eMedicine Specialties > Emergency Medicine > Hematology & Oncology
Thrombotic Thrombocytopenic Purpura: Treatment & Medication
Updated: Sep 16, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Emergency Department Care
Practice diagnostic criteria for initiating therapy are thrombocytopenia, schistocytosis, and significant elevations in serum LDH levels.
- Thrombocytopenia - Platelets
- Schistocytosis - Peripheral smear
- Elevated serum LDH levels
- Look for other disease entities that could explain the thrombocytopenia and microcytic hemolytic anemia such as disseminated intravascular coagulation (DIC).
- Once thrombotic thrombocytopenic purpura (TTP) is included in the differential diagnosis and other causes are eliminated, contact a hematologist. As a team, the patient is managed with plasma exchange, antiplatelet agents (eg, dipyridamole, aspirin, steroids), and supportive care for the various complaints. Splenectomy for refractory cases is not an emergency medicine issue. Survival rate and prognosis are poor, and, in most instances, the chance for survival is time-specific.
Plasma exchange
Use a device with a wide-bore, 2-lumen catheter at the femoral site. Use blood-cell separators so that the patient's plasma is removed and replaced by standard replacement fluid, fresh frozen plasma (FFP), to eliminate ADAMTS-13 autoantibodies. Start with a single plasma volume and exchange FFP at a rate of 40 mL/kg of body mass. A plasma exchange twice a day may be necessary for resolution of thrombocytopenia and neurologic complications if the response to the initial daily exchange is poor. The procedure may be repeated for days to weeks for effect. The target platelet level is 150,000/m L, although this number is variable. A declining lactate dehydrogenase level indicates a positive response to treatment. Complications include death, systemic infections, allergic reaction, catheter or venous thrombosis, serum sickness, fever, and hypocalcemia from citrate.2
Infusion of high-dose FFP (30 mL/kg) is used as a temporizing measure until the patient can be transferred to a facility where plasma exchange is available. Patients with congenital TTP undergo infusion therapy using 10-15 mL of FFP per kg of body weight every 2-3 weeks.24
Other treatments
Cryosupernatant is the residual plasma fraction after the separation of cryoprecipitate that can be used in plasma exchange, but it has not been found to be better than FFP.
Antiplatelet agents aspirin and dipyridamole have been used since the 1970s, but their use is controversial. Hemorrhage is a concern, and these agents' benefit has not been proven. Other antiplatelet agents (eg, ticlopidine, prostacyclin) have variable outcomes.
Platelet-depleted packed RBCs may be necessary for severe hemolytic anemia.
Splenectomy sequesters red blood cells, platelets, and B cells that produce antibodies to VWF-cleaving protease.2 Splenectomy is performed occasionally to treat patients who do not respond to plasma exchange or who relapse chronically. Some patients benefit from splenectomy and others do not. The spleen is a major site of microvascular occlusive lesions in severe TTP.
Hemodialysis as supportive care for end-organ damage may be required.
Medications including angiotensin-converting enzyme (ACE) inhibitors, nitroprusside, or esmolol may be required to control severe hypertension. Anticonvulsants, such as phenytoin, may be required to control seizures.
Contraindications
Platelet transfusion is contraindicated because it is associated with rapid deterioration. The platelet aggregation worsens with platelet transfusions. In some studies, extensive platelet aggregates were found throughout the CNS on postmortem examination.
Heparin and fibrinolytic agents are contraindicated due to their increase bleeding risk and ineffectiveness.2
Desmopressin (DDAVP) is contraindicated because it acts by releasing ULVWF from the endothelium into the circulating blood.
Consultations
Early consultation with a hematologist is beneficial because of the diagnostic and management complexity of TTP.
The differential diagnosis is extensive for thrombocytopenia, but early recognition of TTP is essential for the patient's survival.
Medication
The goal of therapy is to reduce destruction of platelets.
Glucocorticoids
These agents have immunosuppressant activity.
Prednisone (Sterapred)
Glucocorticoids inhibit phagocytosis of antibody-covered platelets. Treatment of hemolytic anemia during pregnancy is conservative unless disease is severe (use lowest dose of glucocorticoids). In neonates, if platelet count drops below 50-75 X 109/L, consider prednisone and exchange transfusions of immune globulin.
Adult
1-2 mg/kg/d PO divided bid/qid; until remission occurs
Pediatric
4-5 mg/m2/d PO; alternatively, 1-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur
Immunosuppressant agents
These agents inhibit key factors involved in immune reactions. In addition to the drugs listed below, treatment of refractory or relapsing TTP includes vincristine, a second-line therapy with an unknown mechanism of action. Vincristine is occasionally given to treat resistant cases, but it has no proven benefit. Dosing is 1 mg/m2, with a maximum dose of 2 mg, given weekly.
Rituximab (Rituxan)
Indicated to reduce signs and symptoms for moderately-to-severely active rheumatoid arthritis in combination with methotrexate. For use in adults who have experienced an inadequate response to one or more TNF antagonist therapies. Antibody genetically engineered. Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of B lymphocytes.
Adult
1000 mg IV infusion for 2 doses, separated by 2 wk; administer methylprednisolone 100 mg IV (or its equivalent) 30 min before each infusion to reduce infusion related reactions
Do not exceed infusion rate of 50 mg/h initially; if hypersensitivity or infusion-related reactions do not occur, may escalate infusion rate by 50 mg/h increments q30min; not to exceed 400 mg/h
Pediatric
Not established
Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Documented hypersensitivity; IgE-mediated reaction to murine proteins
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use with caution in patients with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion, do not administer IV push or bolus
Cyclophosphamide (Cytoxan, Neosar)
Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic.
When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.
In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T-cell functions.
Adult
500-750 mg/m2 IV qmo
Pediatric
Administer as in adults
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; severely depressed bone marrow function
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Cyclosporine (Neoral, Sandimmune)
An 11-amino acid cyclic peptide and natural product of fungi. Acts on T-cell replication and activity.
Specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle suggested.
Binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin 2 and the subsequent recruitment of activated T cells.
Has about 30% bioavailability, but there is marked interindividual variability. Specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.
Suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.
Adult
Clinical and immunological effects correlate with serum concentration, and dose usually adjusted to achieve trough serum level of 100-200 ng/mL (as determined by HPLC)
4-10 mg/kg/d PO in 2-3 divided doses has been used
Pediatric
Administer as in adults
Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another resulting in increased plasma levels of each drug
Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO
More on Thrombotic Thrombocytopenic Purpura |
| Overview: Thrombotic Thrombocytopenic Purpura |
| Differential Diagnoses & Workup: Thrombotic Thrombocytopenic Purpura |
 Treatment & Medication: Thrombotic Thrombocytopenic Purpura |
| Follow-up: Thrombotic Thrombocytopenic Purpura |
| Multimedia: Thrombotic Thrombocytopenic Purpura |
| References |
| « Previous Page | Next Page » |
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Further Reading
Keywords
thrombocytopenic purpura, Moschcowitz disease, thrombotic thrombocytopenic purpura, TTP, multisystem disorder, plasma exchange, fresh-frozen plasma, FFP, microangiopathic hemolytic anemia, hemolytic uremic syndrome, HUS, familial thrombotic thrombocytopenic purpura, familial TTP, acquired idiopathic thrombotic thrombocytopenic purpura, acquired idiopathic TTP, von Willebrand factor multimers, vWF, vWF multimers, vWF-cleaving protease, anemia, petechiae, microscopic hematuria, disseminated microvascular thrombi, thrombocytopenia, renal dysfunction, Escherichia coli, E coli O157:H7, Shigalike toxin, microangiopathic hemolysis, platelet microthrombi, ultralarge von Willebrand factor multimers, ULVWF multimers, ADAMTS-13 gene mutations, ULVWF multimer–induced platelet thrombosis, ULVWF-cleaving protease, petechial hemorrhages, seizures, CNS bleeding, heart failure, arrhythmias, gross hematuria, purpuric spots, plasmapheresis, plasma transfusion, thrombotic microangiopathic
