Hospital Medicine

Thrombotic thrombocytopenic purpura

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Thrombotic thrombocytopenic purpura

I. What every physician needs to know.

Thrombotic Thrombocytopenic Purpura (TTP) is a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, microvascular thrombi, and varying levels of organ damage. It can be a hereditary or acquired condition, secondary to mutations or antibody inhibitors to the protein ADAMTS13; a protease that cleaves von Willebrand factor (VWF). VWF plays a significant role in platelet adhesion and is usually secreted as an ultra-large multimer. If left uncleaved, these large mulitmers polymerize to form even larger molecules which have an increased avidity to platelets, leading to occlusive thrombi and organ ischemia. Although it is a rare disease, TTP has a high rate of morbidity and mortality unless recognized and treated promptly.

II. Diagnostic Confirmation: Are you sure your patient has Thrombotic Thrombocytopenic Purpura?

For diagnosis, a minimum of thrombocytopenia and microangiopathic hemolytic anemia (MAHA) must be present, without an apparent alternative cause. Microangiopathic hemolytic anemia is defined as a non-immune hemolytic process marked by at least two schistocytes per microscopic field at a magnification of 100.

Previously, when plasma exchange had not yet been discovered as an effective therapy for TTP, the diagnosis was thought to require the presence of a pentad of findings: thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic abnormalities and renal dysfunction. However, since the institution of plasma exchange, fever has been found to be uncommon; and neurologic and renal abnormalities may evolve only later in the untreated clinical course of the disease.

Pertinent Medical History

While idiopathic TTP is most common, there are a number of systemic diseases and drugs that can cause TTP. These include the following:

-Advanced human immunodeficiency virus (HIV)

-Malignancy

-Autoimmune diseases

-Pregnancy

-Drug toxicity

-Quinine

-Mitomycin C

-Cisplatin

-Gemcitabine

-Cyclosporine/tacrolimus

-Ticlodipine/clopidogrel

A. History Part I: Pattern Recognition:

The clinical manifestations of TTP are exceedingly non-specific. Gastrointestinal symptoms are the most common presenting features, including abdominal pain, nausea, vomiting, and diarrhea. Neurologic findings are present in roughly half of patients, ranging from the more common headache and confusion to the rarer focal motor and sensory deficits, seizures and coma. With regard to renal involvement, there are almost always abnormal laboratories, but rarely any clinical manifestations. While myocardial involvement is common on pathology, overt clinical manifestations are infrequent, but can include myocardial infarction (MI), sudden cardiac death and arrhythmias. Fever was included in the classic pentad of findings, but as discussed above, is actually uncommon; when present, it is usually low-grade.

B. History Part 2: Prevalence:

Hereditary TTP (Upshaw-Schulman syndrome) is related to any number of mutations in the ADAMTS 13 gene. Otherwise, in small case series, patients with idiopathic TTP were more likely to be female, obese, of African-Caribbean descent, or have other features of auto-immunity.

Incidence of idiopathic TTP: 4.5 cases/million.

C. History Part 4: Competing diagnoses that can mimic Thrombotic Thrombocytopenic Purpura.

Because of the non-specific nature of the features of this disease, distinguishing TTP from other conditions is a challenge. The major diagnoses that should be included in the differential include:

Hemolytic-Uremic Syndrome (HUS)

Sepsis

Malignant Hypertension

Disseminated Malignancy

Disseminated Intravascular Coagulation

Heparin-induced Thrombocytopenia

Vasculitis

Catastrophic Antiphospholipid Syndrome

Evans Syndrome

Pregnancy:

Pre-eclampsia/Eclampsia

Hemolysis Elevated Liver enzymes Low Platelets (HELLP) Syndrome

Acute Fatty Liver of Pregnancy (AFLP)

Unfortunately many of the above conditions may either predispose to the development of TTP or be a result of progressive TTP, and thus may be present simultaneously. Because of this, other diagnoses must always be considered, especially when patients are unresponsive to plasma exchange therapy.

D. Physical Examination Findings.

Constitutional

-Low-grade fever may be present

Neurologic

-Alteration of mental status, seizures and focal motor and sensory deficits may be present

-Decreased visual acuity may be present

Cardiovascular

-Hypertension may be present if there is significant renal dysfunction

Abdominal

-Abdominal tenderness may be present, related to microvascular thrombi in the gastrointestinal (GI) tract, leading to splenic pain and acute pancreatitis

E. What diagnostic tests should be performed?

-Complete blood count (CBC)

-Peripheral smear

-Basic metabolic panel

-Liver function tests

-Lactate dehdyrogenase (LDH)

-Direct antiglobulin (Coombs) testing (DAT)

-Prothrombin time/International normalized ratio (PT/INR), partial thromboplastin Time (PTT), D-dimer, fibrinogen

-ADAMTS 13 activity and inhibitor testing

-Review of prior and current medication list

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

-Complete blood count: evaluation for anemia and thrombocytopenia.

-Peripheral smear: evaluation for significant schistocytosis. However, in the first 24-48 hours after presentation, significant schistocytosis may not be present. Thus, if the diagnosis is being entertained, serial evaluation of peripheral smears should be performed.

-Basic metabolic panel: evaluation for renal dysfunction.

-Liver function tests: evaluation for significant transaminitis/hyperbilirubinemia that might be more consistent with HELLP Syndrome or AFLP in pregnant women.

-LDH: evaluation for evidence for hemolysis and further multiorgan ischemia related to microvascular thrombi. LDH levels in TTP are generally very high.

-Direct antibody test (Coombs test): evaluation for immune-mediated hemolysis. Coombs test is negative with TTP. A positive Coombs test suggests an autoimmune hemolytic anemia.

-PT/PTT, D-dimer, and fibrinogen: evaluation for evidence for disseminated intravascular congestion (DIC) or the presence of antiphospholipid antibodies.

-ADAMTS 13 activity and inhibitor testing: evaluation for severe deficiency. As discussed previously, a normal ADAMTS 13 assay or a partial deficiency is not sufficient to rule-out or rule-in TTP.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There is no imaging study that reliably or consistently aids in diagnosing or ruling-out TTP.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

NA

III. Default Management.

1. Plasma Exchange: the mainstay of treatment for both heredity and acquired TTP:

2. Corticosteroids: only in those patients with presumed idiopathic TTP.

3. In drug-induced TTP, withdraw the offending agent if possible.

A. Immediate management.

1. Plasma Infusion: this is a temporizing measure until a central venous catheter (CVC) can be placed and plasma exchange initiated.

2. Telemetry versus intensive care unit (ICU) monitoring.

3. CVC placement.

4. Plasma exchange: as above.

B. Physical examination tips to guide management.

With plasma infusion:

  • Transfusion associated circulatory overload (TACO): jugular venous pressure (JVP), heart/lung sounds, peripheral edema.

  • Transfusion-related acute lung injury (TRALI): pulse oximetry, temperature curve, heart rate, heart/lung sounds.

  • Anaphylaxis: vital signs, heart/lung sounds, skin examination.

With plasma exchange:

  • TACO: JVP, heart/lung sounds, peripheral edema

  • TRALI: pulse oximetry, temperature curve, heart rate, heart/lung sounds

  • Anaphylaxis: vital signs, heart/lung sounds, skin examination

  • Bleeding: CVC-site examination

  • Catheter-related sepsis: CVC-site examination

  • Infection: temperature curve

  • Venous Thromboembolism: extremity examination, heart rate, heart/lung sounds

  • Hypotension: blood pressure

  • Hypocalcemia: musculoskeletal/facial exam for tetany, muscle spasms/cramps, heart sounds/heart rate for arrhythmia

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

1. Daily CBC

2. Daily LDH

3. Daily PT/PTT and fibrinogen

4. Daily ionized calcium (iCa)

5. Daily chemistry panel if renal dysfunction is present

D. Long-term management.

Plasma Exchange

While daily plasma exchange may only be necessary for 1-2 weeks, there have been reported cases where daily plasma exchange was continued for up to 5 months. There is also some controversy regarding when to discontinue plasma exchange. The Society for Hemostasis and Thrombosis recommends continuing plasma exchange for at least two more days after remission. While there is no data to support tapering plasma exchange treatments over abrupt discontinuation, and none of the professional pheresis bodies advocate the practice, there are many centers that taper therapy after remission is achieved.

Steroids

Steroids are typically used in addition to plasma exchange to achieve relatively rapid remission. They are used only in acquired TTP, as hereditary TTP is not immune mediated. The exact duration of steroid therapy has not been defined. However, based on available data, it would be reasonable to treat with the aforementioned daily dosing for at least 2 weeks, followed by a 1 week taper.

Rituximab (Rituxan®)

Rituximab has been shown to be an effective treatment for acquired TTP. It was shown to decrease the number of plasma exchanges required to achieve remission in Caucasian patients, to shorten the length of inpatient stay, and reduce the risk of relapse by >80%. It is not recommended by some clinicians as a first-line therapy but perhaps reserved for patients with severe acquired TTP without prompt response from plasma exchange and steroids.

Splenectomy

This is not a recommended treatment modality.

E. Common Pitfalls and Side-Effects of Management.

See above. Monitor PT/PTT, fibrinogen and calcium daily while receiving plasma exchange, as coagulopathy and hypocalcemia can develop as a consequence of plasma exchange itself.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

No change in standard management. There is no data presently regarding whether continuing plasma exchange would benefit patients with normalized platelet counts but with persistent renal dysfunction.

B. Liver Insufficiency.

No change in standard management. Monitor closely for hemorrhage given plasma exchange will remove procoagulant factors.

C. Systolic and Diastolic Heart Failure.

No change in standard management. Monitor closely for volume overload during plasma exchange and plasma infusion (if prescribed).

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

If the TTP is thought to be due to the HIV infection, then highly active antiretroviral therapy (HAART) should be initiated in addition to standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

For patients with coagulopathy, they will need to be monitored closely for hemorrhage in consultation with a hematologist.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

A. Sign-out considerations While Hospitalized.

Night Coverage

-No unique considerations

Weekend Coverage

-Follow trends in daily labs closely (CBC, LDH, PT/PTT, fibrinogen, iCa)

B. Anticipated Length of Stay.

1-2 weeks

C. When is the Patient Ready for Discharge.

When the patient's clinical status is stable, and the platelet count is normal (and LDH is normal to near-normal) and stable for at least 24-48 hours.

D. Arranging for Clinic Follow-up.

The patient will need to follow-up with a hematologist or nephrologist at a center with plasma exchange capability very soon after discharge to evaluate the need for further treatment. As immediate recurrence is a real possibility, when possible, it would also be reasonable to discharge the patient with the pheresis line in place until follow-up demonstrates stable labs.

1. When should clinic follow up be arranged and with whom.

The patient should follow-up with hematology or nephrology (depending on which specialty provides plasma exchange services) several days after discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

-CBC

-LDH

-Chemistry panel if renal dysfunction present

E. Placement Considerations.

Long-Term Acute Care Facility

-This would be appropriate if the patient is stable but will likely require further regular plasma exchange therapy.

F. Prognosis and Patient Counseling.

Overall mortality: 10-22%

-Severe ADAMTS 13 deficiency: 5-10%

-Time from presentation to initiation of plasma exchange is a strong predictor, with delays over 24 hours correlating directly with increasing mortality.

Exacerbation (recurrence within 30 days): 22-45%

Relapse (recurrence after 30 days): 13-40%

-The presence of severe ADAMTS 13 deficiency on presentation and continued severe ADAMTS 13 deficiency despite plasma exchange therapy portends a higher risk for relapse.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Pharmacologic deep vein thrombosis (DVT) prophylaxis and the risk for bleeding will need to be weighed in this patient population based on the absolute platelet count and derangements in PT/PTT that result related to plasma exchange therapy.

If the patient is discharged with a pheresis catheter, appropriate line-care education for the patient and family and the arrangement for home-health nursing visits are imperative to maintain catheter integrity.

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