Overview of TTP, ITP, DIC, and HUS with Treatment Approaches
Thrombotic Thrombocytopenic Purpura (TTP)
Immediate therapeutic plasma exchange (TPE) is the cornerstone of TTP treatment and must be initiated emergently, as untreated TTP is fatal. 1, 2
Pathophysiology and Clinical Features
- TTP results from autoantibody-mediated deficiency of ADAMTS-13, the von Willebrand factor cleaving protease 3, 4
- Classic pentad includes thrombocytopenia, microangiopathic hemolytic anemia, fever (89%), neurological abnormalities (82.8%), and renal dysfunction (78.5%), though only thrombocytopenia and microangiopathic hemolytic anemia are mandatory for diagnosis 2
- Median time to cardiovascular complications is 6 weeks but can range from 2-54 weeks 5
Primary Treatment
- Daily TPE with 1-1.5 plasma volumes using fresh frozen plasma as replacement fluid should continue until platelet count >150×10⁹/L and LDH normalizes, then slowly taper 2
- TPE achieves complete response in 85.3% of patients, with median 13-15 sessions required for responders 2
- Plasma infusion alone is inferior to plasma exchange, with higher failure rates (RR 2.87) and mortality (RR 1.91) 1
Adjunctive and Refractory Treatment
- Rituximab should be added for refractory TTP, with median response time of 10 days after first dose 6
- Ten of twelve patients treated with rituximab for refractory TTP responded, with nine remaining relapse-free after median 57+ months follow-up 6
- For patients with anaphylactic reactions to plasma, substitute with Octaplas (solvent/detergent-treated pooled plasma) or use albumin with slowly increasing plasma amounts 3
- Corticosteroids combined with TPE reduce mortality compared to TPE alone (3% vs 14%, p<0.001) 2
Critical Distinction from aHUS
- Distinguishing TTP from atypical HUS is now critical, as eculizumab (approved 2011) treats aHUS but not TTP 4
- ADAMTS-13 activity testing helps differentiate: severe deficiency (<10%) indicates TTP 4
Immune Thrombocytopenic Purpura (ITP)
Corticosteroids remain first-line therapy for ITP, with high-dose dexamethasone 40 mg/day for 4 days offering superior response rates (up to 90% initial, 50-80% sustained) compared to conventional prednisone. 7, 8
Treatment Indications and Goals
- Treat when platelet count <30×10⁹/L with bleeding risk, not to normalize counts 8, 9
- Target platelet count of 30-50×10⁹/L to reduce bleeding risk 8, 9
- Treatment rarely needed if platelets >50×10⁹/L unless active bleeding, surgery planned, bleeding comorbidities, or anticoagulation required 7, 8
First-Line Treatment Options
Corticosteroid Regimens:
- Prednisone 0.5-2 mg/kg/day produces initial response in 70-80% but sustained response in only 20-40% after discontinuation 7, 8, 9
- High-dose dexamethasone 40 mg/day for 4 days, repeated every 2-4 weeks for 1-4 cycles, achieves 90% initial response and 50-80% sustained response 7
- Four cycles of dexamethasone every 14 days produced 86% response rate with 74% having responses lasting median 8 months 7
- Strongly avoid prolonged corticosteroid courses exceeding 6-8 weeks due to substantial morbidity including osteoporosis, diabetes, hypertension, avascular necrosis, and opportunistic infections 7
Alternative First-Line:
- IVIg 1 g/kg single dose should be used with corticosteroids when rapid platelet increase required within 24 hours, or as monotherapy if corticosteroids contraindicated 8, 9
- IVIg 2 g/kg administered in divided doses per package insert 5
- IV anti-D 50-75 μg/kg for Rh(D) positive, non-splenectomized patients 5
Second-Line Treatment for Steroid-Refractory ITP
The choice between splenectomy, TPO-RAs, and rituximab depends on ITP duration and patient priorities:
For ITP <12 months duration:
- Prefer TPO-RAs over rituximab due to greater durability of response with ongoing use 5
- Delay splenectomy when possible due to potential for spontaneous remission in first year 5
For ITP >12 months duration:
- For patients avoiding long-term therapy: prefer rituximab over splenectomy despite splenectomy's superior durable response rates, due to operative risks and irreversible nature with long-term infection and thrombosis risks 5
- For patients preferring medical therapy: prefer TPO-RAs over rituximab due to greater durability of response 5
- For patients prioritizing durable response: either TPO-RAs or splenectomy are acceptable, with choice based on cost, accessibility, desire to avoid surgery, and desire to avoid long-term medication 5
Specific Second-Line Agents:
- Splenectomy offers 80% initial response and 66% sustained response for at least 5 years 8, 9
- TPO-RAs achieve 88% platelet response in non-splenectomized and 79% in splenectomized patients, but monitor for bone marrow reticulin formation 8, 9
- Rituximab produces sustained response >3-5 years in 15-20% of responders 5
- Azathioprine 150 mg/day achieves complete response in 45% of patients, though continued therapy generally required 5
- Cyclosporin A 2.5-3 mg/kg/day produces clinical improvement in >80% with 42% complete response, with mean 29-month durable remissions 5
Special Populations
- Pregnant patients: use only corticosteroids or IVIg 8, 9
- HIV-associated ITP: treat HIV with antivirals before other ITP treatments unless clinically significant bleeding 8, 9
- H. pylori-positive ITP: administer eradication therapy based on urea breath test, stool antigen, or endoscopic biopsy 8, 9
- Patients on antiplatelet therapy: target platelets >50×10⁹/L to compensate for increased bleeding risk 8, 9
Critical Pitfalls
- Plasmapheresis has no role in ITP—no chronic ITP patients showed response in studies 5
- Performing plasmapheresis immediately after IVIG removes immunoglobulin 5
- Must evaluate for TTP, DIC, and myelodysplastic syndrome when assessing thrombocytopenia 5
Disseminated Intravascular Coagulation (DIC)
DIC treatment focuses on addressing the underlying cause while providing supportive care, as no specific therapy reverses the coagulopathy without treating the precipitating condition.
Pathophysiology and Recognition
- DIC represents consumptive coagulopathy with simultaneous thrombosis and bleeding 5
- Must be distinguished from ITP and TTP when evaluating thrombocytopenia 5
- Presents with bleeding manifestations including nose/mouth bleeding, petechiae, and evidence of microvascular thrombosis 5
Treatment Approach
- Identify and aggressively treat underlying cause (sepsis, malignancy, obstetric complications, trauma)—this is the definitive treatment
- Transfusion support with platelets, fresh frozen plasma, and cryoprecipitate based on bleeding severity and laboratory parameters
- Maintain hemoglobin at minimum 10 g/dL to improve hemostasis 5
- Desmopressin may improve hemostasis independent of platelet count through direct vascular effects 5
Monitoring
- Serial coagulation studies including PT/PTT, fibrinogen, D-dimer, and platelet counts
- Assess for end-organ damage from microvascular thrombosis
Hemolytic Uremic Syndrome (HUS)
For typical post-diarrheal HUS in children, supportive care alone is the standard treatment, as no intervention has proven superior to supportive therapy. 1
Classification and Clinical Features
- Typical (post-diarrheal) HUS: follows Shiga toxin-producing bacterial infection, primarily affects children 1
- Atypical HUS (aHUS): complement-mediated, distinct from TTP, now treated with eculizumab 4
- Classic triad: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury 1
Treatment by Type
Post-Diarrheal HUS:
- Supportive care only: fluid management, electrolyte correction, blood pressure control, and renal replacement therapy if needed 1
- Seven RCTs in 476 children with post-diarrheal HUS showed no benefit from fresh frozen plasma transfusion, heparin with/without urokinase or dipyridamole, Shiga toxin-binding protein, or steroids over supportive therapy alone 1
- Monitor for chronic reduced kidney function, persistent proteinuria, and hypertension at follow-up 1
Atypical HUS:
- Eculizumab (approved 2011) is the specific treatment for aHUS 4
- Critical to distinguish from TTP, as treatment differs fundamentally 4
- ADAMTS-13 activity normal in aHUS (vs severely deficient in TTP) 4
Critical Distinction from TTP
- Both present with microangiopathic hemolytic anemia and thrombocytopenia 1, 4
- TTP requires immediate plasma exchange; aHUS requires eculizumab 4
- ADAMTS-13 testing is essential for differentiation 4
- Plasma exchange showed no benefit in post-diarrheal HUS 1