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Thrombotic Thrombocytopenic Purpura, Emergency Medicine

Basics

Description

- Microvasculature obstruction with platelet aggregates leads to: - Red cell hemolysis - Accumulation of heme breakdown products - Anemia

- 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

- General: - Weakness - Fatigue - Fever - Malaise

- GI complaints: - Anorexia - Diarrhea - Abdominal pain

- Coagulation studies: - Peripheral blood smear: - Macroangiopathic changes - Schistocytes - Helmet cells - Nucleated RBCs

- Biopsy: - Confirms diagnosis - Reveals hyaline lesions in small vessels - Contraindicated during fulminant presentation (hemorrhage risk)

- HUS: - Triad of thrombocytopenia, schistocytosis, and renal dysfunction - Neurologic symptoms unusual - Often preceded by infectious prodrome and diarrhea

- Evans syndrome: - Autoimmune hemolytic anemia - Prominence of microspherocytes rather than schistocytes - Positive direct Coombs test

- 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

  • Thrombotic thrombocytopenic purpura (TTP) is a severe disorder of abnormal clotting affecting multiple organ systems.
  • Classically characterized by pentad of:ThrombocytopeniaHemolytic anemiaMild renal dysfunctionNeurologic signsFever
  • 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 treatmentReverses to >90% survival with modern treatment
  • Clinical presentations include:IdiopathicFamilial, chronic, or relapsingDrug induced:Allergic or immune mediated (quinine, ticlopidine, clopidogrel)Dose-related toxicity (mitomycin C, cyclosporine)Pregnancy, postpartum associated:Bone marrow transplantation associatedInfection
  • 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 plateletsWidespread microvascular hyaline thrombotic lesions
  • Microvasculature obstruction with platelet aggregates leads to:Red cell hemolysisAccumulation of heme breakdown productsAnemia
  • 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.

Diagnosis

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 fluctuatingHeadacheAltered mentation (confusion, stupor, coma)Behavioral or personality changesFocal sensory or motor deficits or aphasiaSeizuresSpontaneous intracranial hemorrhage
  • Renal insufficiency:Usually mildCreatinine <3 mg/dL
  • Fever:Occurs in acute episodes and prodromal syndromesFever is the least common feature
  • Rare for all components of pentad to be present in the same individual

History

  • General:WeaknessFatigueFeverMalaise
  • Hemorrhage:Easy bruisingEpistaxisMenorrhagiaGI bleedingLoss or change in vision
  • GI complaints:AnorexiaDiarrheaAbdominal pain
  • Neurologic:HeadacheConfusionSeizureBehavioral or personality changesFocal 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:ThrombocytopeniaMicroangiopathic hemolytic anemiaExclude 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/dLThrombocytopenia <20,000/mm3Increased reticulocyte count
  • Coagulation studies:
  • Peripheral blood smear:Macroangiopathic changesSchistocytesHelmet cellsNucleated RBCs
  • Coombs test:Negative direct Coombs test
  • Electrolytes, BUN, creatinine, glucose:Mild elevation of BUN, creatinineHyperkalemia 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 diagnosisReveals hyaline lesions in small vesselsContraindicated during fulminant presentation (hemorrhage risk)
  • EEG:To predict need for anticonvulsant therapy

Differential Diagnosis

  • HUS:Triad of thrombocytopenia, schistocytosis, and renal dysfunctionNeurologic symptoms unusualOften preceded by infectious prodrome and diarrhea
  • Disseminated intravascular coagulation (DIC):Causes deposition of fibrin in microvasculature and not hyalineCoagulation studies abnormal
  • Idiopathic thrombocytopenic purpura (ITP):No evidence of hemolysisLDH and bilirubin normal
  • Pregnancy-related thrombocytopenia:Preeclampsia, eclampsiaPregnancy-associated hemolysisHELLP (hemolysis, elevated liver enzymes, and low platelets)
  • Evans syndrome:Autoimmune hemolytic anemiaProminence of microspherocytes rather than schistocytesPositive 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

Treatment

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 proceduresMay 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 TTPSuccess rate approaching 64%Provides a platelet-antiaggregating factor absent or diminished in patients own serumUsed prophylactically to prevent recurrence in chronic relapsing variant
  • Plasma exchange transfusions:Most important component of treatmentCombination of plasmapheresis and FFP infusionPlasmapheresis removes:Immune complexes responsible for endothelial damage and initiation of TTPCirculating proaggregation factors promoting platelet aggregationPerform daily until:Platelet count normalizesNeurologic symptoms improveLDH normalizesImprovement 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 sicknessSecondary infectionHypotension
  • Corticosteroids:Unproven therapeutic benefitMay limit immunologically mediated endothelial damage and decrease splenic sequestration of platelets and damaged RBCsSupportive benefit if adrenal glands damaged through hemorrhage or ischemia
  • Antiplatelet or immunosuppressive drugs:Aspirin and dipyridamole most commonly usedUse of sulfapyrazine, dextran, and vincristine has been reported.Used with variable effectivenessCan worsen bleeding complications
  • Splenectomy:Historically recommendedOf uncertain efficacy
  • Dialysis:

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

Follow-Up

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.

Followup Recommendations

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

Pearls and Pitfalls

  • 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.

Additional Reading

  • 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

Codes

ICD9

446.6 Thrombotic microangiopathy

ICD10

M31.1 Thrombotic microangiopathy

SNOMED

  • 78129009 Thrombotic thrombocytopenic purpura (disorder)
  • 439007008 Acquired thrombotic thrombocytopenic purpura
  • 441322009 Drug induced thrombotic thrombocytopenic purpura
  • 438476003 Autoimmune thrombotic thrombocytopenic purpura (disorder)