Thrombotic Thrombocytopenic Purpura (TTP): Causes, Symptoms, Diagnosis & Treatment Explained

What is Thrombotic Thrombocytopenic Purpura?

Thrombotic thrombocytopenic purpura (TTP) is a type of microangiopathic hemolytic anemia that classically has been characterized by the pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction. The disease results from a severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13), which is the enzyme responsible for cleaving von Willebrand factor (vWF) multimers.

Concise Yet Detailed Definition

TTP is a thrombotic microangiopathy caused by either congenital or acquired deficiency of the ADAMTS13 enzyme. Low levels of ADAMTS13 result in microthrombi formation, which leads to end-organ ischemia and damage due to the inability of ADAMTS13 to inactivate the large multimer von Willebrand factor (VWF) that is necessary to prevent spontaneous coagulation. The unchecked large multimers have tremendous avidity to bind platelets and initiate thrombi formation throughout the microvasculature.

Affected Body Parts/Organs

The central nervous system (CNS) and kidneys are the two most common organ systems affected by TTP. However, TTP is a systemic disorder that can affect virtually any organ, including:

• Central Nervous System: Confusion, seizures, stroke, focal neurological deficits
• Cardiovascular System: Myocardial ischemia, heart failure, arrhythmias
• Renal System: Acute kidney injury (though less common than in HUS)
• Hematologic System: Severe thrombocytopenia, microangiopathic hemolytic anemia
• Gastrointestinal System: Abdominal pain, nausea, vomiting
• Skin: Purpura, petechiae, bleeding

Prevalence and Significance

TTP is a rare disease with studies citing incidences between 1 and 13 cases per million people depending on geographic location. The current rate of occurrence for TTP is about 3.7 cases per million people each year. The disease predominantly affects adults, with most cases occurring after 40 years of age, though congenital forms can occur in children. TTP is more common in women with a 2:1 female to male predominance.

2. History & Discoveries

First Identification and Discovery

Eli Moschcowitz reported the first case of thrombotic thrombocytopenic purpura (TTP) 100 years ago in 1924. A 16-year-old girl presented with 1 week of fever, joint pain, and progressive upper extremity weakness to Beth Israel Hospital in New York City. Eli Moschcowitz (2 August 1879 – 23 February 1964) was an American doctor best known for his role in discovering thrombotic thrombocytopenic purpura (TTP), which was originally called “Moschcowitz syndrome”.

Who Discovered It?

Eli Moschcowitz (1879 – 1964) was a Hungarian born, American pathologist and physician. In 1925, Moschcowitz first described thrombotic thrombocytopenic purpura (TTP) in a 16-year-old girl who died 2 weeks after the abrupt onset and progression of petechial bleeding, pallor, fever, paralysis, hematuria and coma.

Major Discoveries and Breakthroughs

1940s-1960s: Recognition of the classical pentad

• In 1966, a review of 16 new cases and 255 previously reported cases led to the formulation of the classical pentad of symptoms and findings (i.e., thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, kidney failure, fever); in this series, mortality rates were found to be very high (90%)

1970s-1990s: Development of plasma therapy

• While a response to blood transfusion had been noted before, a 1978 report and subsequent studies showed blood plasma was highly effective in improving the disease process. In 1991, plasma exchange was reported to provide better response rates compared to plasma infusion

1997-2002: Discovery of ADAMTS13

• Although Furlan et al and Tsai simultaneously reported the purification of a new VWF-cleaving protease from normal human plasma, the work for this discovery was also paved by Ruggeri et al, who had identified the cleavage site for the VWF subunit by the protease
• In 1998, the majority of cases were shown to be caused by the inhibition of the enzyme ADAMTS13 by antibodies. Knowledge of this relationship between reduced ADAMTS13 and the pathogenesis of TTP is credited to two independent groups of researchers (Furlan and Tsai) who published their research in the same issue of the New England Journal of Medicine

2010s-2020s: Targeted therapies

• Caplacizumab was approved for treatment of TTP in 2018 (Europe) and 2019 (United States). Clinical trials documented that its addition to the standard therapy caused more rapid platelet recovery with fewer days of PEX and then fewer exacerbations when PEX was stopped

Evolution of Medical Understanding

The understanding of TTP has evolved from a mysterious, uniformly fatal condition to a well-characterized, treatable disorder. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. The discovery of ADAMTS13 transformed both diagnosis and treatment, enabling targeted therapies and improved outcomes.

3. Symptoms

Early Symptoms vs Advanced-Stage Symptoms

Early Symptoms:

• Patients with TTP typically report an acute or subacute onset of symptoms related to neurologic dysfunction, anemia, or thrombocytopenia
• The initial presentation includes fatigue, dyspnea, petechiae, or bleeding
• Many people experience an influenza-like or diarrheal illness before developing TTP

Advanced-Stage Symptoms:

• Neurologic manifestations include alteration in mental status, seizures, hemiplegia, paresthesias, visual disturbance, and aphasia
• These blood clots can restrict blood flow, leading to complications like stroke, heart attack, kidney failure, and seizures

Common vs Rare Symptoms

Common Symptoms:

• The more prevalent findings are profound thrombocytopenia (usually less than 30×10⁹/L) and microangiopathic hemolytic anemia (with schistocytes seen on the blood smear)
• In patients with idiopathic TTP, neurologic complaints were noted to be the most common (44%), and the most common symptom was reported to be abdominal pain (23.5%)

Rare Symptoms:

• Less than 10% of patients reported bleeding secondary to thrombocytopenia as a presenting symptom. Pulmonary involvement is also rare
• Today, the classic pentad of fever, impaired mental status, anemia, thrombocytopenia, and renal failure appears in fewer than 10% of cases

How Symptoms Progress Over Time

As TTP progresses, blood clots form within small blood vessels (microvasculature), and platelets (clotting cells) are consumed. As a result, bruising, and rarely bleeding can occur. The progression is typically rapid, and patients with TTP can also have cardiac involvement, and an elevation of serum troponin in patients presenting with TTP is considered a bad prognostic sign.

4. Causes

Biological and Environmental Causes

TTP is fundamentally caused by ADAMTS13 deficiency, but several factors can trigger or precipitate episodes:

Biological Triggers:

• Known triggers include bacterial infections, certain medications, autoimmune diseases such as lupus, and pregnancy
• Patients frequently have a history of recent infection in the days or weeks preceding an acute episode

Environmental Factors:

• Other factors associated with a higher risk of TTP include female sex, African American descent, and pregnancy
• Certain medications, particularly ticlopidine and clopidogrel

Genetic and Hereditary Factors

Hereditary TTP (Upshaw-Schulman Syndrome):

• Less commonly TTP is inherited, known as Upshaw–Schulman syndrome, such that ADAMTS13 dysfunction is present from birth
• People with this syndrome generally have 5–10% of normal ADAMTS-13 activity
• A 2024 study estimated the global prevalence of hereditary TTP at 40 per million, in contrast to previously reported estimates of 0.5 to 2.0 per million

Genetic Distribution: Considering only the 140 previously reported variants, the highest estimated prevalence was in East Asians (42 per 10⁶). The estimated prevalences of other populations were: Finnish, 32 per 10⁶; non-Finnish Europeans, 28 per 10⁶; Admixed Americans, 19 per 10⁶; Africans/African Americans, 6 per 10⁶; and South Asians, 4 per 10⁶.

Known Triggers or Exposure Risks

Acquired TTP Triggers:

• Autoimmune diseases (especially lupus)
• Infections (bacterial, viral)
• Pregnancy and childbirth
• Certain medications
• Malignancy
• Immunosuppressive therapies
• TTP occurs within the first two weeks of therapy with certain medications, and skin reactions may be the only harbinger of this reaction

5. Risk Factors

Who is Most at Risk?

Demographics:

• TTP most often occurs after 40 years of age, but congenital forms can occur in children. TTP is more common in women with a 2:1 female to male predominance
• Two-thirds of individuals with iTTP are females. This condition usually affects people between 20 to 50 years of age

Racial/Ethnic Factors:

• Because TTP commonly occurs in young black women, the frequency of systemic lupus erythematosus, as well as other autoimmune disorders, is increased

Environmental, Occupational, and Genetic Factors

Environmental:

• Geographic variation in incidence suggests environmental influences
• Summer demonstrated significantly lower incidence for idiopathic TTP, compared with other seasons

Genetic Predisposition:

• Family history of autoimmune disorders
• Specific HLA types may confer increased risk
• Congenital thrombotic thrombocytopenic purpura (cTTP) is a thrombotic microangiopathy (TMA) characterized by severe hereditary ADAMTS13 deficiency caused by ADAMTS13 mutations

Impact of Pre-existing Conditions

Associated Conditions:

• TTP appears to occur more frequently in people who have untreated human immunodeficiency virus (HIV) infection
• Childhood-onset or iTTP often occurs concurrently with systemic lupus erythematosus (SLE)
• Malignancy
• Organ transplantation
• Other autoimmune disorders

6. Complications

What Complications Can Arise from TTP?

Acute Complications:

• Acute morbidities include ischemic events such as stroke, transient ischemic attacks, myocardial infarction and cardiac arrhythmia, bleeding, and azotemia
• The blood clots can block blood flow, leading to complications like stroke, heart attack, kidney failure, and seizures

Long-term Neurological Complications:

• Stroke during the median observation follow-up period (3.08 years) after recovery from TTP occurred in 13.1% of patients, which is five-fold higher than the expected prevalence from an age- and sex-matched reference population
• Neuropsychological assessment revealed lower scores than the Italian general population pertaining to direct, indirect and deferred memory

Long-term Impact on Organs and Overall Health

Cardiovascular Impact:

• Cardiovascular disease, tied with iTTP relapse, is a leading cause of death in patients who survive their first episode of iTTP
• Mortality rate was 1.8 times higher than expected from an age-, sex-, and race-adjusted reference population

Neuropsychiatric Complications:

• Depression is common in those recovering from TTP; 59% of recovered TTP patients screened positive for depression within 11 years after recovery
• Severe or moderate depression has occurred in 44% of Oklahoma Registry patients
• Anxiety and depression were detected in seven (20%) and 15 (43%) patients, respectively

Cognitive Impairment:

• Minor cognitive impairment is also common. The recognition that cognitive impairment is related to the preceding TTP can provide substantial emotional support for both the patient and her family
• Long-term neurologic manifestations are especially common, including decreases in concentration, information processing, rapid language generation, and memory

Potential Disability or Fatality Rates

Mortality:

• Without treatment, the mortality of thrombotic thrombocytopenic purpura is 90%. Early treatment (with plasma exchange and corticosteroids) decreases the mortality to 15%
• About 80% of patients respond to initial treatment, and the post-treatment mortality is 10 to 15%

Relapse Rates:

• Relapses are not uncommon, occurring in 13-36% of patients
• Most recurrences occur during the first year or two, but they can occur as late as 10 or 20 years after an episode of TTP

7. Diagnosis & Testing

Common Diagnostic Procedures

Clinical Diagnosis:

• Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia are seen, and therapy is started
• Clinical suspicion of TTP is often established with an initial emergent presentation of one or more classic symptoms and a complete blood count revealing severe thrombocytopenia

Medical Tests

Laboratory Tests:

• Laboratory studies for suspected TTP include a CBC, platelet count, peripheral blood smear, coagulation studies, BUN and creatinine, and serum bilirubin and lactate dehydrogenase
• The dominant morphologic abnormality seen on peripheral blood smear is the presence of schistocytes, which are secondary to passing through a partially occluded vessel, causing shear injury

ADAMTS13 Testing:

• A lab test showing ≤5% of normal ADAMTS13 levels is indicative of TTP
• Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product

Differential Diagnosis:

• Both TTP and HUS are characterized by fever, anemia, thrombocytopenia, renal failure, and neurological symptoms. Generally, TTP has higher rates of neurological symptoms (≤80%) and lower rates of renal symptoms (9%) than HUS (10–20% and 90%, respectively)

Early Detection Methods and Their Effectiveness

Clinical Recognition:

• A high index of suspicion is necessary for a timely diagnosis because the initial findings may be nonspecific and include weakness, headache, confusion, nausea, vomiting, and diarrhea
• High clinical suspicion is required to make the diagnosis, and all TTP patients should be placed in an intensive care unit (ICU) setting

Rapid Testing:

• Emergency ADAMTS13 activity assays (though results may be delayed)
• Clinical scoring systems to aid in diagnosis
• Point-of-care testing developments in progress

8. Treatment Options

Standard Treatment Protocols

First-Line Treatment:

• Since the early 1990s, plasmapheresis has become the treatment of choice for TTP. This is an exchange transfusion involving removal of the person’s blood plasma through apheresis and replacement with donor plasma
• The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter

Immunosuppression:

• Corticosteroids (prednisone or prednisolone) are usually given
• Usually, it is administered in 4 weekly doses. Rituximab has a low incidence of adverse effects but can take up to 2 weeks to show clinical improvement

Medications, Surgeries, and Therapies

Caplacizumab:

• Caplacizumab is a humanized monoclonal antibody that initially was identified or isolated from a llama. It’s a single chain monoclonal antibody and is specifically targeted at von Willebrand factor
• Among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period

Recombinant ADAMTS13:

• Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13—the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP
• Recombinant ADAMTS13 has been shown to have enough to neutralize some of the antibodies in patients with acquired TTP. This may in the future replace the plasma exchange

Other Therapies:

• Other drugs like vincristine, cyclosporine A, cyclophosphamide, and bortezomib could also be helpful in refractory cases by suppressing the production of autoantibodies

Emerging Treatments and Clinical Trials

Novel Approaches:

• ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy
• We pack the recombinant ADAMTS13 inside the platelet and allow the platelet to carry recombinant ADAMTS13 in the circulation so that the antibody will not see the recombinant ADAMTS13 until the platelet gets activated

Treatment Without Plasma Exchange:

• Can patients with immune thrombotic thrombocytopenic purpura (iTTP) be managed safely and effectively with caplacizumab and immunosuppression without the addition of therapeutic plasma exchange (TPE)?

9. Prevention & Precautionary Measures

How Can TTP Be Prevented?

Primary Prevention: TTP cannot be completely prevented, especially in cases of hereditary forms. However, several measures can reduce risk:

Risk Reduction Strategies:

• Prompt treatment of infections
• Careful monitoring during pregnancy in high-risk individuals
• Avoidance of known triggering medications when possible
• Management of underlying autoimmune conditions

Lifestyle Changes and Environmental Precautions

General Health Measures:

• Maintaining good overall health
• Stress management
• Regular medical follow-up for those with autoimmune conditions
• Awareness of early warning signs

Medication Awareness:

• Understanding which medications may trigger TTP
• Careful monitoring when starting new medications known to be associated with TTP

Vaccines and Preventive Screenings

Monitoring for Relapse:

• Longitudinal testing has established persistent or recurrent ADAMTS13 deficiency as a strong risk factor for recurrence
• Regular ADAMTS13 activity monitoring in patients with history of TTP
• Patients who survive an acute episode of TTP are at risk of relapse and long-term morbidity. Thus, TTP should be seen as a chronic disease with acute episodes

Prophylactic Treatment:

• emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission

10. Global & Regional Statistics

Incidence and Prevalence Rates Globally

Overall Incidence:

• Studies cite incidences between 1 and 13 cases per million people depending on geographic location
• aTTP is an ultra-orphan disease with a reported annual incidence between 1.5 and 6.0 cases per million

Hereditary TTP:

• Based on the frequency of 140 documented pathogenic variants, the worldwide prevalence of hTTP was estimated to be 23 per 10⁶ people, with a carrier frequency of 1 per 100 people

Mortality and Survival Rates

Historical vs Modern Outcomes:

• The mortality in TTP without treatment is 90%, but this drops to a mortality of 10% to 15% with proper treatment
• The survival rate is upwards of 100% with PEX; however, the rate falls to 27% with a delay of diagnosis

Long-term Survival:

• In the authors’ series of 126 patients, the estimated 10-year survival rate of patients without comorbid conditions was 82%, compared with a survival rate of 50% in those with comorbid conditions

Country-wise Comparison and Trends

Regional Variations:

• There were substantial geographical disparities across reports for unspecified TTP, including a large difference in prevalence estimates between France (13 cases per million) and the US (1–2.7 cases per million)

Genetic Prevalence by Population: The estimated prevalences of hereditary TTP by population were: East Asians (42 per 10⁶), Finnish (32 per 10⁶), non-Finnish Europeans (28 per 10⁶), Admixed Americans (19 per 10⁶), Africans/African Americans (6 per 10⁶), South Asians (4 per 10⁶), Middle Eastern (1 per 10⁶), and Ashkenazi Jews (0.7 per 10⁶).

11. Recent Research & Future Prospects

Latest Advancements in Treatment and Research

2024 Developments:

• Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hemolytic disorder with severe implications during pregnancy, characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and systemic microvascular thrombosis
• This rare autosomal recessive genetic disorder is often misdiagnosed as immune thrombocytopenia (ITP) or hemolytic uremic syndrome (HUS)

Caplacizumab Real-World Data:

• In this issue of Blood, Mingot-Castellano et al, on behalf of the Spanish Apheresis Group and the Spanish Thrombotic Thrombocytopenic Purpura Registry, present important data on caplacizumab treatment of patients with acute autoimmune thrombotic thrombocytopenic purpura (iTTP)

Ongoing Studies and Future Medical Possibilities

Recombinant ADAMTS13 Development:

• Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events
• Stanislas Faguer, Prophylactic use of recombinant ADAMTS-13 during pregnancy for congenital thrombotic thrombocytopenic purpura

Novel Therapeutic Approaches:

• Emerging data suggest that TTP may be associated with complement activation, perhaps through ultra-large VWF–mediated effects, and the successful use of the terminal complement inhibitor, eculizumab, in TTP has been reported

Potential Cures or Innovative Therapies Under Development

Gene Therapy Prospects:

• Gene therapy is a potentially curative strategy
• mRNA-based ADAMTS13 replacement therapy
• At the moment, I would think caplacizumab plus rituximab and a corticosteroid, or recombinant ADAMTS13 on top of this, or recombinant ADAMTS13 plus rituximab and corticosteroid

Treatment Paradigm Shifts:

• It is interesting to speculate that by reducing dependence of PEX, caplacizumab (perhaps in combination with rADAMTS13 and immunosuppression) could usher in a new paradigm of treating TTP with minimal, if any, PEX
• Management of immune thrombotic thrombocytopenic purpura without therapeutic plasma exchange

12. Interesting Facts & Lesser-Known Insights

Uncommon Knowledge About TTP

Historical Naming:

• Her blood vessels were largely filled with platelets. Modern reports still occasionally refer to TTP as “Moschcowitz disease” or “Moschcowitz syndrome”

Underdiagnosis:

• A 2024 study suggested that hereditary TTP is underdiagnosed and should be considered in cases of unexplained stroke, neonatal jaundice, and severe pre-eclampsia
• Many patients with hTTP may not be diagnosed or may have died during the neonatal period

Seasonal Patterns:

• Summer demonstrated significantly lower incidence for idiopathic TTP, compared with other seasons

Myths and Misconceptions vs Medical Facts

Misconception: TTP always presents with the classic pentad Fact: The complete classic pentad of TTP symptoms is only seen in about 10% of acute cases at initial presentation

Misconception: TTP only affects older adults Fact: This condition usually affects people between 20 to 50 years of age, but people of any age may be affected

Misconception: TTP cannot be treated effectively Fact: The main body of knowledge within the field was gathered in the latest three decades with new treatments and biomarkers with improvements on prognosis and management

Impact on Specific Populations or Professions

Pregnancy Considerations:

• Pregnancy itself exacerbates TTP due to physiological reductions in ADAMTS13 activity, necessitating a high degree of clinical vigilance
• TTP during pregnancy may precipitate fetal loss

Connection to Chess:

• Moschcowitz was a member of the Manhattan Chess Club. When the former world chess champion José Raúl Capablanca collapsed in what would prove to be his fatal stroke, Moschcowitz arranged the ambulance to take him to Mount Sinai Hospital

Research Collaboration:

• These discoveries are a result of the collaborative efforts of investigators worldwide that have been fostered by the frequent interactions of investigators via the International TTP Working Group meetings and TMA workshops held regularly at international meetings

Conclusions

Thrombotic thrombocytopenic purpura represents one of medicine’s remarkable transformation stories—from a uniformly fatal “mystery disease” discovered by Eli Moschcowitz in 1924 to a well-understood, treatable condition with multiple targeted therapies. The discovery of ADAMTS13 in the late 1990s revolutionized both understanding and treatment, leading to the development of caplacizumab, recombinant ADAMTS13, and promising future therapies including gene therapy approaches.

Despite these advances, TTP remains a medical emergency requiring immediate recognition and treatment. The condition’s rarity, combined with its potential for devastating complications including long-term neurological and cardiovascular sequelae, underscores the importance of continued research, improved diagnostic tools, and enhanced physician awareness. Current treatment paradigms are shifting toward more targeted approaches that may eventually reduce or eliminate dependence on plasma exchange, offering hope for improved outcomes and quality of life for TTP patients worldwide.

References

This report synthesizes information from multiple peer-reviewed sources, medical databases, and current clinical research as of 2024-2025. Key sources include publications from Blood, New England Journal of Medicine, Nature Medicine, StatPearls, NCBI databases, and international TTP registries and research consortiums.