Written by:
Samantha Kerester, MD
Naillid Felipe, MD

Edited by:
Gregg Chesney, MD
Jonathan Kobles, MD


Thrombotic thrombocytopenic purpura (TTP) is a hematologic disorder caused by platelet aggregation and thrombus formation in the microvasculature, resulting in severe thrombocytopenia, hemolytic anemia, and multi-organ ischemia. 

Annual incidence of approximately 2-4 cases/million/year (Kappler, 2017), with 90% of cases occurring in adulthood. (Joly, 2017) 

Risk factors include: 

  • Female,  2:1 female to male predominance (Terrell, 2010) 
  • Black race  
  • Obesity  

TTP is a life-threatening condition with mortality of 10-20% despite targeted therapies. (Kappler, 2017) 


TTP is caused by a severe deficiency in ADAMTS-13, a protease that cleaves the glycoprotein von Willebrand factor (vWF) necessary for platelet adhesion in the coagulation cascade.  

  • In the paucity of ADAMTS-13, large vWF multimers accumulate and activate platelets, leading to platelet consumption and unregulated microthrombi formation. 
  • Microvascular plugging results in tissue ischemia in any organ, though it is most common in high-pressure vasculature, including the brain, heart, kidneys, and pancreas.  
  • Lung and liver involvement are uncommon due to low pressure and low shearing forces. (Sadler, 2017) 


Acquired TTP:  

  • IgG autoantibodies against ADAMTS-13 inhibit its proteolytic activity towards vWF.  
  • Deficient ADAMTS-13 activity alone typically does not result in TTP; therefore, it is essential to consider contributing precipitants, including pregnancy, HIV, acute infection, inflammation (SLE, malignancy, pancreatitis) and medication use (ex., fluoroquinolones, quinine, clopidogrel, and ticlopidine) 


Congenital/Familial TTP: 2% of cases occur in childhood via autosomal recessive mutations in the ADAMTS-13 gene. 

Clinical Presentation:

Classic pentad (mnemonic FAT RN) is rare and seen in less than 7% of cases. (Long, 2021)  

  • Fever 
  • Anemia (microangiopathic hemolytic anemia) 
  • Thrombocytopenia with purpura 
  • Renal dysfunction (acute kidney injury) 
  • Neurologic abnormalities 


Suspect TTP in all patients with: 

  • Severe thrombocytopenia (<30×10^9/L)  
  • Microangiopathic hemolytic anemia with schistocytes on the blood smear 


Clinical symptoms may be transient and relate to microvascular ischemia in specific organs (Fodil, 2022): 

  • CNS injury (60%): headache, confusion, seizure, stroke, focal neurological deficits 
  • Cardiac injury (25%): chest pain, isolated EKG changes, elevated troponin, congestive heart failure, myocardial infarction 
  • GI injury (35%): abdominal pain, vomiting, elevated lipase >3x normal limit, bloody diarrhea 
    • In TTP, bloody stools occur during the initial presentation, whereas bloody stools often precede the development of symptoms in HUS. 
  • Renal injury: isolated proteinuria or hematuria, moderate acute kidney injury with serum creatinine levels <2 mg/dL
  • Skin: petechiae and purpura
  • Despite severe thrombocytopenia, clinically significant bleeding is rare

Figure 1. An example of petechiae and purpura frequently seen with thrombocytopenic disorders.

(source: “Thrombotic Thrombocytopenic Purpura (TTP)”, 2022, National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health/thrombotic-thrombocytopenic-purpura) 

Laboratory Evaluation:

Clinical presentation and laboratory findings can help suggest TTP in the emergency department. Patients should undergo comprehensive work-up to rule out alternative causes of thrombocytopenia, evaluate for end-organ damage, and identify underlying infectious or autoimmune etiologies. 

    • CBC with differential and peripheral smear 
    • Severe thrombocytopenia (<30×10^9/L) 
    • Mild anemia  
    • Presence of schistocytes 
    • Comprehensive metabolic panel to assess for renal involvement  
        • While TTP and hemolytic uremic syndrome have considerable overlap in presentation, renal involvement is more commonly seen in hemolytic uremic syndrome 
    • Hemolysis labs and coagulation testing (PT/INR/PTT, Fibrinogen, and D-dimer) 
        • An elevated fibrinogen level or abnormal coagulation (elevated PT/PTT/INR) suggests an alternative diagnosis, such as DIC 
    • Evidence of hemolytic anemia: 
        • Increased LDH 
        • Increased indirect bilirubin 
        • Decreased haptoglobin 
        • Increased reticulocyte count 
    • β-hCG (for female patients of reproductive age) 
        • Pregnancy-related TTP often occurs during 2nd and 3rd trimester (Joly, 2017) 
        • May have features similar to pre-eclampsia-eclampsia, HELLP syndrome, and fatty liver disease of pregnancy 
    • Type and screen 
    • Troponin, serum lactate, lipase, viral serologies (HIV, HCV, HBV), anti-nuclear antibody, urine analysis for proteinuria and hematuria, urine/blood/stool cultures, EKG, imaging studies including a chest x-ray or head CT as clinically indicated 


Confirmatory testing is often not available in the emergency department. Do not delay treatment for confirmatory testing.  

  • ADAMTS13 activity (sensitivity 97%, specificity 100%) (Chiasakul, 2018) 
  • Anti-ADAMTS13 antibodies confirm the majority of cases of immune-mediated TTP 
  • ADAMTS-13 antigen levels and ADAMTS-13 gene analysis confirm congenital TTP 

The Plasmic Score:

The PLASMIC score can help stratify the likelihood of TTP, as patients ought to have therapy initiation prior to confirmatory testing results. 

Patients with a score < 5 are unlikely to have TTP, with a negative predictive value of 99%. (Paydary, 2020) Patients with a score of 5 or greater require ADAMTS-13 levels to be sent along with expert consultation and likely initiation of empiric therapy. 

  • The factors considered include:  
    • Platelets <30×10^9/L 
    • One or more indicators of hemolysis (reticulocyte count >2.5%, undetectable haptoglobin, or indirect bilirubin >2 mg/dL) 
    • MCV <90 fL 
    • INR <1.5 
    • creatinine <2 mg/dL 
    • No active cancer in the preceding year 
    • No history of solid organ or hematopoietic stem cell transplant 


TTP requires prompt initiation of treatment in the emergency department in conjunction with a hematology consultation to select the best combination of therapies for each patient

  • Therapeutic plasma exchange (TPE) is the cornerstone of treatment for all patients with TTP. It repletes functioning ADAMTS-13 and removes circulating autoantibodies when present.  
    • TPE requires the placement of a hemodialysis catheter. 
    • Platelet transfusion (correction of thrombocytopenia) before the placement of a hemodialysis catheter is not indicated and may worsen disease course. 
    • The first TPE session should be completed prior to administration of any biologic therapies. 
    • Prompt initiation of TPE has significantly decreased mortality for an initial episode of TTP from 90% to 10-20%. (Joly, 2017; Sawler, 2020) 
  • Fresh frozen plasma (FFP) (contains ADMTS-13) may be used to supplement ADAMTS-13 if there is a delay in initiating TPE in the emergency department (i.e. if the patient is being transferred to another hospital). 
  • Steroids reduce the production of auto-antibodies in acquired TTP.  
    • Oral prednisone 1 mg/kg/day.  
    • IV methylprednisolone 1000 mg/day may be used in the presence of severe neurological deficits or cardiac injury. (Balduini, 2010)
  • Rituximab, the humanized anti-CD20 monoclonal antibody. 
    • Decreases production of anti-ADAMTS13 antibodies by removing the B cells that mature into autoantibody-secreting plasma cells. In conjunction with TPE, its use has been associated with reduced hospital length-of-stay and fewer relapses. Initiation and dosing should be discussed with hematology.  
  • Caplacizumab, a humanized monoclonal antibody, binds to vWF to block its interaction with platelet glycoproteins and ultimately reduce the formation of microthrombi.  
    • Its use has been associated with decreased time to normalization of platelet count and decreased mortality; however, the therapy does not address the underlying autoimmune pathology and has been associated with a high risk of 30-day relapse. Initiation and dosing should be discussed with hematology. 

Special considerations  

  • TTP with severe features may require critical care interventions, including PRBC transfusion, anticonvulsants, antihypertensives, and hemodialysis. 
  • Discontinue inciting medications in all cases of suspected drug-associated TTP. 
  • Platelet transfusion should only be considered for clinically significant bleeding or intracranial hemorrhage, as it has been associated with acutely worsening thrombosis, renal failure, and death.
  • Immune TTP during pregnancy should be managed with TPE, despite the risk of removing pregnancy-maintaining hormones, given the high risk of maternal and fetal mortality without treatment. Rituximab can be given during the first trimester when immunoglobulins do not cross the placenta. Of note, there is no clinical indication for premature delivery.  

Next Steps:

  • TTP is a life-threatening hematologic disorder that requires rapid clinical diagnosis and prompt initiation of therapeutic plasma exchange in the emergency setting.  
  • TTP relapse (new case onset that occurs 30 days after discontinuation of remission achieving interventions) occurs in approximately 1/3 of patients. Those with low residual ADAMTS-13 activity are at the highest risk of recurrence. (Scully, 2012) 


Balduini CL, et al. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol. 2010 Jun;89(6):591-6. doi: 10.1007/s00277-009-0877-5. 

Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):530-538. doi: 10.1182/asheducation-2018.1.530.  

Fodil S, Zafrani L. Severe Thrombotic Thrombocytopenic Purpura (TTP) with Organ Failure in Critically Ill Patients. J Clin Med. 2022 Feb 19;11(4):1103. doi: 10.3390/jcm11041103.   

Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846. doi:10.1182/blood-2016-10-709857. 

Kappler S, Ronan-Bentle S, Graham A. Thrombotic Microangiopathies (TTP, HUS, HELLP). Hematol Oncol Clin North Am. 2017;31(6):1081-1103. doi:10.1016/j.hoc.2017.08.010. 

Long B, Bridwell RE, Manchanda S, Gottlieb M. Evaluation and Management of Thrombotic Thrombocytopenic Purpura in the Emergency Department. J Emerg Med. 2021;61(6):674-682. doi:10.1016/j.jemermed.2021.07.045. 

Paydary, Koosha, et al. “Diagnostic Accuracy of the PLASMIC Score in Patients with Suspected Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta‐Analysis.” Transfusion, 2020;60(9):2047-2057. doi:10.1111/trf.15954. 

Sadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. Blood. 2017 Sep 7;130(10):1181-1188. doi: 10.1182/blood-2017-04-636431. 

Sawler D, Parker A, Britto J, et al. Time from suspected thrombotic thrombocytopenic purpura to initiation of plasma exchange and impact on survival: A 10-year provincial retrospective cohort study. Thrombosis Research. 2020;193:53-59. doi: 10.1016/j.thromres.2020.05.045.  

Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-335. doi:10.1111/j.1365-2141.2012.09167.x.  

Terrell DR, Vesely SK, Kremer Hovinga JA, Lämmle B, George JN. Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes. Am J Hematol. 2010 Nov;85(11):844-7. doi: 10.1002/ajh.21833. 

Figure 1: From “Thrombotic Thrombocytopenic Purpura (TTP)”, 2022, National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health/thrombotic-thrombocytopenic-purpura