Thrombotic thrombocytopenic purpura

Last updated: August 24, 2022

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Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, a condition in which microthrombi, consisting primarily of platelets, form and occlude the microvasculature (i.e., the arterioles and capillaries). TTP occurs primarily in adults and is typically due to acquired autoantibodies against a proteolytic enzyme (ADAMTS13) that cleaves von Willebrand factor (vWF). The classic pentad of findings (fever, neurological abnormalities, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function) is seen in a minority of patients. TTP is a hematologic emergency. If TTP is strongly suspected and initial laboratory tests support the diagnosis, treatment with plasma exchange should begin immediately, as the condition may be fatal if left untreated.

  • Primarily adult individuals (median age at diagnosis: ∼ 40 years)
  • More common in women and in Black populations

Epidemiological data refers to the US, unless otherwise specified.

TTP is a thrombotic microangiopathy, a condition in which microthrombi form and occlude the microvasculature. The other main thrombotic microangiopathy is hemolytic uremic syndrome (HUS). Although TTP and HUS share similarities in both pathophysiological findings and clinical features, these conditions differ in etiology; TTP, unlike HUS, is caused by a deficiency of ADAMTS13.

  1. Autoantibodies or gene mutationsdeficiency of ADAMTS13; (a metalloprotease that cleaves von Willebrand factor)
  2. ↓ Breakdown of vWF multimers → vWF multimers accumulate on endothelial cell surfaces
  3. Platelet adhesion and microthrombosis
  4. Microthrombi → fragmentation of RBCs with schistocyte formation → hemolytic anemia
  5. Arteriolar and capillary microthrombosis → end-organ ischemia and damage, especially in the brain and kidneys (potentially resulting in acute kidney injury or stroke)

ADAMTS13 deficiency → excess vWF → microthrombus formation → blockage of small vesselsRBC fragmentation (hemolysis) and end-organ damage

TTP patients are typically previously healthy adults. Microangiopathic hemolytic anemia and thrombocytopenia may be the only presenting signs. However, the classic pentad of clinical findings consists of: [2][3][4]

The typical patient is a previously healthy adult presenting with mental status changes, fever, petechiae, fatigue, and pallor. Laboratory tests will then indicate hemolytic anemia and possibly acute kidney injury (AKI). Impaired kidney function may not be present, and only a minority of patients will present with all five clinical findings.

Nasty Fever Ruined My Tubes:” Neurological symptoms, Fever, Renal function impairment, Microangiopathic hemolytic anemia, Thrombocytopenia are the clinical features of TTP.

Approach [4]

Laboratory studies [4][5]

Initial tests [3][6][7]

While PT and aPTT are normal or only mildly elevated in TTP and HUS (no consumption coagulopathy), they are markedly elevated in disseminated intravascular coagulation (consumption of platelets and all coagulation factors).

Confirmatory tests [5][6]

Obtain ADAMTS13 activity and inhibitor testing in all patients.

  • ADAMTS13 activity
    • < 10%: positive (severe deficiency)
    • 10–20%: borderline
    • > 20%: negative
  • ADAMTS13 inhibitor or anti-ADAMTS13 IgG
    • Positive: immune-mediated TTP
    • Negative: Further testing (e.g., genetic testing) may be indicated to assess for congenital TTP.

Obtain ADAMTS13 testing before the initiation of plasma exchange or administration of blood products; do not delay treatment waiting for results. [4]

PLASMIC score

The PLASMIC score is a clinical risk assessment tool, based on easily attainable clinical information, that is used to predict the likelihood of severe ADAMTS13 deficiency in patients with suspected TTP. The total score helps direct further management.

PLASMIC score [5][8]
Criteria Points
Platelet count < 30,000/mm3 1

Hemolysis

1
No active malignancy in the past year 1
No history of stem cell or solid organ transplant 1
MCV < 90 μm3 1
INR < 1.5 1
Serum creatinine < 2.0 mg/dL 1

Likelihood of severe ADAMTS13 activity deficiency (activity level < 10%) [5]

  • Total score 0–4 points: 0–4% (low risk)
  • Total score 5 points: 5–24% (intermediate risk)
  • Total score 6–7 points: 62–82% (high risk)

PLASMIC score criteria include Platelets, hemoLysis, no Active malignancy, no Solid or Stem-cell transplant, MCV, INR, Creatinine.

Additional testing [3]

Consider the following studies as indicated to identify serious complications and secondary causes of TTP.

See “Differential diagnosis of platelet disorders, “Diagnostic studies for hemolytic anemia”, and “Diagnostics in suspected MAHA.”

The differential diagnoses listed here are not exhaustive.

Approach [4][5]

TTP requires urgent diagnosis and treatment. Do not delay treatment while awaiting test results to confirm ADAMTS13 deficiency.

Supportive care [4]

Empiric therapy [4]

Do not start caplacizumab if there is no access to ADAMTS13 activity testing, regardless of the pretest probability of TTP. [5]

Response to treatment [11]

Clinical signs of response include : [7]

  • Platelet level: sustained ≥ 150,000/mm3
  • LDH: < 1.5× the ULN
  • No signs of new or worsening ischemic organ injury

TTP can result in microthrombus formation and complications in many organs of the body. [12]

We list the most important complications. The selection is not exhaustive.

The prognosis depends primarily on prompt initiation of treatment. Timely treatment can prevent acute complications (AKI, coma, and death), as well as progression to chronic renal failure.

  1. Who Is at Risk for Thrombotic Thrombocytopenic Purpura?. https://www.nhlbi.nih.gov/health/health-topics/topics/ttp/atrisk. Updated: February 1, 2016. Accessed: April 16, 2017.
  2. What Are the Signs and Symptoms of Thrombocytopenia?. https://www.nhlbi.nih.gov/health/health-topics/topics/thcp/signs. Updated: September 25, 2012. Accessed: April 16, 2017.
  3. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017; 129 (21): p.2836-2846. doi: 10.1182/blood-2016-10-709857 . | Open in Read by QxMD
  4. Zheng XL, Vesely SK, Cataland SR, et al. Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020; 18 (10): p.2503-2512. doi: 10.1111/jth.15009 . | Open in Read by QxMD
  5. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020; 18 (10): p.2486-2495. doi: 10.1111/jth.15006 . | Open in Read by QxMD
  6. Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ Program. 2018; 2018 (1): p.530-538. doi: 10.1182/asheducation-2018.1.530 . | Open in Read by QxMD
  7. Thachil J. Thrombotic Thrombocytopenic Purpura. J Intensive Care Soc. 2011; 12 (3): p.215-220. doi: 10.1177/175114371101200308 . | Open in Read by QxMD
  8. Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017; 4 (4): p.e157-e164. doi: 10.1016/s2352-3026(17)30026-1 . | Open in Read by QxMD
  9. Fontana S, Kremer Hovinga JA, Lammle B, Mansouri Taleghani B. Treatment of thrombotic thrombocytopenic purpura. Vox Sang. 2006; 90 (4): p.245-254. doi: 10.1111/j.1423-0410.2006.00747.x . | Open in Read by QxMD
  10. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019; 380 (4): p.335-346. doi: 10.1056/nejmoa1806311 . | Open in Read by QxMD
  11. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood. 2021; 137 (14): p.1855-1861. doi: 10.1182/blood.2020009150 . | Open in Read by QxMD
  12. Brandenburg VM, Gaertner S, Lindemann-Docter K, et al. Underestimated complications in thrombotic thrombocytopenic purpura--haemolytic uraemic syndrome. Nephrol Dial Transplant. 2004; 19 (8): p.2142-2146. doi: 10.1093/ndt/gfh230 . | Open in Read by QxMD

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