. Bone Marrow Transplantation. vol. 40. 2007. pp. 709-719. An excellent up-to-date review on the diagnostic criteria, pathophysiology, prognosis, and treatment of post-transplant thrombotic microangiopathy.
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