1. THROMBOTIC THROMBOCYTOPENIC PURPURA Emily O. Jenkins MD AM Report 10.21.09

2. Presentation  Nonspecific:  Abdominal pain  Nausea  Vomiting  Weakness  ½ of patients will have severe neurologic abnormalities such as seizures and fluctuating focal deficits

3. The Pentad  Microangiopathic hemolytic anemia  Thrombocytopenia, often with purpura but not usually severe bleeding  Acute renal insufficiency that may be associated with anuria and may require acute dialysis  Neurologic abnormalities, usually fluctuating  Fever  With the advent of plasma exchange, however, the full pentad is rare  Only MAHA and thrombocytopenia without another apparent cause are necessary to initiate PLEX therapy

4. Peripheral blood smear from a patient with a microangiopathic hemolytic anemia with marked red cell fragmentation. The smear shows multiple helmet cells (small black arrows), other fragmented red cells (large black arrow); microspherocytes are also seen (blue arrows). The platelet number is reduced; the large platelet in the center (red arrow) suggests that the thrombocytopenia is due to enhanced destruction. Fragmented red cells (schistocytes), polychromatophilic red cells (reticulocytes), and a lack of platelets, consistent with the presence of microangiopathic hemolysis.

5. Epidemiology  Suspected TTP-HUS — 11 cases/million population per year  Idiopathic TTP-HUS — 4.5 cases/million per year  Severe ADAMTS13 deficiency — 1.7 cases/million per year  Incidence rates are higher for women, african americans and obese patients  91% of HUS cases in children survive without PLEX therapy and supportive care only

6. Renal Disease  Renal thrombotic microangiopathy: usually associated with a urinalysis that is near normal with only mild proteinuria (usually between 1 to 2 g/day) and few cells or casts  Chronic renal failure, as defined by a creatinine clearance <40 mL/minute one year after diagnosis, has occurred in about one-fourth of our patients with TTP-HUS

7. Concentric onion-skin thickening of a muscular renal artery, leading to complete obliteration of the vascular lumen, during the later healing phase of previous fibrinoid injury in any of the forms of the hemolytic- uremic syndrome, including scleroderma and malignant hypertension. Immunofluorescence microscopy in the hemolytic-uremic syndrome shows fibrin deposition (bright yellow areas) in branches of a muscular renal artery

8. Subintimal fibrin deposition without inflammation (arrow) in an interlobular artery as can be seen acutely in any of the forms of the hemolytic-uremic syndrome, including scleroderma. The marked narrowing of the vascular lumen will diminish distal perfusion, potentially leading to tissue necrosis if there is near total or total occlusion. Mucoid intimal thickening of muscular renal arteries (arrows) as an early healing response to previous fibrinoid injury in any of the forms of the hemolytic-uremic syndrome, including scleroderma and malignant hypertension.

9. Neurologic Symptoms  Present in most patients  Most common are more subtle changes such as confusion or severe headache  Focal, objective abnormalities (eg, transient ischemic attack, stroke) are less frequent, but grand mal seizures and coma can occur  Even in patients with typical TTP associated with severe acquired ADAMTS13 deficiency, approximately one-third of patients will have no neurologic abnormalities, confusion, or headache

10. Cardiac Involvement  Diffuse platelet thrombi and associated hemorrhage in cardiac tissues (eg, coronary arteries, myocardium, conducting system)  May lead to complications such as arrhythmia, sudden cardiac death, myocardial infarction, cardiogenic shock, and/or heart failure in patients with TTP-HUS  Incidence of acute heart failure - about 10%  High mortality if present (38 versus 17 percent)  Acute MI - 18% in one series  Lactate dehydrogenase >1000 IU/L + serum troponin I level >0.20 ng/mL at presentation had a sensitivity and specificity of 86% and 95% to predict AMI

11. A specimen from the heart shows multiple intramyocardial microthrombi, hemorrhage, and early ischemic changes, with scattered foci of contraction-band necrosis.

12. Causes  Idiopathic — 37 percent  Drug-associated — 13 percent  Autoimmune disease — 13 percent  Infection — 9 percent  Pregnancy/postpartum — 7 percent  Bloody diarrhea prodrome — 6 percent  Hematopoietic cell transplantation — 4 percent

13. ADAMTS13 Deficiency  VWF-cleaving protease; normally cleaves long VWF multimers secreted by endothelial cells  Without ADAMTS13, long sticky VWF multimers accumulate, react with platelets and and cause formation of disseminated platelet thrombi

14. In Panel A, in normal subjects, normal ADAMTS 13 molecules attach to binding sites on endothelial-cell surfaces and cleave unusually large multimers of von Willebrand factor as they are secreted by stimulated endothelial cells. The smaller von Willebrand factor forms that circulate after cleavage do not induce the adhesion and aggregation of platelets during normal blood flow. In Panel B, absent or severely reduced activity of ADAMTS 13 in patients with thrombotic thrombocytopenic purpura prevents timely cleavage of unusually large multimers of von Willebrand factor as they are secreted by endothelial cells. The uncleaved multimers induce the adhesion and aggregation of platelets in flowing blood.

15. Testing for ADAMTS13 Deficiency  Assay not always available  Results may take a long time to come back  Assay techniques for ADAMTS13 are not completely standardized and can yield different or inconsistent results  However, if present, severe deficiency predicts an increased risk of relapse

16. Treatment ** More intensive immunosuppressive therapies include rituximab, cyclophosphamide, vincristine, or cyclosporine.