A. Syndromes

1. Intravascular coagulation defects leading to abnormal clotting or bleeding
   1. Syndromes share similar / overlapping pathology
   2. These are distinct syndromes
2. Thrombotic Thrombocytopenic Purpura (TTP)
   1. Microvascular (capillary) hemolysis
   2. Formation of platelet rich clots with little fibrin deposition
   3. Initially present with hemolytic anemia and thrombocytopenia
   4. Thrombotic events prominant, usually stroke or myocardial infarction (MI)
   5. Central nervous system (CNS) dysfunction: confusion, seizures, focal neurologic deficits
   6. Platelet consumption predominant, may lead to paradoxical purpura or bleeding
   7. TTP more common in adults and high clinical suspicion required
   8. Incidence is ~5 per 1 million per year
   9. Low threshold to treat adults with anemia, thrombocytopenia and no other likely cause [3]
3. Hemolytic Uremic Syndrome (HUS)
   1. Microvascular (capillary) hemolysis
   2. Uremia (renal failure) - proteinuria <1.5 gm/day
   3. Hypocomplementemia (~50%)
   4. Fibrin clots predominantly in kidney
   5. HUS more common in children
4. Disseminated Intravascular Coagulopathy (DIC)
   1. Hemolytic anemia
   2. Predominantly fibrin clots with little von Willebrand factor (vWF)
   3. Consumption of coagulation proteins (prolonged PT, aPTT)
   4. Bleeding is predominant
   5. Frequently accompanied by renal dysfunction
   6. May progress to multiorgan failure syndromes
5. Pregnancy associated HELLP syndrome probably related

B. Pathophysiology of TTP [1]

1. Microvascular thrombi common
   1. Platelet rich thrombi
   2. Very little fibrin
   3. Rich in vWF
2. No perivascular inflammation or overt endothelial damage
3. Abnormal vWF in TTP
   1. Abnormally large vWF multimers are found in TTP
   2. These abnormally large multimers form due to absence of vWF cleaving protease
   3. These multimers are extremely thrombogenic and attract platelets
   4. The multimers cause platelet thrombi to form
   5. Platelets are not activated, and endothelial damage does not occur
4. vWF Cleaving Protease (ADAMTS 13)
   1. ADAMTS is a disintegrin and metalloprotease, with thrombospondin-1 like domains
   2. Activity of this cleaving protease is reduced in acute episodes of TTP [4,5]
   3. IgG antibodies against ADAMTS found in ~65% of acute TTP [4,5]
   4. Inhibitory antibodies to ADAMTS also found in ticlopidine-induced TTP (see below) [6]
   5. ADAMTS activity <5% of normal probably required for pathology
   6. Patients with familial TTP have no activity of ADAMTS in their plasma
   7. Plasma exchange provides active vWF cleaving protease and reduces IgG antibodies
5. Prognosis
   1. Untreated mortality ~90% due to MI, stroke, renal failure
   2. Prompt plasma exchange reduces mortality to <20% with excellent recovery

C. Pathophysiology of HUS [1]

1. HUS is a severe prothrombotic disturbance likely initiated in the kidney
   1. Most cases are associated with diarrhea and found in children
   2. Toxins (shigatoxin producing bacteria, others) cause endothelial damage
   3. Endothelial damage is particularly pronounced in renal vasculature
   4. Endothelial damage promotes marked IL8 and MIP-1
   5. Neutrophils enter areas of inflammation and increase damage
   6. Platelets bind to desquamated regions of vasculature
   7. Activated Factor VII and tissue factor play a key role
2. Familial HUS [22]
   1. 5-10% of all cases
   2. High mortality rate
   3. Most of these patients have deficiency or defect in complement (C') factor H (HF1)
   4. Factor H normally protects host cells from accidental alternative C' pathway damage
   5. Mutations in MCP, a surface bound complement regulator, also associated with HUS
   6. MCP is membrane cofactor protein and regulates C3 levels in glomeruli
3. vWF abnormalities are not present
   1. VWF multimers are not typically present in HUS
   2. Levels of the vWF cleaving protease are normal in HUS
4. Presymptomatic Prothrombotic Changes in HUS [7,8]
   1. A platelet aggregating factor is found in diarrhea associated HUS
   2. A number of coagulation factors are highly elevated prior to HUS onset in plasma from children who develop HUS after E. coli O15:H7 infection:
   3. Prothrombin fragments 1+2
   4. Tissue plasminogen activator (TPA) antigen
   5. TPA-plasminogen activator inhibitor type 1 (TPA-PAI-1) complex
   6. Thus, thrombin generation and inhibited fibrinolysis precede renal injury in HUS
   7. Decreased plasminogen activator release
5. Renal Injury
   1. Due to thrombi in glomeruli and arterioles in both HUS and TTP
   2. Widening of subendothelial wall due to fibrin deposition
   3. HUS has much more prominent renal pathology than TTP
6. Cardiac Injury [8]
   1. Non-inflammatory focal myocardial degeneration found in the heart
   2. Likely apoptotic cell death
   3. Affects both myocytes and conduction system
   4. Arrhythmias including complete heart block can occur

D. Pathophysiology of DIC

1. Underlying associated syndrome: sepsis, pancreatitis, shock, pregnancy
2. Low circulating fibrin with prolonged PT and PTT
3. DIC typically has very high levels of fibrin D-Dimer, higher than HUS/TTP
4. However, HUS may have elevated levels of D-Dimer [8]
5. DIC has very high levels of fibrin degradation products (FDP)

E. Causes of Microangiopathic Hemolytic Anemias

1. Overall
   1. About 90% of HUS preceded by acute gastroenteritis (usually bloody) in children
   2. Nearly 10% of HUS preceded by upper respiratory symptoms in children
   3. DIC associated with sepsis and underlying neoplasm
2. Drugs and HUS
   1. Mitomycin C (dose dependent)
   2. Bleomycin + cisplatin
   3. Cyclosporin (dose dependent)
   4. OKT3
3. Drugs and TTP
   1. Quinine (dose independent; likely autoimmune) [10]
   2. Ticlopidine (uncommon) - induces antibodies to vWF metalloproteinase [6]
   3. Clopidogrel (very uncommon) - <1 per 20,000 persons [11]
   4. Valacyclovir in immunocompromised (mainly HIV+) persons [12]
4. Bacterial Cytotoxins
   1. Most commonly associated with HUS, occasional HUS/TTP overlap
   2. Essentially all bacterial cytotoxin cases associated with shigatoxin-producing bacteria
   3. Toxigenic E. coli (majority): Types O157:H7 (most common), 0111:H2, 0103:H2 [13,14]
   4. Shigella ssp - producing Shiga-Toxin types 1 or 2 or both
   5. Campylobacter ssp.
   6. Yersinia enterocolitica
   7. Pneumococcal infection - uncommon; follows severe pneumonia
   8. Antimotility agents must be avoided as they increase risk of HUS
5. E. coli O157:H7 [1,14,16]
   1. Causes almost exclusively HUS (primarily in children), usually not TTP
   2. Produce high titers of Shiga-Like Toxin Type I
   3. Transmissions from a number of contaminated sources have been documented
   4. Undercooked hamburger, apple cider [2], contaminated swimming pools [8]
   5. Transmissions due to petting contaminated farm animals documented [15]
   6. Nearly 70% of children with HUS have O157:H7 infection
   7. 10-25% of persons with 0157:H7 or related strains will develop HUS
   8. HUS develops 3-7 days following initial bloody diarrheal illness
   9. Antibiotics given to children with O157:H7 have ~15X increased risk for developing HUS [14]
   10. Antimotility agents, narcotics, and NSAIDs should not be given to acutely ill patients [16]
   11. >95% of affected children recover from HUS
   12. Hospital admission with supportive care; no specific therapies currently exist
   13. However, severe HUS may lead to chronic renal failure, HTN, or proteinuria
6. Cancer
   1. Often presents as "chronic DIC"
   2. Prolonged PT, aPTT with reduced fibrinogen
   3. Elevated fibrin degradation products (FDP) and fibrin D-dimers
   4. Mucinous adenocarcinomas primarily of pancreas or other gastrointestinal tract
   5. Prostate Cancer
7. Lupus Anticoagulant
8. Pregnancy
   1. Post-partum period
   2. Acute renal failure can occur alone
   3. HELLP Syndrome - hemolysis, elevated liver enzymes, low platelets (preeclampsia)
   4. HELLP syndrome is a hemolytic anemia with prominent liver damage
9. AIDS
   1. Uncommonly can cause a TTP type illness
   2. Excellent response to plasma exchange
10. Oral Contraceptives

F. Differential Diagnosis

1. Systemic Vasculitis
   1. Usually have arthralgias
   2. Often have a rash
2. Antiphospholipid Syndrome (APLS)
   1. Lupus anticoagulant can prolong PTT, but usually not PT
   2. Presents with thrombocytopenia; anemia less common
   3. Thrombotic events can lead to pregnancy loss, renal dysfunction, MI, CNS events
   4. Both arterial and venous events can occur
3. Malignant Hypertension
   1. Microangiopathic hemolytic anemia and renal dysfunction occurs
   2. Thrombocytopenia less common
   3. Schizocytes and polychromatophilia (reticulocytes) may be seen
4. Pregnancy - Hypertension Syndromes
   1. HELLP
   2. Pre-eclampsia
   3. Eclampsia

G. Treatment

1. TTP [3]
   1. Goal is to restore functional ADAMTS 13
   2. Plasma exchange is superior to Infusion of fresh-frozen plasma (FFP)
   3. Daily plasma excange in adults and older children with acquired acute TTP
   4. Continue plasma exchange (1.0-1.5X plasma volume exchange daily) until platelet count is normalized (for at least 2 days)
   5. Infants or young children with familial TTP require new plasma every ~3 weeks
   6. Autoantibody production may be blocked with rituximab (Rituxan®) or cyclophosphamide
   7. Low threshold to treat since therapy is very effective
2. HUS [17]
   1. Plasma infusion and exchange - proved benefit of exchange over infusion alone
   2. Goal is replace missing inhibitors and remove pro-thrombotic factors
   3. Continued until platelet count is normal and hemolysis has decreased (LDH < 400)
   4. Thirty day mortality 10% (versus >90% without plasma exchange)
   5. Two year survival >60% (versus <5% without plasma exchange)
   6. Plasma exchange was effective in older persons with E. coli O157:H7 associated TTP [18]
   7. Oral shiga-toxin binding agent did not improve outcomes in diarrhea associated HUS [19]
   8. Hospital admission with supportive care for most cases
   9. No specific therapies have been discovered to date for toxin-associated HUS
3. Glucocorticoids [3]
   1. Methylprednisoloneone, 250-1000mg per day IV, may be helpful
   2. May use divided dose oral steroids (for example, prednisone 60mg po tid-qid)
   3. Recommended in relapsed and some moderate-severe disease
4. Modulation of B Lymphocytes / Plasma Cells
   1. Block production of vWF autoantibodies in TTP
   2. Rituximab is probably best tolerated
   3. Rituximab + cyclophosphamide effective in patient with severe chronic TTP [20]
   4. Intravenous Gamma Globulin
   5. Vincristine has also been used
5. Splenectomy during TTP remission prevented relapses in 6 of 6 patients
6. Role of aspirin, ticlopidine, clopidogrel or (LMW) heparin unclear at this time
7. Avoid antibiotics, antimotility agents, narcotics and NSAIDs in toxin-associated HUS [16]
8. Dialysis
9. Peritoneal dialysis may be preferable
10. Complete recovery of renal function common in HUS

H. Prognosis

1. HUS
   1. Mortality up to 10%
   2. Residual disabilities - HTN, chronic renal failure, neurologic deficits (up to 25%)
   3. Post-diarrheal HUS death + end stage renal disease in 12% overall with treatment [21]
   4. Adult HUS has high renal morbidity without therapy ~75% may become dialysis dependent
   5. Presentation with less severe renal failure is better prognostic indicator
2. TTP
   1. Mortality without treatment was >80%
   2. Mortality 10-40% depending on treatment;
   3. Neurologic symptoms may improve first (2-3 days)
   4. Majority of patients have complete response to plasma manipulation
   5. Some have residua including neurological and/or renal dysfunction
3. Relapses
   1. Common within 30-60 days - usually treat by plasma exchange successfully
   2. Overall relapse rate is about 35% over ten years after initial episode

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