Thrombotic Micro Angiopathies- TTP, HUS Flashcards
(19 cards)
Q. Pathophysiology
Formation of small clots within microvasculature → leads to:
Erythrocyte fragmentation → Microangiopathic Hemolytic Anemia (MAHA)
Diagnostic features of Acute TMA
Key Diagnostic Features of Acute TMA
- Schistocytes on peripheral blood smear:
- Pathological level: >0.5–1%
- Must exclude alternative causes (e.g., Impella, ECMO, LVAD, mechanical valves)
- Elevated Lactate Dehydrogenase (LDH):
* >1.5× upper limit of normal (~>420 IU/L)
* Reflects both hemolysis and organ injury
* LDH <420 IU/L: Casts doubt on TMA
-Used as a threshold to stop plasma exchange in TTP - Thrombocytopenia:
* Platelets <150,000/µL (or <100,000 in pregnancy)
* OR ≥25% drop from patient’s baseline - Ischemic tissue damage from microvascular occlusion:
* Organs affected may include:
* Kidney
* Brain
* Heart
* Lungs
* Gastrointestinal tract
* Skin
* Acute kidney injury (AKI) may also occur from plasma-free hemoglobin
Causes of TMA
- TTP
2.HUS(complement mediated
3.HUS (shiga toxin mediated)
4.CAPLA
5.Infections
6.Malignancy
7.Transplant
8.Immunosuppression
9.Drugs
10.HITTS
11.DIC
12.Malignant HTN
13.Scleroderma
14.Other non TMA mimics -eg- vit B12 def
- Thrombotic Thrombocytopenic Purpura (TTP)
Q.Key lab findings
Q.type of vessels inv.
Q.organs inv.
- Labs: Low ADAMTS13, severe thrombocytopenia (<30), profuse schistocytes, normal PT/PTT
- Vessels: Small
- Organs: Mild renal (Cr <2.5), CNS, heart, GI (n/v, diarrhea)
Complement-mediated HUS
(C-HUS)
Q.Triggers
Q.Key lab findings
Q.type of vessels inv.
Q.organs inv.
- Triggers: Pregnancy, malignant HTN, stem cell transplant
- Labs: Schistocytes, platelets >30, normal PT/PTT
- Vessels: Small
- Organs: Kidneys, GI (n/v, diarrhea)
Shiga-toxin HUS
Q.Triggers
Q.Key lab findings
Q.type of vessels inv.
Q.organs inv.
- Trigger: Diarrhea (E. coli O157:H7, Shigella)
- ⚠️ Diarrhea also occurs in C-HUS
- Labs: Schistocytes, normal PT/PTT
- Vessels: Small
- Organs: Kidneys only
Catastrophic Antiphospholipid Syndrome (CAPS)
Q.Triggers
Q.Key lab findings
Q.type of vessels inv.
Q.organs inv.
- Triggers: APLS, lupus, pregnancy, infection, trauma, malignancy
- Labs: Antiphospholipid Ab, scant schistocytes, possible DIC, ↑PTT, ↑ferritin
- Vessels: Small ± large
- Organs: Kidney, CNS, heart, lungs, skin necrosis
Infection-Associated TMA
Q. Common pathogens
- Pathogens:
- S. pneumoniae (positive DAT)
- Klebsiella, RMSF, malaria, babesia, histoplasmosis
- Viruses: HIV, CMV, EBV, HCV, influenza, COVID
- ⚠️ Infection can trigger other TMAs (TTP, C-HUS, CAPS, DIC)
Malignancy-Associated TMA
Q. common causes
.
* Microvascular tumor emboli (gastric, breast, lung, etc.)
* Hematologic cancers
* Chemo-related (see drug-induced)
* CAPS trigger
* Infection post-chemotherapy
Transplant-Associated TMA
Q. Mechanisms
- Recurrence of C-HUS
- Antibody-mediated rejection
- GVHD or its treatment
- Calcineurin inhibitors
- Myeloablative chemotherapy
- Opportunistic infections (CMV)
Drug-Induced TMA
Q.Mechanisms
Q.Treatment
- 5a. TTP-like: Thienopyridines (clopidogrel), quetiapine
- 5b. Immune-mediated (acute): Quinine, TMP-SMX, metronidazole, penicillins, vancomycin, chemo (gemcitabine), biologics (adalimumab)
- 5c. Non-immune (toxic):
- Immunosuppressants: Cyclosporine, tacrolimus, mTOR inhibitors, IFN
- Substances: Cocaine, IV oxycodone, MDMA
- Cancer drugs: Proteasome inhibitors, VEGF inhibitors, TKI, vincristine
- Others: Emicizumab, simvastatin, valproate
- Treatment: TTP-like—PEX; otherwise supportive ± complement inhibition
Heparin-Induced Thrombocytopenia (HIT)
Q. Trigger
Q.Labs
Q.vessels involved
- Trigger: Heparin (UFH > LMWH), post-surgery
- Labs: +/- schistocytes, anti-PF4 antibodies
- Vessels: Small ± large
Malignant Hypertension
Q. clues
Q.Labs
Q. vessels involved
Q.Organs affected
- Clues: Men >45, LVH, severe HTN (MAP >135), abrupt cessation of meds
- Response: Improves with BP control
- Labs: Some schistocytes (not profuse), not severely low platelets
- Vessels: Small
- Organs: Kidney, brain
Disseminated Intravascular Coagulation (DIC)
Q. Trigger
Q.Labs
Q.vessels involved
Q.Organs affected
- Triggers: Sepsis, trauma, obstetric issues, malignancy
- Labs: ↑PT/PTT, ↑D-dimer, ↓fibrinogen, +/- schistocytes
- Vessels: Small ± large
- Organs: Skin necrosis, renal failure, adrenal infarct, ARDS
Scleroderma Renal Crisis
Q.Triggers
Q.Labs
Q.Vessels involved
- Trigger: Scleroderma (can be presenting feature)
- Labs: +/- schistocytes
- Vessels: Small
Non-TMA Mimics
- B12 deficiency: Macrocytic anemia, low retic index, empiric PEX may be tried
- Mechanical fragmentation: Prosthetic valves, TIPS, VADs
How will you Investigate for TMA?
🧪 Initial Laboratory Workup
* CBC with differential
* Hemolysis panel:
- Manual blood smear
- LDH (↑ with hemolysis and tissue damage)
- Haptoglobin (↓ in hemolysis)
- Direct antiglobulin test (DAT/Coombs): Usually negative in TMA, but, Can be positive in pneumococcal-associated TMA
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🧬 Disseminated Intravascular Coagulation (DIC) Panel
* INR
* PTT
* Fibrinogen
* D-dimer
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🏥 End-Organ Damage Evaluation
* Liver function tests (including indirect bilirubin)
* Troponin & ECG (cardiac involvement)
* Urinalysis & urine microscopy (renal involvement)
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👩⚕️ Additional Screening Tests
* Pregnancy test (when appropriate)
* Infectious workup:
- Blood cultures
* Other relevant tests:
- HIV testing
- Urine pneumococcal antigen
⸻
🔬 Specific Diagnostic Tests
* ADAMTS13 testing:
- ADAMTS13 antigen level
- Anti-ADAMTS13 antibody or inhibitor
* Autoimmune testing:
- ANA (antinuclear antibody)
*Stool testing for Shiga toxin (for HUS):
-Stool PCR for Shiga toxin genes
- Stool culture
- Stool bioassay for Shiga toxin
* ⚠️ Indicated for all patients with TMA and renal failure—even in absence of diarrhea
⸻
📌 Other Investigations (Case-Dependent)
* Skin biopsy (if skin lesions present)
* Renal biopsy (to confirm TMA or exclude other causes)
* Vitamin B12 level (if B12 deficiency suspected)
* CAPS (Catastrophic Antiphospholipid Syndrome) panel:
- Anticardiolipin antibodies (IgG & IgM)
- Anti-β2-glycoprotein I (IgG & IgM)
* Dilute Russell viper venom time (DRVVT)
Interpretation of Labs to Elucidate TMA Etiology
🧠
Platelet Count
* <30,000: Suggests TTP
* >30,000: More consistent with C-HUS
Coagulation Parameters
* Normal INR/PTT/fibrinogen: Suggests classic TMA
* Abnormal labs: Suggest DIC, sepsis, CAPS
* Isolated ↑PTT: Suggests lupus anticoagulant
Renal Function
* Mild/No AKI: Suggests TTP
* Severe AKI: Suggests C-HUS, ST-HUS, CAPS, scleroderma renal crisis, drug-induced TMA
Urinalysis
* Muddy brown casts: Acute tubular necrosis → non-TMA
* RBC casts: Suggests glomerulonephritis-related TMA
⸻
🧬 ADAMTS13 Testing
* <10% activity: Highly suggestive of TTP
* 10–20%: Suspicious, especially post-PEX
* 10–60%: Seen in inflammatory states or HUS
* >60%: Excludes TTP
Inhibitor Testing
* Detects acquired TTP (autoantibodies inhibit ADAMTS13)
* Negative inhibitor but low ADAMTS13: Could be clearance-type antibody
ELISA for Anti-ADAMTS13 Ab
* Increases sensitivity for acquired TTP (less specific)
⸻
🧪 ANA & Autoimmune Clues
* Positive ANA may suggest:
* TTP (common; up to 50%)
* CAPS
* Lupus nephritis or lupus-associated TMA (10% of lupus nephritis cases)
* Lupus may present with multiple TMA types (C-HUS, TTP, CAPS, hypertensive emergency)
Q. Key principles for empiric therapy for
⚠️ Empiric Therapy of TMA:
Key Principles
* Timing is critical: Treatment should not be delayed while awaiting lab results (e.g., ADAMTS13), which can take time.
* Empiric treatment is guided by clinical suspicion, based on labs, organ involvement, and presentation.
* As data returns (e.g., ADAMTS13 results), the initial treatment approach may be adjusted.
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⚡️ Empiric Therapy for Suspected TTP
* Start plasma exchange (PEX) immediately if TTP is suspected.
* Often combined with:
* High-dose corticosteroids
* Caplacizumab (where available)
* Rationale: TTP is rapidly fatal if untreated, but highly treatable with early intervention.
⸻
⚡️ Empiric Therapy for Suspected C-HUS
* Start eculizumab if C-HUS is strongly suspected:
* Especially in patients with:
* Severe renal failure
* Less profound thrombocytopenia
* Normal ADAMTS13 activity
* Eculizumab blocks complement activation (C5 inhibition).
* Can be started empirically and discontinued if alternative diagnosis becomes clear.
