What Is ADAMTS13?
ADAMTS13 stands for “A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13.”
If you can't remember that, von Willebrand factor-cleaving protease gets the point across considerably faster.
It also sounds suspiciously like someone's old AIM screen name. I wouldn't be surprised if ADAMTS13 is already taken on PathLabTalk.
ADAMTS13 is an enzyme that regulates the size and activity of von Willebrand factor (VWF) multimers. VWF plays a critical role in platelet adhesion, particularly under the high shear conditions found in small blood vessels.
Newly released VWF can form very large, highly adhesive multimers. Under shear stress, portions of VWF unfold and expose a cleavage site within the A2 domain. ADAMTS13 cleaves these ultralarge VWF multimers into smaller, less thrombogenic forms.
Without adequate ADAMTS13 activity, ultralarge VWF multimers remain in circulation and can bind platelets excessively. The result is formation of platelet-rich microthrombi throughout the small vasculature.
This produces two characteristic problems:
Thrombocytopenia, as platelets are consumed in the microthrombi
Microangiopathic hemolytic anemia (MAHA), as red blood cells are mechanically damaged while passing through affected small vessels
The microvascular thrombosis can also cause ischemic injury to organs, particularly the brain, heart, kidneys, and gastrointestinal tract.
Despite the often extremely low platelet count, spontaneous bleeding is not usually the dominant clinical problem in TTP. The major danger is widespread microvascular thrombosis and resulting organ injury.
TTP and Severe ADAMTS13 Deficiency
Severe ADAMTS13 deficiency is the defining laboratory abnormality of thrombotic thrombocytopenic purpura (TTP).
An ADAMTS13 activity of less than 10% of normal in the appropriate clinical setting strongly supports the diagnosis of TTP and helps distinguish it from other thrombotic microangiopathies.
Ideally, the specimen for ADAMTS13 activity and inhibitor testing should be collected before plasma therapy or therapeutic plasma exchange begins, since donor plasma contains ADAMTS13 and can alter the result.
However, TTP is a medical emergency. When clinical suspicion is high, treatment should not be delayed while waiting for the ADAMTS13 result.
TTP can broadly be divided into two forms:
Immune TTP
The majority of TTP encountered clinically is immune-mediated TTP (iTTP).
In iTTP, autoantibodies target ADAMTS13. These antibodies can directly inhibit ADAMTS13 activity, increase its clearance from circulation, or do both.
The resulting severe ADAMTS13 deficiency allows ultralarge VWF multimers to persist, promoting uncontrolled platelet adhesion and microvascular thrombosis.
Congenital TTP
A much rarer form, congenital TTP (cTTP), results from pathogenic variants in the ADAMTS13 gene that cause severe inherited ADAMTS13 deficiency.
Congenital TTP has historically also been called Upshaw-Schulman syndrome.
Unlike immune TTP, there is no underlying anti-ADAMTS13 autoantibody driving the disease. The problem is insufficient functional ADAMTS13 itself.
What About HUS and Other TMAs?
Reduced ADAMTS13 activity can occur in a number of illnesses, including other thrombotic microangiopathies and severe systemic disease.
The important distinction is severe deficiency.
An activity below 10% is strongly associated with TTP, whereas patients with complement-mediated HUS, Shiga toxin-associated HUS, HELLP syndrome, malignant hypertension, transplant-associated TMA, and many other causes of microangiopathic hemolysis generally do not demonstrate the profound ADAMTS13 deficiency characteristic of TTP.
This is one reason ADAMTS13 testing has become so important in the evaluation of patients presenting with thrombocytopenia and MAHA.
Should TTP Patients Receive Platelets?
Generally, no—not prophylactically simply because the platelet count is extremely low.
TTP is fundamentally a thrombotic disorder in which platelets are already being consumed in platelet-rich microthrombi. Routine platelet transfusion has therefore traditionally been avoided because of concern that additional platelets could contribute to ongoing microvascular thrombosis.
Platelet transfusion may still be appropriate in exceptional circumstances, particularly life-threatening or critical-site bleeding, with the decision based on the clinical situation rather than the platelet count alone.
Treatment of Immune TTP
TTP was historically associated with extremely high mortality. Modern treatment has dramatically changed its prognosis, but rapid recognition and treatment remain essential.
Current therapy for acute immune TTP generally attacks the disease from several directions at once.
Therapeutic Plasma Exchange
Therapeutic plasma exchange (TPE) remains a central treatment for acute immune TTP.
During TPE, the patient's plasma is removed and replaced with donor plasma. This provides functional ADAMTS13 while simultaneously removing circulating anti-ADAMTS13 autoantibodies and other pathogenic plasma components.
This is more than simply giving plasma. Plasma exchange allows large amounts of the patient's antibody-containing plasma to be removed while repeatedly replacing ADAMTS13.
TPE is generally performed daily during the acute phase, with treatment continued according to the patient's platelet recovery, hemolysis, clinical response, and the overall treatment protocol.
It is not simply a matter of reaching a platelet count of 150,000/µL and automatically stopping.
Corticosteroids
Because most acquired TTP is autoimmune, corticosteroids are used to suppress the immune response responsible for producing anti-ADAMTS13 antibodies.
Corticosteroids are generally used alongside plasma exchange rather than as an alternative to it.
Rituximab
Rituximab is a monoclonal antibody directed against CD20 on B lymphocytes.
By reducing the B-cell population, rituximab suppresses production of the autoantibodies responsible for ADAMTS13 deficiency.
Rituximab is commonly incorporated into treatment of immune TTP and is also used in selected patients during remission when ADAMTS13 activity falls and the risk of relapse increases.
Caplacizumab
One of the biggest changes in modern TTP treatment has been the introduction of caplacizumab.
Caplacizumab targets the A1 domain of VWF and prevents its interaction with platelet glycoprotein Ib. In other words, while plasma exchange and immunosuppression address the underlying ADAMTS13 deficiency and autoantibody, caplacizumab rapidly interrupts the VWF-platelet interaction responsible for the microvascular thrombosis.
This can rapidly improve thrombocytopenia and reduce continued formation of platelet-rich microthrombi while the underlying autoimmune disease is brought under control.
Current treatment strategies for acute immune TTP therefore commonly combine:
Plasma exchange + corticosteroids + caplacizumab, with rituximab frequently added for immunosuppression.
Treatment of Congenital TTP
Congenital TTP is different because there is no autoimmune inhibitor to remove.
Historically, treatment relied primarily on plasma infusion to replace the missing ADAMTS13 enzyme.
That changed with the development of recombinant ADAMTS13.
ADAMTS13, recombinant-krhn (Adzynma) is an enzyme-replacement therapy approved for both prophylactic and on-demand treatment of congenital TTP in adults and children.
Instead of supplying ADAMTS13 indirectly through donor plasma, recombinant ADAMTS13 replaces the deficient enzyme directly.
This represents a major shift in the management of congenital TTP and avoids many of the limitations associated with repeated plasma infusions.
ADAMTS13 Is Also Useful After the Acute Episode
ADAMTS13 isn't useful only for making the initial diagnosis.
In patients with immune TTP, ADAMTS13 activity can remain severely reduced or fall again even after the platelet count and hemolysis have normalized.
Persistently or recurrently low ADAMTS13 activity during clinical remission can indicate an increased risk of relapse. Monitoring ADAMTS13 activity can therefore help identify patients who may benefit from additional immunosuppressive treatment before another full clinical episode develops.
The Takeaway
ADAMTS13 normally keeps highly adhesive VWF multimers under control.
When ADAMTS13 activity becomes severely deficient, ultralarge VWF multimers remain in circulation and recruit platelets, producing widespread platelet-rich microthrombi. Platelets are consumed, red blood cells are fragmented in the microcirculation, and organ ischemia can rapidly develop.
In immune TTP, the problem is usually an autoantibody against ADAMTS13. Treatment therefore combines replacement and removal through plasma exchange, suppression of the autoimmune response, and—with caplacizumab—direct interruption of VWF-mediated platelet adhesion.
In congenital TTP, the underlying problem is inherited ADAMTS13 deficiency, and recombinant ADAMTS13 now allows direct enzyme replacement.
A protein with an absurdly long name turns out to be one of the most important regulators preventing normal hemostasis from turning into uncontrolled microvascular thrombosis.