ASTHMA

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Discover a solution to control mixed Eosinophilic and Allergic Asthma

Consider this biologic for Patients with mixed Phenotypes.

It’s time to address the full spectrum of Type 2 Inflammation in Asthma 50% to 70%a of adult patients with Asthma have Type 2 Inflammation¹
<h2>GINA Guidelines for difficult - to - treat and severe Asthma</h2>
<h3>Type 2 inflammation is indicated by elevated levels of one or more of the following markers²:</h3>
<ul>
 <li>Blood eosinophils ≥ 150 cells/µL</li>
 <li>Sputum eosinophils ≥ 2 %</li>
 <li>Asthma is clinically allergen-driven IgE ≥ 20 IU/mL</li>
 <li>FeNO ≥ 20 ppb</li>
</ul>
Biomarkers of Type 2 inflammation may be suppressed by systemic corticosteroid use. This should be taken into consideration when determining Type 2 status in patients taking oral corticosteroids³
ᵃN=205. ᵇN=37.

Abbreviations

<h2>Type 2 Inflammation</h2>
<h3>IL-4 and IL-13: Central Cytokines that mediate Type 2 Inflammation, including Allergic and Eosinophilic1,2,3</h3>
<h3>Type 2 inflammation plays an important role in uncontrolled asthma, contributing to increased exacerbations and decreased lung function²</h3>

References

<h2>Type 2 Inflammation CoMorbidities</h2>
<h3>Type 2 Inflammatory Diseases Share Common Inflammatory Cells and Mediators¹⁻³</h3>

<h2>Type 2 Asthma includes a range of phenotypes</h2>
<h3>Type 2 Asthma GINA phenotypes¹</h3>

<h2>Real World Evidence on Pheno Types</h2>
<h3>Saudi Arabia Real World Evidence Data for Mixed Phenotype Refractory Asthma¹</h3>
<h4>From Local Saudi Arabia Data, Almost 78% of Severe Ashtma patients with elevated Serum IgE and eosinophilic count1</h4>
The 78% mixed phynotyping patients have been subcategorized as following1

<h3>Methods:</h3>
A retrospective cross-sectional real-life study was conducted on patients attending adult refractory asthma outpatient clinic between 2015 and 2018.1
Serum total IgE level and blood EOS count on matched dates with spirometry and Asthma Control Test (ACT) scores were collected.1
All data were obtained while patients were not on biological agents.1

Fig. 1.&nbsp;Serum IgE levels and eosinophils count subgroups of patients with refractory severe asthma.

Reference

<h2>Severe Asthma treatment goals</h2>
<h3>Patients with uncontrolled persistent Asthma have a high disease burden1-9</h3>

<h2>FEV1&nbsp;Correlation with AAER</h2>
<h3>Low Fev1&nbsp;is a significant predictor of future severe exacerbations</h3>
Patients aged ≥18 years with moderate-to-severe asthma over a 36-month follow-up period (n=1865)

**p&lt;0.01; ****p&lt;0.0001. aCox proportional hazard model analysis adjusted for age at index date, smoking status, BMI, gender, rhinitis, chronic sinusitis, nasal polyps, atopic dermatitis, diabetes, anaphylaxis, ischemic heart disease, heart failure, food allergy, anxiety, depression, and psoriasis. BMI, body mass index; CI, confidence interval; HR, hazard ratioKhan A, et al. Ann Allergy Asthma Immunol. 2018;121:S22–S62

About Type 2 Inflammation – Asthma

Dupixent® (dupilumab) Mechanism of Action

Dupixent binds to IL-4Rα, blocking IL-4 and IL-13 intracellular signaling, Two Type 2 Cytokines that contribute to Inflammation in Asthma.

How does Dupixent support lung function improvement in Pediatric Asthma?

KOL Expert on Lung Function for Pediatric asthma.

Consider Dupixent for Asthmatic patients with high EOS

Dupixent showed great results to control patients exacerbations and improve lung function for Severe Asthmatic patients with high EOS.

<h2>The prognosis of thrombotic thrombocytopenic purpura (TTP) can be unpredictable1,2</h2>
Patients can experience refractory disease or recurrence of their TTP (exacerbation or relapse), highlighting the need for vigilant monitoring3,4
The risks and effects of TTP extend beyond the first acute events that patients experience.5-7
Here are some of the various ways TTP can affect your patients after diagnosis and treatment.

<h3 style="text-align: center;">TTP episode</h3>
Even with plasma exchange therapy (PEX), mortality risk persists8-10

acute mortality associated with episodes of aTTP9,10

DAY 0

<h3 style="text-align: center;">Refractory TTP</h3>
 
 Occurs when patients do not have a clinical response after 5 sessions of PEX. Clinical response is defined as sustained platelet count ≥150 × 109/L and LDH &lt;1.5 times ULN and no clinical evidence of new or progressive organ injury.4
Refractory TTP can indicate poor prognosis for survival3

of aTTP patients experience unpredictable refractoriness

5 DAYS

<h3 style="text-align: center;">TTP exacerbation</h3>
A platelet count decrease after a clinical response and before a clinical remission. A clinical exacerbation is defined as platelet count decrease to &lt;150 × 109/L (with other causes of thrombocytopenia excluded), with or without clinical evidence of new or progressive ischemic organ injury, within 30 days of stopping plasma exchange or anti-vWF therapy.4
TTP exacerbation is a threat to patient recovery

of patients have ≥1 TTP episode within 30 days of stopping plasma exchange* 
 *Retrospective review of French Reference Centre for TMA registry (N=388).

≤ 30 Days

<h3 style="text-align: center;">TTP relapse</h3>
A new episode of TTP after achieving clinical remission.† A clinical relapse is defined as platelet count decrease to &lt;150 × 109/L (with other causes of thrombocytopenia ruled out), with or without clinical evidence of new ischemic organ injury and a confirmed documentation of severe ADAMTS13 deficiency.4
ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
†Clinical remission is defined as sustained clinical response with no plasma exchange and no anti-vWF therapy for ≥30 days or attainment of ADAMTS13 remission.
TTP exacerbation is a threat to patient recovery11

reported relapse rate in studies of TTP7

> 30 Days

ACQUIRED-THROMBOTIC-THROMBOCYTOPENIA-PURPURA-ATTP

RARE-BLOOD-DISORDERS

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:500px;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(241, 135, 0);">Monitor patients closely. Make them aware of the potential for recurrence (exacerbation or relapse) and educate on symptoms and triggers so they know to reach out immediately.</td>
 </tr>
 </tbody>
</table>
ULN=upper limit of normal.

<h2>The long-term impact of thrombotic thrombocytopenic purpura (TTP)</h2>
<h3>Patients can experience the effects of TTP long after their first episodes</h3>
The consequences of TTP can lead to many long-term complications and health risks. Approaching TTP with a long-term mindset can help ensure comprehensive care for your patients.1-3

63% of patients with TTP have neurological signs and symptoms during their first event, including2-4

Microthrombi may result in long-term neurocognitive decline in patients with TTP1

black

<ul>
 <li>Coma</li>
 <li>Focal neurological signs</li>
 <li>Personality changes</li>
 <li>Transient ischemic attack</li>
 <li>Seizures</li>
 <li>Stroke</li>
</ul>
In these patients, studies have shown4

Persistent neurological impairment during remission (49%)
<ul>
 <li>Disorientation</li>
 <li>Loss of concentration</li>
 <li>Dizziness</li>
 <li>Lack of balance</li>
 <li>Headache</li>
 <li>Diplopia</li>
</ul>

Significant impairment in memory domains
(direct, backward, and deferred memory) vs the general population

Higher prevalence of relapse in TTP
vs those without neurological symptoms (41% vs 8%)

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.

Patients with TTP may have increased risk of stroke after recovery5

<h4>Stroke risk is common after recovery from TTP and is associated with ADAMTS13 levels</h4>
ADAMTS13=a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13.
Low ADAMTS13 activity after recovery from an acute episode is associated with an increased risk of ischemic stroke during the follow-up period (P=0.007).

of patients with &gt;70% ADAMTS13 levels experienced stroke (0/22)

TTP affects patients’ quality of life over the long term, owing to exacerbations, relapses, and sustained neurocognitive defects. Patients’ responses across health-related quality of life measures suggest that living with TTP is a considerable emotional burden.
&nbsp;
<h4>Clinical anxiety and depression are serious risks for patients with TTP4</h4>

Patients with TTP reported decreased quality of life1,4

<table border="1" cellpadding="1" cellspacing="1" style="width:600px;">
 <tbody>
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 <td style="background-color: rgb(241, 135, 0); text-align: center;">It’s important to monitor the physical and mental health of your patients with TTP.1,4,5</td>
 </tr>
 </tbody>
</table>

TTP is a life-threatening thrombotic microangiopathy (TMA) that requires quick diagnosis and urgent treatment. 1,2

Monitoring TTP

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 <td style="text-align: center; background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">First TTP clinical guidelines 
 published by ISTH</td>
 </tr>
 </tbody>
</table>

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 <tbody>
 <tr>
 <td style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181); text-align: center;">Evidence-based guidelines to address 
 diagnosis and treatment of TTP</td>
 </tr>
 </tbody>
</table>

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 <tbody>
 <tr>
 <td style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181); text-align: center;">Developed by an international panel of experts 
 and patient representatives</td>
 </tr>
 </tbody>
</table>

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 <tbody>
 <tr>
 <td style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181); text-align: center;">Applicable to adults diagnosed with acquired 
 or hereditary (congenital) TTP</td>
 </tr>
 </tbody>
</table>

<h3>Need for Treatment Guidelines</h3>
<h4>Despite recent advances in diagnosis and treatment, TTP remains a serious challenge to HCPs and patients1</h4>
<ul>
 <li>TTP is a life-threatening blood disorder with substantial mortality and morbidity in the acute phase. Due to the rare nature of the disease, many HCPs have limited experience with managing TTP</li>
 <li>Evidence on optimizing early diagnosis and management of acute and recurrent episodes is limited</li>
 <li>There is large variation in clinical practice among experts for disease management</li>
 <li>Two guidance documents have been published for the diagnosis and management of TTP to date, by the following groups 
 <ul>
 <li>British Committee for Standards in Haematology2</li>
 <li>Japan’s Blood Coagulation Abnormalities Research Team3</li>
 </ul></li>
 <li>There have since been significant advances in the diagnosis and treatment of TTP; more published data are now available on impact of diagnostic strategies on objective health outcomes</li>
</ul>

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:1000px;">
 <tbody>
 <tr>
 <td style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 The ISTH identified a need for updated, evidence-based TTP guidelines that adhere to rigorous methodologic standards1</td>
 </tr>
 </tbody>
</table>
HCP, healthcare provider;&nbsp;ISTH, International Society on Thrombosis and Haemostasis;&nbsp;TTP, thrombotic thrombocytopenic purpura

<h2>Guideline Development</h2>
<h3>Multidisciplinary panel1,2</h3>
<ul>
 <li>Clinical experts in the diagnosis and management of aTTP (including hematologists and pathologists) and physicians in other relevant disciplines</li>
 <li>Patient representatives</li>
</ul>
<h3>Literature review</h3>
<ul>
 <li>
 A search of electronic databases MEDLINE, Embase, and the Cochrane Library (treatment) or MEDLINE and Embase up to February 5, 2019 (diagnosis)1,2</li>
 <li>Included RCTs and observational studies (including registry data)1</li>
 <li>Population of interest: platelet counts &lt;150 × 109/L, anemia, preserved renal function, and schistocytes2</li>
 <li>Subjects must have been receiving ≥1 treatment of interest: TPE with/without adjuvant corticosteroids, rituximab, or caplacizumab2</li>
</ul>
<h3>Scope</h3>
<ul>
 <li>Diagnosis and treatment of adults with suspected or diagnosed TTP (acquired and congenital) during acute events and while in remission1,2</li>
 <li>Risk assessment models (ie, PLASMIC and French scores) were considered out of scope2</li>
</ul>

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 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">These guidelines are not meant to replace clinical judgment2</td>
 </tr>
 </tbody>
</table>
aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;iTTP, immune-mediated thrombotic thrombocytopenic purpura.&nbsp;RCT, randomized controlled trial;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura.

<h3>PICO Framework for Treatment Questions</h3>
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 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">The panel used the PICO framework to develop 12 treatment questions relating to aTTP or cTTP treatment1</td>
 </tr>
 </tbody>
</table>
<h4>For patients experiencing a first acute event or a relapse event of aTTP (iTTPa)2</h4>
<ul>
 <li>Should TPE plus corticosteroids versus TPE alone be used?</li>
 <li>Should rituximab be added or not to TPE and corticosteroids?</li>
 <li>Should caplacizumab be used or not?</li>
</ul>
<h4>For patients with aTTP (iTTP) or cTTP in remission2</h4>
<ul>
 <li>Should prophylactic rituximab therapy be used or not?</li>
 <li>Should plasma infusion versus a watch-and-wait strategy be used?</li>
 <li>Should a FVIII concentrate infusion versus a watch-and-wait strategy be used?</li>
 <li>Should plasma infusion versus a FVIII concentrate infusion be used?</li>
</ul>
<h4>For patients with aTTP (iTTP) or cTTP in remission during pregnancy2</h4>
<ul>
 <li>Should prophylactic immunosuppression versus a watch-and-wait strategy be used for patients with a decreased level of plasma ADAMTS13 but without other signs/symptoms of TMA?</li>
 <li>Should plasma infusion versus a FVIII concentrate infusion be used?</li>
</ul>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;cTTP, congenital thrombotic thrombocytopenic purpura;&nbsp;FVIII, factor VIII;&nbsp;PICO, population, intervention, comparison, outcome;&nbsp;iTTP, immune-mediated thrombotic thrombocytopenic purpura;&nbsp;TMA, thrombotic microangiopathy;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aNote that aTTP and iTTP are synonyms.

<h3>GRADE Approach to Summarize Evidence</h3>
<h4>GRADE approach: focus on outcomes “important” for decision-making, defined as outcomes that are relevant to patients, measurable, and clearly defined</h4>
<ul>
 <li>Assessed the certainty of the evidence based on three scenarios 
 <ol>
 <li>Where ADAMTS13 activity measurement is readily available (ie, within 72 hours)</li>
 <li>Where ADAMTS13 measurement is NOT available</li>
 <li>Where ADAMTS13 activity measurement is available with a delay (ie, after 72 hours, but &lt;7 days)</li>
 </ol></li>
</ul>

<h4>Strong recommendation</h4>
<ul>
 <li>Usually based on high-quality evidence in which experts have high confidence</li>
 <li>The panel is confident that the desirable effects outweigh the undesirable effects</li>
 <li>Most patients would accept the recommended course of action</li>
 <li>Most clinicians should follow the recommended course of action, which can be largely adopted as a policy</li>
</ul>

<h4>Conditional recommendation</h4>
<ul>
 <li>The panel believes that the desirable effects probably outweigh the undesirable effects</li>
 <li>Most patients would accept the suggested course of action, but many may not</li>
</ul>

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 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">For rare diseases like aTTP, high certainty data from RCTs is limited because of small patient populations; therefore, it is challenging to develop strong recommendations</td>
 </tr>
 </tbody>
</table>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;GRADE, Grading of Recommendations Assessment, Development and Evaluation;&nbsp;RCT, randomized controlled trial

<h2>Population of Interest</h2>
<h3>Diagnostic pathways apply to patients presenting with clinical thrombotic microangiopathy and suspected TTP</h3>
<ul>
 <li>Patient populations of interest: 
 <ul>
 <li>Thrombocytopenia (&lt;150 ×109/L)</li>
 <li>Microangiopathic hemolytic anemia 
 <ul>
 <li>Hemoglobin and hematocrit &lt; LLN</li>
 <li>Low haptoglobin</li>
 <li>Elevated lactate dehydrogenase</li>
 <li>Schistocytes present in blood smear</li>
 </ul></li>
 <li>Relatively preserved renal function</li>
 </ul></li>
</ul>
LLN, lower limit of normal;&nbsp;TTP,&nbsp;thrombotic thrombocytopenic purpura.

<h3>Summary of Diagnostic Recommendations</h3>
<table border="0" cellpadding="1" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Recommendation number</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Clinical suspicion of TTP</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Key recommendations</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Evidence grade</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td colspan="5" style="background-color: rgb(134, 132, 133); border-color: rgb(134, 132, 133);">
 Timely access to ADAMTS13 testing</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 1</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 High</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;Start TPE and corticosteroids before receiving ADAMTS13 test results
 •&nbsp;Consider starting caplacizumab early before receiving ADAMTS13 test results
 •&nbsp;Adjust therapies based on ADAMTS13 results (details in following slides)</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Low certainty</td>
 </tr>
 <tr>
 <td>
 2</td>
 <td>
 Low certainty</td>
 <td>
 •&nbsp;Consider starting TPE and corticosteroids before receiving ADAMTS13 test resultsa
 •&nbsp;Do NOT start caplacizumab until ADAMTS13 test results are received
 •&nbsp;Adjust therapies based on ADAMTS13 results (details in following slides)</td>
 <td>
 Conditional</td>
 <td>
 Low certainty</td>
 </tr>
 <tr>
 <td colspan="5" style="background-color: rgb(134, 132, 133); border-color: rgb(134, 132, 133);">
 ADAMTS13 testing not available</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 3</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 N/A</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;Caplacizumab should NOT be used, regardless of the probability of TTP</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 &nbsp;&nbsp; &nbsp;Low certainty</td>
 </tr>
 </tbody>
</table>

ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;N/A, not applicable;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. Depending on the clinician’s judgment and assessment of the individual patient.

<h3>In Settings With Timely Access to ADAMTS13 Activity Testing</h3>
<h4>Patients with high clinical suspicion of TTP1</h4>
<ul>
 <li>Determined by clinical assessment&nbsp;OR&nbsp;a formal clinical risk assessment method (such as PLASMIC2&nbsp;or French score3)</li>
 <li>Availability of ADAMTS13 activity results is ideally in &lt;72 hrs; acceptable &lt;7 days1</li>
</ul>

<table border="0" cellpadding="1" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Recommendation number</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Key recommendations</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Evidence grade</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 1</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;Acquire a plasma sample and test for ADAMTS13 activity and inhibitor/anti-ADAMTS13 IgG levels before TPE or blood product use
 •&nbsp;Start TPE and corticosteroids before receiving ADAMTS13 test result
 •&nbsp;Consider early administration of caplacizumab before receiving ADAMTS13 test results (see&nbsp;Recommendation 5&nbsp;in Management Guidelines4)
 •&nbsp;If ADAMTS13 activity &lt;10 IU/dL or &lt;10% of normal (positive result): continue caplacizumab and consider starting rituximabb,c as soon as possible to reduce autoantibody production
 •&nbsp;If ADAMTS13 activity 10–20 IU/dL or 10–20% of normal (equivocal result): continue or stop TPE, corticosteroids, rituximab, and caplacizumab, based on clinical judgment</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Low certainty</td>
 </tr>
 </tbody>
</table>

<ul>
 <li>Evidence for specific scores was not evaluated; therefore, no specific scoring system is recommended</li>
</ul>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aThe recommendation applies irrespective of the timing and availability of ADAMTS13 results.&nbsp;bThe majority of these patients have antibodies against ADAMTS13.&nbsp;cRituximab is not approved for the treatment of TTP episodes.

<h3>Suggested Diagnostic Strategy: High Pretest Probability of aTTP</h3>
Patients with&nbsp;high clinical suspicion&nbsp;of aTTP (pretest probability ≥90%), based on clinical assessment&nbsp;OR&nbsp;a formal clinical risk assessment method

<ol>
 <li>Determine pretest probability of TTP using clinical judgment or a risk assessment model (PLASMIC or French score)</li>
 <li>If patient has high pretest probability, begin TPE and corticosteroids</li>
 <li>If timely ADAMTS13 testing is available (ideally in &lt;72 hours; acceptable &lt;7 days), acquire plasma samples (before initiating TPE or use of any blood product) to test for ADAMTS13 activity and inhibitor levels</li>
 <li>Consider starting early caplacizumab before ADAMTS13 test results are available</li>
 <li>Upon receiving ADAMTS13 test results: if positive, continue caplacizumab and consider adding rituximab; if borderline, use clinical judgment to guide treatment and consider other diagnoses; if negative, stop caplacizumab and consider other diagnoses</li>
 <li>If ADAMTS13 testing is not available, do not use caplacizumab; consider rituximab</li>
</ol>

ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;IgG, immunoglobulin G;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aRituximab is not approved for the treatment of TTP episodes.

<h3>In Settings With Timely Access to ADAMTS13 Activity Testing</h3>
<h4>Patients with low or intermediate clinical suspicion of TTP</h4>
<ul>
 <li>Pretest probability determined by clinical assessment&nbsp;OR&nbsp;a formal clinical risk assessment method</li>
</ul>

<table border="0" cellpadding="1" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Recommendation number</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Key recommendations</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Evidence grade</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 2</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 &nbsp;&nbsp; &nbsp; 
 • Acquire a plasma sample and test for ADAMTS13 activity and inhibitor/anti-ADAMTS13 IgG levels before TPE or blood product use
 • Consider starting TPE and corticosteroids before receiving ADAMTS13 test results
 • Do NOT start caplacizumab until ADAMTS13 test results are received
 • If ADAMTS13 activity &lt;10 IU/dL or &lt;10% of normal (positive result with inhibitors): consider starting caplacizumab and rituximabc (see Recommendation 2 and Recommendation 5 in Management Guidelines2)
 • If ADAMTS13 activity &gt;20 IU/dL or &gt;20% of normal (negative result): do NOT start caplacizumab and consider other diagnoses
 • If ADAMTS13 activity 10–20 IU/dL or 10–20% of normal (equivocal result): continue or stop TPE and corticosteroids, or add caplacizumab or rituximab based on clinical judgment</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Low certainty</td>
 </tr>
 </tbody>
</table>

<ul>
 <li>&nbsp;Evidence for specific scores was not evaluated; therefore, no specific scoring system is recommended</li>
</ul>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aThe recommendation applies irrespective of the timing and availability of ADAMTS13 results.&nbsp;bDepending on the clinician's judgment and assessment of the individual patient.&nbsp;cRituximab is not approved for the treatment of TTP episodes.

<h3>Suggested Diagnostic Strategy: Low or Intermediate Pretest Probability of aTTP</h3>
Patients with&nbsp;low or intermediate&nbsp;cal suspicion of aTTP (pretest probability &lt;90%), based on clinical assessment&nbsp;OR&nbsp;a formal clinical risk assessment method

<ol>
 <li>Determine pretest probability of TTP using clinical judgment or a risk assessment model (PLASMIC or French score)</li>
 <li>If patient has low or intermediate pretest probability (&lt;90%) of TTP, consider early TPE and corticosteroids</li>
 <li>If timely ADAMTS13 testing is available (ideally in &lt;72 hours; acceptable &lt;7 days), acquire plasma samples (before initiating TPE or use of any blood product) to test for ADAMTS13 activity and inhibitor levels</li>
 <li>If ADAMTS13 testing is not available, do not use caplacizuma</li>
</ol>

ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;Ig, immunoglobulin G;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aRituximab is not approved for the treatment of TTP episodes.

<h3>In Settings Without Reasonable Access to ADAMTS13 Activity Testing</h3>
Regardless of pretest probability of aTTP
<table align="center" border="0" cellpadding="1" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Recommendation number</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Key recommendations</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Evidence grade</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 3</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;Do NOT use caplacizumab</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Low certainty</td>
 </tr>
 </tbody>
</table>
<ul>
 <li>*The bleeding risk, cost, and resource use of caplacizumab do not justify its use in this setting</li>
 <li>It is important to provide clinicians with timely access to plasma ADAMTS13 activity and antibody testing</li>
 <li>For treatment of relapses in patients with a previous aTTP diagnosis, there is no need for a confirmatory ADAMTS13 test</li>
</ul>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura.

<h2>Summary of aTTP Treatment Recommendations</h2>
<table align="center" border="0" cellpadding="10" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Treatment recommendationa</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Event</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence grade</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 1.&nbsp;Add corticosteroids to TPE</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 First acute</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Few studies with heterogenous populations and varied interventions</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Strong</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Very low certainty</td>
 </tr>
 <tr>
 <td>
 2.&nbsp;Add rituximabb&nbsp;to corticosteroids and TPE</td>
 <td>
 First acute</td>
 <td>
 Nonrandomized studies with possible selection bias</td>
 <td>
 Conditional</td>
 <td>
 Very low certainty</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 3.&nbsp;Add corticosteroids to TPE</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Relapse</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Indirect data from use in first acute events of aTTP</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Strong</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Very low certainty</td>
 </tr>
 <tr>
 <td>
 4.&nbsp;Add rituximabb to corticosteroids and TPE</td>
 <td>
 First acute</td>
 <td>
 Indirect data from use in first</td>
 <td>
 Conditional</td>
 <td>
 Very low certainty</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 5.&nbsp;Use caplacizumab</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 First acute or relapse</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Two randomized controlled studies</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Moderate certainty</td>
 </tr>
 <tr>
 <td>
 6.&nbsp;Use rituximab for prophylaxis</td>
 <td>
 Remission, with low plasma ADAMTS13 activityb</td>
 <td>
 A small nonrandomized study</td>
 <td>
 Conditional</td>
 <td>
 Very low certainty</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 9.&nbsp;Prophylactic treatment</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Pregnancy, with decreased plasma ADAMTS13 activityc</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Paucity of data; high value placed on potentially life-saving benefit of prophylaxis</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Strong</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Moderate certainty</td>
 </tr>
 </tbody>
</table>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura; TPE, therapeutic plasma exchange.&nbsp;aRecommendations 7, 8, 10a, and 10b are for treatment of hereditary (congenital) TTP, which is not covered in this presentation.&nbsp; bRituximab is not approved for the treatment of TTP episodes. cWith no other clinical signs/symptoms.

<h3>First Acute Event of aTTP</h3>
<table align="center" border="0" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <th style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Treatment recommendation</th>
 <th style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Strength of recommendation</th>
 <th style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence grade</th>
 <th colspan="2" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Considerations</th>
 </tr>
 <tr>
 <td>
 1.&nbsp;Add corticosteroids to TPE over TPE alone</td>
 <td>
 Strong</td>
 <td>
 Very low certainty</td>
 <td colspan="2">
 •&nbsp;Moderate reduction in mortality risk with adverse events not severe in the short-term
 •&nbsp;Supported by small studies with heterogenous populations and varied interventions
 •&nbsp;Small incremental cost and resource use relative to the potential benefits
 •&nbsp;No detailed recommendation on dose and types of corticosteroids</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 2.&nbsp;Add rituximaba&nbsp;to corticosteroids and TPE over corticosteroids and TPE alone</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Very low certainty</td>
 <td colspan="2" style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;Supported by&nbsp;nonrandomized studies&nbsp;that assessed a narrow range of outcomes
 •&nbsp;Possible concern for selection bias (patients receiving rituximab may have had more severe disease)
 •&nbsp;Primary effect appears to be on preventing relapse; however, not many patients with aTTP may experience a relapse
 •&nbsp;Primary effect appears to be on preventing relapse; however, not many patients with aTTP may experience a relapse
 •&nbsp;Rituximab may be considered for patients with known comorbid autoimmune disorder, although evidence is limited</td>
 </tr>
 </tbody>
</table>
aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aRituximab is not approved for the treatment of TTP episodes.

<h3>aTTP Relapse</h3>
<table align="center" border="0" cellpadding="10" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Treatment recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence grade</th>
 <th colspan="2" scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Considerations</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td>
 3.&nbsp;Add corticosteroids to TPE over TPE alone</td>
 <td>
 Strong</td>
 <td>
 Very low certainty</td>
 <td colspan="2">
 • May reduce mortality in a life-threatening situation
 No prohibitive short-term adverse events
 •&nbsp;Largely informed by indirect data in the setting of the first acute aTTP event
 •&nbsp;Only single arm and registry data exclusively for treatment of relapses
 •&nbsp;Serious morbidities associated with repeated use may limit acceptability
 •&nbsp;Small incremental cost and resource use relative to the potential benefits
 •&nbsp;Dose and types of corticosteroids cannot be recommended
 •&nbsp;Corticosteroids should be used with caution in patients susceptible to adverse events</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 4.&nbsp;Add rituximaba&nbsp;to corticosteroids and TPE over corticosteroids and TPE alone</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Very low certainty</td>
 <td colspan="2" style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 • Sparse evidence
 • Indirect data&nbsp;support the benefit of adding rituximab for preventing relapse
 •&nbsp;Patients may consider rituximab more acceptable than corticosteroids after the first acute event
 •&nbsp;Risk of subsequent relapse may be higher in patients who have already relapsed
 •&nbsp;Primary effect appears to be on preventing relapse; however, not many patients with aTTP may experience a relapse
 •&nbsp;Rituximab should be considered for patients with a known comorbid autoimmune disorder, although subgroup evidence is limited</td>
 </tr>
 </tbody>
</table>
aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;TPE, therapeutic plasma exchange;&nbsp;TTP, thrombotic thrombocytopenic purpura. aRituximab is not approved for the treatment of TTP episodes.

<h3>First Acute Event of aTTP or Relapse</h3>
<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Treatment recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence grade</th>
 <th colspan="2" scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">
 Considerations</th>
 </tr>
 <tr>
 <td colspan="1" rowspan="2" style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 5.&nbsp;Use caplacizumab 
 over not using 
 caplacizumab</td>
 <td colspan="2" rowspan="1" style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Only recommendation in the guideline with moderate certainty evidence</td>
 <td colspan="2" rowspan="2" style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;Evidence from&nbsp;two published RCTs, one of which was double-blinded2,3
 •&nbsp;Low mortality rate in both treatment groups may not reflect true mortality rates in other patient populations; this suggests possible selection bias or that patients had less severe disease
 •&nbsp;Data suggest clinically important bleeding side effects with caplacizumab and relapse after stopping drug treatment
 •&nbsp;Data do not differentiate effects on first and relapse events
 •&nbsp;Data do not differentiate effects on first and relapse events
 •&nbsp;Use is conditional on rapid identification of patients with a high likelihood of TTP (ie, evidence of severe plasma ADAMTS13 deficiency and inhibitors present)
 •&nbsp;Use will depend on local cost considerations and availability</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(255, 255, 255);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(255, 255, 255);">Moderate</td>
 </tr>
 </tbody>
</table>
 ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;RCT, randomized controlled trial;&nbsp;TTP, thrombotic thrombocytopenic purpura.

<h3>First Acute Event of aTTP or Relapse</h3>
<h4>Practical considerations for caplacizumab use1</h4>
<ul>
 <li>Physicians should consider administering caplacizumab treatment before ADAMTS13 activity test results are available (see&nbsp;Recommendations 1–3 in the Diagnosis Guidelines2)</li>
 <li>Caplacizumab should be used only under the guidance of a trained TTP expert (hematologist or transfusion medicine specialist); however, few clinicians are familiar with caplacizumab use and monitoring1</li>
 <li>Clinicians must develop better understanding of the mode of action for caplacizumab1</li>
 <li>Caplacizumab does not correct underlying ADAMTS13 deficiency; therefore, other treatments might be required1</li>
 <li>Discontinuing caplacizumab after platelet count normalization with persistently low ADAMTS13 activity &lt;10 IU/dL may result in an exacerbation1,3</li>
 <li>Implementation of caplacizumab therapy is dependent on clinicians’ access to timely and reliable ADAMTS13 testing1</li>
 <li>Further data on the optimal use of caplacizumab and cost-effective strategies are needed</li>
 <li>Caplacizumab use in these patient populations is considered feasible for patients in an outpatient or in-home setting via subcutaneous administration1</li>
</ul>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;RCT, randomized controlled trial;&nbsp;TTP, thrombotic thrombocytopenic purpura.

<h3>Patients With aTTP in Remission</h3>
<ul>
 <li>Patients with aTTP who are in remission and still have low plasma ADAMTS13 activity but no other clinical signs/symptoms</li>
</ul>
<table align="center" border="0" cellpadding="10" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Treatment recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence grade</th>
 <th colspan="2" scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Considerations</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 6.&nbsp;Use rituximaba&nbsp;over not using rituximab for prophylaxis</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Conditional</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Very low certainty</td>
 <td colspan="2" style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 •&nbsp;A&nbsp;small nonrandomized study&nbsp;suggests that rituximab reduces the rate of relapses
 •&nbsp;No clear differentiation between first and subsequent remissions
 •&nbsp;Rituximab does not appear to affect survival
 •&nbsp;Issues surround cost, resources, and continued monitoring
 •&nbsp;Rituximab prophylaxis without ADAMTS13 testing is not an evidence-based strategy</td>
 </tr>
 </tbody>
</table>
<h3>Practical considerations for rituximab use</h3>
<ul>
 <li>There is no guidance on appropriate interval for ADAMTS13 testing for patients in remission</li>
 <li>This strategy may not be acceptable or feasible in all centers or patients</li>
</ul>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;TTP, thrombotic thrombocytopenic purpura. aRituximab is not approved for the treatment of TTP episodes.

<h3>Patients With aTTP Who Are Pregnant</h3>
<ul>
 <li>Patients with aTTP who are in remission and still have low plasma ADAMTS13 activity but no other clinical signs/symptoms</li>
</ul>
<table align="center" border="0" cellpadding="10" cellspacing="1">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Treatment recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Strength of recommendation</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Evidence grade</th>
 <th colspan="2" scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Considerations</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td>
 9.&nbsp;Prophylactic treatment 
 over no prophylactic over no prophylactic prophylaxis</td>
 <td>
 Strong</td>
 <td>
 Very low certainty</td>
 <td colspan="2">
 •&nbsp;Potentially life-saving benefits of prophylactic treatment likely outweigh the risks
 •&nbsp;There is a paucity of data on the effect of available treatment regimens
 •&nbsp;May reduce maternal and infant mortality</td>
 </tr>
 </tbody>
</table>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura.

<h2>PLASMIC and French Scores For Predicting ADAMTS13 Deficiency</h2>
<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:1000px;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">PLASMIC score or French score predicts the likelihood of severe ADAMTS13 deficiency in case of suspected TTP1,2</td>
 </tr>
 </tbody>
</table>
&nbsp;
<table align="center" border="0" cellpadding="10" cellspacing="1" style="width: 1000px;">
 <thead>
 <tr>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">Parameters</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">French score</th>
 <th scope="col" style="background-color: rgb(5, 109, 181); border-color: rgb(5, 109, 181);">PLASMIC score</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Platelet count</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 &lt;30 × 109/L (+1)</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 &lt;30 × 109/L (+1)</td>
 </tr>
 <tr>
 <td>
 Serum creatinine level</td>
 <td>
 &lt;2.26 mg/dL (+1)</td>
 <td>
 &lt;2.0 mg/dL (+1)</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 Hemolysis 
 Indirect bilirubin &gt;2 mg/dL 
 Reticulocyte count &gt;2.5% 
 Undetectable haptoglobin</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 *</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 +1</td>
 </tr>
 <tr>
 <td>
 No active cancer in previous year</td>
 <td>
 *</td>
 <td>
 +1</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 No history of solid organ or SCT</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 *</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 +1</td>
 </tr>
 <tr>
 <td>
 INR &lt;1.5</td>
 <td>
 *</td>
 <td>
 +1</td>
 </tr>
 <tr>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 MCV &lt;90 fL</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 NA</td>
 <td style="background-color: rgb(237, 246, 254); border-color: rgb(237, 246, 254);">
 +1</td>
 </tr>
 <tr>
 <td>
 Likelihood of severe deficiency of ADAMTS13 activity (&lt;10%)</td>
 <td>
 0: 2% 
 1: 70% 
 2: 94%</td>
 <td>
 0–4: 0–4% 
 6: 5–24% 
 6–7: 62–82%</td>
 </tr>
 </tbody>
</table>
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13;&nbsp;aTTP, acquired thrombotic thrombocytopenic purpura;&nbsp;INR, international normalized ratio;&nbsp;MCV, mean corpuscular volume;&nbsp;NA, not available;&nbsp;SCT, stem cell transplantation;&nbsp;TMA, thrombotic microangiopathy. 
 French score considered patients with TMA that included hemolysis and schistocytes in their definition and assumed that there was no history or clinical evidence for associated cancer, transplantation or disseminated coagulation. Therefore, these items were intrinsic to the scoring system. NA and MCV were not incorporated in the French score. Table adapted from Joly BS, et al.

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ISTH Guidelines for the Diagnosis and Management of aTTP (iTTPa)

<h2>Identifying thrombotic thrombocytopenic purpura (TTP) among thrombotic microangiopathies (TMAs)</h2>
<h3>TMAs require urgent management, but variable presentation can make them difficult to distinguish1,2</h3>
TMA is a pathologic term used to describe occlusive microvascular or macrovascular disease, often with intraluminal thrombus formation.3&nbsp;Presentation of TMAs varies widely, including but not limited to stroke, neurologic complications, severe renal failure, flu-like symptoms, and simple fatigue.4,5 
 This leads to the involvement of several physician specialists at the outset of patient care in clinic and hospital settings. Both—the variability of TMAs and the involvement of many specialties—pose a challenge to prompt recognition and diagnosis of TTP.4,5
<h3>Your role is crucial to the diagnosis and speed of appropriate treatment for TMAs6</h3>
In most cases, patients present at the emergency department for a nonspecific somatic complaint, and thrombocytopenia is subsequently discovered. More rarely, the results of a CBC can reveal thrombocytopenia during an appointment in a non-hospital setting.6
It is critical to suspect TMA when you see7,8:

Thrombocytopenia 
 (often platelets &lt;30 × 109/L)

Microangiopathic hemolytic anemia (MAHA) 
 characterized by the presence of schistocytes in blood smear

Organ failure 
 of varying severity

Thrombocytopenia associated with MAHA should suggest a TMA syndrome, even in the absence of organ failure.9
Important TMA lab markers6,10,11
<h3>Biological report sheet</h3>

<table align="center" border="0" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td colspan="1" rowspan="2">Blood count</td>
 <td>Thrombocytopenia</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>
 Hemolytic anemia</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>
 Reticulocyte count</td>
 <td>
 High (&gt;120 g/L)*</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>Hemoglobin</td>
 <td>Low</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>
 Schistocytes on blood smear</td>
 <td>
 Present†</td>
 <td>A hallmark of TTP, but absence 
 does not rule out a diagnosis</td>
 </tr>
 <tr>
 <td>
 Coombs test</td>
 <td>
 Negative‡</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td colspan="1" rowspan="3">
 Hemolysis evaluation</td>
 <td>Hyperbilirubinemia</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>
 Haptoglobin low, even undetectable</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>&nbsp;High LDH rate§</td>
 <td>While not diagnostic, elevated LDH 
 may predict organ damage</td>
 </tr>
 <tr>
 <td colspan="1" rowspan="3">
 Hemostasis assessment</td>
 <td>
 Most often normal</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>D-dimer rate may be moderately elevated</td>
 <td>&nbsp;</td>
 </tr>
 </tbody>
</table>

<h3>Understanding the types of TMAs can change how you treat the patient1,12</h3>
TMAs are classified into 2 types: primary and secondary. Primary TMAs have no clear underlying cause, while secondary TMAs may be caused by a number of clinical conditions. Recognizing the underlying cause, or lack thereof, can determine treatment course.1,12
Types of TMAs1,12

Primary TMAs
<ul>
 <li>TTP (acquired/immune-mediated and hereditary)</li>
 <li>HUS (atypical/complement-mediated and Shiga toxin–producing E coli)</li>
</ul>

Secondary TMAs
<ul>
 <li>Systemic lupus erythematosus</li>
 <li>Pregnancy-associated (eg, hemolysis, elevated liver enzymes, low platelet count [HELLP] syndrome)</li>
 <li>Hematopoietic progenitor cell transplantation</li>
 <li>Drug-induced</li>
</ul>

<h3>The 2 primary TMAs—TTP and HUS—are often confused, but differentiating them is critical to determining appropriate treatment1,2</h3>
Historically, TTP and hemolytic uremic syndrome (HUS) were classified based on clinical findings: TTP for predominant neurologic involvement and HUS for the kidney-dominant diseases.1,13&nbsp;With recent understanding of the molecular basis of TMAs, definitions have changed.1,7,8,11,13

TTP is now defined as 
 ADAMTS13 deficiency

vs

HUS may be caused by Shiga toxin-producing E coli (STEC-HUS) OR genetic mutations in complement regulatory proteins (atypical or complement-mediated HUS)

Differentiation of TTP from HUS can be confounded by kidney involvement in TTP.&nbsp;25% of patients with TTP had kidney injury&nbsp;in the Oklahoma TTP Registry.5,14,15

<h4>Variable presentation of TMAs, potential confusion with HUS, and lack of diagnostic protocols can result in a missed or delayed diagnosis of aTTP2,16</h4>

of patients with aTTP were misdiagnosed&nbsp;16&nbsp; 
 According to a retrospective review of the French Reference Centre for TMA registry (N=423).

This number may be underestimated due to the study being unable to exclude the possibility that some misdiagnosed patients may have died before their TTP diagnosis was made.16

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width: 1000px;">
 <tbody>
 <tr>
 <td style="background-color: rgb(241, 135, 0); border-color: rgb(241, 135, 0);">
 The consequences of delayed diagnosis and treatment of TTP can be devastating, including organ failure or even death.7,11,15-17</td>
 </tr>
 </tbody>
</table>

aTTP=acquired thrombotic thrombocytopenic purpura; CBC=complete blood count; E coli=Escherichia coli; LDH=lactate dehydrogenase. *Emphasizes the regenerative nature of anemia. †Nonsystematic presence of schistocytes, possibly late onset, hence the importance of repeating this test several times to increase the sensitivity of the examination.16 ‡Test may turn out to be slightly positive in an autoimmune environment.16 §Related to hemolysis and organ tissue damage.6

<h2>How to diagnose thrombotic thrombocytopenic purpura (TTP)</h2>
<h3>Diagnosing TTP rapidly is critical and can save a life1</h3>
When a patient presents with2

<h4 style="text-align: center;">Severe thrombocytopenia</h4>
(often platelets &lt;30 × 109/L).

<h4 style="text-align: center;">Microangiopathic hemolytic anemia (MAHA)</h4>
characterized by the presence of schistocytes in blood smear

<h4 style="text-align: center;">With no identified cause</h4>

The risk of death is acute and imminent if TTP remains undiagnosed and untreated1,3,4

<h4 style="text-align: center;">of untreated patients1,3,4</h4>

<h4 style="text-align: center;">of the acute event if untreated1</h4>

<h3>Why TTP can be difficult to diagnose</h3>
TTP is rare and presents similarly to other thrombotic microangiopathies (TMAs), making it a challenge to diagnose. All TMAs result in thrombosis of capillaries and arterioles due to endothelial injury.5,6 
 A delay in diagnosing TTP can leave patients at risk for organ damage and death. The uncertainty around what’s happening to these patients can cause fear and frustration.5,7-9

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:1000px;">
 <tbody>
 <tr>
 <td style="background-color: rgb(241, 135, 0); border-color: rgb(241, 135, 0);">
 It's critical to differentiate TTP from other TMAs quickly so patients can get started on appropriate treatment</td>
 </tr>
 </tbody>
</table>
&nbsp;
<h2 style="text-align: center;">Diagnosing TTP in adults: Step-by-step1,7,10-15</h2>
Presentation

Headache and/or confusion and/or seizures and/or other cerebral abnormalities

Neurological symptoms

Abdominal pain, nausea, and diarrhea

Gastrointestinal symptoms

Chest pain and/or hypotension and/or myocardial infarction and/or congestive heart failure and/or sudden cardiac arrest and/or other cardiac abnormalities

Cardiac symptoms

Hematuria and proteinuria; creatinine &lt;2 mg/dL; typically not severe

Renal impairment

Diagnosing aTTP?

<h3 style="text-align: center;">Important TTP lab markers</h3>

The presence of schistocytes on the blood smear&nbsp;is the morphologic hallmark of the disease, but the absence of schistocytes does not rule out TTP.2,16

Although&nbsp;serum creatinine is typically &lt;2.0 mg/dL&nbsp;at presentation, the Oklahoma TTP-HUS Registry reported kidney injury 25% of the time.2,15

While not diagnostic,&nbsp;elevated LDH&nbsp;may be predictive of severe organ damage, and&nbsp;elevated troponin&nbsp;may indicate cardiovascular risk.1,2

ADAMTS13 activity &lt;10% confirms a TTP diagnosis&nbsp;and supports TTP treatment, but ADAMTS13 levels of 10% to 20% do not rule out TTP. TTP management will rely on clinical judgment.2,7,13

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:1000px;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(241, 135, 0); border-color: rgb(241, 135, 0);">
 ADAMTS13 &lt;10% confirms TTP. Test as soon as possible when TMA is suspected.2,7,13</td>
 </tr>
 </tbody>
</table>

LDH=lactose dehydrogenase; MAHA=microangiopathic hemolytic anemia; TMA=thrombotic microangiopathy; TTP=thrombotic thrombocytopenic purpura.

<h2>Guidelines for diagnosing and treating thrombotic thrombocytopenic purpura (TTP)</h2>

The International Society on Thrombosis and Haemostasis (ISTH) published guidelines are the first comprehensive, evidence-based, international guidelines on the diagnosis, treatment, and management of TTP.1

Most recent publication
The ISTH Guidelines for Diagnosis and Treatment were published July 2020.

About ISTH
With more than 5000 members across 100 countries, the ISTH is the leading thrombosis and hemostasis–related professional organization in the world.2

<h3>Why the ISTH Guidelines were developed</h3>
Diagnosing and treating TTP can be complicated.1
<ul>
 <li>The rarity of TTP—and its similar presentation to other TMAs—can make recognition a challenge info icon</li>
 <li>Management of TTP varies among healthcare professionals (HCPs)</li>
 <li>Treatment recommendations in TTP have evolved</li>
</ul>
<h3>ISTH created the guidelines as a comprehensive, uniform, international resource to inform the diagnosis and management of TTP1</h3>
The ISTH Guidelines can aid HCPs—both those with limited experience with TTP and those considered experts in TTP—in making a TTP diagnosis and following an appropriate treatment strategy.
These include1
<ul>
 <li>Emergency/critical care physicians</li>
 <li>Hematologists</li>
 <li>Nephrologists</li>
 <li>Neurologists</li>
 <li>Transfusion medicine specialists</li>
 <li>Hospitalists</li>
 <li>Policy makers</li>
</ul>

<table align="center" border="0" cellpadding="1" cellspacing="1" style="width:1000px;">
 <tbody>
 <tr>
 <td style="background-color: rgb(241, 135, 0); border-color: rgb(241, 135, 0);">
 The ISTH has created the first evidence-based guidelines to support rapid TTP diagnosis and treatment.</td>
 </tr>
 </tbody>
</table>

TTP is a life-threatening thrombotic microangiopathy (TMA) that requires quick diagnosis and urgent treatment. 1,2

Diagnosing TTP

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