Symptoms
The presentation of TTP is variable. The initial symptoms, which force the patient to medical care, are often the consequence of lower platelet counts like purpura (present in 90% of patients), ecchymosis and hematoma [21]. Patients may also report signs and symptoms as a result of (microangiopathic) hemolytic anemia, such as (dark) beer brown urin, (mild) jaundice, fatigue and pallor. Cerebral symptoms of various degree are present in many patients, including headache, paresis, speech disorder, visual problems, seizures and disturbance of consciousness up to coma. The symptoms can fluctuate so that they may only be temporarly present but may reappear again later in the TTP episode. Other unspecific symptoms are general malaise, abdominal, joint and muscle pain. Severe manifestations of heart or lung involvements are rare, although affections are not seldomly measurable (e.g. ECG-changes) [11].
Diagnosis
A diagnosis of TTP is based on the clinical symptoms with the concommitant presence of thrombocytopenia (platelet count <100 x10
9/L) and microangiopathic hemolytic anemia with schistocytes on the blood smear, a negative direct antiglobulin test (coombs test), elevated levels of hemolysis markers (e.g. total bilirubin, LDH, free hemoglobin and an unmeasurable haptoglobin), after exclusion of any other apparent cause [1][2].
USS can present similar to the following diseases which have to be excluded: fulminant infections, disseminated intravascular coagulation, autoimmune hemolytic anemia, Evans syndrome, the typical and atypical form of hemolytic uremic syndrome (HUS), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, pre-eclampsia, heparin-induced thrombocytopenia (HIT), cancer that is often accompanied with metastasis, kidney injury, antiphospholipid antibody syndrome and side effects from hematopoietic stem cell transplantation [1][2].
Of note is that pregnancy associated affections like pre-eclampsia, eclampsia and HELLP syndrome can overlap in their presentation as pregnancy can trigger TTP episodes [22].
Patients with fulminant infections, disseminated intravascular coagulation, HELLP syndrome, pancreatitis, liver disease and other active inflammatory conditions may have reduced ADAMTS13 activity but almost never a relevant severe ADAMTS13 deficiency <10% of the normal [2][23].
A severe ADAMTS13 deficiency <5% or <10% of the normal (depending on the definitions)[1][24] is highly specific for the diagnosis of TTP [18][25]. ADAMTS13 activity assays are based on the direct or indirect measurement of VWF-cleavage products. Its activity should be measured in blood samples taken before therapy has started, to prevent false high ADAMTS13 activity [2]. If a severe ADAMTS13 deficiency is present an ADAMTS13 inhibitor assay is needed to distinguish between the acquired, autoantibody-mediated and the congenital form of TTP (USS) [1]. The presence of antibodies can be tested by ELISA or functional inhibitor assays. The level of ADAMTS13 inhibitor may be fluctuating over the course of disease and depends on free circulatory antibodies, therefore an onetime negative test result does not always exclude the presence of ADAMTS13 inhibitors and thereby an autoimmune origin of TTP [2]. A severe ADAMTS13 deficiency in the absence of an inhibitor, confirmed on a second time point in a healthy episode of a possible USS patient, usually sets the trigger to perform a molecular analysis of the
ADAMTS13 gene to confirm a mutation. In unclear cases a plasma infusion trial can be done, showing an USS in the absence of anti-ADAMTS13-antibodies a full recovery of infused plasma-ADAMTS13 activity as well as a plasma half-life of infused ADAMTS13 activity of 2–4 days. A deficiency of ADAMTS13 activity in first-degree relatives is also a very strong indicator for an Upshaw-Schulman Syndrome [1][2][6].
Therapy
The therapy of an acute TTP episode has to be started as early as possible [1][2]. The standard treatment is the daily replacment of the missing ADAMTS13 protease in form of plasma infusions or in more severe episodes by
plasma exchange. In the latter the patients plasma is replaced by donated plasma [26]. The most common sources of ADAMTS13 is platelet-poor
fresh frozen plasma (FFP)[3] or solvent-detergent plasma.
The benefit of plasma exchange compared to plasma infusions alone may result from the additional removal of ULVWF [1][26]. In general both plasma therapies are well tolerated, several mostly minor complications may be observed [2][26]. The number of infusion/exchange sessions needed to overcome a TTP episode are variable but usually take less than a week in USS [1][6]. The intensive plasma-therapy is generally stopped when platelet count increases to normal levels and is stable over several days [1][2].
Preventive therapyNot all affected patients seem to need a regular preventive plasma infusion therapy, especially as some reach longterm remission without it [27]. Regular plasma infusions are necessary in patients with frequent relapses and in general situations with increased risk to develop an acute episode (as seen above) such as pregnancy. Plasma infusions are given usually every 2–3 weeks to prevent acute episodes of USS [18] but are often individually adapted.
Outlook
Several therapy developments for TTP emerged during recent years. Artificially produced ADAMTS13 has been used in mice [28] and testing in humans has been announced. Another drug in development is targeting VWF and it's binding sites, thereby reducing VWF-platelet interaction, especially on ULVWF during a TTP episode [29]. Among several (multi-)national data bases a world wide project has been launched to diagnose USS patients and collect information about them to gain new insights into this rare disease with the goal to optimize patient care [30].