Thrombotic Trombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura

by Trevor Wilson, MD

Thrombocytopenia Differential:
- decreased production
- Splenic sequestration (rare)
- Increased destruction
  - Immune:
    - ITP:
      - Acute – children (2-6 y/o), supportive care, steroids/IgG if bleeding
      - Chronic – diagnosis of exclusion. Hospitalize given risk of bleeding. Stop all meds. Steroids. IgG.
    - lupus
    - Malignancy
    - medication (quinine coats platelets with drug-Ab and “innocent bystander mechanism causes platelets destruction), digitoxin, sulfonamides, phenytoin, ASA, cocaine
    - Post transfusion
    - Heparin Induced Thrombocytopenia (LMWH>UFH, usually 5-7 days after, prothrombotic)
  - Non-immune:
    - Consumptive
    - Mechanical
    - TTP

Thrombotic Thrombocytopenic Purpura

This illness script mostly from Marx, Walls, and Hockberger 2013
Epidemiology: Majority 10-40 y/o, 2:1 F/M. 2-6 p / million.
RFs: pregnancy, peri-partum, AA, obesity, HLA-DRB1
Patho:
- Subendoteial and intraluminal deposits of fibrin and platelets aggregates in capillaries/arterioles
- autoantibodies (IgG > IgA/IgM) against ADAMTS13
- ADAMTS13 – VWF (platelet adhesion) cleaving protease.
- Low ADAMTS13 -> “unusually large” “unregulated” rough VWF -> prothrombotic, microvascular thrombotic state

(Kaushansky et al. 2015)

Precipitants: quinine (malaria med), antiplatelet agents (clopidogrel), antecedent URI, idiopathic
Symptoms:
- Purpura or petechiae, bleeding, neuro sz (all and any), abd pain, n/v/d
- Timing: acute or insidious.
Signs: fever, anemia, jaundice, schistocytes, +/-hematuria/AKI
DDx (for thrombocytopenia):
- Spectrum of HUS to TTP. HUS w/ oliguric renal failure, prodrome of diarrhea. TTP w/ neuro.
- Other MAHAs (e.g. DIC)
- ITP
- Sepsis
- SLE
- HELLP (LFTs higher in HELLP. Anemia/platelets/LDH more abnormal in TTP)
- Non-acute etiologies for thrombocytopenia
Diagnosis:
- “Classic Pentad not commonly seen”
- “FAT RN” Pneumonic
  - Fever
  - Anemia
  - Thrombocytopenia
  - Renal
  - Neuro Sx
- Diagnosis:
  - thrombocytopenia AND microangiopathic hemolytic anemia w/o other cause. Thrombocytopenia w/o hemolysis may herald onset of dz (Kaushansky et al. 2015)
    - Platelets: 20k / mm^3 avg (10-50k)

- - - MAHA: schistocytes (fragmented RBCs, “helmeted cells”)
  - Fever (in 90% of pts)
  - Anemia 30%
    - Hg 8 (avg)
  - Neuro 50%
    - classically fluctuating neruo sx: “coma, headache, visual disturbances, vertigo, personality change, confusion, lethargy, syncope, coma, seizures, aphasia, hemiparesis, and other focal sensory or motor deficits”
  - Macrovascular thrombosis 50%, Mesenteric ischemia, MI
Diagnostically:
- Labs:
  - To help rule in/out (parenthetically expected in TTP):
    - Hemolysis labs: retic (high), LDH (high – released in hemolysis), haptoglobin (low), bili (high), schistocytes (8.3% avg in TTP. >1% suspect TTP over mechanical hemolysis)
    - ADAMTS13 (< 10%), most specific but not 100% unique to TTP
    - Direct Coombs neg (suggesting Ab’s are not attacking rbc’s)
    - ANA (50% +)
    - Eval for DIC: fibrinogen (norm), PT/PTT (norm)
    - Eval for sepsis: lactate (norm), cultures (neg), UA, imaging
    - Eval for HUS: Cr (usually <2), Shiga toxin
  - Review of DIC:
    - Low: fibrinogen (degraded), haptoglobin (used up), platelets
    - High: PT/INR/PTT, FDPs/D-dimer, indirect bili, schistocytes
  - TTP v DIC
    - DIC = high coags, dimer, FDP, low fibrinogen
    - TTP/HUS = normal coags, dimer, FDP, fibrinogen

(wikem.org)

- - Eval for complications:
    - MI: EKG, trop
    - Renal microvascular injury: UA – microhematuria, granular or red cell casts, and proteinuria
    - Cr: usually < 2
Therapeutically:
- Hematology (prior to tx)
- Plasma exchange (plasmapheresis)
  - Removes auto-antibodies to ADAMTS-13
  - Replaces insufficient ADAMTS-13
  - 1 – 1.5x plasma volumes daily to BID until platelets >150k x 2 days
  - avg 11 plasma exchanges
  - serious catheter-related complications 26%
- FFP
  - if delay in plasmapheresis > hrs. (FFP has ADAMTS-13)
  - 20-40mL / kg /day
  - Cryosupernatant is depleted in the largest VWF multimers but has normal ADAMTS13 levels,62 which could make cryosupernatant particularly suitable for the treatment of TTP. Nevertheless, small randomized trials suggest that cryosupernatant is not superior to fresh-frozen plasma for the initial treatment of TTP.
- Steroids
  - Methyprednisolone 125 mg (George 2010) or 1 g x 3 days (Scully et al. 2012).
  - Makes sense given autoimmune
  - Benefiet not conclusively demonstrated
- Supportive Care “Aggressive”
  - Transfuse RBCs PRN
  - Empiric Abx
  - Folic acid
  - Anticoagulation: When > 50 k platelets, DVT ppx and ASA, +/-dextran
- Antiplatelet agents (ASA and dipyridamole)
  - Controversial
  - ASA 80 mg/day when platelets > 50k
- Platelets
  - relative contraindicated given they cause additional thrombi (“fuel to the fire”) exception of life threatening bleeding (Rosen’s)
  - Not need as ppx before venous access for plasmapheresis (Doerfler, Kaufman, and Goldenberg 1996)
  - reserved for the treatment of life-threatening hemorrhage (Kaushansky et al. 2015)
- Rituximab
  - indicated when refractory to plasmapheresis
  - Can give initially but removed with plasmapheresis
  - *should be screened for hep B if not vaccinated
- Splenectomy
  - removing a major site of anti-ADAMTS13 antibody production
  - after stabilized
  - Laparoscopic splenectomy can be performed safely in most patients regardless of platelet count (Katkhouda et al. 1998)
- Prognosis:
  - 90% mortality, average 14 days before plasma exchange ((Kaushansky et al. 2015))
  - Tx was steroids, splenectomy, anticoagulation, exchange transfusion (RBCs, platelets), dextran (antiplatelet)
  - <20% mortality now with plasmapheresis
    - Plasma infusion 63% survival
    - Plasma exchange 78% survival
  - 25-50% recurrence within 2 weeks after tx
  - sequelae of TTP: neuro deficits, CKD