Thrombotic Thrombocytopenic Purpura (TTP)

A 35 year old female presents with a 3-day history of fatigue, headache, and confusion. She also reports petechiae on her legs. On examination, she has pallor, petechiae, and mild jaundice. Vital signs show blood pressure of 130/80 mm Hg, pulse rate of 98 beats per minute, respiratory rate of 18 breaths per minute, and temperature of 99.9 F. Laboratory studies reveal hemoglobin of 8.0 g/dL, platelet count of 30,000/µL, elevated LDH, elevated indirect bilirubin, low haptoglobin, and serum creatinine of 1.8 mg/dL. Peripheral blood smear shows schistocytes. Coombs test is negative. ADAMTS13 activity is severely reduced (<10%). Diagnosis?

Diagnosis is Thrombotic Thrombocytopenic Purpura (TTP).

1. Definition

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia (MAHA) caused by severe deficiency of ADAMTS13, leading to platelet-rich microvascular thrombosis and end-organ ischemia, especially involving the central nervous system and kidneys.

2. Pathophysiology

2.1 Core Mechanism

1. ADAMTS13 activity <10%
2. Accumulation of ultra-large von Willebrand factor multimers
3. Platelet aggregation and microthrombi formation

2.2 Consequences

1. Thrombocytopenia due to platelet consumption
2. Hemolytic anemia due to mechanical RBC destruction
3. Microvascular ischemia affecting multiple organs

2.3 Etiology

1. Acquired autoimmune inhibition of ADAMTS13, most common
2. Congenital ADAMTS13 deficiency
3. Clinical disease is often triggered by infection, pregnancy, or medications

3. Clinical Features

3.1 Core Features

1. Microangiopathic hemolytic anemia
2. Thrombocytopenia

These two findings are sufficient to suspect TTP

3.2 Additional Features

1. Neurologic symptoms, most prominent, such as confusion, seizures, or focal deficits
2. Acute kidney injury, typically less severe than in HUS
3. Fever, present in a minority of cases

Note: The classic pentad is rarely seen in full (<5%)

4. Diagnostic Evaluation

4.1 Hematology

1. Low hemoglobin
2. Low platelet count
3. Increased reticulocyte count

4.2 Hemolysis Markers

1. Elevated LDH
2. Elevated indirect bilirubin
3. Low haptoglobin
4. Coombs negative hemolysis

4.3 Peripheral Blood Smear

1. Schistocytes

4.4 Coagulation Profile

1. Normal PT and aPTT

4.5 Renal Function

1. Elevated creatinine

4.6 ADAMTS13 Testing

1. Activity <10% is highly suggestive in the appropriate clinical context
2. May detect anti-ADAMTS13 antibodies

4.7 Clinical Scoring

1. PLASMIC score helps estimate probability of severe ADAMTS13 deficiency

5. Key Diagnostic Insight

MAHA + thrombocytopenia with normal coagulation profile = presume TTP and treat immediately

6. Differential Diagnosis

1. Hemolytic uremic syndrome (HUS) with more severe renal involvement
2. Disseminated intravascular coagulation (DIC) with abnormal coagulation profile
3. Drug induced or cancer associated thrombotic microangiopathy
4. Autoimmune hemolytic anemia, Coombs positive

7. Management

7.1 Emergency Treatment

1. Immediate plasma exchange (PEX) is life saving
2. Do not delay treatment while awaiting ADAMTS13 results

7.2 First Line Therapy

1. Plasma exchange combined with corticosteroids

7.3 Adjunct Therapy

1. Rituximab to reduce relapse and for severe or refractory disease
2. Caplacizumab used in combination with PEX and immunosuppression to inhibit vWF platelet interaction

7.4 Supportive Care

1. Platelet transfusion should be avoided unless life threatening bleeding
2. Packed red blood cell transfusion if clinically indicated

7.5 Alternative

1. Plasma infusion if PEX is not immediately available

8. Complications

1. Multiorgan ischemia
2. Stroke, seizures, or coma
3. Cardiac ischemia
4. Death if untreated, mortality up to 90%

9. Key Clinical Insight

TTP is a hematologic emergency and early plasma exchange reduces mortality from about 90% to 10–15%

10. Exam Level Pearls

1. Schistocytes indicate microangiopathic hemolysis
2. Normal PT and aPTT distinguish TTP from DIC
3. ADAMTS13 activity <10% is diagnostic in the right clinical setting
4. Neurologic symptoms are more prominent than renal involvement
5. Classic pentad is rare
6. Never delay plasma exchange

Wolff Parkinson White Syndrome

A 25 year old male presents to the emergency department with sudden onset palpitations that began 30 minutes ago during exercise. He also reports lightheadedness, chest discomfort, and shortness of breath. There is no significant past medical history. Vital signs show blood pressure of 110/70 mm Hg, pulse rate of 158 beats per minute, respiratory rate of 18 breaths per minute, oxygen saturation of 98 percent on room air, and temperature of 96.9 F. Physical examination is unremarkable. ECG shows short PR interval less than 120 ms, widened QRS complex greater than 120 ms, and a delta wave, which is a slurred upstroke of the QRS complex. Diagnosis?

Diagnosis is Wolff Parkinson White syndrome with orthodromic atrioventricular reentrant tachycardia.

1. Definition

Wolff Parkinson White syndrome is a pre-excitation syndrome caused by an accessory conduction pathway between the atria and ventricles, known as the Bundle of Kent, which bypasses the AV node and leads to early ventricular depolarization.

2. ECG Features in Sinus Rhythm

1. Short PR interval less than 120 ms
2. Delta wave, a slurred upstroke of the QRS complex
3. Widened QRS complex greater than 120 ms

3. Pathophysiology

1. Presence of an accessory pathway allowing conduction outside the AV node
2. Formation of reentrant circuits
3. Leads to paroxysmal supraventricular tachyarrhythmias

4. Types of Tachyarrhythmias

1. Orthodromic atrioventricular reentrant tachycardia
• Conduction down the AV node and back via the accessory pathway
• Produces regular narrow complex tachycardia
2. Antidromic atrioventricular reentrant tachycardia
• Conduction down the accessory pathway and back via the AV node
• Produces regular wide complex tachycardia

5. Atrial Fibrillation in Wolff Parkinson White Syndrome

1. Accessory pathway has a short refractory period
2. Allows rapid conduction of atrial impulses to the ventricles
3. Leads to irregular wide complex tachycardia with very high ventricular rates
4. May degenerate into ventricular fibrillation

6. Management

6.1 Stable Orthodromic AVRT (Regular Narrow Complex)

1. Vagal maneuvers
2. Adenosine
3. Beta blockers or calcium channel blockers if needed

6.2 Antidromic AVRT (Regular Wide Complex)

1. Procainamide is the drug of choice
2. Treat as ventricular tachycardia if diagnosis is uncertain

6.3 Atrial Fibrillation with Wolff Parkinson White Syndrome

1. Procainamide or ibutilide
2. Avoid AV nodal blocking agents, including:
• Adenosine
• Beta blockers
• Calcium channel blockers
• Digoxin

These drugs increase conduction through the accessory pathway and may precipitate ventricular fibrillation

6.4 Hemodynamically Unstable Patient

1. Synchronized DC cardioversion

6.5 Definitive Treatment

1. Radiofrequency catheter ablation of the accessory pathway

7. Key Clinical Insight

Young patient with paroxysmal palpitations and ECG showing short PR interval, delta wave, and widened QRS strongly suggests Wolff Parkinson White syndrome

8. Exam Level Pearls

1. Short PR interval with delta wave is diagnostic of WPW pattern
2. Orthodromic AVRT is the most common arrhythmia and is narrow complex
3. Antidromic AVRT produces wide complex tachycardia
4. Irregular wide complex tachycardia suggests atrial fibrillation with WPW
5. Avoid AV nodal blockers in atrial fibrillation with WPW

Gout

A 48 year old male presents to his primary care physician with sudden onset severe pain in the great toe of the left foot for 24 hours. The pain is sharp and intense, preventing him from bearing weight and performing daily activities. He has a history of hypertension and takes losartan and hydrochlorothiazide. He drinks alcohol regularly. On examination, there is a swollen, erythematous, and tender first metatarsophalangeal joint. Laboratory studies show normal serum uric acid levels. Synovial fluid analysis shows needle-shaped, negatively birefringent crystals. X ray of the foot is normal. Diagnosis?

Diagnosis is Acute gouty arthritis.

1. Definition

Gout is an acute inflammatory arthritis caused by deposition of monosodium urate crystals in joints, most commonly affecting the first metatarsophalangeal joint (podagra).

2. Epidemiology and Risk Factors

1. Male predominance
2. Peak incidence in the 4th to 6th decade
3. Risk factors include:
1. Hypertension
2. Obesity
3. Alcohol use
4. Chronic kidney disease
5. Thiazide diuretics
6. Metabolic syndrome

Hydrochlorothiazide increases uric acid levels, whereas losartan has a mild uricosuric effect.

3. Pathophysiology

1. Hyperuricemia leads to supersaturation of urate
2. Deposition of monosodium urate crystals in joints
3. Activation of neutrophil-mediated inflammation
4. Results in acute painful monoarthritis

4. Causes

4.1 Underexcretion (most common, ~90%)

1. Renal impairment
2. Thiazide and loop diuretics
3. Low dose aspirin
4. Lactic acidosis or ketoacidosis

4.2 Overproduction (~10%)

1. High cell turnover
• Malignancy, chemotherapy, psoriasis
2. Genetic enzyme defects
• Lesch Nyhan syndrome
• Von Gierke disease
3. Alcohol use

5. Clinical Features

1. Acute monoarthritis, classically involving the first MTP joint
2. Severe pain, swelling, erythema, and warmth
3. Joint is extremely tender to touch
4. Often occurs at night or early morning
5. May be triggered by alcohol, heavy meals, illness, or medications

6. Diagnosis

1. Synovial fluid analysis (gold standard)
• Needle-shaped, negatively birefringent monosodium urate crystals
2. Serum uric acid
• May be normal during acute attack
3. Laboratory findings
• Leukocytosis
• Elevated ESR and CRP
4. Imaging
• Early: normal
• Late: punched-out erosions with overhanging edges

7. Acute Management

1. NSAIDs
• Indomethacin, naproxen
• Avoid aspirin
2. Colchicine
• Effective if given early
• Side effects: diarrhea, nausea
3. Corticosteroids
• Oral or intra-articular if NSAIDs or colchicine are contraindicated

8. Chronic Management

Indicated for recurrent attacks, tophi, or complications

1. Lifestyle modification
• Reduce alcohol intake
• Avoid purine-rich foods
• Weight loss
2. Urate-lowering therapy
• Allopurinol (first line)
• Febuxostat as alternative
• Target serum urate <6 mg/dL
3. Uricosuric agents
• Probenecid
4. Uricase therapy
• Pegloticase for refractory disease
5. Prophylaxis during initiation of urate-lowering therapy
• Low-dose colchicine or NSAIDs

Urate-lowering therapy can be initiated during an acute flare if appropriate anti-inflammatory treatment is provided.

9. Key Clinical Insight

Acute monoarthritis of the first MTP joint with needle-shaped negatively birefringent crystals confirms gout, even if serum uric acid is normal

10. Exam Level Pearls

1. Podagra is the classic presentation of gout
2. Serum uric acid may be normal during an acute attack
3. Thiazide diuretics increase risk of gout
4. Needle-shaped, negatively birefringent crystals are diagnostic
5. Treat-to-target goal is serum urate <6 mg/dL