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thrombotic thrombocytopenic purpura (TTP)

Acute disorder of increased platelet consumption. TTP is a medical emergency. Etiology: 1) non familial form of TTP is due to an inhibitor of vWF-cleaving protease 2) familial form of TTP is due to deficiency of vWF-cleaving protease (ADAMTS13) 3) organ transplantation 4) malignancies 5) pharmaceuticals: a) mitomycin C b) bleomycin c) gemcitabine [10] d) cyclosporin A e) quinine f) clopidogrel g) ticlopidine 6) radiation 7) association with pregnancy & use of oral contraceptives 8) immune-mediated drug hypersensitivity 9) E. coli 0157 & Shigella more common with hemolytic-uremic syndrome [4] Epidemiology: 1) generally affects younger adults 2) peak incidence in 3rd decade of life 3) 70% of patients are female Pathology: 1) thrombocytopenic & microangiopathic hemolytic anemia 2) ultra-large von-Willebrand factor multimers may be observed - deficiency in ADAMTS13 (vWF-cleaving protease) - platelet aggregates & microvascular thrombosis 3) endothelial cell injury 4) subendothelial cell deposits 5) glomerular lesion also seen with: a) malignant hypertension b) scleroderma c) post-partum renal failure 6) fever likely from microinfarcts [4] 7) thrombocytopenia of thrombotic thrombocytopenia is a comsumptive process whereby thrombocytopenia occurs by platelet activation of the clotting system with resultant depletion of platelets [12] 8) antibodies to platelet factor 4 in nearly all patients [12] Genetics: (familial form) 1) autosomal recessive 2) defects in ADAMTS13 are associated with congenital thrombotic thrombocytopenic purpura (TTP) Clinical manifestations: 1) severe thrombocytopenia 2) microangiopathic hemolytic anemia (all patients) [4] 3) fluctuating neurologic signs a) confusion b) focal neurologic signs c) headache [4] d) transient numbness e) coma [4] 4) renal insufficiency, renal failure - progressive renal failure is uncommon 5) fever (variable) 6) severe hypertension 7) purpura, petechiae 8) pallor 9) abdominal pain - nausea, vomiting, diarrhea due to intestinal ischemia [4] 10) chest pain, cardiac arrhythmia due to myocardial injury [4] 11) familial form: a) neonatal onset b) response to fresh plasma infusion c) frequent relapses Laboratory: 1) complete blood count (CBC) a) anemia b) thrombocytopenia (100%) 2) peripheral smear a) erythrocyte fragments, schistocytes (100%) b) diminished platelets 3) increased reticulocyte count (reticulocytosis) 4) serum chemistries a) serum lactate dehydrogenase (LDH) increased b) serum urea nitrogen increased c) serum creatinine increased d) serum bilirubin: increased unconjugated (indirect) bilirubin e) serum haptoglobin is diminished 5) urinalysis a) WBC (pyuria) b) RBC c) hemoglobin (hematuria) from microthrombi [4] d) large amounts of albumin (albuminuria) 6) prothrombin time (PT) is generally normal 7) activated partial thromboplastin time (aPTT) is generally normal 8) direct antiglobulin test (Coomb's test) is negative 9) plasma fibrinogen is normal 10) antinuclear antibody (rule out lupus erythematosus) 11) ADAMTS13 in plasma may be useful for prognosis [4] a) decreased plasma ADAMTS13 activity b) positive plasma ADAMTS13 inhibitor [4] Radiology: - neuroimaging (CT of brain) - may show ischemic stroke - transient microthrombi may lead to reversible findings [4] Differential diagnosis: 1) immune thrombocytopenic purpura (ITP) a) normal LDH b) no erythrocyte fragments on peripheral smear 2) severe vasculitis 3) hemolytic-uremic syndrome 4) HELLP syndrome 5) disseminated intravascular coagulation (DIC) a) prolonged PT & aPTT b) elevated fibrin-split products (D-dimer) c) diminished plasma fibrinogen 6) Evan's syndrome - Coomb' positive hemolytic anemia - direct antiglobulin test is positive [13] 7) paroxysmal nocturnal hemoglobinuria - no microangiopathic hemolytic anemia, no schistocytes [13] Complications: - mortality rate is high (15%) Management: 1) plasmapheresis [4] - do not wait for laboratory confirmation (ADAMTS13 in plasma) [4] - continue until patient improves or expires - superior to plasma infusion 2) other treatments if plasmapheresis not available a) high-dose gamma globulin b) plasma exchange with fresh frozen plasma (FFP) 1] 30 mL/kg in the 1st 24 hours 2] then 15 mL/kg/day, until apheresis can be performed 3] plasma exchange removes ADAMTS13 inhibitor & replaces ADAMTS13 4] fluid overload is common, begin diuretic therapy simultaneously c) prednisone & rituximab suppress autoantibody formation d) other treatments suggested in the past - whole blood exchange transfusion - anti-platelet drugs (if FFP is ineffective) - vincristine - caplacizumab [9] - prevents formation of platelet aggregates & microvascular thrombosis by inhibiting von Willebrand factor - for lasting remission in acquired TTP, may be necessary to restore normal levels of ADAMTS13, (vWF-cleaving protease) 3) glucocorticoids may also be useful because of difficulty distinguishing TTP from vasculitis 4) do not order platelet transfusions, may exacerbate microvascular occlusion [4] 5) anticoagulation - argatroban, danaparoid, fondaparinux, or direct oral anticoagulants [12] 6) discontinue offending medications 7) splenectomy 7) mortality rate is 25% 9) best prognostic indicators a) platelet count return to normal b) decreasing LDH c) resolution of neurologic symptoms 10) relapse months to years later in 20-30% - prior to plasma exchange, patients either died (75%) or recovered without relapse (25%)

Related

A disintegrin & metalloproteinase with thrombospondin type 1 motif 13; ADAMTS-13; ADAM-TS 13; ADAM-TS13; von Willebrand factor-cleaving protease; vWF-cleaving protease; vWF-CP (ADAMTS13, C9orf8, UNQ6102/PRO20085) HELLP syndrome hemolytic uremic syndrome (HUS)

General

thrombotic microangiopathy thrombocytopenia hypercoagulability

Database Correlations

OMIM 274150

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 590
  2. Furlan M et al von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. NEJM 339:1578-84, 1998 PMID: 9828245
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 418, 611
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. Moake J Thrombotic microangiopathies: multimers, metalloprotease, and beyond. Clin Transl Sci. 2009 Oct;2(5):366-73 PMID: 20443921
  6. Moake J. Thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies. Best Pract Res Clin Haematol. 2009 Dec;22(4):567-76 PMID: 19959109
  7. Crawley JT, Scully MA. Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013:292-9 PMID: 24319194
  8. George JN, Al-Nouri ZL. Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes. Hematology Am Soc Hematol Educ Program. 2012;2012:604-9 PMID: 23233641
  9. Peyvandi F et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016 Feb 11; 374:511. PMID: 26863353 - Veyradier A. Von Willebrand Factor - A new target for TTP treatment? N Engl J Med 2016 Feb 11; 374:583. PMID: 26863360
  10. Lim MY Non-Small Cell Lung Cancer: 5 Management Challenges. Medscape. Nov 30, 2016 http://reference.medscape.com/features/slideshow/non-small-cell-lung-cancer
  11. Bhandari S, Kumar R. Images in Clinical Medicine. Thrombotic Thrombocytopenic Purpura. N Engl J Med 2019; 380:e23 PMID: 30995377 https://www.nejm.org/doi/full/10.1056/NEJMicm1813768
  12. Hackethal V Why Clotting Happens When Platelets Are Low. A hematologist explains the counterintuitive concept of clots with low platelets. MedPage Today April 23, 2021 https://www.medpagetoday.com/special-reports/exclusives/92243
  13. NEJM Knowledge+