Understanding Thrombotic Microangiopathy: A Case Based Approach
- caitlinraymondmdphd
- Jan 11
- 8 min read
Updated: Feb 8
Case Introduction
A 27-year-old man presents with chronic granulomatous disease (CGD). CGD is a collection of inherited immune deficiencies in which phagocytes, particularly neutrophils, are unable to generate reactive oxygen species and kill certain types of bacteria and fungi due to mutations in the NADPH oxidase enzyme complex. The definitive treatment for CGD is a stem cell transplant from a healthy donor to replace the phagocyte lineage with functioning cells. In this case, our patient presents for gene therapy in which his own stem cells are collected, genetically modified to be able to produce normal NADPH oxidase, and then reinfused.
We first meet our patient about a month after his gene therapy while he is still battling multiple chronic fungal infections related to his underlying CGD. We see he underwent myeloablative conditioning, which means he received high doses of chemotherapy to complete remove all his blood cells before he received the new, genetically modified stem cells. It’s important to note that myeloablative conditioning causes more toxicity to the patient, which we will come back to later.
Looking in his chart, we see that that the new stem cells seemed to have found a home in his bone marrow because his red blood cells and platelets initially recovered. However, over the past week, he has experienced worsening anemia and thrombocytopenia. We also see elevated hemolysis markers, up-trending BUN and creatinine, and normal coagulation tests. Finally, the team performed a peripheral smear and found schistocytes.
What is this all suspicious for? Why thrombotic microangiopathy (TMA)!
What is TMA?
TMA is fundamentally a disorder of endothelium and primarily affects small blood vessels and capillaries. In TMA, damaged endothelium acts as a nexus for the accumulation of platelet-rich microthrombi which function as a physical barrier and cause mechanical destruction of red blood cells, resulting in the hallmark schistocytes seen in this disorder. This mechanical hemolytic anemia results in the classic laboratory values of TMA – low hemoglobin and undetectable haptoglobin, with elevated bilirubin and LDH. The build up of the toxic byproducts combined with reduced flow through capillary beds leads to end organ damage, particularly of the kidneys which are especially vulnerable to excess free hemoglobin. For this reason, TMA is often associated with kidney injury or failure.
Pathophysiology of TMA
There are number of pathways through which TMA can occur, which can be generally grouped into ADAMTS13 deficiency, inappropriate complement activation, Shiga toxin, and inappropriate coagulation activation.
ADAMTS13 Deficiency: ADAMTS13 is an enzyme that cleaves von Willebrand factor (vWF) multimers into a ‘goldilocks’ size: neither too big nor too small. Absence or deficiency of ADAMTS13, either through an inherited defect or the acquisition of an autoantibody, leads to the accumulation of large vWF multimers, which then bind to platelets and result in the development of platelet rich microthrombi. Also known as thrombotic thrombocytopenic purpura (TTP), ADAMTS13 deficiency has a mortality rate of ~90% without treatment; thus, when it is suspected treatment must be initiated immediately. Suspicion of TTP is a hematologic emergency.
Inappropriate Complement Activation: systemic endothelial injury leads to systemic complement activation and increased soluble C5b-9 levels. Pathologically activated complement then interacts with damaged endothelium, eventually leading to platelet activation and the accumulation of platelet rich microthrombi.
Shiga Toxin: Shiga or Shiga-like toxin released by microorganisms enters cells and irreversibly inhibits protein synthesis by damaging the ribosome, ultimately resulting in cell death. Endothelium anywhere in the body can be damaged by these toxins, resulting in complement activation and the generation of platelet rich microthrombi in a similar fashion to the above; however, the endothelium of the kidney is particularly prone to damage following exposure to Shiga or Shiga-like toxin, resulting in the hallmark renal failure of hemolytic uremic syndrome (HUS).
Inappropriate Coagulation Activation: While inappropriate complement activation is a well-characterized underlying cause of TMA, inappropriate coagulation activation can also result in platelet-rich microthrombi in small vessels. Coagulation-mediated TMA is much rarer, usually resulting from genetic mutations in coagulation regulators, and typically presents in young children.
Causes of TMA
Most TMA is secondary to systemic endothelial injury, which can be from a variety of sources. Examples include HELLP syndrome in pregnancy, malignant hypertension, infections, malignancy, some classes of drugs, and stem cell transplant. Primary causes of TMA are less frequent, but when present typically arise from either acquired autoantibodies to ADAMTS13, resulting in ADAMTS13 deficiency, or acquired autoantibodies to complement regulators, resulting in inappropriate complement activation. In rare cases, ADAMTS13 or complement regulator deficiency can arise from inherited genetic disorders.
Differential Diagnosis of This Case
In the case we present above, a 27-year-old man underwent a transplant with his own stem cells after genetic modification. To prepare for this transplant, he received an intensive chemotherapy regimen, and in the wake of his transplant he develops signs and symptoms of TMA. We discussed that stem cell transplants are associated with TMA, and this entity is formally known as Transplant Associated TMA, or TA-TMA, which we discuss in further detail below. However, because ADAMTS13 deficiency/TTP cannot be immediately ruled out, and because the mortality rate is so high, this must also be considered in the differential.
What is TA-TMA?
Unfortunately, diagnostic criteria for TA-TMA vary, and moreover this entity exists in a spectrum of other transplant associated syndromes involving damage to the endothelium, making TA-TMA difficult to recognize and diagnose. While current estimates are that TA-TMA occurs in ~8% of all stem cell transplants, this is likely an under-estimate and the true prevalence of TA-TMA is unknown.
Pathophysiology of TA-TMA
Current literature suggests that TA-TMA is likely a multifactorial process involving multiple hits. First, there is likely an underlying predisposition through either pre-existing systemic complement activation or systemic endothelial injury. Second, this underlying predisposition is exacerbated by a toxic conditioning regimen, such as the intensive, myeloablative chemotherapy that our patient underwent. Finally, the third hit is infection. Infections are common in the peri-transplant period while patients have additional immunosuppression, and in the case of our patient, he had multiple chronic infections from his underlying CGD.
Studies are also elucidating additional factors that may impact the development of TA-TMA following a stem cell transplant. For example, there is some evidence that acquisition of complement regulator variants from a donor may increase risk of TA-TMA, although this does not apply to our patient as his transplant was autologous. Research has also found a higher rate of TA-TMA in cases with co-morbid graft versus host disease, indicating that the course of the transplant itself may influence the health of endothelial cells and the development of TA-TMA. Finally, there are factors specific to the recipient that influence TA-TMA. Studies have found that recipients with the HLA-DRB1*11 allele have better outcomes if they do develop TA-TMA.
Treatment for TA-TMA
Eculizumab
There is a diversity of treatments for TA-TMA that target different aspects of the pathophysiology, and in some cases overlap with treatment for the spectrum of endothelial disorders that can arise in the peri-transplant setting. Despite all this diversity, most experts agree that eculizumab, a monoclonal antibody that neutralizes C5 and thus inhibits complement activation, is a mainstay of treatment for TA-TMA. In most institutions, the regimen for TA-TMA will include eculizumab, although this may be in the setting of other drugs or treatment modalities.
TPE in TA-TMA
Therapeutic plasma exchange (TPE) is not a mainstay of treatment for TA-TMA. In fact, some studies report worse outcomes in patients with TA-TMA who have undergone a course of TPE, although there may be a role for TPE if TA-TMA occurs in the setting of autoantibodies to complement regulators. These cases are rare, and currently guidelines recommend that TPE be deferred until such autoantibodies can be definitively identified by laboratory methods.
Treatment for TTP
First Line
Unlike TA-TMA, TPE is a first-line therapy for TTP. Through TPE, autoantibodies to ADAMTS13 and large vWF multimers are removed, while the infusion of donor plasma restores some functional ADAMTS13. Generally, a course of daily 1.0 volume TPE with plasma as a replacement fluid is started on an emergent basis when TTP is suspected, given the extremely high mortality rate of untreated TTP. Steroids also have a role to dampen the immune response and inhibit further production of autoantibodies.
Emerging
While TPE and steroids remain first-line, there have been advancements in therapy for TTP. Recent evidence suggests a role for early rituximab, a monoclonal antibody to CD20 that results in the removal of antibody-producing B-cells. While rituximab was previously used in refractory cases of TTP, studies have found earlier remission and significant reductions in relapses over a 10-year follow-up when rituximab is utilized early in the disease course – within 3 days of symptoms onset.
There is also a newer antibody-based treatment for TTP: caplacizumab. This drug is not a traditional monoclonal antibody but is a modified version of a camelid antibody. Found only in the Camelid family of mammals, camelid antibodies are a unique type of immunoglobulin that are smaller and more maneuverable than traditional monoclonal antibodies. Because these molecules can fit into tight spaces, they act as excellent neutralizing agents. Caplacizumab is specific for the A1 domain of vWF, through which vWF binds platelets. By neutralizing the A1 domain, the accumulation of platelets on large multimers of vWF and the development of platelet-rich microthrombi is prevented. Caplacizumab was shown to reduce time to remission but remains prohibitively expensive for most institutions to carry in their formulary.
Wrap Up of the Case
In our case, the patient develops signs and symptoms of TMA following an autologous transplant with genetically modified stem cells. The leading diagnosis is TA-TMA, but TTP cannot be initially ruled out. To work up TTP, a sample to test for ADAMTS13 activity is drawn. It is critical to draw this sample BEFORE any donor plasma enters the patient, as donor plasma will falsely increase the ADAMTS13 activity level. Because TTP is a rare entity, most hospitals don’t have ADAMTS13 activity levels performed in house but rather send them out; thus, it can take several days for the results to return and provide insight on the likelihood of TTP.
While awaiting the ADAMTS13 activity level results it is standard to perform a short course of TPE. In the case of our patient, coordination of the staff and materials to perform TPE took about 12 hours, and this is not uncommon across institutions. However, an initial delay in TPE does not prohibit any treatment at all. In such instances, a simple plasma transfusion can help restore ADAMTS13 activity and prevent mortality while awaiting definitive therapy. In the case of our patient, he did receive an infusion of 2 units of FFP prior to his first full TPE.
Additional work-up to assess the likelihood of TA-TMA was also performed. First, levels of complement proteins were assayed. In general, levels of complement protein are significantly elevated in TA-TMA and other forms of complement mediated TMA. Soluble levels of C5b-9, and plasma levels of C3b and Ba, can all provide insight on the activity of the complement system. However, these assays simply measure levels and do not determine function. While rarely performed, the CH50 assay will provide functional information on the complement system. In the CH50 assay, patient serum is added to sheep red blood cells that are coated in antibody. The amount of RBC lysis is then measured, with higher levels of lysis indicating excessive complement activity. In the case of our patient, complement levels were elevated, and a CH50 assay was not performed.
After 2 sessions of daily TPE, our patient’s ADAMTS13 result returned as normal (ADAMTS13 activity > 70%). Because further TPE could produce worse outcomes in the likely diagnosis of TA-TMA, no further TPE was performed. Instead, the patient was started on regimen of eculizumab and slowly began to improve. After an additional week in the ICU, he was discharged to the floor.
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