• 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

• 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

Logistically:

• Hematology

• Talks to pathology for plasmapheresis

• Nephrology for Quintin

• MICU for admission

Factoids:

• First case TTP 16 y/o F, diagnose on autopsy, Dr Eli Moschocowitz, called Moschocowitz disease until 1947 renamed TTP (Kaushansky et al. 2015)

References:

Campbell, W. B. 1988. “Surgical Morbidity and Mortality Meetings.” Annals of the Royal College of Surgeons of England 70 (6): 363–65.

Doerfler, M. E., B. Kaufman, and A. S. Goldenberg. 1996. “Central Venous Catheter Placement in Patients with Disorders of Hemostasis.” Chest 110 (1): 185–88.

Gawande, Atul. 2010. Complications: A Surgeon’s Notes on an Imperfect Science. Profile Books.

George, James N. 2010. “How I Treat Patients with Thrombotic Thrombocytopenic Purpura: 2010.” Blood 116 (20): 4060–69.

Katkhouda, N., M. B. Hurwitz, R. T. Rivera, M. Chandra, D. J. Waldrep, J. Gugenheim, and J. Mouiel. 1998. “Laparoscopic Splenectomy: Outcome and Efficacy in 103 Consecutive Patients.” Annals of Surgery 228 (4): 568–78.

Kaushansky, Kenneth, Marshall A. Lichtman, Josef Prchal, Marcel M. Levi, Oliver Press, Linda Burns, and Michael Caligiuri. 2015. Williams Hematology, 9E. McGraw Hill Professional.

Marx, John, Ron Walls, and Robert Hockberger. 2013. Rosen’s Emergency Medicine – Concepts and Clinical Practice. Elsevier Health Sciences.

Scully, Marie, Beverley J. Hunt, Sylvia Benjamin, Ri Liesner, Peter Rose, Flora Peyvandi, Betty Cheung, Samuel J. Machin, and British Committee for Standards in Haematology. 2012. “Guidelines on the Diagnosis and Management of Thrombotic Thrombocytopenic Purpura and Other Thrombotic Microangiopathies.” British Journal of Haematology 158 (3): 323–35.