- Name the differential diagnosis of a hemolytic anemia and thrombocytopenia
- Recognize the common clinical features of TTP
- Differentiate TTP from other thrombotic microangiopathies
- Manage a patient with TTP
30 yo F presents with a history of epilepsy 2 weeks of subjective fevers/chills and 1 week of nausea/vomiting/diarrhea. Her GI symptoms started after she ate at a Chinese buffet with her family but no other family members developed similar symptoms. She reports nonbloody, nonbilious emesis and denies melanotic or bloody diarrhea. She has been unable to keep down any fluids or medications. ROS is notable for a frontal headache and an increased frequency of seizures. She also reports fatigue, malaise and menorrhagia, but no other spontaneous bleeding or bruising.
She has a history of epilepsy and is on leveteracitam, topiramate and carbamazepine, without recent changes in medications. She has a 10 pack smoking history, but no other substance use.
On exam, she is afebrile, HR 90s, BPs 123/54 and appears comfortable on exam. She has scant dried blood and a blood blister on her lower lip, dry mucus membranes. She has multiple ecchymoses around her IV site but no signs of active bleeding. Her initial labs are notable for a Cr of 1.64, WBC of 7.5, hct 13, platelets of 9 (all normal at baseline).
What additional work-up would you want?
What is your differential diagnosis?
- TTP – this is a hematologic emergency!
- DIC – associated with ↑ D-dimer, ↓ fibrinogen
- ITP – typically does not present with hemolytic anemia (exception is Evan’s syndrome – AIHA + ITP)
- Differentiated by Coombs positive hemolytic anemia (warm autoimmune hemolytic anemia)
- PNH – causes a Coombs-negative hemolytic anemia and can be associated with other cytopenias
- Forty percent of patients have vessel thrombosis (large vessels)
- Can be associated with renal insufficiency
- MDS (differentiated by hypoproliferative anemia)
What would you do next?
- Consult hematology urgently given concern for possible TTP!
- Transfuse RBCs for low hct < 21
- Do not transfuse platelets
- Additional work-up:
- DIC panel – fibrinogen elevated, d-dimer elevated
- DAT negative
- ADAMTS13 – pending
Our concern was for secondary TTP, drug-induced TTP or hereditary TTP. Work-up for secondary causes such as infections and pregnancy were negative. ADAMSTS 13 activity was 0%, inhibitor level 0%, which suggests ADAMTS13 deficiency or hereditary TTP.
TTP is a type of thrombotic microangiopathy (TMA). TMA describes a pathologic lesion in which abnormalities in the vessel wall of arterioles/capillaries lead to microvascular thrombosis (George & Nester, 2014 in NEJM). Other TMA syndromes include complement-mediated TMA and HUS.
When should you suspect this diagnosis?
You should suspect a TMA when there is a microangiopathic hemolytic anemia (MAHA) + thrombocytopenia
- MAHA is a non-immune hemolytic anemia
- Shearing of RBCs to produce schistocytes
- Negative Coombs (DAT)
- ↑ LDH, ↑ indirect Tbili, ↓ haptoglobin
- MAHA is a non-immune hemolytic anemia
- Thrombocytopenia occurs because of consumption in microthrombi
How do you diagnose it?
ADAMTS13 activity <10% of normal activity support diagnosis of acquired TTP. Low levels of ADAMTS13 activity of 10-50% is nonspecific and can be seen in multiple inflammatory states.
What are the signs and symptoms of this disease?
HUS is traditionally described as a triad of “MAHA, thrombocytopenia, acute renal failure”
TTP is described as pentad of “MAHA, thrombocytopenia, acute renal failure, fever, and neurologic symptoms.” Only 5% of patients had complete pentad in an Oklahoma TTP-HUS registry
#Oklahoma TTP-HUS Registry (65 patients total), originally cited in Uptodate article “Acquired TTP: Clinical manifestations and diagnosis”
#Gerber, et al, 2002 in Journal of infectious Disease, originally cited in Uptodate article “Clinical manifestations and diagnosis of diagnosis of Shiga toxin-producing E.coli HUS in children”
How do you treat it?
- Urgent plasmapheresis or FFP infusion
- Immunosuppressive agents are additionally used for acquired TTP
- High dose steroids
Can you transfuse platelets in patients with this disease?
Platelets transfusions are uncommon in patients with TTP except in severe life threatening bleeds because of a concern that these transfusions can precipitate thrombotic events. In a 2009 systematic review and prospective cohort by Swisher, et al., there was insufficient evidence to conclude that platelet transfusions necessarily contributed to adverse events or mortality. However, in several other studies including a more recent study in Blood (2015), platelet transfusions were associated with a higher odds of arterial thrombosis (OR = 5.8), AMI (OR = 2.0) and mortality (OR = 2.0).5
Overall, there is still debate over whether platelet transfusions are truly harmful in patients with TTP, but general practice is to avoid platelet transfusions in this population except in episodes of severe bleeding.
TAKE HOME POINTS:
- Suspect TTP in patients with evidence of MAHA and thrombocytopenia
- The classic pentad of symptoms: fever, neurologic symptoms, MAHA, thrombocytopenia, and acute renal insufficiency is rare
- AKI is uncommon or mild in TTP, which helps distinguish it from other thrombotic microangiopathies
- If you have a high clinical suspicion, consult Hematology immediately for consideration of plasma exchange
- Platelet transfusions are not recommended except in patients with severe bleeding.
- George, JN & Nester, C. Approach to the patient with suspected TTP, HUS, or other TMA. In: UpToDate, Timauer, JS (Ed), UpToDate, Waltham, MA. (Accessed on March 04, 2017.)
- George, JN & Nester, CM. 2014. Syndromes of Thrombotic Microangiopathy. NEJM. 371:654-666.
- George, JN & Cuker, A. Acquired TTP: Clinical manifestations and diagnosis. In: UpToDate, Timauer, JS (Ed), UpToDate, Waltham, MA. (Accessed on March 04, 2017.)
- Niaduet, J. Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children. In: UpToDate, Kim, MS (Ed), UpToDate, Waltham, MA. (Accessed on March 04, 2017.)
- Swisher, KK, et al. 2009. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura. Transfusion. 49:873-887
- Goel, R, et al. 2015. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. BLOOD. 125(9):1470-1476