A 33-year-old woman presents with confusion, abdominal pain, and fever. Her vital signs are:

• Blood pressure of 118 over 93
• Heart rate of 120
• Respiratory rate of 18

She has a history of lupus. CBC shows a thrombocytopenia of 27 x 109/L platelets.

What is the best management of this condition?

For six decades, the pentad of fever, thrombocytopenia, hemolytic anemia, renal injury, and neurological manifestations has remained the classic clinical diagnostic criteria for Thrombotic Thrombocytopenic Purpura (TTP).¹ Unfortunately, fewer than 10 percent of patients present with this constellation of symptoms. Although the treatment of TTP has improved significantly over the past 30 years, the disease still has a dangerously high mortality rate of approximately 20 percent. Most of these deaths can be attributed to a delay in diagnosis.²

TTP often presents abruptly, and most patients that develop it first visit the emergency department (ED) as their symptoms worsen. It is thus imperative that emergency physicians be able to recognize and properly treat this disease, especially in the absence of its classical presentation.³

In TTP, patients undergo microangiopathic hemolytic anemia that leads to severe thrombocytopenia and, in severe cases, organ dysfunction. The disease may be congenital (cTTP) or immune-mediated (iTTP). The vast majority of cases are immune-mediated, with 90 percent presenting in adulthood, typically with a first incidence between 30-50 years of age.⁴ Women have a two to three times increased risk, and African-American patients have an eight-fold increased risk compared to the general population.¹ Both cTTP and iTTP are caused by a deficiency in ADAMTS13, an enzyme that regulates Von Willebrand Factor (VWF) multimers. When severe ADAMTS13 deficiency—less than 10 percent—is present, there is no regulated proteolysis of VWF, directly leading to uncontrolled platelet adhesion and aggregation. In TTP, this ultimately manifests as microvascular thrombosis, endothelial damage, and organ dysfunction.¹ iTTP is primarily due to acquired anti-ADAMTS13 antibodies, which can be either inhibitory via neutralization of the proteolytic function of ADAMTS13 or non-inhibtory, accelerating the clearance of ADAMTS13 from the circulatory system. Even relatively small amounts of anti-ADAMTS13 autoantibodies can lead to TTP.¹

Primary iTTP has no defined cause, but secondary iTTP has been associated with a number of etiologies, including pregnancy, autoimmune disorders, HIV infection, malignancy and iatrogenic medications.⁴

Diagnosis

Fewer than 10 percent of patients with TTP present with the classical clinical pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, neurological deficits, and renal insufficiency.¹ However, many clinical features are common: more than 60 percent of patients present with a degree of neurological involvement, ranging from confusion to stroke and coma.¹ 35 percent of patients present with gastrointestinal symptoms secondary to ischemic microthrombi.¹ 25 percent of patients may present with evidence of myocardial ischemia, including abnormal ECGs and elevated troponin levels.¹ Laboratory testing will show significant thrombocytopenia (below 30 x 109/L), in addition to markers of hemolysis such as erythrocyte fragmentation and elevated LDH.¹

Pregnant patients are particularly vulnerable to misdiagnosis of TTP in the ED. One 2009 study of four tertiary hospitals found that emergency physicians often misdiagnosed this presentation in pregnant women as “panic attack, domestic violence, or gastroenteritis.”⁵ Pregnant women comprise up to seven percent of TTP/Hemolytic Uremic Syndrome (HUS) patients. When thrombocytopenia is found in pregnant patients, clinicians should have a high degree of suspicion for TTP in addition to HELLP Syndrome, eclampsia, and HUS.⁵

Testing for TTP should include a CBC, CMP, blood smear, coagulation panel, fibrinogen, D-Dimer, LDH, troponin, HIV PCR, urinalysis, Coomb’s testing and ECG.⁴ ADAMTS13 level can be considered to assist the inpatient team. In TTP, Coomb’s testing will be negative, and the coagulation panel will typically not be significantly deranged. In the long term, the mechanism of ADAMTS13 deficiency should be determined—whether due to inhibitory or non-inhibitory autoantibodies, or due to the hereditary form of the disease. The labs that assess this, such as the FRETS-VWF73-based assay, take several days to result and are best pursued in an inpatient setting.⁷ Given the prolonged time that these labs may take to result, clinicians may consider using the PLASMIC score to aid in predicting the likelihood of TTP. One point is given for platelet count less than 30,0000, presence of hemolysis, mean corpuscular volume less than 90 fL, INR less than 1.5, creatinine less than 2.0 mg/dL, absence of cancer, and the absence of solid organ or stem cell transplant. A PLASMIC score higher than 5 suggests a high probability of TTP, with a sensitivity of approximately 99 percent and a specificity of 57 percent.⁶

Management

TTP’s mortality ranges from 4 to 31 percent, but the disease is associated with multiple comorbidities, including hypertension, major depressive disorder, and cognitive abnormalities. Thus, early management is essential for patient outcomes.⁴ Early hematology consultation should be obtained when TTP is suspected.

Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) is the first-line treatment, by simultaneously supplying fresh ADAMTS13 and removing anti-ADAMTS13 autoantibodies. Delays in this treatment are directly correlated with increases in patient mortality.¹ The International Society of Thrombosis and Haemostasis also recommends corticosteroids in addition to TPE, given their possible mortality benefit.⁷ High dose pulse steroids, such as methylprednisolone 10 mg/kg/day for 3 days, or an oral prednisone taper may be used.¹ Rituximab may be given as well, largely due to prevention of relapse.⁷ Caplacizumab, a new medication that targets the A1 domain of VWF and prevents platelet aggregation has shown remarkable efficacy in improving clinical outcomes and reducing patient mortality and risk of relapse.^7,8 Much like TPE and steroids, earlier treatment with caplacizumab is associated with improved patient outcomes.⁸

One third of TTP patients will experience a relapse within 30 days of initial treatment.4 Serial ADAMTS13 activity should be monitored monthly for 3 months, every 3 months for 1 year, and then every 6-12 months thereafter.¹

Dr. Bates is an assistant professor of emergency and internal medicine at the Penn State Milton S Hershey Medical Center.

Dr. Turner originally trained at the Medical University of South Carolina, is an EM intern at Hershey Medical Center in Hershey, PA.

References

1. Sukumar S, Lämmle B, et al. Thrombotic thrombocytopenic purpura: pathophysiology, diagnosis, and management. J Clin Med. 2021;10(3):536.
2. Kessler CS, Khan BA, et al. Thrombotic thrombocytopenic purpura: a hematological emergency. J Emerg Med. 2012;43(3):538-44.
3. Li XM, Mo XY, et al. Therapeutical plasma exchange for thrombotic thrombocytopenic purpura in the emergency department: A single center experience. Am J Emerg Med. 2021;46:556-9
4. Long B, Bridwell RE, et al. Evaluation and management of thrombotic thrombocytopenic purpura in the emergency department. J Emerg Med. 2021;61(6):674-82.
5. Stella CL, Dacus J, et al. The diagnostic dilemma of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the obstetric triage and emergency department: lessons from 4 tertiary hospitals. Am J Obstet Gynecol. 2009;200(4):381-e1.
6. Stanley M, Killeen RB, et al. Thrombotic thrombocytopenic purpura. In:StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK430721/. Updated April 7, 2023. Accessed March 26, 2024.
7. Zheng XL, Vesely SK, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496-502.
8. Izquierdo CP, Mingot-Castellano ME, et al. Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura. Blood Adv. 2022;6(24):6219-27.