Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura

What every physician needs to know:

Thrombotic thrombocytopenic purpura (TTP) is a severe, life-threatening disorder caused by extensive, systemic platelet adhesion and aggregation.

TTP is a type of thrombotic microangiopathy. It is characterized by organ ischemia, profound thrombocytopenia, erythrocyte fragmentation, and severe deficiency of a plasma von Willebrand factor (VWF)-cleaving protease, ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin domains, member number 13).

ADAMTS-13 deficiency may be familial (defective enzyme production) or acquired (ADAMTS-13 autoantibody-mediated).

Severe deficiency of ADAMTS-13 correlates with failure to cleave ultra-large (UL) VWF multimeric strings as they are secreted by stimulated endothelial cells.

Uncleaved ULVWF multimeric strings anchored to endothelial cells, or present as soluble ULVWF forms in plasma, are hyper-adhesive to platelets. ULVWF strings or soluble ULVWF forms with adherent/aggregated platelets occlude the microvasculature (arterioles and capillaries).

Some patients with thrombotic microangiopathies do not have plasma deficiency of ADAMTS-13. These types of acquired thrombotic microangiopathy not associated with ADAMTS-13 deficiency are described in several of the sections that follow.

Are you sure your patient has thrombotic thrombocytopenic purpura? What should you expect to find?

You should expect to find:

• Severe thrombocytopenia (platelet counts often less than 20,000/microliter)
• Ischemia of one or more of the following organs:

– Brain (confusion, seizures, coma)

– Gastrointestinal (GI) tract (abdominal pain)

– Heart (cardiac conduction defects)

– Kidneys (increased creatinine)

• Fragmented erythrocytes (schistocytes or “split” red cells) on blood films (often called “microangiopathic hemolytic anemia”)
• Extremely elevated serum lactate dehydrogenase (LDH); released from fragmenting red cells and ischemic tissue cells

Attention – The triad of severe or evolving thrombocytopenia, schistocytosis, and extremely elevated LDH, suggests the diagnosis of TTP.

Beware of other conditions that can mimic thrombotic thrombocytopenic purpura:

Other conditions that can mimic TTP are:

• The hemolytic-uremic syndrome (HUS)

Caused by Shiga toxin-producing bacteria (for example, Escherichia coli O157:H7, diarrhea-associated HUS) or defective control or hyperactivity of the alternative complement pathway (“atypical” HUS).

• Disseminated intravascular coagulation (DIC)
• Malignant hypertension
• Collagen vascular disease/severe vasculitis
• Malfunctioning prosthetic heart valve
• Evans syndrome (autoimmune thrombocytopenia + autoimmune hemolytic anemia)
• Preeclampsia (eclampsia and the HELLP syndrome [hemolysis with elevated liver enzymes and low platelets])
• Antiphospholipid syndrome
• Heparin-induced thrombocytopenia (HIT)

Note – Plasma ADAMTS-13 levels are usually within a broad normal range in the above disorders.

Common clinical diagnostic dilemma (TTP versus HUS versus DIC):

• TTP: Acute renal failure is unlikely
• HUS: Acute renal failure is prominent
• DIC: Plasma D-dimers are elevated. Venous thromboembolism is common

Which individuals are most at risk for developing thrombotic thrombocytopenic purpura:

TTP occurs occasionally:

• Late in pregnancy or immediately after delivery
• In HIV/AIDS
• In the first weeks after initiating clopidogrel (Plavix) or ticlopidine (Ticlid) therapy

Thrombotic microangiopathies are sometimes associated with exposure to:

• Cyclosporine or tacrolimus immunosuppression during hematopoietic stem cell or solid organ transplantation
• Anti-angiogenesis therapy

For example, bevacizumab (Avastin), a monoclonal antibody against vascular endothelial cell growth factor (VEGF); or “tinib” drugs (for example, sunitinib), that inhibit VEGF receptor-mediated kinase signaling.

• Mitomycin, gemcitabine or quinine
• Total body irradiation and/or multiple chemotherapeutic agents

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Before beginning treatment, citrated plasma should be obtained and either tested immediately or frozen and stored for subsequent testing (at a local or remote test site).

The citrated plasma sample should be tested for ADAMTS-13 activity, in order to determine if the enzyme is: absent or severely reduced (less than 5 to 10% of normal), or within a broad normal range.

If ADAMTS-13 is less than 5 to 10%, then it should be determined if an inhibitor of the enzyme (ADAMTS-13 autoantibody) is present.

Interpretation

Patients with familial TTP have absent or severely reduced plasma levels of ADAMTS-13 at all times, unless they are receiving periodic infusions of normal plasma containing the enzyme.

An absent or severely reduced plasma level of ADAMS-13, in association with an inhibitor of the enzyme, indicates acquired ADAMTS-13 autoantibody-mediated TTP. The inhibitor decreases in titer, or disappears following recovery.

Non-severely deficient ADAMTS-13 indicates that TTP is not present.

Note – Plasma ADAMTS-13 activity in healthy adults ranges from about 50 to 180% of normal pooled plasma using currently available assays.

ADAMTS-13 is often reduced below the normal range in liver disease, disseminated malignancies, sepsis, pregnancy, and newborns. With the exception of occasional peri-partum women, who develop overt TTP, the ADAMTS-13 level in these conditions is not generally reduced to the extremely low values (less than 5 to 10%) found in patients with familial or autoantibody-mediated TTP.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of thrombotic thrombocytopenic purpura?

Computerized tomography (CT) or magnetic resonance imaging (MRI) can detect thrombotic or hemorrhagic lesions that are large enough to cause (or worsen) cerebral symptoms.

If you decide the patient has thrombotic thrombocytopenic purpura, what therapies should you initiate immediately?

Familial ADAMTS-13-deficient TTP

Normal fresh-frozen plasma (FFP) or cryoprecipitate-poor plasma (cryosupernatant) infusion alone at about 10ml/kg/day (no plasmapheresis required), is sufficient to reverse episodes of familial TTP within 1 to a few days.

Acquired ADAMTS-13 autoantibody-mediated TTP

FFP or cryosupernatant infusion (at about 30ml/kg/day) is often used initially to treat an acquired TTP episode, until a large bore catheter is inserted (usually within hours) and daily plasma exchange commences (about one plasma volume/day, or 3 to 4 liters/day, in adults).

FFP or cryosupernatant infusion alone is less effective than plasma exchange in acquired TTP, and may result in volume overload.

Note – Both normal FFP and cryosupernatant contain active ADAMTS-13.

Both solvent/detergent-treated plasma and methylene blue/light-treated plasma inactivate lipid envelope viruses (HIV, hepatitis B and C) and contain active ADAMTS-13.

Acquired thrombotic microangiopathy not associated with ADAMTS-13 deficiency

Any agent that may induce this disorder should be discontinued, if possible. These include: clopidogrel (Plavix) or ticlopidine (Ticlid), bevacizumab (Avastin) or “tinib” drugs, mitomycin, gemcitabine, quinine, total body irradiation, chemotherapeutic agents, and cyclosporine or tacrolimus.

An untreated patient with HIV/AIDS should receive Highly Active Antiretroviral Therapy (HAART).

Plasma exchange should be performed daily until platelet count recovery.

More definitive therapies?

Familial ADAMTS-13-deficient TTP

The periodic infusion of FFP or cryosupernatant into familial TTP patients who lack effective ADAMTS-13 synthesis/release prevents or reduces the frequency of TTP episodes. Infusion is usually required about every 3 weeks in patients with frequent relapses.

Acquired ADAMTS-13 autoantibody-mediated TTP

First line therapy

Patients with acquired ADAMTS-13 autoantibody-mediated TTP require daily plasma exchange until remission.

Plasma exchange combines the infusion of FFP or cryosupernatant (containing uninhibited ADAMTS-13) with plasmapheresis (to remove ADAMTS-13 autoantibodies).

Plasma exchanges enable about 80 to 90% of patients with TTP to survive an episode, usually with minimal organ damage. Lower titers of ADAMTS-13 autoantibodies are associated with better responses to plasma exchanges.

Second line therapy

Production of ADAMTS-13 autoantibodies may be suppressed by: high doses of glucocorticoids (for example, methylprednisolone IV at 200mg/day); and/or rituximab (the monoclonal antibody against CD20 on B-lymphocytes) at 375mg/m² weekly for 4 to 8 weeks.

Caution: There is a slight risk of progressive multifocal leukoencephalopathy (PML) associated with rituximab therapy.

Acquired thrombotic microangiopathy not associated with ADAMTS-13 deficiency

These patients sometimes respond favorably to plasma exchange; however, this outcome is less likely than in acquired ADAMTS-13 autoantibody-mediated TTP.

If plasma exchange is ineffective, then glucocorticoids and vincristine may be tried.

Effective “supportive care” may allow using the physician’s time to organize some new approach, if therapy is failing.

If none of the approaches above work, then a newer experimental therapy should be considered (see “What if scenarios” below).

What other therapies are helpful for reducing complications?

Red cell transfusions may be necessary to alleviate symptoms of organ ischemia. The need for red cells will depend upon the extent of a patient’s anemia from intravascular hemolysis or hemorrhage.

If the platelet count is extremely low and bleeding into the brain or from the GI tract is the primary problem, then transfusion of platelets will be necessary. Otherwise, platelet transfusions should be used with caution, because they have, on occasion been temporally associated with possible disease exacerbation.

The following may be helpful in TTP patients who do not respond adequately to first and second line therapy:

• Vincristine (dosage in adults up to 2mg on day 1; then 1mg on days 4, 7, and 10).

Vincristine depolymerizes platelet microtubules, and may inhibit platelet adhesion/aggregation, by impairing the exposure of platelet GP Ib-IX-V or GP IIb-IIIa receptors for on platelet surfaces.

• Splenectomy (laparoscopic or open) removes immunological cells that produce anti-ADAMTS-13 autoantibodies

However, the procedure is dangerous in severely thrombocytopenic patients.

• Other immunosuppressive agents may suppress the production of anti-ADAMTS-13 autoantibodies

For example, cyclophosphamide [Cytoxan], azathioprine [Imuran]).

What should you tell the patient and the family about prognosis?

Familial ADAMTS-13-deficient TTP

Episodes are often (usually) recurrent. They can usually be treated successfully with brief infusions of FFP or cryosupernatant.

If episodes recur in a regular/predictable pattern, they can often be prevented or reduced in frequency by the periodic infusion of FFP or cryosupernatant (sometimes this is about every 3 weeks).

When TTP episodes may commence in infancy or childhood (Upshaw-Schulman syndrome), progressive renal failure is a prominent complication later in life.

Acquired ADAMTS-13 autoantibody-mediated TTP

About 80% of patients with acquired anti-ADAMTS-13 autoantibody-mediated TTP enter clinical remission after about ten or more plasma exchange procedures using FFP or cryosupernatant.

After recovery, there is usually minimal overt organ dysfunction. However, modest cognitive impairment has been observed in some patients.

Relapses occur in about one third of patients, often within the first year after the initial episode.

Any subsequent episodes occur irregularly and unpredictably, and may respond to plasma exchange even more rapidly than the initial episode.

Caution: It is critical that incipient recurrent TTP, even years after an initial or previous episode, be diagnosed and treated promptly. Physicians must be informed immediately about a patient’s history of TTP.

“What if” scenarios.

If standard therapy is incompletely effective in treating an episode, then the following new types of therapy under development warrant consideration for ADAMTS-13-deficient types of TTP.

Anti-VWF “nanobody” (Caplacizumab)

An anti-VWF “nanobody,” initially designated ALX-0081 (Ablynx, Brussels), and currently marketed as “Caplacizumab,” is a humanized single, variable domain antibody fragment that suppresses VWF-platelet adhesion by binding to, and blocking VWF A1 domains in the VWF monomers that comprise ULVWF multimers. Caplacizumab inhibits VWF A1 domain attachment to the glycoprotein (GP) Ib component of platelet GP Ib-IX-V complexes. Caplacizumab has been used to increase the effectiveness of plasma exchange in acquired TTP.

N-acetylcysteine (NAC)

N-acetylcysteine (NAC) is a drug long ago approved by the FDA for the treatment (in high dosage) of acetaminophen (Tylenol) toxicity, or (in low dosage as Mucomyst) of bronchoalveolar obstruction. NAC also inhibits the adherence of platelets to endothelial cell-anchored ULVWF (ultra-large von Willebrand factor) multimeric strings and reduces soluble VWF multimers to smaller forms. NAC is not currently FDA approved for use in TTP. It has recently been reported to be effective in 5 patients with TTP caused by ADAMTS-13 autoantibody who were refractory to therapy with plasma exchange.

Recombinant (r) ADAMTS-13

Recombinant (r) ADAMTS-13 is under development by Baxalta as Bax930. It has been successfully used in pre-clinical animal studies.

Caution – Caplacizumab (and NAC) will need to be used in association with plasma infusion or exchange (as a source of ADAMTS-13). Otherwise, response to the experimental agent will be transient.

Pathophysiology

The pathophysiology of TTP is related to ADAMTS-13 deficiency

VWF

Subunit vWF monomers (approximately 275,000 Daltons) are linked by disulfide bonds into vWF multimers (polymers) with molecular weights that reach millions of Daltons. VWF multimers are constructed predominantly within endothelial cells and stored in Weibel-Palade bodies as immense, coiled, ultra-large (UL) vWF multimers.

Upon stimulation, endothelial cells secrete the ULVWF multimers in long strings anchored to the cell membrane.

A1 domains in the monomeric subunits of ULVWF multimeric strings, are extremely “sticky” to GP Ib components of platelet GP Ib-IX-V surface receptors. The initial adherence of platelets via GP Ib to A1 domains in endothelial cell-anchored ULVWF strings, and the subsequent coherence of additional platelets to each other (aggregation) via activated GP IIb-IIIa receptors, produce occlusive platelet thrombi.

ADAMTS-13

A specific vWF-cleaving protease in normal plasma rapidly cleaves the highly platelet-adhesive ULVWF strings as they are secreted by, and anchored to, endothelial cells. Cleavage occurs at tyrosine 1605-6 methionine peptide bonds in one or more susceptible A2 domains of ULVWF monomeric subunits. The vWF-cleaving protease, ADAMTS-13, is number 13 in a family of 19 distinct ADAMTS enzymes.

ADAMTS-13 is composed of:

• An amino-terminal metalloprotease domain
• A disintegrin domain
• A thrombospondin-1-like domain
• A cysteine-rich domain and an adjacent spacer portion
• Seven additional thrombospondin-1-like domains
• Two similar, but not identical CUB domains (CUB-1 and CUB-2) at the carboxyl-terminal end of the molecule

CUB domains, found only in ADAMTS-13 among the ADAMTS enzymes, contain peptide sequences present in the complement subcomponents (C1r/C1s), the sea urchin protein (EGF [epidermal growth factor}), and a bone morphogenic protein.

ADAMTS-13 is a Zn²⁺and Ca²⁺ requiring 190,000-dalton glycosylated protein that is encoded on chromosome 9q34. It is produced in endothelial cells and hepatic stellate cells for release into the circulation.

Endothelial cells are stimulated to secrete ULVWF multimeric strings by inflammatory cytokines (tumor necrosis factor [TNF], interleukin [IL]-8 and IL-6), Shiga toxins, and high concentrations of histamine. The spacer and CUB-1 domains of ADAMTS-13 bind ADAMTS-13 to the ULVWF strings secreted by/anchored to endothelial cells, and position the enzyme to cleave tyr 1605-6 met peptide bonds in susceptible A2 domains.

TTP

Severe deficiency of ADAMTS-13 activity in familial or acquired ADAMTS-13 autoantibody-mediated TTP patient plasma correlates with inadequate cleavage of ULVWF multimers secreted by/anchored to stimulated endothelial cells.

Platelet adhesion/aggregation onto un-cleaved, cell-anchored, hyperadhesive ULVWF strings causes microvascular thrombosis.

Thrombosis is accentuated by soluble ULVWF multimers that are also hyper-adhesive to platelets, and are released into the microcirculation by minimal cleavage of ULVWF strings. Soluble ULVWF forms are often observed on sodium dodecyl sulfate (SDS) -1% agarose gels in ADAMS-13-deficient types of TTP.

• Familial ADAMTS-13-deficient TTP

Familial TTP usually (but not always) appears initially in infancy or childhood, and is recurrent. Rarely, familial TTP recurs in a chronic relapsing form with episodes at 2 to 3 week intervals. Patients with familial TTP have less than about 5 to 10% of normal plasma ADAMTS-13, both during and between episodes.

The absent or severely reduced plasma ADAMTS-13 activity in familial TTP is a consequence of homozygous (or double heterozygous) mutations in both of the ADAMTS-13 alleles located on chromosome 9q34. The result is defective production or release of ADAMTS-13 molecules. Mutations in familial TTP have been detected all along the gene, in regions encoding different domains.

In severe familial ADAMTS-13 deficiency, TTP episodes usually commence in infancy or childhood. In some patients with slightly higher plasma ADAMTS-13 levels, overt TTP episodes may not develop until later in life (for example, during a first pregnancy). In vivo plasma ADAMTS-13 activity may sometimes exceed measurement of activity using non-physiological in vitro assays. Additionally, or alternatively, the accentuated secretion of ULVWF multimeric strings by endothelial cells stimulated by estrogen (as during menses or pregnancy) or inflammatory cytokines may be required to provoke TTP episodes in some patients with very low, but not absent, plasma ADAMTS-13 values.

• Acquired ADAMTS-13 Autoantibody-Mediated TTP

Adults and, sometimes, older children with acquired ADAMTS-13-deficient TTP have transient inhibition of ADAMTS-13 to less than about 5 to 10% of normal during acute initial episodes or later recurrence. Plasma ADAMTS-13 levels may then increase toward normal as clinical recovery occurs, though some patients continue to have severe deficiency even in clinical remission.

Recurrences occur at irregular intervals in about one third of patients.

Polyclonal IgG (immunoglobulin G) autoantibodies that inhibit plasma ADAMTS-13 activity during episodes are detected in most of these patients, indicating transiently defective immune regulation.

The IgG autoantibodies against ADAMTS-13 are of restricted clonality, containing VH 1-69 heavy chain variable region gene-encoded components. The preferred, but not exclusive, epitope target of autoantibodies is the spacer portion of the cysteine-rich/spacer domain that is essential for docking ADAMTS-13 to endothelial cell-anchored ULVWF multimeric strings.

Some patients with Plavix- or Ticlid-associated TTP, and some patients with HIV/AIDS-associated TTP, have ADAMTS-13 autoantibody-mediated disease.

Acquired thrombotic microangiopathies not associated with ADAMTS-13 deficiency

Often resemble HUS clinically.

Symptoms may appear weeks to months after initial exposure to one of the agents mentioned below.

Bevacizumab (Avastin) is a monoclonal antibody against VEGF. Tinib drugs (for example, sunitinib) inhibit VEGF receptor-mediated kinase signaling. These are anti-angiogenesis agents that block VEGF binding to, and signalling between, glomerular endothelial and other renal cells.

Mitomycin, gemcitabine, quinine; pathophysiology unknown.

Total body irradiation, chemotherapeutic agents; pathophysiology unknown.

Cyclosporine and tacrolimus are frequently used as immunosuppressants for hematopoietic stem cell or solid organ transplantation. They are inhibitors of protein phosphatase 2B (calcineurin) in immune and endothelial cells.

The biochemical effect is to maintain some proteins in a phosphorylated state for a prolonged time. Cyclosporine, or tacrolimus treated endothelial cells profusely secrete ULVWF multimeric strings in vitro.

This vigorous ULVWF string secretion may slowly overwhelm the capacity of ADAMTS-13 to defend the microvasculature against excessive ULVWF string secretion/anchorage to endothelial cells, excessive platelet adherence to the hyper-adhesive ULVWF strings, and thrombotic microangiopathy.

What other clinical manifestations may help me to diagnose thrombotic thrombocytopenic purpura?

In some individuals with familial ADAMTS-13-deficient TTP, episodes may not develop until later in life. This may be during a first pregnancy, surgery, or a serious infection.

In these patients, the in vivo plasma ADAMTS-13 level may exceed estimates of enzyme activity using in vitro assays.

The accentuated secretion of ULVWF multimeric strings from endothelial cells stimulated by estrogen (during pregnancy) or inflammatory cytokines (during surgery or infection) may provoke TTP episodes in these individuals with low levels of ADAMTS-13 – and, therefore, a familial propensity for TTP.

What additional laboratory studies may be ordered?

Additional laboratory studies:

• Red cell direct anti-globulin (Coombs) test. Result will be positive in autoimmune hemolytic anemia, but not in TTP
• Plasma D-dimer. Result will be positive in DIC, but not in TTP (unless there is extensive tissue necrosis with secondary DIC)
• Stool sample for enterohemorrhagic Escherichia coli or Shigella. Result may be positive in diarrhea-associated (acquired) HUS, but not in TTP
• Heparin-induced thrombocytopenia (HIT) tests. Results will be negative in TTP (unless there is superimposed HIT)
• Anti-cardiolipin antibody and “lupus anticoagulant” tests. Results will be positive in anti-phospholipid syndrome, but not in TTP

What’s the evidence?

Moake, JL, Rudy, CK, Troll, JH. “Unusually large factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura”. N Engl J Med. vol. 307. 1982. pp. 1432-5. (Initial description of the failure to process ULVWF forms as the cause of TTP.)

Moake, JL. “Thrombotic microangiopathies”. N Engl J Med. vol. 347. 2002. pp. 589-600. (Review of TTP and Shiga toxin-related HUS with excellent illustrations.)

Zheng, XL, Sadler, JE. “Pathogenesis of thrombotic microangiopathies”. Annu Rev Pathol. vol. 3. 2008. pp. 249-77. (Excellent review and illustrations.)

Moake, JL. “Thrombotic microangiopathies: multimers, metalloprotease and beyond”. Clinical and Translational Science. vol. 2. 2009. pp. 366-373. (Concise, recent review with many illustrations.)

Elliott, MA, Heit, JA, Pruthi, RK. “Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated ADAMTS-13 deficiency: a report of four cases and a systematic review of the literature”. Eur J Haematol. vol. 83. 2009. pp. 365-72.

Scully, M, McDonald, V, Cavenaugh, J. “A phase II study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura”. Blood,. vol. 118. 2011. pp. 1746-53.

Page, EE, Kremer Hovinga, JA, Terrell, DR. “Rituximab reduced risk for relapse in patients with thrombotic thrombocytopenic purpura”. Blood,. vol. 127. 2016. pp. 3092-4. (Three reviews of rituximab therapy in TTP.)

Swisher, KK, Terrell, DR, Vesely, SK. “Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura”. Transfusion. vol. 49. 2009. pp. 873-87. (Recent review of a controversial clinical issue in TTP.)

Peyvandi, F, Scully, M, Kremer Hovinga, JA. “Caplacizumab for acquired thrombotic thrombocytopenic purpura”. N Engl J Med,. vol. 374. 2016. pp. 511-522. (Recent review of the development of caplacizumab for the therapy of TTP.)

Chen, J, Rebeman, A, Gushiken, FC. “N-acetylcysteine reduces the size and activity of von Willebrand factor: a potential therapy for thrombotic thrombocytopenic purpura”. J Clin Invest. vol. 121. 2011. pp. 593

Li, GW, Rambally, S, Kamboj, J. “Treatment of refractory thrombotic thrombocytopenic purpura with N-acetylcysteine: a case report”. Transfusion,. vol. 54. 2014. pp. 1221-4.

Cabanillas, G, Popescu-Martinez, A. “N-acetylcysteine for relapsing thrombotic thrombocytopenic purpura. More evidence of a promising drug”. Am J Ther. Dec. 29, 2015.

Rottenstreich, A, Hochberg-Klein, S, Rund, D, Kalish, Y. “The role of N-acetylcysteine in the treatment of thrombotic thrombocytopenic purpura”. J Thromb Thrombolysis,. vol. 41. 2016. pp. 678-683. (Four papers describing a possible new therapy for TTP.)

Plaimauer, B, Scheiflinger, F. “Expression and characterization of recombinant human ADAMTS-13”. Semin Hematol. vol. 41. 2004. pp. 24-33.

Kopic, A, Benamara, K, Piskernik, B. “Preclinical assessment of a new recombinant ADAMTS-13 drug product (BAX930) for the treatment of thrombotic thrombocytopenic purpura”. J Thromb Haemost. 2016, July 2. (Descriptions of rADAMTS-13 for potential therapy of TTP.)

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