DESCRIPTION

• Thrombotic thrombocytopenic purpura (TTP) is a severe disorder of abnormal clotting affecting multiple organ systems.
• Classically characterized by pentad of:
  • Thrombocytopenia
  • Hemolytic anemia
  • Mild renal dysfunction
  • Neurologic signs
  • Fever
• Uncommon to see all 5 features in 1 patient; if present, severe end-organ damage or ischemia has likely taken place.
• Thrombocytopenia and hemolytic anemia are the most common features.
• Associated with acquired or congenital deficiency of plasma von Willebrand factor–cleaving protease (VWFcp)
• Patients who present with severe neurologic abnormalities with acute renal failure are best described by the comprehensive term TTP-HUS

Classic Course

• Acute onset
• Fulminant course lasting days to a few months
• Nearly always fatal without treatment:
  • > 90% mortality without treatment
  • Reverses to > 90% survival with modern treatment
• Clinical presentations include:
  • Idiopathic
  • Familial, chronic, or relapsing
  • Drug induced:
    • Allergic or immune mediated (quinine, ticlopidine, clopidogrel)
    • Dose-related toxicity (mitomycin C, cyclosporine)
  • Pregnancy, postpartum associated:
    • 10–25% of cases
  • Bone marrow transplantation associated
  • Infection
• More common in the 3rd–6th decades of life
• Uncommon in pediatric or geriatric populations
• Women affected about twice as frequently as men

ETIOLOGY

• Unknown primary stimulant; possibly systemic endothelial cell damage results inactivation of coagulation pathway
• Platelet aggregation and fibrin deposition occurring in arterioles and capillaries leading to microthrombi and obstruction to blood flow
• Platelet aggregation leads to:
  • Consumption of platelets
  • Widespread microvascular hyaline thrombotic lesions
• Microvasculature obstruction with platelet aggregates leads to:
  • Red cell hemolysis
  • Accumulation of heme breakdown products
  • Anemia
• End-organ ischemia results from diffuse thrombosis in small vessels:
  • Most common in heart, brain, kidney, pancreas, and adrenal glands
• Deficiency of vWFcp causes failure of control of coagulation pathway.

RISK FACTORS

Genetics

• Some cases are genetic/familial.
• VWFcp was recently identified as new member of ADAMTS family and designated ADAMTS13.
• Mutations in ADAMTS13 gene cause autosomal recessive form of chronic relapsing TTP.

[Outline]

• DESCRIPTION
• ETIOLOGY
• RISK FACTORS

SIGNS AND SYMPTOMS

5 major clinical features: Classic pentad

• Thrombocytopenia:
  • Platelet count < 20,000/mm³
• Microangiopathic and hemolytic anemia:
  • Hb < 10 g/dL (< 6 g/dL in 40%)
• Neurologic symptoms:
  • Presenting complaint in 60%, occur in 90%
  • Typically fluctuating
  • Headache
  • Altered mentation (confusion, stupor, coma)
  • Behavioral or personality changes
  • Focal sensory or motor deficits or aphasia
  • Seizures
  • Spontaneous intracranial hemorrhage
• Renal insufficiency:
  • Usually mild
  • Creatinine < 3 mg/dL
• Fever:
  • Occurs in acute episodes and prodromal syndromes
  • Fever is the least common feature
• Rare for all components of pentad to be present in the same individual

History

• General:
  • Weakness
  • Fatigue
  • Fever
  • Malaise
• Hemorrhage:
  • Easy bruising
  • Epistaxis
  • Menorrhagia
  • GI bleeding
  • Loss or change in vision
• GI complaints:
  • Anorexia
  • Diarrhea
  • Abdominal pain
• Neurologic:
  • Headache
  • Confusion
  • Seizure
  • Behavioral or personality changes
  • Focal sensory or motor deficits or aphasia

Physical Exam

• Purpura
• GI hemorrhage
• Epistaxis
• Jaundice
• Shock
• Altered mental status
• Focal sensory or motor deficits
• Pulmonary infiltrates and edema
• Alteration of vision, retinal hemorrhage/detachment.
• Abnormalities of cardiac conduction

ESSENTIAL WORKUP

Clinical Diagnosis

• Because of success of treatment, base diagnosis on:
  • Identification of 2 major findings:
    • Thrombocytopenia
    • Microangiopathic hemolytic anemia
  • Exclude other major differential diagnoses.
• Comprehensive history and physical exam with directed lab testing
• Identify possible drug-associated disease and avoid re-exposure.

DIAGNOSIS TESTS & INTERPRETATION

Lab

• CBC/platelet count/reticulocyte count:
  • Anemia: Hemoglobin < 10 g/dL
  • Thrombocytopenia < 20,000/mm³
  • Increased reticulocyte count
• Coagulation studies:
  • Normal
• Peripheral blood smear:
  • Macroangiopathic changes
  • Schistocytes
  • Helmet cells
  • Nucleated RBCs
• Coombs test:
  • Negative direct Coombs test
• Electrolytes, BUN, creatinine, glucose:
  • Mild elevation of BUN, creatinine
  • Hyperkalemia owing to RBC lysis
• Lactate dehydrogenase (LDH):
  • Elevated 5–10 times due to hemolysis and tissue ischemia
• Bilirubin:
  • Increased unconjugated bilirubin
• Urinalysis:
  • Hematuria (microscopic to gross)
• ADAMTS13 assay may be used to distinguish chronic recurring TTP, TTP secondary to presence of ADAMTS13 inhibitor, and hemolytic-uremic syndrome (HUS):
  • ADAMTS13 deficiency does not detect all patients who may respond to plasma exchange transfusions.

Imaging

• CT head:
  • To rule out intracranial hemorrhage

Diagnostic Procedures/Surgery

• Biopsy:
  • Confirms diagnosis
  • Reveals hyaline lesions in small vessels
  • Contraindicated during fulminant presentation (hemorrhage risk)
• EEG:
  • To predict need for anticonvulsant therapy

DIFFERENTIAL DIAGNOSIS

• HUS:
  • Triad of thrombocytopenia, schistocytosis, and renal dysfunction
  • Neurologic symptoms unusual
  • Often preceded by infectious prodrome and diarrhea
• Disseminated intravascular coagulation (DIC):
  • Causes deposition of fibrin in microvasculature and not hyaline
  • Coagulation studies abnormal
• Idiopathic thrombocytopenic purpura (ITP):
  • No evidence of hemolysis
  • LDH and bilirubin normal
• Pregnancy-related thrombocytopenia:
  • Preeclampsia, eclampsia
  • Pregnancy-associated hemolysis
  • HELLP (hemolysis, elevated liver enzymes, and low platelets)
• Evans syndrome:
  • Autoimmune hemolytic anemia
  • Prominence of microspherocytes rather than schistocytes
  • Positive direct Coombs test
• Malignant hypertension
• Bacterial sepsis
• Subacute bacterial endocarditis
• Autoimmune disorders (e.g., systemic lupus erythematosus [SLE])
• Disseminated malignancy
• Heparin-associated thrombocytopenia
• Prosthetic valves or severely calcified aortic stenosis

[Outline]

• SIGNS AND SYMPTOMS
• ESSENTIAL WORKUP
• DIAGNOSIS TESTS & INTERPRETATION
• DIFFERENTIAL DIAGNOSIS

PRE-HOSPITAL

• ABCs
• Evaluate for other possible causes of altered mental status (hypoglycemia, overdose)

INITIAL STABILIZATION/THERAPY

• ABCs
• 0.9% normal saline (NS) IV fluid resuscitation for shock or GI hemorrhage
• RBC transfusions:
  • For significant anemia or bleeding complications
• Platelet transfusions:
  • Reserve for life-threatening hemorrhage (e.g., CNS bleeds) or required invasive procedures
  • May aggravate the thrombotic, microvascular obstructive process and worsen the end-organ ischemia and shock

ED TREATMENT/PROCEDURES

• Fresh frozen plasma (FFP) or fresh unfrozen plasma:
  • Initiated as bridge to exchange transfusions on diagnosis of TTP
  • Success rate approaching 64%
  • Provides a platelet-antiaggregating factor absent or diminished in patient's own serum
  • Used prophylactically to prevent recurrence in chronic relapsing variant
• Plasma exchange transfusions:
  • Most important component of treatment
  • Combination of plasmapheresis and FFP infusion
  • Plasmapheresis removes:
    • Immune complexes responsible for endothelial damage and initiation of TTP
    • Circulating proaggregation factors promoting platelet aggregation
  • Perform daily until:
    • Platelet count normalizes
    • Neurologic symptoms improve
    • LDH normalizes
  • Improvement of renal function may lag behind other findings.
  • Taper frequency based on empiric judgment of response; may need to resume if relapse occurs.
  • Complications include:
    • Allergy or serum sickness
    • Secondary infection
    • Hypotension
• Corticosteroids:
  • Unproven therapeutic benefit
  • May limit immunologically mediated endothelial damage and decrease splenic sequestration of platelets and damaged RBCs
  • Supportive benefit if adrenal glands damaged through hemorrhage or ischemia
• Antiplatelet or immunosuppressive drugs:
  • Aspirin and dipyridamole most commonly used
  • Use of sulfapyrazine, dextran, and vincristine has been reported.
  • Used with variable effectiveness
  • Can worsen bleeding complications
• Splenectomy:
  • Historically recommended
  • Of uncertain efficacy
• Dialysis:
  • For renal failure

MEDICATION

• Aspirin: 325–650 mg PO q4–6h
• Dipyridamole: 75–100 mg PO QID
• FFP:
  • Plasma infusion: 30 mL/kg/d (75–100 mL/h)
  • Plasma exchange transfusion: 3–4 L/d
• Methylprednisolone: 0.75 mg/kg q12h
• Prednisone: 1–2 mg/kg/d (high dose up to 200 mg/d)
• Rituximab: 375 mg/m² IV once per week for 4–8 doses
• Vincristine: 1.4 mg/m² once per week IV

[Outline]

• PRE-HOSPITAL
• INITIAL STABILIZATION/THERAPY
• ED TREATMENT/PROCEDURES
• MEDICATION

DISPOSITION

Admission Criteria

• Newly diagnosed serious platelet disorder, especially with bleeding complications or altered mental status or renal dysfunction
• ICU admission for TTP with active bleeding or neurologic findings:
  • Transport to tertiary care center with appropriate specialty care facilities.

FOLLOW-UP RECOMMENDATIONS

Patients with known disease and found to be stable may follow up with a hematologist.

[Outline]

• DISPOSITION
• FOLLOW-UP RECOMMENDATIONS

• TTP can be confused with HELLP syndrome in pregnant females.
• Because of the high mortality of untreated TTP, recognition of the disease and initiation of treatment is key.

ICD9

446.6 Thrombotic microangiopathy

ICD10

M31.1 Thrombotic microangiopathy

[Outline]

• ICD9
• ICD10

• George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927–1935.
• George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010;116:4060–4069.
• George JN, Woodson RD, Kiss JE, et al. Rituximab therapy for thrombotic thrombocytopenic purpura: A proposed study of the Transfusion Medicine/Hemostasis Clinical Trials Network with a systematic review of rituximab therapy for immune-mediated disorders. J Clin Apher. 2006;21:49–56.
• Kremer Hovinga JA, Meyer SC. Current management of thrombotic thrombocytopenic purpura. Curr Opin Hematol. 2008;15(5):445–450.

See Also (Topic, Algorithm, Electronic Media Element)

• Disseminated Intravascular Coagulation
• HELLP Syndrome
• Idiopathic Thrombocytopenia
• Renal Failure

Hany Y. Atallah