I. General
A. Probably more than one syndrome; associated with multiple causes
B. 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
C. More common in women (3:2 ratio)
D. Peak incidence in 3rd decade of life
II. Clinical features: "pentad" of A, B, C, D, & E below. Use plat. count & LDH to monitor disease activity.
A. Thrombocytopenia
1. Purpura is initial manifestation in 90% of pts
2. Other abnormal bleeding from anywhere may follow
3. Coagulation is usually intact (i.e. nl PT/PTT); if not, think DIC
B. Microangiopathic hemolytic anemia
1. Often severe with Hb 7-9g/dl; severity not related to other organ system dysfunction
2. Coombs-negative
3. Smear shows helmet & burr cells; schistocytes, & spherocytes
4. As usual with hemolysis, see high LDH, low haptoglobin, high unconj. bili, circulating NRBC?s, & reticulocytosis
5. Traditionally thought to result from passage of RBC?s through damaged small vessels.
6. However, intrinsic RBC defect may be operative: RBC?s in TTP have less antioxidant potential, thus are more susceptible to mecahnical injury. May be related to low plasma Vit. E levels
C. Neurologic dysfunction
1. 60% have at presentation; 90% have at some time in illness
2. HA, change in MS inc. coma, paresthesias, paresis, aphasia, dysarthria, syncope, vertigo, ataxia, CN palsies, sz, & CVA have been reported
3. Us. transient & fluctuating
D. 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 HUS
a. Can require dialysis or renal transplantation
E. Fever--almost always occurs at some point in illness
F. Prodromal viral-like illness occurs in 40% (more often with HUS)
G. Cardiac--reports exist of CHF & conduction disturbances
H. Pulm--reports exist of alveolar & insterstitial infiltrates
III. Differential diagnosis: other things which can cause thrombocytopenia, hemolysis, & renal failure
A. Septicemia with DIC
B. Hantavirus
C. Dengue hemorrhagic fever
D. Malaria
E. Leptospirosis
F. Snake bites
IV. Classification scheme
A. Idiopathic
1. Acute--us. 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
B. Secondary
1. Pregnancy-associated/postpartum (may be related to preeclampsia)
2. Bacterial endocarditis
3. Autoimmune disease: SLE (most common), RA, polyarteritis, Sjogren?s syndrome
4. Neoplasm: lymphoma, adenocarcinoma (mainly gastric)
5. Drug-induced
a. Sulfonamides
b. Iodine
c. Oral contraceptives (no clear cause-effect relationship)
d. Antineoplastics (inc. mitomycin & cyclosporin)
e. Ticlopidine (Lancet paper)
6. HIV-associated (50% with HIV & TTP had no prev. symptomatic HIV disease)
V. Pathogenesis
A. Probably, all patients have an underlying disease or genetic predisposition
B. TTP is set in motion by exposure to a precipitant (viral or bacterial product, drug, etc.)
C. First step is probably endothelial damage
1. Drugs & microbes (e.g. E. coli 0H:0157; Shigella) ass?d with TTP/HUS are known to damage endothelium
2. Loss of thromboresistant function of endothelium (e.g., PGI2 synthesis) can lead to platelet aggregation
D. 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
E. Platelet aggregation in arterioles--produces ischemic damage, as well as a consumption thrombocytopenia.
VI. Treatment: n.b. very few controlled studies to support most treatments
A. Plasma treatments
1. Plasma exchange--treatment of choice
a. Survival up to 90%; response rate 70-75%
b. Us. do 2-3l plasma exchange daily x 7d then QOD until response
2. Plasma infusion
a. Case reports of effectiveness
b. More likely to cause fluid overload than plasma exchange
c. HOCNAm authors recommend FFP load with 30-40ml/kg then 15-20/kg/d
B. Steroids
1. Anecdotal reports of response but widely considered to be ineffective
2. Most patients gave gotten it anyway
3. Us. give equivalent of 100-400mg prednisone/d x 1wk then taper
C. Heparin
1. Conflicting data in effectiveness: prospective trial showed no benefit in kids with HUS; retrospective trial showed improved outcomes in postpartum HUS. HOCNAm authors don?t recommend it.
D. Antiplatelet agents
1. Recommended in TTP (not shown to be effective in HUS), because
a. Case reports of positive response, &
b. Not very risky
c. Use recommended when plat. count starts to rise again
2. ASA 325-1500mg/d; dipyridamole 400-600mg/d; sulfinpyrazone 400/d have been used
E. Prostacyclin (PGI2)--used rarely; controversy over results. Can causes hypotension
F. Immunosuppressives
1. Vincristine, azathioprine, & cyclophosphamide have been used. Unproven
G. Splenectomy
1. Reports exist of favorable response, but now widely considered ineffective
H. Other: IVIG, Vit E tried; no controlled trials
I. Note that platelet tranfusions are contraindicated; can make disease worse!
VII. Hemolitic uremic syndrome & its relationship to TTP
A. 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
B. HUS defined in 1955 as hemolytic anemia, thrombocytopenia, & renal failure
C. Main difference from TTP is the predominance of renal effects in HUS
D. 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
E. 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
F. 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. Who knows?
(Sources: Heme/Onc Clin N. Am. 4:219, 1990; Lancet 343:393, 1994; Lancet 343:398, 1994)