Hereditary TTP acquired through liver transplantation: a case report

Abstract

A 62-year-old received an orthotopic liver transplantation. Three weeks later, thrombotic microangiopathy developed. Testing revealed thrombotic thrombocytopenic purpura (TTP) characterized by low ADAMTS13 activity and no inhibitor to ADAMTS13 protein. Retrospective attainment of donor records revealed a TTP diagnosis, without mention of inhibitor; presumably hereditary TTP (hTTP). As the graft liver does not produce ADAMTS13 protein, the recipient now functionally has hTTP and will likely need plasma transfusions indefinitely. While hTTP is extremely rare, it should be considered to be a contraindication to liver donation outside of exceptional circumstances, and if a potential liver donor has “TTP” listed on a medical history, attempts should be made to determine whether it is autoimmune or hereditary. An accurate medical history is critical as the only reliable way to identify hTTP, as outside of acute exacerbations of TTP, donors with hTTP can have normal laboratory values, including normal hemoglobin, platelets, and renal function.

Case report

A 62-year-old female with history of alcohol- related cirrhosis underwent orthotopic liver transplant from a deceased donor without surgical complications and good perfusion of the graft. Two days after surgery, she was diagnosed with stress-induced (Takotsubo’s) cardiomyopathy with an ejection fraction of 40%, and she was discharged 9 days after transplant (post-operative day [POD] +9). On the day of discharge, her hemoglobin was 8.8 g/dL, and platelets were 54×10³/microliter, similar to her baseline prior to surgery. Blood tests were monitored twice weekly thereafter; on POD +12, hemoglobin was 8.4 g/dL and platelets were 32 ×10³/microliter.

She was admitted POD+24 for expedited evaluation of abnormal blood tests characterized by elevated total bilirubin (2.5mg/dL) and direct bilirubin (0.7 mg/dL), hemoglobin of 5.8 g/dL and platelets of 48 ×10³/microliter. She was found to have schistocytes on peripheral smear, elevated LDH (758 u/L) and undetectable haptoglobin (<30mg/dL), consistent with a thrombotic microangiopathy (TMA). Prothrombin time and activated partial thromboplastin time were not prolonged, inconsistent with disseminated intravascular coagulopathy. As PLASMIC score¹ was 4, indicating a low-risk of thrombotic thrombocytopenic purpura (TTP), plasma exchange was not started; however, the ADAMTS activity level was sent to referral laboratory. The TMA was thought to be most likely related to tacrolimus, which was stopped. However, the TMA persisted despite cessation of tacrolimus, and 5 days later, platelets were 22 ×10³/microliter, and hemoglobin was 6.5 g/dL (Figure 1). Five days after admission, ADAMTS13 activity level returned <5%, and she was started on therapeutic plasma exchange (TPE). Testing for an inhibitor against ADAMTS13 returned negative (undetectable). After 2 days of TPE, platelets rapidly improved to 86 ×10³/microliter. TPE was continued, platelets normalized, LDH decreased, and haptoglobin became detectable. Eight days after discontinuation of TPE, thrombocytopenia recurred with evidence of TMA. Repeat ADAMTS13 activity level prior to TPE initiation again returned at <5%, with no inhibitor. A presumptive diagnosis of TTP acquired from liver donor was made. Therefore, the patient was restarted on TPE with improvement in the TMA. Patient has since transitioned to maintenance fresh frozen plasma (FFP) transfusions to prevent a TMA relapse.

Figure 1:

Platelet and hemoglobin trend following liver transplant

Donor health information was re-reviewed and confirmed that the donor had TTP as listed on his medical history. It did not specify the type of TTP. Upon request for additional medical records for the donor, it was noted that he had received FFP periodically throughout his life. There was no mention of inhibitor or autoimmune TTP, and therefore, we presume that the donor had hereditary TTP. The donor’s cause of death was listed as intracerebral hemorrhage (ICH); limited results obtained from donor’s terminal admission show a platelet nadir of 12 ×10³/microliter (from 157) and hemoglobin of 9.1 g/dL (from 15.2), suggesting ICH and death were likely due to a TTP exacerbation.

Discussion

TTP has two distinct subtypes: (1) immune TTP, in which an acquired inhibitor to the ADAMTS13 protein leads to reduced ADAMTS13 activity, and (2) hereditary TTP, caused by mutations in the ADAMTS13 gene, which results in severely reduced activity of ADAMTS13 protein. Clinicians treating adults are much more likely to encounter acquired TTP; in adults, hTTP is estimated to represent <5% of all TTP cases.

Hereditary TTP is an extremely rare disease, with an estimated prevalence of about 1 per million persons. The ADAMTS13 protease is responsible for cleaving ultra-large von Willebrand factor (UL-VWF) in order to regulate its interaction with platelets. Without cleavage in setting of ADAMTS13 deficiency, UL-VWF can lead to thrombosis, which can cause organ ischemia, neurologic abnormalities, kidney dysfunction and thrombotic microangiopathy (TMA), consisting of microangiopathic hemolytic anemia and thrombocytopenia. While TTP is often thought of as a “platelet problem”, instead it is a deficiency of a coagulation protein, with a secondary consequence of thrombocytopenia in the setting of TMA.

Patients with hTTP are at risk for “exacerbations”, particularly in times of physiological stressors, wherein there is an acute increase in disease severity leading to life-threatening TMA and ischemic events. Exacerbations of hTTP have identical clinical features and similar laboratory findings to acquired TTP, with risk of macro and microthrombosis, evidence of TMA, and low ADAMTS13 activity levels. The only test that distinguishes hereditary from acquired TTP is the ADAMTS13 inhibitor, which is absent (normal) in hTTP and present (abnormal/elevated) in acquired TTP. If there is uncertainty, an ADAMTS13 inhibitor result is needed to define the type of TTP. While most cases of hTTP are diagnosed in earlier age, with a median age of diagnosis at 16.7 years,² a later age at presentation does not eliminate the possibility of hTTP, and an earlier presentation does not eliminate an autoimmune/acquired TTP.

Outside of episodic exacerbations, patients with hTTP have normal blood counts and no hemolysis, and therefore normal laboratory values alone at time of potential donation are not sufficient. Instead, careful attention should be paid to a medical history that lists TTP: if a potential donor has TTP, then efforts should be made to understand whether the disease is congenital or acquired prior to accepting a donor liver.

In our case, the engrafted liver cells carry the ADAMTS13 hTTP gene mutation, and therefore are unable to produce the ADAMTS13 protein. Our patient received 7 units of FFP and 2 units of cryoglobulin during the transplant surgery, both sources of ADAMTS13, in addition to her baseline circulating levels. Post-operatively, the engrafted liver failed to synthesize ADAMTS13, and with half-life of 2–3 days,³ the accumulated ADAMTS13 protein declined to undetectable levels, leading to TMA that developed approximately 3 weeks post-operative. Our previously unaffected patient now functionally has hTTP and will be dependent on regular FFP transfusions to provide ADAMTS13 protein in attempt to prevent hTTP-associated complications.

Discussions have been raised about whether to perform a second transplant for the patient; considerations to weigh include (1) the liver graft is otherwise functioning well, (2) repeat surgery carries risks of surgical complications and potential for graft failure, and (3) life-long hTTP carries a risk of life-threatening thrombotic complications, a potential for plasma reactions, and may increase healthcare utilization.

To the best of our knowledge, this represents the first report of hTTP arising from liver transplantation. We present this case to increase awareness of hTTP, and while extremely rare, livers from donors with hTTP should be used only under exceptional circumstances and with fully informed recipient consent regarding risk of morbidity and mortality with hTTP and need for life-long plasma transfusions to prevent exacerbations. (Of note, hTTP would not be a contraindication to other organ donations.) Collaboration with United Network of Organ Sharing is ongoing to prevent future liver donation from patients with hTTP.

Abbreviations:

ADAMTS13

ADAM metallopeptidase with thrombospondin type 1 motif 13

TTP

thrombotic thrombocytopenic purpura

hTTP

hereditary thrombotic thrombocytopenic purpura

POD

post-operative day

TMA

thrombotic microangiopathy

ICH

intracerebral hemorrhage

UL-VWF

ultra-large von Willebrand factor

FFP

fresh frozen plasma