Thrombocytopenic Purpura (TTP)

Classification

• Acute idiopathic TTP (most common form)
• Congenital TTP
• HIV-associated TTP
• Pregnancy-associated TTP
• Drug-associated TTP
• Pancreatitis-associated TTP
  
  

Core Pathophysiological Mechanism

• ADAMTS13 function: This metalloprotease cleaves ultralarge vWF multimers released from endothelial cells, converting them into smaller, less thrombogenic forms.
• Deficiency effect: In the absence of sufficient ADAMTS13 activity, these multimers remain intact and abnormally bind circulating platelets.

Resulting pathology

• Formation of platelet-rich microthrombi.
• Mechanical destruction of erythrocytes (schistocyte formation).
• Consumptive thrombocytopenia and microangiopathic haemolytic anaemia (MAHA).
• End-organ ischaemia, especially in the brain and kidneys.

Acquired (Immune-Mediated) TTP

Aetiology

• Caused by inhibitory autoantibodies directed against ADAMTS13.
• These autoantibodies either neutralise enzyme function or accelerate its clearance.

Precipitating factors

• Medications:
  • Thienopyridines (e.g. clopidogrel, ticlopidine): associated with both antibody-mediated and non-immune endothelial injury variants.
  • Immunosuppressants (e.g. cyclosporine, tacrolimus): implicated via endothelial damage and possible immune dysregulation.
• Infections:
  • HIV infection is strongly associated with TTP, especially in patients with advanced disease or those not on antiretroviral therapy.
• Hormonal factors:
  • Oestrogen exposure (e.g. from combined oral contraceptives) can be a contributing factor.
• Pregnancy:
  • Particularly in the peripartum and postpartum periods; immune dysregulation and increased endothelial stress are likely mechanisms.

Epidemiology

• More common than congenital forms.
• Frequently affects women and individuals of African descent.

Congenital TTP (Upshaw-Schulman Syndrome)

Genetic basis

• Inherited biallelic mutations in the ADAMTS13 gene, leading to severely reduced or absent enzymatic activity.

Clinical features

• Patients may remain asymptomatic until exposed to a physiological stressor.

Triggering events

• Commonly includes:
  • Systemic infections (e.g. viral, bacterial).
  • Pregnancy: increases vWF levels and hypercoagulability.
  • Surgery or trauma: provokes endothelial activation and heightened haemostatic demand.

Diagnosis

• Typically presents in childhood or adolescence, but can also first manifest in adulthood.
• Severe ADAMTS13 deficiency (<10%) is persistent and non-immune.

Historical and Pathological Background

Moschcowitz’s description (1925)

• Reported terminal arteriolar hyaline thrombi in organs such as the kidneys and heart.
• These were later identified as platelet-rich, vWF-dense microthrombi.

Mechanistic insight

• Accumulation of ultralarge vWF multimers on endothelial surfaces in the absence of ADAMTS13.
• Spontaneous binding of these multimers to platelets under high shear stress leads to microvascular obstruction.

Distinct from fibrin-based thrombi

• Unlike DIC, TTP thrombi do not contain fibrin or reflect consumptive coagulopathy.

Clinical and Therapeutic Implications

Diagnostic hallmark

• ADAMTS13 activity <10% confirms TTP diagnosis; <5% is highly specific.

Autoantibody testing

• Detection of anti-ADAMTS13 inhibitors supports acquired TTP.

Treatment rationale

• Immunosuppression (e.g. corticosteroids, rituximab) to reduce autoantibody production.
• Plasma exchange to remove autoantibodies and replenish ADAMTS13.
• Antiplatelet agents (e.g. aspirin) in selected patients to counteract vWF-platelet interactions.

Normal Physiological Role of vWF and ADAMTS13

von Willebrand factor (vWF)

• Serves two critical haemostatic roles:
  • Acts as a carrier for coagulation factor VIII, preventing its degradation.
  • Facilitates platelet adhesion by bridging subendothelial collagen and platelet glycoprotein receptors.

ADAMTS13

• A zinc-containing metalloprotease produced by hepatic stellate cells, endothelial cells, and megakaryocytes.
• Cleaves ultra large vWF multimers into smaller, less reactive forms.
• Prevents spontaneous platelet aggregation in areas of high shear stress (e.g. arterioles and capillaries).

Mechanism of Disease in TTP

Deficiency of ADAMTS13

• In >95% of acquired TTP cases, the enzyme is inhibited by circulating IgG autoantibodies.
• In congenital TTP (Upshaw-Schulman syndrome), mutations in the ADAMTS13 gene result in markedly reduced or absent enzyme activity.

Pathogenic sequence

• Unprocessed ultralarge vWF multimers accumulate on endothelial surfaces.
• These multimers spontaneously bind circulating platelets.
• Platelet-rich microthrombi form in arterioles and capillaries, occluding blood flow.
• Red blood cells are mechanically sheared as they pass through partially occluded vessels, forming schistocytes.
• Platelet consumption leads to thrombocytopenia.
• Tissue ischaemia follows, primarily affecting the CNS and kidneys.

Histological and Clinical Features

Thrombi characteristics

• Composed primarily of platelets and vWF with minimal fibrin content.
• Unlike disseminated intravascular coagulation, there is no systemic activation of coagulation or widespread fibrin deposition.

Target organs

• Central nervous system: headache, confusion, seizures, and stroke-like symptoms.
• Kidneys: mild to moderate dysfunction; less severe than in haemolytic uraemic syndrome.
• Peripheral blood: presence of schistocytes, thrombocytopenia, and haemolytic anaemia.

Triggering Events and the 'Two-Hit' Hypothesis

• ADAMTS13 deficiency alone may not be sufficient to cause symptomatic TTP.
• Secondary endothelial activation (a “second hit”) appears necessary to trigger the full clinical syndrome.
  • Triggers include:
    • Infections: including Shiga toxin–producing E. coli O157 and COVID-19.
    • Pregnancy: hormonal and vascular changes contribute.
    • Autoimmune disorders.
    • Drugs: mitomycin, cyclosporine, quinine, cisplatin, ticlopidine, and alemtuzumab.
    • Malignancy and transplantation: may also contribute to endothelial dysfunction or provoke immune activation.

Unidentified TTP Variant

• A third subtype has been proposed: “unidentified TTP”.
  • Distinguished from immune TTP by:
    • Lack of anti-ADAMTS13 antibodies.
    • ADAMTS13 circulates in a "closed" conformation, not accessible to autoantibodies.
  • Clinical features differ:
    • More common in older patients.
    • Less frequent in women.
    • Often associated with malignancy.
    • Rarely accompanied by autoimmune disease.

Relation to Other Microangiopathies

Classic haemolytic uraemic syndrome (HUS)

• Caused by Shiga toxin-producing bacteria.
• Presents with similar clinical features (e.g. thrombocytopenia and renal injury).
• ADAMTS13 activity is usually normal, supporting a distinct pathogenic mechanism.

Atypical HUS (aHUS)

• Driven by uncontrolled complement activation.
• Shares overlapping clinical features but differentiated by complement dysregulation and normal ADAMTS13.

Incidence and Prevalence

General population estimates

• Global incidence of immune TTP ranges from 1.81 to 3.93 cases per million people per year.
• Prevalence is approximately 10 cases per million at any given time.

Country-specific data

• France: 13 cases per million people per year.
• United States:
  • Estimated incidence: 4 to 11 cases per million annually.
  • Some datasets suggest up to 1 in 50,000 hospital admissions.
• United Kingdom: 2.2 cases per million annually.
• Saskatchewan, Canada: 3.2 cases per million annually.
• A combined registry analysis (TTP + HUS) in the US reported 6.5 cases per million per year.

Demographics and Risk Factors

Sex

• TTP affects women disproportionately, with a female-to-male ratio of approximately 2:1.
• Between 65–75% of cases in the US occur in women.

Age

• Median age at diagnosis is typically between 39 and 52 years.
• Congenital TTP may present in childhood but is rare in the general paediatric population.

Ethnicity

• African ancestry is associated with increased incidence; up to 44% of US patients are Black.

Pregnancy

• A known precipitant of TTP, particularly in the peripartum period.

HIV Infection

• Especially prevalent in sub-Saharan Africa.
• TTP occurs more frequently in HIV-positive women and in those not adherent to antiretroviral therapy.

Mortality and Morbidity

Mortality

• Without treatment, TTP has a fatality rate approaching 90%.
• Introduction of plasma exchange has reduced this to approximately 10–20%.

Acute complications

• Thrombotic events: stroke, transient ischaemic attacks, myocardial infarction, cardiac arrhythmias.
• Renal involvement: azotaemia is frequent but typically less severe than in HUS.
• Obstetric complications: TTP in pregnancy can lead to fetal loss.

Long-term outcomes

• Most survivors do not develop significant chronic sequelae.
• However, permanent neurological deficits occur in a minority.
• Relapse rates range from 13–36%, necessitating long-term monitoring.

Paediatric Considerations

• TTP is exceedingly rare in children.
• When it does occur, congenital TTP is more commonly represented than in adults.
• In contrast, haemolytic uraemic syndrome (HUS) accounts for the majority of thrombotic microangiopathy in paediatric patients (~90%).

Common Presenting Symptoms

Neurological manifestations

• Present in ~70% of cases (most frequent)
• Major symptoms: seizures, coma, stroke-like focal deficits, transient ischaemic attacks (≈41%).
• Minor symptoms: headache, confusion, lethargy, visual disturbance, paresthesia (≈26%).

Constitutional symptoms

• Fatigue: common and often related to underlying haemolytic anaemia.
• Dyspnoea: frequently reported, due to anaemia or cardiac involvement.

Gastrointestinal symptoms

• Occur in ~69% of patients.
• Include nausea, vomiting, diarrhoea, and abdominal pain—likely from intestinal microthrombi.
• Abdominal pain was noted as the most frequent single symptom in some studies.

Bleeding manifestations

• Less than 10% report spontaneous bleeding despite thrombocytopenia.
• Petechiae are common.
• Other symptoms include menorrhagia and ecchymosis (≈20%).

Fever

• Observed in 10–50% of cases.
• High, spiking fevers are uncommon and may suggest alternative diagnoses (e.g., sepsis).

Dark urine

• May be reported due to haemoglobinuria from intravascular haemolysis.

Symptom Timeline and Pattern

• Median duration from onset to diagnosis is typically within 7 days.
• The course is often subacute but can rapidly progress to life-threatening complications.

Organ-Specific Symptoms from History

Renal

• Usually mild or absent in TTP (distinguishing it from HUS).
• When present, may manifest as dark urine or non-specific malaise.

Pulmonary

• Involvement is rare, but patients may present with shortness of breath due to anaemia or cardiac compromise.

Cardiac

• May present as chest discomfort or palpitations.
• Troponin elevation is associated with worse prognosis and should raise concern during initial evaluation.

High-Risk Historical Factors

Demographic and comorbid clues

• Age range typically 20–59 years; median ~40 years.
• Female predominance (65–75% of cases).
• African ancestry (up to 44% of US cases; ninefold higher relative incidence).

Pregnancy/post-partum period

• TTP often occurs around the time of delivery.
• Responsible for 12–25% of diagnoses in female patients.

Obesity

• BMI >30 is associated with increased risk (odds ratio 7.6).

Previous drug exposures

• High-risk medications:
  • Clopidogrel (1 per 1600–5000 treated individuals), ticlopidine.
  • Mitomycin, ciclosporin, gemcitabine, tacrolimus, alemtuzumab.
  • Quinine: linked to 11% of TTP cases in a case series of 123 patients.

Underlying conditions

• HIV infection: particularly in patients not on antiretroviral therapy (odds ratio 30–35).
• Malignancy and chemotherapy: common in secondary TTP.
• Haematopoietic stem cell transplant: linked to poor response to standard therapy.

General Physical Findings

Pallor

• Reflects anaemia secondary to ongoing intravascular haemolysis.

Jaundice

• Typically mild; scleral icterus may be visible.
• Caused by unconjugated hyperbilirubinaemia from haem breakdown.

Petechiae and ecchymoses

• Common on dependent areas of the skin.
• Indicate underlying thrombocytopenia.
• Menorrhagia may also occur, though significant bleeding is uncommon.

Neurological Signs

• Most prominent and diagnostically significant domain on examination.

Altered mental status

• Ranges from confusion and agitation to coma.

Focal neurological deficits

• May include hemiparesis, aphasia, or cranial nerve palsies.

Seizures

• Can occur at presentation or during disease evolution.

Transient ischaemic episodes

• Symptoms may be brief and fully reversible, complicating recognition and diagnosis.

Prevalence

• Major neurological signs: ~41% of cases.
• Minor neurological symptoms (e.g., headache, dizziness, mild confusion): ~26%.

Cardiovascular Findings

Tachycardia

• Often present due to anaemia or systemic physiological stress.

Signs of myocardial ischaemia

• May be clinically silent.
• Elevated troponin levels are frequently detected and correlate with worse outcomes.

Arrhythmias or heart failure

• May appear in severe or refractory cases.

Renal Findings

• Typically minimal or absent on examination.
• TTP seldom presents with overt clinical features of renal failure.
• Proteinuria and elevated creatinine are usually detected through laboratory testing.
• Severe renal impairment is more characteristic of haemolytic uraemic syndrome (HUS).

Pulmonary and Abdominal Findings

Pulmonary

• Rarely involved.
• Dyspnoea may result from anaemia or associated cardiac dysfunction.

Abdominal

• Examination often unremarkable.
• Abdominal tenderness may suggest mesenteric ischaemia from microvascular thrombosis.
• Hepatosplenomegaly or organomegaly is not typical.

Systemic and Constitutional Signs

Fever

• Occurs in ~10–20% of patients.
• Typically low-grade; high fevers raise suspicion for alternative diagnoses such as sepsis.

Generalised weakness

• Non-specific but common, reported in over 60% of patients.

Composite Clinical Patterns (Oklahoma Registry Data)

• Gastrointestinal symptoms: 69%
• General weakness: 63%
• Petechiae or purpura: 54%
• Major neurological signs: 41%
• Minor neurological symptoms: 26%
• Fever and chills: 10%
• Complete classical pentad (MAHA, thrombocytopenia, neurological signs, fever, renal impairment): <5%

Essential Initial Laboratory Tests

Full Blood Count (FBC)

• Platelet count: Markedly reduced in nearly all patients; <20 × 10⁹/L in ~95%.
• Haemoglobin: Mild to moderate anaemia (usually <8 g/dL); seen in ~80% of cases.
• White cell count: Often normal or mildly elevated.

Peripheral Blood Film

• Schistocytes (fragmented red cells) indicate microangiopathic haemolysis.
• May be absent early in the disease but typically present at diagnosis.

Markers of Haemolysis

• Reticulocyte count: Elevated due to bone marrow compensation.
• Lactate dehydrogenase (LDH): Markedly raised; levels may exceed 1000 IU/L.
• Unconjugated (indirect) bilirubin: Elevated due to breakdown of red cells.
• Haptoglobin: Significantly decreased or undetectable as it binds free haemoglobin.
• Direct Coombs’ test: Negative, ruling out autoimmune haemolytic anaemia.

Renal Function Tests

• Creatinine and urea: May be mildly elevated; severe renal failure in only ~5%.
• Urinalysis: Can show proteinuria; present in ~40% of patients.

Coagulation Profile

• PT/INR and aPTT: Typically normal in TTP, helping to distinguish from DIC.
• D-dimer: Normal or mildly elevated.
• Fibrinogen: High-normal to elevated; low levels suggest alternative diagnoses such as DIC.

PLASMIC Score

One point each for

• Platelet count <30 × 10⁹/L
• Evidence of haemolysis (elevated reticulocytes, LDH, or indirect bilirubin; undetectable haptoglobin)
• MCV <90 fL
• INR <1.5
• Creatinine <176.8 μmol/L (2.0 mg/dL)
• Absence of active cancer
• No history of solid organ/stem cell transplant
• Interpretation:
  • Score ≥6: High probability of TTP
  • Score ≤4: Low probability
  • Sensitivity ≈99%, specificity ≈57%; useful as a rapid screening tool

ADAMTS13 Activity Assay

Diagnostic role

• Activity <10% in the setting of MAHA and thrombocytopenia confirms TTP.
• Some advocate <5% for greater specificity.

Inhibitor testing

• Helps differentiate acquired TTP (presence of inhibitory autoantibodies) from congenital forms.

Limitations

• Activity may also be reduced in conditions like sepsis, cancer, or pregnancy.
• Results are not always rapidly available, so should not delay initiation of treatment.

Prognostic use

• Persistently low activity post-treatment predicts relapse.
• Failure to rise >10% after plasma exchange within 7 days indicates poorer outcomes.

Additional Investigations

Troponin

• May be elevated; associated with cardiac involvement and poor prognosis.

HIV Serology

• Recommended for all patients due to strong association with HIV, particularly in untreated cases.

Neuroimaging (CT/MRI)

• Reserved for patients with focal deficits, seizures, or altered mental status.
• Aims to exclude infarction or haemorrhage.

Histopathology (if available, not required)

• Platelet-rich, fibrin-poor microthrombi.
• Most commonly affect kidneys and CNS.
• Biopsy not recommended routinely due to bleeding risk and limited diagnostic yield.

Haemolytic Uraemic Syndrome (HUS)

Typical HUS

• More common in children.
• Preceded by diarrhoeal illness, especially due to E. coli O157:H7.
• Prominent renal dysfunction; neurological signs are less severe.

Atypical HUS (aHUS)

• Caused by dysregulation of the complement pathway.
• Presents with similar features to TTP.
• Recurrent episodes and lack of response to plasma exchange suggest aHUS.
• Normal ADAMTS13 activity and absence of E. coli in stool are distinguishing factors.
• Genetic testing for complement regulatory mutations may assist, although often negative in ~30–50% of cases.

Malignant Hypertension

• Severe elevation in blood pressure (e.g. systolic >200 mmHg, diastolic >130 mmHg).
• Microangiopathic haemolysis may occur.
• Thrombocytopenia resolves with control of hypertension.
• Renal and neurological abnormalities may mimic TTP, but hypertension is the primary driver.

Disseminated Intravascular Coagulation (DIC)

• Prolonged PT, aPTT, and elevated D-dimer levels.
• Associated with systemic illness (sepsis, malignancy).
• Peripheral smear shows fewer schistocytes than in TTP.
• Bleeding tendencies and organ dysfunction are typically more profound.
• Coagulation studies help differentiate from TTP (which usually has normal PT/aPTT).

Sepsis

• May present with thrombocytopenia and organ dysfunction.
• Signs: Fever, hypotension, altered mental state, tachycardia, and possible DIC.
• Blood cultures and inflammatory markers (CRP, procalcitonin) help confirm infection.
• Thrombocytopenia typically resolves with treatment of the underlying infection.

Immune Thrombocytopenic Purpura (ITP)

• Isolated thrombocytopenia.
• No haemolysis, no schistocytes, no organ dysfunction.
• Peripheral smear is otherwise normal.
• Coombs test may be positive if autoimmune haemolysis is present.

HELLP Syndrome and Pre-eclampsia

• Occur in pregnancy, especially during the third trimester.
• HELLP: Haemolysis, Elevated Liver enzymes, and Low Platelet count.
• Pre-eclampsia: New-onset hypertension with proteinuria after 20 weeks’ gestation.
• Distinguishing features:
  • Raised blood pressure and liver enzymes more typical of HELLP.
  • TTP can occur at any stage of pregnancy and does not generally involve hypertension.

Drug-Induced TMA

• Caused by numerous agents
  • Chemotherapeutics: Mitomycin C, gemcitabine, interferon.
  • Antibiotics: Trimethoprim, penicillin, rifampin.
  • Cardiovascular drugs: Clopidogrel and ticlopidine (thienopyridines).

Clopidogrel-associated TTP

• Typically occurs within the first 2 weeks of initiation.
• Frequently normal ADAMTS13 levels, suggesting endothelial injury rather than enzyme deficiency.
• Clinical features: Cutaneous signs may precede systemic involvement.
• Treatment requires plasma exchange and corticosteroids; discontinuing clopidogrel alone is insufficient.

Haematopoietic Stem Cell Transplantation-Associated TMA

• Related to:
  • Conditioning regimens (e.g., total body irradiation).
  • Calcineurin inhibitors (e.g., tacrolimus, ciclosporin).
  • Graft-versus-host disease and infections.
• Typically refractory to standard plasma exchange.

Cancer-Associated TMA

• Most commonly linked with adenocarcinomas (e.g., gastric, breast, prostate).
• Microangiopathy may be due to direct marrow invasion or release of prothrombotic factors.
• ADAMTS13 activity may be reduced but is rarely <10%.

Connective Tissue Disorders and Vasculitides

• Systemic lupus erythematosus (SLE) and antiphospholipid syndrome may mimic TTP.
• Testing:
  • Positive ANA, anti-dsDNA, antiphospholipid antibodies.
  • May coexist with true TTP or act as an independent TMA trigger.

Haemorrhagic Fevers

• Travel to endemic areas is a key historical clue.
• Manifestations include petechiae, ecchymoses, and mucosal bleeding.
• May be misinterpreted as TTP.
• Confirmed via serological testing.

Initial Management

Plasma Exchange (PEX)

• First-line treatment in acquired TTP.
• Removes circulating ADAMTS13 inhibitors and ultralarge vWF multimers, while replenishing functional ADAMTS13.
• Recommended to start within 24 hours of presentation.
• Protocol:
  • Initial: 1.5 plasma volume exchange daily.
  • Titrate based on clinical response (platelet count, LDH).
  • Taper gradually after 3 days of platelet and LDH stability.
• If unavailable:
  • Plasma infusion (30 mL/kg/day) may be used temporarily.
  • Transfer to a centre with PEX capability.

Corticosteroids

• Administered concurrently with PEX.
• Typically initiated as high-dose methylprednisolone or oral prednisolone.
• Helps suppress autoantibody production against ADAMTS13.

Caplacizumab

• Monoclonal nanobody targeting vWF-platelet interaction.
• Added to PEX and corticosteroids in adults with acquired TTP.
• Reduces time to platelet count normalisation and risk of relapse or thromboembolic complications.
• Continued for 30 days post-last plasma exchange.

Adjunctive Measures

Aspirin

• May be used cautiously once platelet count exceeds 50 × 10⁹/L.
• Long-term use to prevent microvascular thrombosis is debated.
• Should be avoided if platelets are <10 × 10⁹/L due to bleeding risk.

Supportive Care

• Folate supplementation for haemolysis-induced deficiency.
• Red cell transfusions for symptomatic anaemia.
• Platelet transfusion only if there is active bleeding or planned invasive procedure (e.g., central line placement).
• HIV, hepatitis B/C, and pregnancy testing prior to PEX if feasible.

Monitoring and Outcome Assessment

ADAMTS13 Activity

• Baseline levels aid in diagnosis and classification.
• Post-treatment monitoring informs risk of relapse.
• Definitions:
  • Partial remission: ADAMTS13 ≥20% but <lower limit of normal (LLN).
  • Complete remission: ADAMTS13 ≥ LLN.
• Clinical remission can occur with or without biochemical remission.

Clinical monitoring

• Platelet count and LDH to monitor response.
• Troponin for cardiac involvement (a poor prognostic marker).
• MRI brain if neurological symptoms persist or progress.

Refractory or Relapsing Disease

Criteria

• Lack of platelet response after 4–7 days.
• Worsening neurological or organ dysfunction.
• Persistent low ADAMTS13 activity post-treatment.

Therapeutic Options

Rituximab

• Anti-CD20 monoclonal antibody.
• Targets B cells producing anti-ADAMTS13 autoantibodies.
• Used increasingly in the frontline setting to reduce relapse risk.

Vincristine

• Alkylating agent with observed benefit in small case series.

Cyclophosphamide

• Immunosuppressive; considered in refractory cases.

Ciclosporin

• Calcineurin inhibitor; modest evidence of benefit.
• Caution due to association with post-transplant TMA.

Splenectomy

• Considered in multi-relapsing or refractory cases.
• Associated with durable remissions in some patients.
• Preoperative preparation: Pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines required.
• Postoperative infection risk necessitates long-term vigilance.

Short-Term Outcomes

• Untreated TTP has a mortality rate of up to 90%.
• With prompt plasma exchange and corticosteroids, mortality decreases to 10–30%.
• Most patients respond within 10 days, and 90% will achieve response by 3 weeks of treatment initiation.

Factors Associated with Early Mortality

• Cardiac involvement:
  • Coronary thrombosis leading to myocardial infarction, heart failure, or sudden cardiac death is a recognised cause of early death.
  • Elevated troponin at presentation correlates with a significantly increased risk of mortality or treatment refractoriness.
• Neurological compromise, need for mechanical ventilation, and older age are also linked to poor early outcomes.
• Delayed treatment initiation worsens prognosis significantly.

Laboratory Predictors of Poor Prognosis

• Failure to normalise platelet counts within 7 days of starting plasma exchange.
• Persistently elevated LDH by day 5 of therapy.
• Low albumin or total serum protein levels at presentation.
• Elevated complement activation markers (e.g., Bb, sC5b-9).
• Prolonged aPTT, high fibrinogen, and raised troponin at admission are all correlated with higher mortality.

Clinical Severity Scores

• Retrospective studies have developed severity scores using parameters such as:
  • Platelet count
  • Haemoglobin level
  • Creatinine level
  • Presence of neurological symptoms
• These scores may help predict 30-day mortality, though external validation is limited.

Long-Term Outcomes

Relapse

• Occurs in 30–36% of survivors within 10 years.
• Relapsing disease is more likely in patients with persistently low ADAMTS13 activity.

10-year survival

• Approximately 82% in patients without serious comorbidities.
• Drops to around 50% in those with cancer, HIV, or a history of solid organ transplantation.

Autoimmune Complications

• Individuals with a history of TTP have an increased long-term risk of developing autoimmune diseases, such as:
  • Systemic lupus erythematosus (SLE)
  • Sjögren syndrome
• This risk is especially elevated in those with anti-dsDNA or anti-SSA antibodies at the time of diagnosis.
• These findings support the recommendation for long-term monitoring for autoimmune disorders.

Disease-Related Complications

Ischaemic Stroke

• Caused by cerebral microthrombi resulting from platelet aggregation on ultralarge vWF multimers.
• Can manifest as focal neurological deficits or seizures.
• Some neurological deficits resolve fully with treatment; others may result in permanent sequelae.

Renal Dysfunction

• Microvascular thrombi in renal vasculature can cause acute kidney injury (AKI).
• Renal dysfunction is typically less severe than in haemolytic uraemic syndrome.
• Usually reversible with effective TTP treatment.

Acute Myocardial Infarction (MI)

• Microthrombi may involve coronary arteries.
• Studies suggest cardiac involvement occurs in up to 18% of TTP patients, potentially higher in broader thrombotic microangiopathy cohorts.
• TTP does not alter standard MI management protocols.

Complications of Plasma Exchange (PEX)

Central Venous Catheter-Related Issues

• Required in most patients for PEX.
• Risks include:
  • Infection: including bloodstream infections.
  • Mechanical complications: bleeding, pneumothorax, catheter-associated venous thrombosis.
• Reported overall complication rate: ~25%; mortality due to PEX complications: ~2–4.4%.

Systemic Effects of PEX

• Hypotension: due to rapid fluid shifts.
• Anaphylaxis: rare but serious, due to donor plasma exposure.
• Transfusion-related acute lung injury (TRALI): a potentially fatal pulmonary complication.

Transfusion-Transmitted Infections

• Although rare, risks are present due to frequent plasma exposure:
  • HIV: ~1 in 2,100,000 units.
  • HCV: ~1 in 1,900,000.
  • HBV: ~1 in 58,000 to 1 in 269,000.
  • HTLV: ~1 in 2,000,000.
• Rigorous blood screening has significantly reduced incidence in high-resource settings.

Medication-Related Complications

Corticosteroids (long-term use)

• Common side effects include
  • Osteoporosis
  • Glucose intolerance
  • Hypertension
  • Immunosuppression with risk of opportunistic infections.
• Risk increases with treatment duration and cumulative dose.

Caplacizumab

• Generally well tolerated.
• Increased risk of mucocutaneous bleeding reported due to antiplatelet effects.

Other Considerations

Congestive Heart Failure from Plasma Infusion

• When plasma infusion is used as an interim measure in absence of immediate PEX access, volume overload can precipitate heart failure.
• Typically reversible once PEX is instituted.

Decreased Frequency of Complications Over Time

• Studies have shown a decline in PEX-related complications over the past 15 years, likely due to improved protocols and early adjunctive therapies.

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