Thrombotic Thrombocytopenic Purpura, Emergency Medicine

Basics

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.

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 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

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 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 patients 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

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.

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)

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