VISUALem

Case Report of Thrombotic Thrombocytopenic Purpura

in a Previously Healthy Adult
Jessica L Sea, PhD*, Stephen F Gassner, MD, MPH* and Jonathan Smart, MD*
*
University of California, Irvine, Department of Emergency Medicine, Orange, CA
Correspondence should be addressed to Jon Smart, MD at jsmart1@[Link]
Submitted: July 23, 2020; Accepted: October 23, 2020; Electronically Published: January 15, 2021; [Link]
Copyright: © 2021, Sea et al. This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See:
[Link]

ABSTRACT:
This case report details the presentation of a 24-year-old male presenting with headache, palpitations,
gingival bleeding, and pallor. The ultimate diagnosis of thrombotic thrombocytopenic purpura (TTP) is a rare
but life-threatening condition which is typically hallmarked by thrombotic microangiopathy (TMA) and
dysfunctional ADAMTS13 enzymatic activity. This patient displayed classically described findings, including
marked anemia, thrombocytopenia, and acutely elevated creatinine as well as a brief period of newly onset
word-finding difficulty while in the emergency department. His diminished ADAMTS13 activity level (<5%)
and the presence of autoantibodies against ADAMTS13 confirmed a diagnosis of TTP. Fortunately, the
patient's outcome was favorable after treatment with plasmapheresis, prednisone, and rituximab. This case
report provides a review of the clinical presentation, diagnostic criteria, potentially confounding differential
diagnosis, and expected course of treatment for patients with TTP.

Topics: Thrombotic thrombocytopenic purpura (TTP), ADAMTS13, anemia.

Sea JL, et al. Case Report of Thrombotic Thrombocytopenic Purpura in a Previously Healthy Adult. JETem
2021. 6(1):V1-4. [Link]
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Introduction: reddish-brown, which he then reported had been similarly
Thrombotic thrombocytopenic purpura (TTP) is a rare, life- discolored for the past 7 days.
threatening thrombotic microangiopathy (TMA) often occurring
in adulthood with a sudden, unpredictable onset.1 A complete blood count and metabolic panel revealed an
Deficiency of ADAMTS13 enzyme activity represents the central elevated anion gap metabolic acidosis, severe anemia,
feature of TTP and is traditionally attributed to either a thrombocytopenia, and acute renal injury. The patient’s blood
congenital or acquired condition. Congenital TTP (cTTP) may urea nitrogen (BUN; 27mg/dL) and serum creatinine (1.4 mg/dL)
result from one of more than a hundred well-characterized levels were elevated, and his serum HCO2 was low (21mmol/L)
gene mutations; whereas, acquired or immune-mediated TTP with an anion gap of 14. The patient’s hemoglobin (4.7 G/DL),
(iTTP) is an acute immunologically mediated episode hematocrit (14.2%), platelet count (10,000/mcl), and
hallmarked by autoantibodies targeting ADAMTS13. Antibodies haptoglobin (<30 mg/dL) were all severely decreased while his
against ADAMTS13 have long been thought to be either LDH (1885 U/L) and indirect bilirubin (3.2 mg/dL) were
inhibitory or non-inhibitory, thus limiting the enzyme's activity significantly elevated. A peripheral blood smear (image) also
or resulting in severe enzyme deficiency, respectively. Recent revealed an abnormally high reticulocyte count (18.7%) and
research suggests both types of antibodies likely function to presence of schistocytes. When taken these findings together
accelerate clearance of ADAMTS13 leading to diminished or with the significantly elevated LDH, diminished hemoglobin,
undetectable levels in circulation.2 and nearly undetectable haptoglobin, a hemolysis picture was
supported. Direct antiglobulin test (DAT) was negative;
While recent studies have increased our understanding of the decreasing the likelihood of autoimmune-mediated hemolytic
mechanism, less is known about specific stimuli that trigger anemia. As prothrombin time (PT; 15.2 sec), partial
acute episodes of iTTP. Associations have been made between thromboplastin time (PTT; 30.2 sec), and INR (1.2) were only
iTTP and connective tissue disorders, pregnancy, certain forms slightly abnormal, TTP was suspected over disseminated
of cancer, and surgeries.3–7 There have also been a few reported intravascular coagulation (DIC). A PLASMIC score of 6 was
cases of iTTP secondary to severe trauma.8 Here, we describe a obtained, indicating a 72% chance of ADAMTS13 activity <15%.
case of spontaneous iTTP in a previously healthy 24-year-old
male that highlights the variability in clinical presentation of Patient course:
iTTP and its unique management, focusing on emergency care. Presenting initially as neurologically intact, the patient
We also discuss the classical clinical manifestations, diagnostic displayed a nonfocal lack of strength that resulted in a slow, but
criteria, and therapeutic recommendations, as well as the overall normal gait. However, four hours after initial
challenges of each of these. presentation to the ED, the patient developed difficulty with
word-finding. He was otherwise neurologically intact,
demonstrated by an ability to comprehend and repeat back in
Presenting concerns and clinical findings: his own words what was conveyed to him. Additionally, a
A 24-year-old male presented to the emergency department repeat head CT at this time of neurological change was
(ED) with a chief complaint of headache and palpitations. The unremarkable.
patient ranked his headache, which had begun 7 days prior, as 6
out 10 on a pain scale and described it as sharp and constant. A provisional diagnosis of TTP was made based on the clinical
He also reported 2-3 days of fatigue, palpitations, skin pallor, findings and PLASMIC score of 6. The patient was admitted to
and gingival bleeding. He was afebrile, tachycardic (HR=119), the ICU and his serum was sent to an external laboratory for
and had a blood pressure of 131/68. His SpO2 was 100% on confirmation of insufficient ADAMTS13 activity. Due to the life-
room air with a respiratory rate of 18. threatening nature of TTP and urgency for immediate
treatment, therapeutic plasma exchange, several units of red
blood cell transfusions, and immunosuppressive corticosteroids
Significant findings: were initiated immediately. The following day, the patient had
The physical exam revealed globalized pallor of his skin as well returned to his neurological baseline and no longer
as conjunctival pallor. Mucous membranes were found to be demonstrated word-finding difficulties. His renal function also
dry and pale with dried gingival hemorrhages apparent significantly improved during this time. Results of the patient’s
between teeth (image). Additionally, mild hepatosplenomegaly serum sample showed an ADAMTS13 activity level less than 5%
was noted. While in the ED, the patient’s urine was dark (normal =61% or higher) as well as antibodies against

Sea JL, et al. Case Report of Thrombotic Thrombocytopenic Purpura in a Previously Healthy Adult. JETem
2021. 6(1):V1-4. [Link]
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ADAMTS13. He continued to receive daily plasmapheresis and between patients.1,9 Further, the gold standard of clinical tests,
prednisone. serum measurement of ADAMTS13 activity, is not accessible in
most hospitals and require physicians to send serum samples to
On day three of ICU admission, there was a significant concern outside labs which often have a turnaround time of 2-3 days.
of relapse due to the continued presence of ADAMTS13
antibodies; therefore, the patient was administered rituximab. While early initiation of plasma exchange is critical for treating
On day six of admission, the patient’s platelet levels normalized TTP, differentiating TTP from DIC, hemolytic uremic syndrome
to 150,000/mcl. He was administered two further treatments of (HUS), and heparin-induced thrombocytopenia (HIT) may be
plasmapheresis. Tapering of steroids was begun while the challenging. The presence of normal PT, PTT, fibrin degradation
patient’s laboratory values were monitored closely. After 10 product (FDP) may be used in some cases to distinguish TTP
days of admission, the patient was discharged as his from DIC as coagulation is usually intact in TPP.13,14 Similar to
hemoglobin and platelet levels remained stable off of DIC, HUS has several shared characteristics with TTP but
plasmapheresis. typically presents in children whereas acquired TTP more often
develops in adults.13 Further, HUS also commonly presents with
In total, he received ten rounds of plasmapheresis, five units of mild to moderate thrombocytopenia and severe renal
red blood cells, and one dose of rituximab, with the intention of dysfunction, though there are exceptions to this as well.13
three additional doses in subsequent follow-up. The patient Additional laboratory tests measuring ADAMTS13 activity and
reported feeling well and was discharged with instructions to anti-ADAMTS13 antibodies can be used to confirm TTP.
continue taking pantoprazole (40mg/day) while tapering off of However, these are not optimal diagnostic tools during
prednisone (60mg) over the following 24 days with a dose emergent situations as they are time consuming and not always
reduction of 10 mg every four days. He was also instructed of available. Therefore, prompt diagnosis of TTP is often based on
the need to follow up in clinic for three additional doses of a thorough medical history, physical exam, and routine
rituximab as well as follow-up labs to monitor ADAMTS13 laboratory results.
activity, CBC, and hemolysis.
Traditionally, diagnostic criteria have centered around the
Discussion: presence of a classic pentad of TTP symptoms:
Thrombotic thrombocytopenic purpura is a rare condition thrombocytopenia, hemolytic anemia, neurological
hallmarked by thrombotic microangiopathy (TMA) and abnormalities, fever, and renal dysfunction.1,9,10 Current
dysfunctional ADAMTS13 enzymatic activity. The cleavage recommendations for early diagnosis include the use of a
enzyme, ADAMTS13, plays a critical role in the regulation of the PLASMIC score based on a cohort study identifying several
clotting cascade via its capacity to limit circulating levels of von covariates among patients with TTP.15 The PLASMIC score is
Willebrand factor (vWF).9 Patients with acute iTTP resulting determined by assigning one point for each of the following:
from ADAMTS13 deficiency lack the ability to prevent platelets < 30 mg/dL, lysis (reticulocytes >2.5%, total bilirubin
spontaneous adhesion of vWF. The resulting unregulated >2.0 or decreased haptoglobin), absence of active cancer,
aggregation of large vWF multimers leads to subsequent absence of stem cell or organ transplant, mean corpuscular
platelet activation and microthrombi formation that occludes volume < 90 fL, INR <1.5, and Cr < 2.0 mg/dL.15 A score of 4 or
systemic microvasculature vital to most major organ functions.9 below indicates low risk of TTP, and a score of 6 or higher
While the introduction of plasmapheresis has dramatically correlates with a high chance of TTP. Our patient had a
improved survival rates, mortality remains between 7-22% in PLASMIC score of 6, indicating a 72% chance that his
those who receive standard treatment.10–12 Delayed diagnosis ADAMTS13 activity would be less than 15% and thus a high
and treatment have been reported to contribute significantly to probability of TTP.
this mortality rate and to an increased risk of relapse.10,11 In a
small retrospective study examining TTP-related deaths at six In this report, we describe a case of iTTP in a previously healthy
institutions, Colling et al. reported an association between 24-year-old man. Acute iTTP episodes have been most
mortality and a delay in the initiation of plasma exchange for commonly associated with risk factors that include a previous
more than 24 hours after presentation, highlighting the urgency diagnosis of an autoimmune disorder, HIV infection, and
for rapid diagnosis and immediate treatment.11 However, early pregnancy while commonly cited triggers include infection and
diagnosis of iTTP can be challenging, as symptoms are often recent surgery. Based on reports of most patients having more
generalized and overlap with various other forms of thrombotic than one risk factor or comorbidity prior to developing TTP, it
microangiopathies, and the clinical presentation can vary widely has been proposed that TTP initiation may be linked to a

Sea JL, et al. Case Report of Thrombotic Thrombocytopenic Purpura in a Previously Healthy Adult. JETem
2021. 6(1):V1-4. [Link]
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multifaceted process of triggering an inflammatory response consideration: cancer-associated microangiopathic
and release of complexed vWF into circulation.16 Some of the hemolytic anemia with thrombocytopenia. Eur J Haematol.
most commonly cited surgeries associated with TTP are vascular Published online March 20, 2010:no-no.
and orthopedic procedures which tend to have high rates of doi:10.1111/j.1600-0609.2010.01448.x
hemolysis and shear stress that may predispose patients to 7. Sharma P, Gurung A, Dahal S. Connective tissue disorders in
developing TTP.3 Consistent with these reports, injuries due to patients with thrombotic thrombocytopenic purpura: a
trauma likely also result in the mass destruction of endothelial- retrospective analysis using a national database. J Clin Med
lining vessels and red blood cells. It is possible that this may Res. 2019;11(7):509-514. doi:10.14740/jocmr3850
contribute to the rare occurrence of iTPP in patients with 8. Ikegami K, Yamagishi T, Tajima J, Inoue Y, Kumagai K, Hirose
severe trauma resulting in hemorrhage and bone fracture. Y, et al. Post-traumatic thrombotic microangiopathy
following pelvic fracture treated with transcatheter arterial
Interestingly, our patient had none of the risk factors associated embolization: a case report. J Med Case Reports.
with TTP, and his past medical history was unremarkable and 2018;12(1):216. doi:10.1186/s13256-018-1757-1
without any family history of autoimmune disorders. This 9. Kremer Hovinga JA, Heeb SR, Skowronska M, Schaller M.
underscores the need for additional studies to fully understand Pathophysiology of thrombotic thrombocytopenic purpura
the mechanisms by which TTP develops as it could assist in and hemolytic uremic syndrome. J Thromb Haemost JTH.
clinical decision making and decrease the time to diagnosis and 2018;16(4):618-629. doi:10.1111/jth.13956
proper treatment. While TTP is rare, this case highlights the 10. Iqbal S, Zaidi SZA, Motabi IH, Alshehry NF, AlGhamdi MS,
importance of including TTP on the differential for patients with Tailor IK. Thrombotic thrombocytopenic purpura - analysis
unexplained thrombocytopenia and microangiopathic of clinical features, laboratory characteristics and
hemolytic anemia. In particular, patients presenting with therapeutic outcome of 24 patients treated at a Tertiary
neurological symptoms, severe anemia, thrombocytopenia, and Care Center in Saudi Arabia. Pak J Med Sci.
acutely elevated creatinine should prompt emergency medicine 2016;32(6):1494-1499. doi:10.12669/pjms.326.11274
physicians to investigate for TTP. 11. Colling M, Sun L, Upadhyay V, Ryu J, Li A, Uhl L, et al.
Deaths and complications associated with the management
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Sea JL, et al. Case Report of Thrombotic Thrombocytopenic Purpura in a Previously Healthy Adult. JETem
2021. 6(1):V1-4. [Link]
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