Thrombotic Thrombocytopenic Purpura (TTP)

A 35-year-old woman 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. Her blood pressure is 130/80 mm Hg, pulse rate is 98 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 99.9°F. Laboratory studies reveal a hemoglobin level 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. The direct antiglobulin test is negative. ADAMTS13 activity is severely reduced to <10%. Diagnosis? 

Diagnosis is Thrombotic Thrombocytopenic Purpura (TTP).

1. Definition

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) characterized by:

1. Microangiopathic hemolytic anemia (MAHA)
2. Thrombocytopenia
3. Severe ADAMTS13 deficiency, defined as ADAMTS13 activity <10 IU/dL, equivalent to <10% of normal activity
4. Platelet-rich microvascular thrombosis causing tissue ischemia and organ dysfunction

TTP is classified into:

1. Immune-mediated TTP (iTTP), caused by autoantibodies against ADAMTS13
2. Congenital TTP (cTTP), caused by biallelic pathogenic variants in the ADAMTS13 gene

Most adult cases are immune-mediated. However, severe ADAMTS13 deficiency alone does not distinguish immune-mediated TTP from congenital TTP.

2. Pathophysiology

ADAMTS13 is a plasma metalloprotease that normally cleaves ultra-large von Willebrand factor (VWF) multimers.

Severe ADAMTS13 deficiency leads to:

1. Persistence of ultra-large VWF multimers
2. Excessive VWF-mediated platelet adhesion and aggregation
3. Formation of platelet-rich microvascular thrombi
4. Platelet consumption, causing thrombocytopenia
5. Mechanical fragmentation of red blood cells within the microcirculation, causing MAHA
6. Microvascular ischemia and organ dysfunction

2.1 Immune-Mediated TTP

Immune-mediated TTP results from anti-ADAMTS13 autoantibodies that inhibit ADAMTS13 activity and/or accelerate its clearance.

It is the most common form of TTP in adults.

2.2 Congenital TTP

Congenital TTP results from biallelic pathogenic variants in the ADAMTS13 gene, causing inherited severe ADAMTS13 deficiency.

The absence of detectable anti-ADAMTS13 antibodies in a patient with severe ADAMTS13 deficiency should raise consideration of congenital TTP, but antibody negativity alone does not establish the diagnosis.

Genomic analysis of the ADAMTS13 gene is required to confirm congenital TTP.

3. Clinical Features

3.1 Core Hematologic Features

The characteristic hematologic findings are:

1. Microangiopathic hemolytic anemia
2. Thrombocytopenia

These findings indicate a thrombotic microangiopathy syndrome, but they are not specific for TTP.

TTP should be considered urgently when otherwise unexplained MAHA and thrombocytopenia are present.

3.2 Neurologic Manifestations

Neurologic involvement is common and may include:

1. Headache
2. Confusion
3. Altered mental status
4. Focal neurologic deficits
5. Aphasia
6. Seizures
7. Encephalopathy
8. Coma in severe disease

Neurologic manifestations may fluctuate.

3.3 Renal Manifestations

Renal involvement may include:

1. Mild to moderate elevation in serum creatinine
2. Proteinuria
3. Microscopic hematuria

Severe acute kidney injury, particularly dialysis-requiring renal failure, is less typical of TTP and should increase consideration of other thrombotic microangiopathies, including HUS.

3.4 Cardiac Manifestations

Cardiac involvement may include:

1. Elevated cardiac troponin
2. Chest pain
3. Myocardial ischemia or infarction
4. Arrhythmias
5. Heart failure

3.5 Other Manifestations

Additional findings may include:

1. Petechiae or purpura
2. Pallor
3. Mild jaundice
4. Fatigue
5. Fever

The traditional pentad of MAHA, thrombocytopenia, neurologic abnormalities, renal dysfunction, and fever is often incomplete and is not required for diagnosis.

4. Diagnostic Evaluation

4.1 Complete Blood Count

Typical findings include:

1. Anemia
2. Thrombocytopenia
3. Reticulocytosis due to compensatory erythropoiesis

4.2 Evidence of Microangiopathic Hemolysis

Typical findings include:

1. Elevated LDH
2. Elevated indirect bilirubin
3. Low or undetectable haptoglobin
4. Reticulocytosis
5. Typically negative direct antiglobulin test

4.3 Peripheral Blood Smear

The characteristic finding is:

Schistocytes

Schistocytes result from mechanical fragmentation of red blood cells within the microcirculation and support the diagnosis of MAHA.

The absence of schistocytes on a single blood film does not completely exclude TTP when clinical suspicion remains high.

4.4 Coagulation Studies

In uncomplicated TTP:

1. PT is usually normal
2. aPTT is usually normal
3. Fibrinogen is usually normal

This pattern helps distinguish TTP from disseminated intravascular coagulation (DIC), in which abnormalities of coagulation are more common.

However, normal coagulation studies are not specific for TTP and may also occur in other thrombotic microangiopathies.

4.5 ADAMTS13 Testing

ADAMTS13 activity <10 IU/dL, equivalent to <10% of normal activity, confirms TTP in the appropriate clinical context.

Blood for ADAMTS13 testing should be obtained before plasma exchange, plasma infusion, or other plasma-containing blood products whenever feasible.

When ADAMTS13 activity is <10 IU/dL:

1. Anti-ADAMTS13 antibody testing should be performed
2. Detection of anti-ADAMTS13 IgG supports immune-mediated TTP
3. A negative antibody result does not completely exclude immune-mediated TTP
4. Absence of antibodies should raise consideration of congenital TTP
5. ADAMTS13 genetic analysis is required to confirm congenital TTP

Current BSH laboratory guidance recommends anti-ADAMTS13 antibody testing within 72 hours of presentation when ADAMTS13 activity is <10 IU/dL.

An ADAMTS13 activity between 10 and 20 IU/dL is an equivocal range that requires interpretation in the clinical context and consideration of alternative diagnoses.

If the ADAMTS13 result is inconsistent with the clinical probability of TTP, confirmation using an alternative assay should be considered.

4.6 PLASMIC Score

The PLASMIC score estimates the probability of severe ADAMTS13 deficiency in a patient presenting with a thrombotic microangiopathy.

It is particularly useful when rapid ADAMTS13 testing is unavailable.

The PLASMIC score does not replace direct measurement of ADAMTS13 activity.

5. Key Diagnostic Principle

The combination of:

Microangiopathic hemolytic anemia + thrombocytopenia

indicates a thrombotic microangiopathy and requires urgent evaluation for TTP and other causes of TMA.

MAHA and thrombocytopenia alone do not establish the diagnosis of TTP.

When the clinical probability of TTP is high:

1. Obtain a pre-treatment sample for ADAMTS13 testing
2. Initiate treatment immediately
3. Do not delay plasma exchange and corticosteroids while awaiting the ADAMTS13 result

In this patient:

1. Hemoglobin is 8.0 g/dL
2. Platelet count is 30,000/µL
3. Schistocytes are present
4. LDH is elevated
5. Indirect bilirubin is elevated
6. Haptoglobin is low
7. Direct antiglobulin test is negative
8. Neurologic symptoms are present
9. Renal impairment is mild
10. ADAMTS13 activity is <10%

These findings establish the diagnosis of TTP.

Anti-ADAMTS13 antibody testing should then help determine whether the severe ADAMTS13 deficiency is immune-mediated.

6. Differential Diagnosis

6.1 Hemolytic Uremic Syndrome

Important forms include:

1. Shiga toxin-associated HUS
2. Complement-mediated HUS

Renal involvement is often more prominent in HUS than in TTP.

Severe ADAMTS13 deficiency is not characteristic of HUS.

6.2 Disseminated Intravascular Coagulation

DIC may also produce thrombocytopenia, microangiopathic hemolysis, and multiorgan dysfunction.

Unlike uncomplicated TTP, DIC is more commonly associated with:

1. Prolonged PT
2. Prolonged aPTT
3. Reduced fibrinogen
4. Elevated fibrin-related markers

6.3 Other Secondary Thrombotic Microangiopathies

Important causes include:

1. Severe hypertension
2. Pregnancy-associated TMA
3. HELLP syndrome
4. Malignancy
5. Hematopoietic stem cell transplantation
6. Solid organ transplantation
7. Certain medications
8. Autoimmune disease
9. Severe infection

These conditions can cause MAHA and thrombocytopenia but generally do not demonstrate the severe ADAMTS13 deficiency characteristic of TTP.

6.4 Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia is usually associated with a positive direct antiglobulin test and does not characteristically produce the combination of MAHA, severe thrombocytopenia, and severe ADAMTS13 deficiency seen in TTP.

7. Management

Acute TTP is a medical emergency.

When TTP is strongly suspected:

1. Obtain blood for ADAMTS13 activity and anti-ADAMTS13 antibody testing before plasma therapy whenever feasible
2. Initiate therapeutic plasma exchange and corticosteroids immediately
3. Do not delay treatment while awaiting ADAMTS13 results

7.1 Therapeutic Plasma Exchange

Urgent therapeutic plasma exchange (TPE), also called plasma exchange (PEX), is the cornerstone of treatment for acute immune-mediated TTP.

Plasma exchange should be initiated as rapidly as possible.

British Society for Haematology guidance recommends starting plasma exchange within 4 to 8 hours of the suspected diagnosis.

Plasma exchange:

1. Removes circulating anti-ADAMTS13 autoantibodies
2. Replaces functional ADAMTS13
3. Removes pathogenic plasma components

Daily plasma exchange should continue until clinical response, including normalization of the platelet count.

Current BSH guidance recommends continuing daily plasma exchange until the platelet count is >150 × 10⁹/L.

Routine tapering of plasma exchange after platelet normalization is not required.

More intensive plasma exchange may be considered in refractory or life-threatening disease under specialist management.

7.2 Corticosteroids

For acute immune-mediated TTP, corticosteroids should be administered together with plasma exchange.

Corticosteroids suppress the autoimmune response responsible for anti-ADAMTS13 antibody production.

The corticosteroid regimen varies according to clinical severity and specialist protocol.

7.3 Rituximab

Rituximab is an anti-CD20 monoclonal antibody that suppresses B-cell production of anti-ADAMTS13 antibodies.

It should not be reserved only for refractory or relapsed disease.

In contemporary management of acute immune-mediated TTP, rituximab is commonly incorporated early during the initial episode.

British Society for Haematology guidance recommends initiation of anti-CD20 therapy within 3 days of admission for acute immune-mediated TTP.

ISTH guidance conditionally recommends adding rituximab to plasma exchange and corticosteroids during a first acute episode of immune-mediated TTP.

Rituximab is also important in:

1. Relapsed immune-mediated TTP
2. Refractory disease
3. Persistent severe ADAMTS13 deficiency
4. Prevention of relapse in appropriately selected patients with low ADAMTS13 activity during remission

7.4 Caplacizumab

Caplacizumab is an anti-VWF nanobody that binds the A1 domain of VWF and prevents VWF-mediated platelet adhesion.

It rapidly inhibits ongoing microvascular platelet aggregation but does not correct the underlying autoimmune ADAMTS13 deficiency.

Therefore, caplacizumab is used together with therapy directed at the underlying disease, including:

1. Plasma exchange
2. Corticosteroids
3. Immunosuppressive therapy

Caplacizumab is an important component of contemporary treatment for acute immune-mediated TTP.

British Society for Haematology guidance recommends initiating caplacizumab when acute TTP is confirmed and continuing treatment for up to 30 days after completion of plasma exchange, with extension considered when severe ADAMTS13 deficiency persists.

ISTH guidance conditionally recommends caplacizumab for acute immune-mediated TTP. The 2025 ISTH focused update reviewed newer evidence and retained the existing immune TTP recommendations.

Because caplacizumab inhibits VWF-mediated platelet adhesion, bleeding is an important adverse effect.

7.5 Plasma Infusion if Plasma Exchange Is Unavoidably Delayed

If therapeutic plasma exchange cannot be initiated promptly because of an unavoidable delay:

Plasma infusion may be used as a temporary bridging measure while urgent arrangements for plasma exchange are made.

Plasma infusion is not equivalent to plasma exchange for acute immune-mediated TTP and should not delay definitive plasma exchange.

A pre-treatment ADAMTS13 sample should be obtained before plasma infusion whenever feasible.

7.6 Red Blood Cell Transfusion

Packed red blood cell transfusion may be administered when clinically indicated for severe or symptomatic anemia.

7.7 Platelet Transfusion

Platelet transfusion should be avoided in acute TTP.

It should not be given prophylactically solely because of thrombocytopenia.

Central venous catheter insertion for plasma exchange does not routinely require platelet transfusion.

Platelet transfusion should generally be reserved for life-threatening bleeding.

8. Monitoring and Complications

Important acute complications include:

1. Neurologic deterioration
2. Seizures
3. Ischemic stroke
4. Cardiac ischemia
5. Arrhythmias
6. Heart failure
7. Acute kidney injury
8. Persistent or recurrent thrombocytopenia
9. Ongoing hemolysis
10. Multiorgan ischemia

During acute treatment, monitoring should include:

1. Platelet count
2. Hemoglobin
3. LDH
4. Bilirubin
5. Renal function
6. Neurologic status
7. Cardiac assessment when clinically indicated

Patients with immune-mediated TTP require long-term follow-up, including serial ADAMTS13 activity monitoring, because declining ADAMTS13 activity during remission is associated with an increased risk of relapse.

9. Key Clinical Insight

TTP is a life-threatening thrombotic microangiopathy defined by severe ADAMTS13 deficiency.

The characteristic diagnostic pattern is:

MAHA + thrombocytopenia + ADAMTS13 activity <10 IU/dL

MAHA and thrombocytopenia alone identify a thrombotic microangiopathy, not specifically TTP.

In a patient with a high clinical probability of TTP:

Obtain a pre-treatment ADAMTS13 sample and initiate urgent plasma exchange and corticosteroids without waiting for the ADAMTS13 result.

For acute immune-mediated TTP, contemporary management consists of:

Plasma exchange + corticosteroids + early immunosuppression with rituximab + caplacizumab according to the clinical setting and guideline recommendations.

In this patient:

Thrombocytopenia + Coombs-negative microangiopathic hemolytic anemia with schistocytes + neurologic manifestations + mild renal impairment + ADAMTS13 activity <10% = Thrombotic Thrombocytopenic Purpura.

Anti-ADAMTS13 antibody testing should be performed when ADAMTS13 activity is <10 IU/dL. Detection of anti-ADAMTS13 IgG supports immune-mediated TTP. A negative antibody result does not exclude immune-mediated TTP and should raise consideration of congenital TTP. Congenital TTP requires confirmation by ADAMTS13 genetic analysis.

References

1. Zheng XL, Al-Housni Z, Cataland SR, et al. 2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura. Journal of Thrombosis and Haemostasis. 2025;23(11):3711-3732. doi:10.1016/j.jtha.2025.06.002.
2. Scully M, Rayment R, Clark A, et al. A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies. British Journal of Haematology. 2023;203(4):546-563. doi:10.1111/bjh.19026.
3. MacDonald S, Pitchford T, Singh D, et al. Diagnosis and monitoring of thrombotic thrombocytopenic purpura: Guidance for laboratories from the British Society for Haematology. British Journal of Haematology. 2026;209(3):928-938. doi:10.1111/bjh.70727.

Orthostatic Hypotension

A 72-year-old man presents after a brief loss of consciousness shortly after standing from bed. Before losing consciousness, he experienced lightheadedness, generalized weakness, and dimming of vision. There were no preceding palpitations, chest pain, prolonged tonic-clonic movements, or postictal confusion. He regained consciousness rapidly after lying flat. Cardiac and neurologic examinations are unremarkable. Supine blood pressure is 142/78 mm Hg with a heart rate of 70 beats per minute. After 3 minutes of standing, blood pressure falls to 110/64 mm Hg with a heart rate of 88 beats per minute, reproducing his typical lightheadedness. A 12-lead ECG shows normal sinus rhythm without significant abnormalities. Diagnosis?

Diagnosis is Syncope Due to Orthostatic Hypotension.

The patient has a sustained fall in systolic blood pressure of 32 mm Hg and diastolic blood pressure of 14 mm Hg within 3 minutes of standing, accompanied by typical orthostatic symptoms and a history of syncope immediately after standing.

1. Definition

Orthostatic hypotension (OH) is an abnormal, sustained fall in blood pressure after assuming the upright position.

Classic orthostatic hypotension is defined as a sustained fall within 3 minutes of standing or head-up tilt of:

1. Systolic blood pressure ≥20 mm Hg

or

2. Diastolic blood pressure ≥10 mm Hg

ESC guidance also considers a sustained fall in systolic blood pressure to <90 mm Hg abnormal in the appropriate clinical setting.

In patients with supine hypertension, a systolic blood pressure fall of ≥30 mm Hg may be a more appropriate threshold.

Syncope due to orthostatic hypotension occurs when the postural fall in arterial pressure causes transient global cerebral hypoperfusion, resulting in brief loss of consciousness with spontaneous complete recovery.

Importantly:

Orthostatic hypotension does not automatically mean that OH caused the syncope.

The diagnosis is strongest when the clinical event is related to standing and the documented orthostatic BP fall reproduces the patient's typical symptoms.

2. Pathophysiology

Standing causes gravitational redistribution of blood into the lower extremities and splanchnic circulation.

This reduces:

1. Venous return
2. Ventricular filling
3. Stroke volume
4. Arterial blood pressure

Normally, baroreflex activation produces:

1. Sympathetic vasoconstriction
2. Increased heart rate
3. Increased cardiac contractility
4. Venous constriction
5. Skeletal muscle pump activation

These mechanisms maintain arterial pressure and cerebral perfusion.

Orthostatic hypotension develops when these compensatory mechanisms are inadequate because of:

1. Volume depletion
2. Medication effects
3. Autonomic dysfunction
4. Age-related impairment of cardiovascular compensation
5. A combination of these factors

When arterial pressure falls sufficiently:

Orthostatic hypotension → cerebral hypoperfusion → presyncope or syncope

3. Types of Orthostatic Hypotension

3.1 Initial Orthostatic Hypotension

Occurs within approximately 15 seconds of standing.

Characterized by a transient fall of:

1. SBP >40 mm Hg

and/or

2. DBP >20 mm Hg

Symptoms may include:

1. Immediate lightheadedness
2. Visual dimming
3. Weakness
4. Unsteadiness
5. Presyncope or syncope

Because the BP fall is brief, routine cuff measurements may miss it.

Continuous beat-to-beat blood pressure monitoring is required for formal documentation.

3.2 Classic Orthostatic Hypotension

Occurs within 3 minutes of standing.

Defined by:

SBP ↓ ≥20 mm Hg OR DBP ↓ ≥10 mm Hg

Common mechanisms include:

1. Volume depletion
2. Medication effects
3. Autonomic dysfunction

3.3 Delayed Orthostatic Hypotension

Develops after more than 3 minutes of upright posture.

The BP usually falls gradually.

Consider delayed OH when:

1. Symptoms are clearly related to prolonged standing
2. Routine 3-minute orthostatic measurements are normal
3. Symptoms develop only after several minutes upright

Prolonged standing assessment or tilt-table testing may be useful.

4. Causes

4.1 Volume Depletion

Important causes include:

1. Hemorrhage
2. Vomiting
3. Diarrhea
4. Poor oral intake
5. Excessive sweating
6. Diuretic-related volume loss

The compensatory heart-rate response is usually preserved or increased.

4.2 Medication-Related Orthostatic Hypotension

Common contributors include:

1. Diuretics
2. Alpha blockers
3. Nitrates and other vasodilators
4. Beta blockers in susceptible patients
5. Central sympatholytic agents
6. Tricyclic antidepressants
7. Other psychoactive medications
8. Dopaminergic medications

A complete medication review is essential.

Do not automatically discontinue all antihypertensive treatment because OH is present.

Identify potentially contributing drugs and optimize the regimen according to the patient's underlying indications, BP pattern, and cardiovascular risk.

4.3 Neurogenic Orthostatic Hypotension

Neurogenic OH results from impaired autonomic sympathetic vasoconstriction during standing.

Important causes include:

1. Parkinson disease
2. Multiple system atrophy
3. Pure autonomic failure
4. Diabetic autonomic neuropathy
5. Amyloidosis
6. Other autonomic neuropathies

Neurogenic OH is often sustained and reproducible and may coexist with supine hypertension.

5. Clinical Features

Symptoms typically occur while upright and improve after sitting or lying down.

Common manifestations include:

1. Lightheadedness
2. Visual dimming or blurred vision
3. Generalized weakness
4. Fatigue
5. Unsteadiness
6. Presyncope
7. Syncope

Symptoms may be worse:

1. On rising in the morning
2. After prolonged standing
3. After meals
4. In hot environments
5. After exercise
6. During dehydration
7. After medications that reduce BP

Rapid improvement after sitting or lying down supports an orthostatic mechanism.

6. Diagnostic Evaluation

6.1 Initial Evaluation

The core evaluation is:

HISTORY + PHYSICAL EXAMINATION + ORTHOSTATIC BP/HR + 12-LEAD ECG

Important questions include:

1. Did the event occur during or shortly after standing?
2. Was there lightheadedness, weakness, or visual dimming?
3. Did symptoms improve after lying down?
4. Was there vomiting, diarrhea, poor intake, or blood loss?
5. Were medications recently started or increased?
6. Are symptoms worse after meals or in the morning?
7. Are there symptoms of autonomic dysfunction?
8. Are there cardiac red flags?

6.2 Measuring Orthostatic Blood Pressure

A practical protocol is:

1. Rest supine for 5 to 10 minutes
2. Measure supine BP and heart rate
3. Have the patient stand
4. Repeat BP and heart rate during the first 3 minutes
5. Record symptoms during testing

Measurements at approximately 1 and 3 minutes are clinically useful.

The key question is:

Does the BP fall reproduce the patient's typical symptoms?

6.3 Heart-Rate Response

The heart-rate response may help identify the mechanism but is supportive, not diagnostic.

Preserved or Exaggerated HR Increase

Favors:

1. Volume depletion
2. Hemorrhage
3. Dehydration
4. Other non-neurogenic aggravating factors

Blunted HR Increase

Supports:

Neurogenic orthostatic hypotension

A ΔHR/ΔSBP ratio <0.5 beats/min per mm Hg supports neurogenic OH.

Interpret heart rate cautiously in patients with:

1. Beta-blocker therapy
2. Other rate-limiting drugs
3. Pacemakers
4. Conduction disease
5. Chronotropic incompetence

6.4 Targeted Testing

Additional testing should be guided by the clinical context.

CBC
→ suspected anemia or hemorrhage

Electrolytes and renal function
→ dehydration or medication effects

Glucose
→ suspected hypoglycemia

Troponin
→ suspected myocardial ischemia or injury

Echocardiography
→ suspected structural cardiac disease

Ambulatory ECG monitoring
→ suspected intermittent arrhythmia

Tilt-table testing
→ suspected delayed OH, reflex syncope, or unresolved orthostatic symptoms after nondiagnostic initial testing

Routine broad laboratory testing, neuroimaging, EEG, or carotid imaging is not indicated without a specific clinical reason.

7. Differential Diagnosis

7.1 Vasovagal Syncope

Features favoring vasovagal syncope include:

1. Emotional or painful trigger
2. Prolonged standing
3. Warmth
4. Nausea
5. Diaphoresis
6. Pallor

OH is favored by a sustained postural BP fall associated with typical symptoms.

Overlap can occur.

7.2 Cardiac Syncope

Do not attribute syncope to OH solely because orthostatic BP criteria are met.

Cardiac red flags include:

1. Exertional syncope
2. Supine syncope
3. Abrupt syncope without prodrome
4. Palpitations immediately before syncope
5. Structural heart disease
6. Abnormal ECG
7. Family history of sudden cardiac death

These findings warrant urgent cardiac evaluation.

7.3 Seizure

Features favoring seizure include:

1. Prolonged postictal confusion
2. Lateral tongue biting
3. Prolonged tonic-clonic activity
4. Stereotyped epileptic aura

Brief myoclonic movements can occur during syncope and do not by themselves establish epilepsy.

7.4 Postural Orthostatic Tachycardia Syndrome

Orthostatic hypotension: an abnormal BP fall is the defining hemodynamic feature.

POTS: excessive orthostatic tachycardia occurs without orthostatic hypotension.

8. Management

Management should treat the underlying mechanism and symptoms, not simply normalize the standing BP.

8.1 Acute Management

When symptoms occur:

1. Sit or lie down immediately
2. Correct volume depletion
3. Identify hemorrhage or another acute cause
4. Review potentially responsible medications

For acute dehydration:

Oral or intravenous fluid resuscitation is appropriate.

If hemorrhage is present:

Identify and treat the bleeding source urgently.

8.2 Medication Review

For medication-related OH:

1. Remove unnecessary contributing medications
2. Reduce doses when appropriate
3. Modify medication timing
4. Substitute lower-risk agents when appropriate

The goal is to identify and modify culprit medications, not indiscriminately stop indicated cardiovascular therapy.

8.3 Nonpharmacologic Treatment

First-line measures include:

1. Adequate hydration
2. Appropriate sodium intake when not contraindicated
3. Slow transition from lying to standing
4. Avoid prolonged standing
5. Avoid excessive heat
6. Limit excessive alcohol intake
7. Smaller meals when postprandial hypotension is problematic
8. Physical counter-pressure maneuvers
9. Compression therapy, particularly abdominal compression

Fluid and sodium intake should be individualized in patients with:

1. Heart failure
2. Chronic kidney disease
3. Hypertension
4. Supine hypertension

9. Pharmacologic Treatment of Neurogenic OH

Pharmacologic therapy is generally reserved for persistent symptomatic neurogenic OH despite correction of reversible causes and nonpharmacologic treatment.

9.1 Midodrine

Midodrine is an oral alpha-1 adrenergic agonist that increases peripheral vascular resistance and standing BP.

Important adverse effects include:

1. Supine hypertension
2. Piloerection
3. Scalp paresthesia
4. Urinary retention

9.2 Droxidopa

Droxidopa is a norepinephrine precursor used for symptomatic neurogenic OH.

Important adverse effects include:

1. Supine hypertension
2. Headache
3. Dizziness
4. Nausea

Midodrine and droxidopa are the two medications approved in the United States for symptomatic neurogenic OH.

9.3 Fludrocortisone

Fludrocortisone promotes sodium retention and expands plasma volume.

Its supporting evidence is weaker than that for midodrine or droxidopa.

Important adverse effects include:

1. Supine hypertension
2. Edema
3. Hypokalemia
4. Fluid retention

Fludrocortisone is contraindicated in heart failure and should be used cautiously, if at all, when significant supine hypertension is present.

10. Supine Hypertension

Neurogenic OH may coexist with:

ORTHOSTATIC HYPOTENSION WHILE UPRIGHT + HYPERTENSION WHILE SUPINE

This complicates treatment because therapies that improve standing BP may worsen supine hypertension.

Therefore:

1. Monitor both standing and supine BP
2. Avoid unnecessary late doses of pressor medications
3. Individualize salt and fluid intake
4. Review medication timing
5. Consider ambulatory BP monitoring in selected patients

The treatment goal is:

Improve upright symptoms and cerebral perfusion while minimizing supine hypertension.

11. Key Clinical Insight

Orthostatic hypotension is a hemodynamic finding. Syncope due to orthostatic hypotension is a clinical diagnosis linking that BP fall to transient cerebral hypoperfusion and loss of consciousness.

The classic pattern is:

Standing + typical orthostatic symptoms + sustained SBP fall ≥20 mm Hg OR DBP fall ≥10 mm Hg within 3 minutes

Then identify the mechanism:

Volume depletion → restore volume and treat the cause

Medication-related OH → identify and modify contributing medications

Neurogenic OH → nonpharmacologic treatment first, followed by selected pharmacologic therapy when necessary

Heart-rate response may help:

Preserved or exaggerated HR increase → favors volume depletion or another non-neurogenic contributor

Inappropriately small HR increase → supports neurogenic autonomic dysfunction

Most importantly:

Do not diagnose syncope due to OH solely because orthostatic BP criteria are met. The relationship to standing, reproduction of typical symptoms, ECG, and competing causes must also be considered.

In this patient:

Syncope shortly after standing + typical orthostatic prodrome + rapid recovery + reproduction of symptoms with a sustained SBP fall ≥20 mm Hg OR DBP fall ≥10 mm Hg within 3 minutes = Syncope Due to Orthostatic Hypotension.

References

1. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. European Heart Journal. 2018;39(21):1883-1948. doi:10.1093/eurheartj/ehy037. PMID: 29562304.
2. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope. Circulation. 2017;136(5):e60-e122. doi:10.1161/CIR.0000000000000499. PMID: 28280231.
3. Juraschek SP, Cortez MM, Flack JM, et al. Orthostatic Hypotension in Adults With Hypertension: A Scientific Statement From the American Heart Association. Hypertension. 2024;81(3):e16-e30. doi:10.1161/HYP.0000000000000236. PMID: 38205630.