CASE 32 An 32 year old woman is brought to the emergency room by a friend because of the onset of confusion and disorientation

over the past day. PE generalized petechial rash, fever and bilateral positive Babinski sign. Your order blood tests which show an elevated LDH, increased indirect bilirubin, thrombocytopenia and anemia. Examination of a peripheral blood smear yields multiple reticulocytes and schistocytes. You admit the patient for an emergency plasmapharesis. BASIC DATA Age: 32 years Gender: woman Chief complains : Confusion and disorientation Review of System Integumentary system: (+) petechial rash, (+) fever Nervous system: (+) confusion, (+) disorientation, (+) bilateral positive Babinski sign

Physical Examination: General survey: confusion and disoriented Skin : generalized petechial rash , fever HEENT: positive bilateral Babinski sign

Neurologic Exam: Mental Status Examination: confused and disorientation Primitive Reflex: (+) Babinski sign

Lab Results elevated LDH increased indirect bilirubin thrombocytopenia anemia

Peripheral blood smear showed: multiple reticulocytes Schistocytes

CURRENT MANAGEMENT Emergency plasmapheresis

Salient features: 32 years old Woman Confusion and disorientated

(+) fever Impression: Thrombotic thrombocytopenic purpura (TTP) Differential Diagnosis: Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia Disseminated malignancy. Hemolytic-uremic syndrome Malignant hypertension. Hemolytic Uremic Syndrome

INTRODUCTION: TTP syndrome: characterized by microangiopathic hemolytic anemia (MAHA) and platelet aggregation. Platelet microthrombi form in the microcirculation throughout the body causing partial occlusion of vessels. Organ ischemia, thrombocytopenia, and erythrocyte fragmentation (ie, schistocytes) occur. The thrombi partially occlude the vascular lumina with overlying proliferative endothelial cells.

 The endothelia of the kidneys, brain, heart, pancreas, spleen, and adrenal glands are particularly vulnerable to TTP. The liver, lungs, gastrointestinal tract, gallbladder, skeletal muscles, retina, pituitary gland, ovaries, uterus, and testes are also affected to a lesser extent. Deep vein thrombosis can also occur. No inflammatory changes History In 1924, Dr.Eli Moschcowitz described a 16- year old girl with abrupt onset of petechiae, pallor, followed by paralysis, coma, and death. Autopsy showed hyaline thrombi occluding terminal arterioles and capillaries. Epidimiogy Prevalence: > 3.7/1,000,000 (US) age of onset: 35 (median age), 40~49 (in average)

Sex: female-to-male ratio of 3:2

F M
Mortality and Recurrence on Survivors Deceased (20%) Alive NR 63% A with recurrence (17%)

ETIOLOGY OF TTP Primary/idiopathic TTP: ~ 80% Decreased activity or amount of ADAMTS-13 (80%) Persistence of ULVWF and abnormal platelet aggregation and microthrombi formation Genetic or acquired (existence of antibody) Secondary TTP: ~ 20% Drugs: anti-platelet drug, eg. clopidogrel (Plavix) Pregnancy: TTP can develop at any time during pregnancy even after the birth. Infections: eg. HIV Systemic lupus erythematosus (SLE) Malignancy: cancer of any type may be complicated by TTP

CLINICAL PRESENTATION

Fever (60%)

Purpura: Nonpalpable small purpuric spots or petechiae occur with thrombocytopenia (platelet count < 50 K/L).

Anemia, hemoglobin levels less than 10 g/dL Altered mental status (36%) Abdominal pain (24%)

 Renal changes (88%) with gross hematuria (15%) Heart failure, arrhythmias Fatal Platelet Thrombi in CNS

Pathophysiology: 1.Genetics

ADAMTS13 has 29 exons (a) and is 37kb long. Dashed lines show the relationship of EXON to the structure (b) Structural domains include signal peptide(S), propeptide (P), metalloprotease disintegrin domains (Dis), thrombospondin 1 repeats Mutations present in inherited TTP are shown

2. ULVWF

Endothelial cells

normal VWF

assembled into large multimers

Large von willebrand Factors

Endothelial Cellderived ULvWf Multimers

Presence of ADAMTS13(cleav ing protease) Absence of ADAMTS13

Degraded into more usual VWF TTP associated S/S. Clots formation

Platelet aggregation

Float in plasma

LAB STUDIES Thrombocytopenia and anemia Fragmented RBCs (schistocytes) LDH level > 1000 mg/dL Indirect bilirubin level: Elevated Reticulocyte count: Elevated PT: Normal DIC panel (fibrinogen, D-dimer): usually normal Urinalysis: Proteinuria and microscopic hematuria

TREAMENT FOR TTP Plasma exchange with FFP(fresh frozen plasma): standard method Steroid: of no proven additional benefit Antiplatelet agents: controversia

Splenectomy

Deacesed (33%)

Alive 66%

It is performed occasionally to treat patients who do not respond to plasma exchange.

 The response may be due to the removal of the site of sequestration of the RBCs and platelets. Another possibility is that the spleen is a major site of microvascular occlusive lesions in severe TTP Vincristine a second-line therapy with an unknown mechanism of action and with unproven benefit

platelet-depleted packed RBCs

Supportive care, anticonvulsants Platelet transfusion is contraindicated because it is associated with rapid deterioration

REVIEW OF THIS CASE: S/S of Typical TTP Fever Petechial rash Altered mental status Positive Babinski sign Abdominal pain Anemia Heart failure Arrhythmia S/S of Our Patient present present Confusion and disorientation present present -

Lab Data of Typical TTP

Lab Data of Our Patient

Anemia w/ Hb < 10 Thrombocytopenia Elevated LDH Schistocytes in PB Increased indirect bilirubin Elevated reticulocyte count

anemia Present present present present Multiple reticulocytes

Conclusions Thrombotic thrombocytopenic purpura is a rare condition associated with abnormal aggregation of platelets, intravascular destruction of RBCs, and the formation of microthrombi. The patient can present with some or all of the characteristics of the classic pentad including thrombocytopenia, fever, renal changes with gross hematuria, neurologic deficit, and hematologic changes. Some patients may exhibit dysfunction of ADAMTS-13 If treated early with plasma exchange, the prognosis is good.