> Table of Contents > Thrombotic Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura
Hedy Smith, MD, PhD
Kellie A. Sprague, MD
image BASICS
DESCRIPTION
  • An acute syndrome of microangiopathic hemolytic anemia (MAHA) and consumptive thrombocytopenia with deposition of hyaline thrombi in terminal arterioles and capillaries leading to ischemic multiorgan damage
  • Thrombotic thrombocytopenic purpura (TTP) is characterized by MAHA and thrombocytopenia, with or without the following signs and symptoms (1):
    • Neurologic symptoms
    • Renal dysfunction
    • Fever
    • Most patients do not show the historic pentad of MAHA, thrombocytopenia, renal dysfunction, neurologic abnormalities, and fever because treatment is initiated before the pentad can develop.
EPIDEMIOLOGY
Incidence
  • Predominant age: 18 to 49 years
  • Predominant sex: female > male (3:1)
  • Incidence ratio in blacks to whites is 7:1
  • The age-sex-race standardized incidence of clinically suspected TTP is 8 million/year and 2 million/year in those with ADAMTS13 levels <10% (2).
ETIOLOGY AND PATHOPHYSIOLOGY
  • In TTP, the aggregating agent responsible for platelet thrombi is unusually large von Willebrand factor (UL vWF) multimers, which are far larger than those found in normal plasma.
  • A metalloproteinase, ADAMTS13, which normally enzymatically cleaves UL vWF multimers to prevent clumping within vessels, is deficient, defective, or absent, allowing UL vWF to react with platelets. This leads to the endothelial cell damage and disseminated thrombi characteristic of TTP.
  • Arterioles most often affected are in the brain, kidney, pancreas, heart, and adrenal glands. Lungs and liver are relatively spared.
  • In familial TTP, patients have an inherited deficiency of ADAMTS13 (1).
  • In acquired idiopathic TTP, autoantibodies are directed against the metalloproteinase ADAMTS13 (1,3).
  • Endothelial injury, either directly from a drug/toxin or indirectly via platelet/neutrophil activation has been proposed as a cause of secondary TTP especially in those without ADAMTS13 deficiency.
    • Drug-induced (see “Risk Factors”)
    • Hematopoietic cell transplantation
Genetics
TTP is most often an acquired disorder. A congenital form of inherited TTP (Schulman-Upshaw syndrome) is due to a mutation at the ADAMTS13 metalloproteinase gene locus on chromosome 9q34. This rare form of TTP has an autosomal-recessive pattern of inheritance (4).
RISK FACTORS
  • Pregnancy and oral contraceptives
  • AIDS and early symptomatic HIV infection
  • Autoimmune disease
    • Antiphospholipid antibody syndrome
    • Systemic lupus erythematosus
    • Scleroderma
  • Cancer
  • Hematopoietic stem cell transplantation
  • Drug toxicity
    • Cancer chemotherapy
      • Mitomycin C and gemcitabine
      • Bleomycin and cisplatin
      • Bevacizumab
    • Calcineurin inhibitors
      • Tacrolimus and cyclosporine
    • Immune-mediated
      • Quinine and quinidine
      • Ticlopidine and clopidogrel
COMMONLY ASSOCIATED CONDITIONS
  • TTP/HUS/atypical HUS (hemolytic uremic syndrome) have similar presentations with MAHA and thrombocytopenia and multiorgan involvement.
  • TTP generally presents with minimal renal involvement and may have neurologic abnormalities, whereas the opposite is more characteristic of HUS/atypical HUS.
  • However, patients with HUS and TTP may have both prominent renal and neurologic manifestations, often making the diagnosis unclear, hence the historical hybrid name “TTP-HUS.”
  • ADAMTS13 levels are diminished in adults with familial or acquired idiopathic TTP but are normal in children diagnosed with HUS following infection with Escherichia coli (particularly type O157:H7), so-called Shiga toxin-HUS, and in “atypical HUS,” is also called complement mediated thrombotic microangiopathy reflecting the pathophysiology which is related to complement dysregulation.
image DIAGNOSIS
  • Most common symptoms are nonspecific: nausea, vomiting, weakness, abdominal pain, fatigue, fever
  • Related to thrombocytopenia
    • Easy bruising, purpura, or petechiae
    • Epistaxis, menorrhagia, bleeding gums
    • GI bleeding
    • Intracranial hemorrhage
    • Visual symptoms due to retinal hemorrhage
  • Related to hemolytic anemia (MAHA): jaundice, fatigue
  • Related to end-organ ischemia
    • Neurologic: CNS symptoms occur in 50%.
      • Often fluctuating symptoms
      • Headache
      • Altered mental status: Spectrum runs from behavioral/personality changes to obtundation/stupor/coma.
      • Seizures
      • Stroke
    • Renal: hematuria, oliguria, or anuria
    • Cardiac: arrhythmia, myocardial infarction, heart failure
PHYSICAL EXAM
  • Fever
  • Mental status/neurologic: confusion, coma, stupor, weakness
  • HEENT: retinal hemorrhage, scleral icterus, epistaxis
  • Abdomen/GI: nonspecific tenderness
  • Skin: jaundice, petechiae, purpura, ecchymoses
DIFFERENTIAL DIAGNOSIS
  • HUS and atypical HUS: See “Commonly Associated Conditions.”
  • Antiphospholipid antibody syndrome: prolonged partial thromboplastin time (PTT) and presence of lupus anticoagulant
  • Systemic lupus erythematosus
  • Malignant hypertension (HTN): diastolic > 130 mm Hg, papilledema, retinal hemorrhages
  • Pregnancy-associated preeclampsia/eclampsia or hemolysis, elevated liver enzyme levels, and low platelet HELLP levels: low ATIII levels
  • Disseminated intravascular coagulation
    • Prolonged prothrombin time (PT)/PTT, low fibrinogen
    • Low factors V and VIII
    • Secondary to sepsis/shock or widely disseminated malignancy
  • Idiopathic thrombocytopenic purpura (ITP)
    • No hemolysis, normal lactate dehydrogenase (LDH) and bilirubin
    • Presence of antiplatelet antibodies
  • Malignancy-associated microangiopathy
  • Evan syndrome (autoimmune hemolytic anemia and thrombocytopenia): positive direct Coombs test
  • Sclerodermal kidney
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC
    • Hemoglobin (decreased): average is 8 to 10 g/dL
    • Platelets decreased: typically in the 10 to 30,000 range
  • Reticulocyte count (increased)
  • Haptoglobin decreased (hemolysis)
  • Peripheral smear
    • Schistocytes (prominent, >1% of RBCs)
    • Helmet cells, RBC fragments
    • Nucleated RBCs
    • Polychromasia (reticulocytosis)
  • Coagulation studies
    • Normal in most; mild elevation in 15%
    • Fibrinogen normal
  • Coombs test: negative direct Coombs test
  • Electrolytes, BUN/creatinine: mild elevation of BUN and creatinine (creatinine <3 mg/dL)
  • Liver function studies: increased indirect bilirubin (hemolysis)
  • LDH: 5 to 10 times normal
  • Urinalysis
    • Proteinuria, microscopic hematuria
    • Positive dipstick for large blood, but minimal RBCs on microscopic exam
  • ECG: sinus tachycardia, heart block
  • Troponin: increased if cardiac involvement
  • HIV, hepatitis A, B, C testing: Exclude underlying viral precipitant.
  • Pregnancy test
  • Pretreatment ADAMTS13 activity level of <10% is useful in distinguishing acquired or familial TTP from other disorders.
  • Head CT/MRI scan: performed if mental status changes are present to rule out possible intracranial hemorrhage or ischemic changes
P.1033

Test Interpretation
Biopsy of affected organs shows platelet thrombi within or beneath damaged endothelium. However, biopsy is rarely obtained because the diagnosis is made on clinical grounds and laboratory findings.
image TREATMENT
  • Prompt treatment of TTP is necessary due to the high mortality (90%).
  • In the absence of another apparent cause, the dyad of MAHA and thrombocytopenia is sufficient to begin treatment for TTP while the workup proceeds (1,3):
    • Plasma exchange transfusion (PEX) is the cornerstone of treatment of classic TTP (3)[A].
    • PEX replaces deficient or defective metalloproteinase (ADAMTS13) and removes UL vWF and antimetalloproteinase antibodies.
    • PEX should begun immediately and continued daily.
    • Optimal PEX duration is variable. Convention is to continue for 2 days after platelet count is ≥150,000, then consider tapering (5)[C].
    • Fresh frozen plasma: temporary measure until PEX can be initiated (3)[B]
MEDICATION
First Line
  • Glucocorticoids may be of benefit in some patients. British guidelines recommend its use for all patients (5)[B].
    • Steroids may work by suppressing the autoantibodies inhibiting ADAMTS13 activity.
    • Use may be in patients with severe ADAMTS13 deficiency, in the setting of exacerbation when PEX is stopped or in relapse after remission.
    • Little benefit of steroids when used as monotherapy
    • Doses: prednisone 1 mg/kg/day and taper once in remission or methylprednisolone 1 g/day IV for 3 days
  • Rituximab, an anti-CD20 antibody that deletes B cells, may reduce relapse when given in conjunction with PEX and steroids (6).
    • Dose: 375 mg/m2 IV weekly for 4 weeks
Second Line
The following medications are used in refractory cases:
  • Rituximab (5)[B]
  • Vincristine, cyclophosphamide cyclosporine
  • Intravenous immunoglobulin (IVIG) (3)
  • Bortezomib (7)[C],(8)
ISSUES FOR REFERRAL
  • Hematology or blood bank for PEX
  • Nephrology for dialysis
  • Cardiology for presence of significant heart block or ischemia
  • Neurosurgery for intracranial hemorrhage
SURGERY/OTHER PROCEDURES
Splenectomy is reserved for severe, refractory cases (9).
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • ABCs, oxygen, IV access, telemetry
  • Volume resuscitation if hypotensive/actively bleeding
  • Packed RBCs can be transfused safely.
  • Platelet transfusion may be used for the treatment of hemorrhage.
Discharge Criteria
On normalization and stabilization of neurologic symptoms, LDH, platelets, and renal function
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • No maintenance therapy is required. After PEX is discontinued, blood counts should be monitored over a few months. If testing results remain normal, testing interval can be lengthened.
  • Promptly evaluate any symptoms of relapse.
PATIENT EDUCATION
  • On discharge, advise patients to self-monitor for signs of relapse (e.g., fever, headache, bruising).
  • Patients should be advised about prolonged periods of fatigue following the acute phase.
  • See National Heart, Lung, and Blood Institute Web site: http://www.nhlbi.nih.gov/health/health-topics/topics/ttp
PROGNOSIS
  • Most patients recover fully from idiopathic TTP when treated promptly:
    • 30-day mortality is 10% in those who receive PEX.
    • 70% respond within 14 days; 90% respond within 28 days.
    • 80% survival in patients with idiopathic TTP treated with PEX (10)
  • Initial LDH and platelet counts are not predictive of the patient's response to treatment.
  • Final platelet count and LDH or the length or intensity of treatment does not predict relapse.
  • Low levels of ADAMTS13 activity during remission are associated with higher risk of relapse (11).
  • In patients with severe ADAMTS13 deficiency, the risk of relapse is estimated to be 41% at 7.5 years, with the greatest risk being in the first year.
REFERENCES
1. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood. 2008;112(1):11-18.
2. Reese JA, Muthurajah DS, Kremer Hovinga JA, et al. Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features. Pediatr Blood Cancer. 2013;60(10):1676-1682.
3. George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354(18): 1927-1935.
4. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488-494.
5. 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.
6. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-1753.
7. Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher. 2014;29(3):148-167.
8. Yates S, Matevosyan K, Rutherford C, et al. Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report. Transfusion . 2014;54(8):2064-2067.
9. Beloncle F, Buffet M, Coindre JP, et al. Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Transfusion. 2012;52(11):2436-2444.
10. Kremer Hovinga JA, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115(8):1500-1511.
11. Peyvandi F, Lavoretano S, Palla R, et al. ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematologica. 2008;93(2):232-239.
Additional Reading
&NA;
George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654-666.
Codes
&NA;
ICD10
  • M31.1 Thrombotic microangiopathy
  • D69.42 Congenital and hereditary thrombocytopenia purpura
  • D69.3 Immune thrombocytopenic purpura
Clinical Pearls
&NA;
  • The diagnosis of TTP is made clinically; common symptoms are nonspecific: nausea, vomiting, weakness, abdominal pain, fatigue, fever, and easy bruising, purpura, or petechiae.
  • The historical pentad of fever, neurologic symptoms, renal dysfunction, MAHA, and thrombocytopenia is not present in most patients.
  • The dyad of MAHA and thrombocytopenia is sufficient to initiate treatment with PEX.
  • Do not wait for results of ADAMTS13 determination to initiate therapy.