I. General

  1. Probably more than one syndrome; associated with multiple causes
  2. The common finding is microvascular thrombosis in multiple organ systems
  1. Platelet thrombi occlude arterioles & capillaries, causing ischemic damage
  2. Endothelial proliferation & disruption is seen in path specimens
  3. Inflammatory reaction does not occur--not a vasculitis
  1. More common in women (3:2 ratio)
  2. Peak incidence in 3rd decade of life

II. Clinical features: Classic "pentad" of A, B, C, D, & E below. Use platelet count & LDH to monitor disease activity.

  1. Thrombocytopenia
  1. Purpura is initial manifestation in 90% of pts
  2. Platelet count usually 20k-50k/mm3; mean platelet volume is generally elevated
  3. Other abnormal bleeding from anywhere may follow
  4. Coagulation is usually intact (i.e. nl PT/PTT); if not, consider possibility of disseminated intravascular coagulation; also, plasma d-dimer is usually no more than 3x normal.
  1. Microangiopathic hemolytic anemia
  1. Often severe with Hb 7-9g/dl; severity not related to other organ system dysfunction
  2. Negative Coombs' test
  3. Smear shows signs of microangiopahy: helmet & burr cells; schistocytes, & spherocytes
  4. As usual with hemolysis, see high LDH (a normal LDH should call the diagnossi into question), low haptoglobin, high unconj. bili, circulating NRBCs, & reticulocytosis
  5. Traditionally thought to result from passage of RBCs through damaged small vessels.
  6. However, intrinsic RBC defect may be operative: RBCs in TTP have less antioxidant potential, thus are more susceptible to mechanical injury. May be related to low plasma Vit. E levels
  1. Neurologic dysfunction
  1. 60% have at presentation; 90% have at some time in illness
  2. Headache, change in mental status coma, paresthesias, paresis, aphasia, dysarthria, syncope, vertigo, ataxia, cranial nerve palsies, seizures, & CVA have been reported
  3. Usually transient & fluctuating
  1. Renal dysfunction
  1. Occurs in 90% of pts
  2. Usually get proteinuria & microscopic or gross hematuria
  3. Renal failure occurs in 40-80%, but is usually mild and temporary, unlike hemolytic uremic syndrome (see below)
  4. Can require dialysis or renal transplantation
  1. Fever-almost always occurs at some point in illness; often accompanied by generalized qweakness and malaise
  2. Prodromal viral-like illness occurs in 40% (more often with HUS)
  3. Cardiac-reports exist of CHF & conduction disturbances
  4. Pulmonary-reports exist of alveolar & insterstitial infiltrates
  5. GI-Abdominal pain, vomiting, diarrhea can occur

III. Differential diagnosis: other things which can cause thrombocytopenia, hemolysis, & renal failure

  1. Septicemia with DIC (associated with RBC fragmentation and platelet consumption, but unlike TTP, also with coagulopathy)
  2. Hantavirus
  3. Dengue hemorrhagic fever
  4. Malaria
  5. Leptospirosis
  6. Snake bites
  7. Evan's syndrome (combination of ITP and autoimmune hemolytic anemia; associated with a positive direct Coomb's test and absence of RBC fragments on peripheral smear, both in contrast to TTP)

IV. Classification scheme

  1. Idiopathic
  1. Acute-usually fulminant, often fatal
  2. Chronic-Rare; insidious onset; us. have other systemic disease
  3. Relapsing-Most common; attacks can be months to years apart
  4. Familial-Rare; prob. autosomal recessive; us. acute pattern
  1. Secondary
  1. Pregnancy-associated/postpartum (may be related to preeclampsia and "HELLP" syndrome)
  2. Bacterial endocarditis
  3. Autoimmune disease: SLE (most common), RA, polyarteritis, Sjogren's syndrome
  4. Neoplasm: lymphoma, adenocarcinoma (mainly gastric)
  5. Drug-induced
  1. Sulfonamides
  2. Iodine
  3. Oral contraceptives (no clear cause-effect relationship)
  4. Antineoplastics (inc. mitomycin & cyclosporin)
  5. Ticlopidine
  6. Quinine
  7. Cyclosporine
  1. HIV-associated (50% with HIV & TTP had no prev. symptomatic HIV disease)

V. Pathogenesis

  1. Probably, all patients have an underlying disease or genetic predisposition
  2. TTP is set in motion by exposure to a precipitant (viral or bacterial product, drug, etc.)
  3. First step is probably endothelial damage
  1. Drugs & microbes (e.g. E. coli 0H:0157; Shigella) associated with TTP/HUS are known to damage endothelium
  2. Loss of thromboresistant function of endothelium (e.g., PGI2 synthesis) can lead to platelet aggregation
  1. One theory posits an "aggregating agent" which causes exaggerated platelet clumping; perhaps von Willebrand factor fragments or unusually large vWF multimers; these are associated with TTP episodes
  2. Platelet aggregation in arterioles--produces ischemic damage, as well as a consumption thrombocytopenia.

VI. Treatment

  1. Plasma treatments
  1.  Plasma exchange-treatment of choice
  1. Removes high-molecular-weight vWF and autoantibody to vWF-cleaving enzyme, and adds active cleaving enzyme
  2. Survival up to 90%; response rate 70-75%
  3. Us. do 2-3l plasma exchange daily until platelet count and LDH normalize, then taper
  4. Relapse occurs in up to 20% of pts in the first 2mos after treatment
  1. Plasma infusion
  1. Less effective than plasma exchange in one controlled trial
  2. More likely to cause fluid overload than plasma exchange
  1. Corticosteroids-Some limited data to support effectiveness
  2. Rituximab (Rituxan)-Some limited data to support effectiveness
  3. Heparin
  1. Conflicting data re effectiveness:a  prospective trial showed no benefit in kids with HUS; retrospective trial showed improved outcomes in postpartum HUS.
  1. Antiplatelet agents
  1. May be effective in TTP (limited evidence)
  1. Prostacyclin (PGI2)--used rarely; controversy over results. Can causes hypotension
  2. Splenectomy-No longer widely used
  3. Note that platelet tranfusions can worsen CNS symptoms and renal failure; given only when there is active central nervous system bleeding.

VII. Hemolitic uremic syndrome & its relationship to TTP

  1. May not be two different diseases after all
  1. No consistent distinguishing clinical or laboratory features exist
  2. TTP & HUS an occur in members of same family; in HIV infection, chemotherapy, etc.; TTP can follow E. coli hemorrhagic colitis
  3. HUS associated with same secondary causes as TTP (see above)
  4. Most of the above info about TTP applies to HUS also
  1. HUS defined in 1955 as hemolytic anemia, thrombocytopenia, & renal failure
  2. Main difference from TTP is the predominance of renal effects in HUS
  3. Pathology of renal damage in HUS
  1. Swelling of endothelial cells with narrowing of lumina of glomerular capillaries
  2. Intraluminal platelet thrombi, leading to
  3. Glomerular & tubular necrosis
  1. Pathogenesis
  1. 90% of cases occur 6mo-5y of age, shortly after hemorrhagic colitis from Shigella or E. coli (2-4% of those with E. coli 0157:H7 will get HUS; more likely in those tx'd with antibiotics (NEJM 342:1930, 2000--JW))
  2. May be precipitated by exposure to exotoxins: Shiga toxin or, with E. coli, shiga-like toxins 1 and 2
  3. Preponderance in plasma of unusually large vWF multimers obtains in HUS as well as TTP; ULvWF multimers are released in vitro by endothelial cells exposed to Shiga toxin
  1. Association with Quinine-induced thrombocytopenia. There is some. It may be that in both, quinine attaches to GPIIIa glycoprotein molecules (on platelets and renal endothelial cells) and alters them antigenically to induce an autoimmune reaction.

(Sources include: Heme/Onc Clin N. Am. 4:219, 1990; Lancet 343:393, 1994; Lancet 343:398, 1994; Core Content Review of Family Medicine, 2012)