Thrombotic Thrombocytopenic Purpura

1. Thrombotic Thrombocytopenic Purpura Christopher Powe, PhD(c), ACNP

2. Objectives • Background (TTP, Idiopathic TP) • Pathophysiology • Frequency/Mortality/Morbidity • Etiologies • Lab Studies / Imaging • Emergency Department Studies

3. Background • TTP – thrombotic thrombocytopenic purpura • Life-threatening multisystem disorder • Considered medical emergency • First described 1924 (Moschcowitz) • Observed 16 y/o female with clinical symptoms • Anemia • Petechiae • Microscopic hematuria • Died of multiorgan failure • Autopsy: disseminated microvascular thrombi prevalent

4. Background • Symptoms remain hallmark pathologic diagnosis • Positive outcomes if recognized early/medical intervention • 1966 Amorosi/Ultmann developed diagnostic criteria • Outlined pentad of clinical features including: • Microangiopathic hemolytic anemia • Thrombocytopenia • Neurologic abnormalities • Fever • Renal dysfunction

5. Background • 1977 Bukowski et al • Reported effective cure • Used whole blood exchange transfusion and FFP • Later, Burnes, et al • Used plasma infusion • Survival Rates • 3% prior to 1966 • 82% to date • 1991 Rock et al • Landmark study • Early recognition • Plasma exchange therapy (aggressive) • Reduced mortality rates from 90% to approximately 10-20%

6. Pathophysiology • Characterized by microangiopathic hemolysis and platelet aggregation/hyaline thrombi • Formation unrelated to coagulation system activity • Definition: microangiopathic hemolysis  subgroup of hemolytic anemia caused by factors in the small blood vessels. Identified by finding of anemia and schistocytes (a red blood cell undergoing fragmentation) on microscopy. • Platelet microthrombi predominate • Form in the microcirculation (e.g. arterioles, capillaries)

7. Schistocytes

8. Pathophysiology • Microthrombi form in microcirculation • Partial occlusion of vessels • Organ ischemia • Thrombocytopenia • Erythrocyte fragmentation occur • Thrombi occlude vascular lumina w/overlying proliferative endthelial cells • Endothelia of kidneys, brain, heart, pancreas, spleen, adrenal glands are most vulnerable • No inflammatory changes occur

9. Mechanism • Von Willebrand factore (VWF) adhesive protein • Mediates thrombus formation vascular injury site • Largest soluble protein found in human plasma • Major pathogenic factor in TTP • Synthesized in endothelieal cells / megakaryocytes • Present in platelets, endothelial cells and subendothelium

10. Mechanism • In TTP, ultralarge VWF multimers identified • These multimers were the same size as those in endothelial cells • Plasma of normal individuals was smaller • Research suggests a deficiency in an enzyme that reduces large VWF to normal size in plasma of TTP patients • Agitated endothelial cells are main source for ULVWF • Bind to specifici surface platelet receptors • ULVWF entangle platelets adhering to subendothelium

11. Mechanism • Pathogenesis of TTP is due to platelet clumping in microvasculature • Increased adherence of ULVWF • Lack of functioning proteolytic enzyme to normalize the multimers • Sheer stress of luid and platelet thrombi does not enhance proteolysis of ULVWF • Unknown how the adhesive bond opposes shear stress in the mricroangiopathic causing platelet initiating thrombus formation

12. Mechanism • Plasma exchange is first-line therapy for TTP since 1991 • Congenital deficiency can replace the deficiency and mutations in the ADAMTS-13 gene by plasma infusion • Acquired deficiency can remove the inhibitor of ADAFTS-13 by plasmapheresis • However, plasma exchange is more effecgte treatment than plasma infusion

13. Future Research Development • Appears VWF plays vital role in occlusive arterial thrombosis • Development of simpler methods of measuring ADAMTS-13 proteolytic multimers, detecting atuoantiboides are currently being researched for more effective treatment and cures

14. Frequency • 75 years of data • Uncommon disorder 1 case per 1 million patients • Incident rate is increasing • 10 years ago: 3.7 cases / 1 million • Incident rate is higher today with greater awareness

15. Mortality/Morbidity • 1980’s: 100% Mortality • Dropped in mortality associated with early dx/trx • Currently: 95% mortality untreated cases • Survival rate: 80-90% early dx/trx • Plasma exchange or plasma infusion • 1/3 patients who survive initial episode experience relapse within 10 years

16. Mortality/Morbity • Race: no significance • Sex: Women>Men (3:2 ratio) • Age: Most common in adults • Can occur in neonates • Can occur in persons as old as 90 • Peak occurs: 4th decade of life • Mean Age: 35

17. History • Pentad of findings: • Rarely found with vague complaints • Thrombocytopenia • Schistocytosis • Elevated serum lactate dehydrogenase (LDH) • Absence of other disease entities that could explain thrombocytopenia and microcytic hemolytic anemia

18. History • Present with non-specific complaints • Fever (60%) • Fatigue/generalized malaise • Arthralgias • Thrombocytopenia with petichial hemorrhages • Anemia – Hgb <10.0 g/dL • Altered Mental Status • Heart failure • Abdominal pain (? Bowel ischemia)

19. Causes • Pregancy/Post-partum state account for 10-25% • HIV patients • Often associated with cancer • Drugs • Immunosuppressive agents • Crack cocaine • Ticlopidine • Oral contraceptives • PCN • Rifampin • Toxins  E.Coli, spider and bee venoms

20. Emergency Treatment • Infuse FFP • Glucocorticoid-steroid and anti-platelet agents • Splenectomy may be performed • Anticonvulsants • Platelet depleted packed red blood cells • Platelet transfusion is contraindicated