Thrombotic thrombocytopenic purpura (TTP) is a rare but acute and potentially life-threatening thrombotic microangiopathy that is caused by acquired or congenital severe deficiency of ADAMTS13. The ADAMTS13 enzyme is required to cleave secreted von Willebrand factor (VWF) and deficiency can lead to unusually large VWF multimers which in turn may precipitate platelet clumping in the microvasculature in a high shear stress atmosphere. Ischemic damage may be the result, which can affect almost any organ in the body but tends to target the brain, digestive tract, heart, and/or kidneys. In nearly all cases, severe ADAMTS13 deficiency, defined as activity levels less than 10%, is mediated by autoantibodies (acquired TTP [aTTP]), while congenital defects (congenital TTP [cTTP]) occur far less frequently and account for less than 5% of cases.
Young women, usually in their 20s and 30s, tend to be the population targeted by TTP as an autoimmune disorder, although a large proportion of patients who develop adult-onset cTTP experience initial symptoms of the disease during their first pregnancy. It is estimated that nearly half of all acute TTP episodes occur in women of childbearing age and 12% to 25% of adult onset cases are pregnancy associated. The association between TTP and pregnancy appears to be related to the hemostatic and immunologic changes that occur during pregnancy and the postpartum period. Physiologic gestation is accompanied by extensive changes in all aspects of hemostasis, culminating in a state of hypercoagulability that peaks towards the end of the third trimester in order to decrease bleeding complications during delivery. Hypercoagulability then gradually normalizes during the first 4 to 6 weeks postpartum.
Overall, acute TTP requires prompt medical attention, especially when it develops during pregnancy or postpartum, and a multidisciplinary team is needed to provide optimal care. In a new paper published in Blood, the authors describe how they currently care for women with TTP during pregnancy.
The clinical features of acute TTP can vary considerably depending on the degree of tissue ischemic injury. Patients often will present with petechiae, neurologic symptoms such as headache, confusion or behavioral changes, and gastrointestinal symptoms such as abdominal pain, vomiting, or diarrhea. Some patients may also complain of palpitations, chest pain, or shortness of breath.
In an acute case, and especially if it is the first episode, laboratory analyses usually show very severe thrombocytopenia (<30,000/μL, but often <10,000/μL) with hemoglobin less than 8 g/dL and lactate dehydrogenase greater than 2 × under the limit of normal, but creatinine and transaminases are usually not elevated or only slightly. In cases of aTTP, disease is often hyperacute, whereas for congenital cases, isolated thrombocytopenia usually occurs prior to overt hemolysis. These changes occur primarily in the second and third trimester and could be misdiagnosed as common gestational or immune thrombocytopenia.
Making a differential diagnosis with other thrombotic microangiopathies can be difficult, especially when it occurs during pregnancy, as there is often overlap between them as far as gestational age of onset and clinical and laboratory features. While there are many potential concomitant disorders, the ones that should be considered for differential diagnosis with TTP are preeclampsia with severe features, low platelet count syndrome, and complement-mediated hemolytic uremic syndrome. In addition, acute systemic vasculitis and disseminated intravascular coagulation may also mimic pregnancy-related TTP.
The authors emphasized that in practice, when a patient is a previously healthy pregnant woman with biochemical features of acute thrombotic microangiopathy with severe thrombocytopenia and mild or no kidney or hepatic involvement, and there are neurological symptoms without hypertension, “we assume acute TTP until proven otherwise, and we start the appropriate treatment as soon as possible if the fetal parameters are not life threatening.”
To confirm or rule out a TTP diagnosis, ADAMTS13 activity levels should be assessed, especially before beginning plasma therapy. However, as the diagnosis of TTP is still based on clinical and laboratory features, appropriate treatment of acute TTP should be initiated and not delayed until ADAMTS13 results are obtained. Both ADAMTS13 activity and anti-ADAMTS13 antibodies will also help in differentiating congenital from acquired TTP.
While it can occur throughout the gestation period, pregnancy-associated TTP generally develops in the third trimester and postpartum period but may occur throughout gestation. But if symptoms present in the first trimester, TTP is the most likely diagnosis, while symptoms at around 20 weeks gestation and in the immediate postpartum period (<48 hours) can also be due to other thrombotic microangiopathies. When symptoms occur while more than 48 to 72 hours after delivery, TTP, complement-mediated hemolytic uremic syndrome, and acute vasculitis all need to ruled out.