TTP in Pregnancy

Overview

• Definitions:
  • Pregnancy-associated thrombotic microangiopathy (TMA) is defined by both of the following:¹
    • The presence of:
      • Platelet count <100 x 10⁹/L
      • Hemoglobin level <10 g/dL
      • Lactate dehydrogenase (LDH) serum level >1.5 upper limit of normal
      • Undetectable serum haptoglobin
      • Negative direct erythrocyte antiglobulin test
    • Schistocytes on blood smear or TMA features in kidney (or another organ) biopsy
  • Pregnancy-associated TTP is defined by a severe deficiency (<20%) in ADAMTS13 activity.²
• Epidemiology:
  • Pregnancy (including the postpartum period) is a risk factor for acute (first or recurrent) episodes of TTP.³
  • Both cTTP and iTTP can present at any time during pregnancy, but most commonly occur in the third trimester and postpartum.⁴
  • Many adult-onset cTTP patients experience their first episode of TTP during their first pregnancy.⁵
  • ADAMTS13 deficiency (enzyme level <20%) is documented in 1 in 17,000 to 1 in 200,000 pregnancies.⁶
  • About 50% of all acute TTP episodes occur in women of childbearing age; pregnancy-associated TTP accounts for 12% to 25% of adult-onset TTP cases.⁷
  • Hereditary TTP makes up a higher proportion of pregnancy-onset TTP (25% in the French TMA National Registry and 67% in the UK TTP Registry) compared to adulthood-onset TTP in general (<5%).⁸
  • For pregnant women with severe ADAMTS13 deficiency, especially those with congenital causes, the risk of pregnancy-associated TTP is almost 100%.⁹
  • Relative incidence of TTP much lower that other pregnancy-associated TMA conditions:¹⁰
    • Pregnancy-associated TTP < 0.00004%
    • Preeclampsia (PE) 3% to 5%
    • HELLP 0.1% to 0.8%
• Pathophysiology:
  • Pregnancy is normally associated with a state of hypercoagulability, especially in the late third trimester as a mechanism to decrease bleeding complications during delivery.¹¹
  • Levels of von Willebrand factor (vWF), which play a key role in TTP pathogenesis, normally increase progressively throughout pregnancy, reaching a peak in the last trimester.¹²
  • In normal pregnancy, ADAMTS13 activity levels progressively and steadily decrease from the second trimester to the end of the early postnatal period (1-3 days after delivery), reaching values as low as 25% to 30%. The reduction is likely the result of increased release of vWF.¹³¹⁴
  • Other possible factors that pay a role in the development of iTTP during pregnancy include:¹⁵
    • Changes in the maternal immune system (gestational immune tolerance)
    • Hormonal regulation
    • Genetic factors
  • Most cases of pregnancy-associated hereditary TTP have been linked to a specific cluster of ADAMTS13 variants.¹⁶
• Differential diagnosis:¹⁷¹⁸¹⁹
  • TTP must be distinguished (ultimately with ADAMTS13 levels) from other causes of TMA in pregnancy including:
    • Preeclampsia
    • HELLP
    • Atypical HUS
• Diagnosis:²⁰
  • Confirmed by low ADAMTS13 activity level.
  • However, ADAMTS13 activity level is usually a send out test, and the results usually takes several days to come back.
  • While waiting for the results, the PLASMIC and French clinical prediction scores (combine clinical and laboratory parameters) are often used in non-pregnant cases to predict severe ADAMTS13 deficiency and inform initial management.
  • Notably, these scores have not been validated in the setting of pregnancy.
• Treatment (for details, see expert opinion and practice guidelines below):
  • General considerations:
    • Delivery does not treat the underlying disease process. Delivery should be considered in emergency only if required by fetal conditions (fetal distress or severe IUGR) or in case of maternal worsening despite proper therapy.
    • Aside from the decision on delivery, treatment of pregnancy-associated TTP does not differ from non–pregnancy-associated TTP, except for the need to consider potential drug toxicity on the fetus.
    • Avoid platelet transfusions if possible.
    • Consider thromboprophylaxis when platelet count is > 50 x 10⁹/L
  • First episode:
    • iTTP episode:
      • Treat with daily TPE and corticosteroids.
      • Caplacizumab and rituximab are not recommended because of possible toxic effects on the fetus. ²¹
      • In the event of refractory or relapsing iTTP additional immunosuppression may be required. Options include azathioprine, ciclosporin and rituximab.²²
    • First hereditary TTP episode:
      • Typically treated as iTTP because the diagnosis relies on absence of anti-ADAMTS13 antibodies and ADAMTS12 gene sequencing which can take time to come back.
      • If a diagnosis of hereditary TTP is secured during pregnancy, regular solvent/detergent fresh frozen plasma (SD-FFP) infusions or TPE should continue throughout pregnancy and postpartum.²³
  • Subsequent pregnancies:
    • Women with iTTP:
      • In women with prior iTTP, normal ADAMTS13 activity levels at onset of pregnancy predict a successful outcome in most cases.²⁴
      • Patients with persistent severe ADAMTS13 deficiency prior to pregnancy may be treated with rituximab, with the aim of normalizing ADAMTS13 activity level before conceiving.
      • Women should continue to be counselled to avoid pregnancy for at least 6 months (ideally 12 months) after rituximab.²⁵
      • ADAMTS13 activity should be monitored at least once in each trimester and more regularly if levels decrease.²⁶
      • For women with falling ADAMTS13 activity in pregnancy (ADAMTS13 relapse), options include prednisolone, azathioprine, ciclosporin, TPE or rituximab.²⁷
    • Women with hereditary TTP:
      • In women with hTTP, plasma infusion or exchange should be initiated as prophylaxis to achieve sufficient ADAMTS13 activity levels to avoid clinical relapse.²⁸
      • Infusion therapy has been recommended at least every other week initially, then weekly from the second trimester onward.²⁹
• Prognosis:
  • Treatment of pregnancy-associated TTP yields a complete response rate of 80% to 90%, similar to that observed globally in TTP.³⁰
  • Risk of fetal loss can be >40%, especially during the second trimester in untreated patients with hereditary or immune TTP.³¹

What the experts say

• Ferrari and Peyvandi, 2020:
  • Pregnancy-associated TTP is a medical emergency for both the pregnant patient and the fetus with both disease-related and treatment-related risks.
  • Clinical presentation:
    • Patients usually present with:
      • Petechiae
      • Cerebral manifestations, mainly:
        • Headache
        • Confusion
        • Behavioral changes
        • Seizure
        • Focal deficits
        • Coma
      • Splanchnic disturbances, mainly:
        • Nausea/vomiting
        • Abdominal pain
        • Non-bloody diarrhea
    • Less frequent presentations include:
      • Cardiac symptoms, including:
        • Palpitations
        • Cain chest
        • Shortness of breath
      • Renal involvement:
        • Dark urine
        • Dipstick positive for hematuria/proteinuria
        • Increased serum creatinine
  • Diagnosis:
    • Diagnostic work up includes:
      • Complete blood count (CBC):
        • Low platelets
        • Low Hb levels
      • Hemolytic markers:
        • Increased total and indirect bilirubin
        • Low haptoglobin
        • High LDH
        • High reticulocytes
        • Negative Coombs test result
        • Schistocytes on peripheral blood smear
      • Markers of organ damage, including:
        • Liver function tests
        • Urea and creatinine
        • Cardiac tests, for example troponin and EKG
      • Rule out other causes of presentation, for example:
        • CRP to exclude sepsis
        • Coagulation screening to rule out disseminated intravascular coagulation [DIC]
        • Autoimmune screening for acute systemic vasculitis
      • Urgent ultrasound to assess fetoplacental status
    • Differences in lab profile in immune TTP vs. hereditary TTP:
      • in iTTP, the onset of disease is typically hyperacute.
      • In hereditary TTP, isolated thrombocytopenia usually precedes overt hemolysis, mainly in the second and third trimester. At this early stage, hTTP women may be asymptomatic.³²
    • Confirm diagnosis with a pretreatment ADAMTS13 activity level.
    • As with TTP in non-pregnant individuals, appropriate treatment of acute TTP should be started as soon as possible and should not be delayed until ADAMTS13 results are obtained.
    • Existing clinical scoring systems to determine probability of having ADAMTS13 <10% in the non-pregnant setting, such as the PLASMIC score and French score, have not been validated in pregnant women.
    • “In practice, when we are facing a previously healthy pregnant woman with biochemical features of acute TMA with severe thrombocytopenia (especially <30 000/mL) and absent-to-mild renal and hepatic involvement (creatinine < 2 mg/dL, AST/alanine aminotransferase (ALT) <2x ULN), especially if neurological impairment is present in the absence of 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”.
  • Treatment:
    • Although delivery is a therapeutic tool for other pregnancy-associated TMAs such as pre-eclampsia or HELLP syndrome, it is not for TTP (or complement-mediated HUS), where delivery should be considered in emergency only if required by fetal conditions (fetal distress or severe IUGR) or in case of maternal worsening despite proper therapy.
    • Apart from the decision about delivery, the treatment of pregnancy-associated TTP does not differ from non–pregnancy-associated TTP, taking into account the potential drug toxicity on the fetus:
      • For iTTP:
        • Start TPE as soon as possible (at least 1 but preferably 1.5 plasma volume exchanges daily).
        • Start immunosuppression with corticosteroids (e.g., 1 mg/kg oral prednisolone daily)
        • Rituximab should be avoided based on the lack of safety evidence in pregnancy and should only be considered postpartum.³³
      • For established hTTP:
        • Plasma infusion is sufficient to correct ADAMTS13 severe deficiency.
    • If patients enter remission as defined by stable clinical picture, normalization of platelet count/hemolytic markers, then pregnancy is carried on as long as maternal and fetal conditions allow it.
    • Maintenance treatment will be necessary in almost all women during pregnancy and in the postpartum period:
      • In iTTP:
        • In the more benign cases, steroids will be sufficient to suppress autoantibody production.
        • In the more severe cases, TPE will be continued throughout pregnancy.
      • In hTTP:
        • 10 to 15 mL/kg daily until clinical remission and platelet and LDH normalization and then regular maintenance infusions throughout pregnancy and puerperium.
    • Once the platelet count is >50 000/mL, low-dose aspirin and/or thromboprophylaxis with low-molecular-weight heparin can be considered.
  • Monitoring:
    • Monitor ADAMTS13 activity level at least monthly after remission.
    • Aim to maintain level > 10% or preferably >20% to 25%.
  • Management of subsequent pregnancy:
    • Risk of recurrence depends on the persistence of severe ADAMTS13 deficiency.
      • In hTTP, the risk of relapse during pregnancy is almost 100%
      • In iTTP, the risk is far more variable, depending on ADAMTS13 levels
    • In iTTP patients:
      • Monitor ADAMTS13 before, during, and after pregnancy in order to assess the risk of relapse and choose appropriate therapies.
      • ADAMTS13 activity should ideally be > 20% to 25%.
      • Pre-pregnancy:
        • Offer patients anti-CD20 therapy (i.e., rituximab) to those patients with persistent severe ADAMTS13 deficiency, with the aim of normalizing ADAMTS13 activity level before conceiving. Consider waiting at least 6 (to 12) months before attempting pregnancy.
      • During pregnancy:
        • Monitor CBC monthly.
        • Monitor ADAMTS13 activity levels at least once per trimester
        • If ADAMTS13 activity levels decrease to <20% to 25% during pregnancy:
          • With normal platelet count and LDH levels, no hemolysis, consider low-dose corticosteroids (oral prednisolone, 0.5 mg/kg daily) to reduce autoantibody production. If this approach is insufficient to correct ADAMTS13, or if levels fall to <10%, consider starting prophylactic TPE, to be continued weekly or every other week based on its efficacy in preventing TTP relapse and correcting ADAMTS13 activity.
          • With overt TTP, then institute daily TPE.
      • At delivery:
        • If the pregnancy is uneventful and the ADAMTS13 activity level remains >20% to 25%, then vaginal delivery at term is advised.
        • Monitor CBC at least every other day for 3 to 5 days after delivery.
        • Monitor ADAMTS13 levels within 3 weeks postpartum.
    • In patients with hTTP:
      • In case of hTTP, regular plasma infusions (standard dose of 10-15 mL/kg) should be started at the very outset of pregnancy and continued until 4 to 6 weeks postpartum.
      • The infusion schedule must be intensified as gestation progresses:
        • Usually, the initial frequency of infusion is every other week
        • In the second/early third trimester it is increased to weekly or even every other day.
      • Regardless of gestational age, the infusion schedule is intensified in case of clinical and/or laboratory worsening (platelet reduction/LDH increase).
      • In some very severe cases, near the end of pregnancy, even daily plasma infusion might not be enough to avoid recurrence of disease, and TPE may help remove ULVWF multimers. For this reason, vaginal delivery is generally induced at 36 to 37 weeks gestation, and plasma infusions are continued for at least 3 weeks after delivery.
• Gounder and Scully, 2024:
  • The criteria for diagnosis of TTP in pregnancy are the same as TTP in the non-pregnant state.
  • Since platelet counts may fall during normal pregnancy a threshold of < 100,000 has been proposed for TMA diagnosis (together with evidence of MAHA).
  • The absence of ADAMTS13 antibodies is supportive of a diagnosis of hTTP, but diagnosis must be confirmed by ADAMTS13 gene sequencing.
  • Acute TTP is treated with TPE and corticosteroids.³⁴
  • Use caution with rituximab, which target fetal B lymphocytes and may increase the risk of infection, and caplacizumab, which crosses the placenta and confers severe von Willebrand disease-like sate with a risk of fetal bleeding. That being said, there are reports of both agents being used in TTP-associated pregnancy.
  • The use of rADAMTS13 is associated with improved maternal and fetal outcome in hTTP.
  • Subsequent pregnancies:
    • iTTP:
      • TTP relapse is less likely in women with normal pre-partum ADAMTS13 activity levels
      • If ADMATS13 is significantly reduced prepartum, consider pre-emptive treatment with rituximab.
      • If ADAMTS13 levels fall during pregancy, options inlcude:
        • Corticosteroids up to 1 mg/kg/day
        • Azathioprine up to maximum 2 mg/kg/day
        • Rituximab, especially if levels fall below 25% or clinical relapse
        • TPE for subacute relapse, e.g. severe ADAMTS13 deficiency and thrombocytoenia
    • hTTP:
      • ADAMTS13 replacement throughout pregnancy is required for all women with hTTP.
      • 10 ml/kg plasma every other week until second trimester increasing to weekly thereafter, guided by platelet count
  • Consider use of LD-ASA and thromboprophylaxis

What the guidelines say

• ISTH guidelines for treatment of thrombotic thrombocytopenic purpura
  • For patients with iTTP who are pregnant and have decreased plasma ADAMTS13 activity (e.g., <30 U/dL or <30% of normal) but with no clinical signs/symptoms, the panel recommends prophylactic treatment over no prophylactic treatment. (A strong recommendation in the context of very low certainty evidence).
  • For patients with hTTP who are pregnant:
    • The panel recommends prophylactic treatment over no prophylactic treatment. (A strong recommendation in the context of very low certainty evidence).
    • The panel suggests prophylactic treatment with plasma infusion over FVIII products. (A conditional recommendation in the context of very low certainty evidence
• A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies
  • Antenatal management and delivery should involve an obstetrician specializing in feto-maternal medicine in a center with experience managing TTP.
  • Patients presenting for the first time with TTP in pregnancy should initially be treated with TPE and steroids as per immune TTP in the nonpregnant patient. (1A)
  • Women presenting with TTP in pregnancy should have investigations to determine whether they have iTTP or a first presentation of hTTP. (1B)
  • For pregnant women with iTTP refractory to PEX and steroids or who relapse, additional treatment options include:(2C)
    • Ciclosporin
    • Azathioprine
    • Rituximab
  • The use of caplacizumab during pregnancy is not suggested because caplacizumab can cross the placenta and the risk of pregnancy-related bleeding is unclear.
  • For women with a prior episode of iTTP:
    • Normalization of ADAMTS13 activity prior to pregnancy is recommended. (1B)
    • Consider monitoring the ADAMTS13 activity at least every trimester and more frequently if the levels begin to decrease.
    • If the ADAMTS13 levels begin to fall during pregnancy, consider treatment with prednisolone, azathioprine, cyclosporine, plasma exchange, or rituximab.
    • Pregnancy should be avoided for ≥ 6 months (≥ 12 months is preferred) after treatment with rituximab.
  • For women with a prior episode of hereditary iTTP:
    • For pregnant women with hereditary TTP, regular SD-FFP replacement therapy should be given prophylactically to prevent clinical TTP relapse (1B). Plasma infusions and plasma exchange should be continued for the rest of pregnancy and postpartum.
    • Consider administering plasma infusions at least every other week at first, then every week from the second trimester onwards.
    • If the patient is already on intermediate purity factor VIII prophylaxis, consider switching to plasma infusions which is associated with higher posttreatment ADAMTS13 recovery and lower potential for thrombotic complications.
• International Working Group
  • Platelet transfusions:
    • May be required for obstetric procedures (e.g., caesarean section) or central catheter insertion prior to plasma exchange.
    • Should be avoided in patients with TTP due to concerns regarding thrombosis and worsening of neurological symptoms.
    • If platelet transfusion is urgently required, it should be administered along with plasma exchange.
  • First episode of pregnancy-associated immune TTP:
    • Standard treatment of immune TTP during pregnancy is:
      • Plasma exchange (1.0-1.5 plasma volume, 40-60 mL/kg fresh-frozen plasma)
      • Steroids, either as a pulsed dose of methylprednisolone or oral therapy (1 mg/kg per day with tapering over 2-3 months).
    • In case the positive results of anti-ADAMTS13 antibodies are available before delivery, the use of immunosuppressive drugs is limited to azathioprine, calcineurin inhibitors, and rituximab.
    • Regarding the use of rituximab in pregnancy:
      • The use of rituximab in pregnancy-associated TTP has been reported in very rare patients with no documented maternal or fetal toxicity.
      • However, a review of rituximab use in 231 pregnancies confirmed its ability to cross the placenta via active transport (placental Fc receptors) especially by the end of the third trimester.
      • Besides, hematologic abnormalities or malformations have been reported in a series of 90 live births after rituximab use in pregnancy (including 3 maternal TTP cases), prompting caution in its use.
      • Thus, data supporting the use of rituximab in pregnancy are currently limited, and other therapies are preferred.
      • However, refractory immune TTP not responding to treatment, or evidence of maternal or fetal compromise, may necessitate delivery, allowing for the use of further immunosuppressive therapy, including rituximab.
    • To date, no data are available regarding the use during pregnancy of caplacizumab, a monoclonal nanobody directed against VWF, and this therapy should not be used in pregnancy.
  • First episode of pregnancy-associated hereditary TTP:
    • The diagnosis of hereditary TTP is unlikely to be made during the initial phase of the disease; therefore, patients most frequently undergo plasma exchange as for immune TTP and repeat ADAMTS 13 testing and mutational analysis are usually available after achieving TTP remission with plasma exchanges.
    • Rapid normalization of platelet count with plasma exchange may suggest the absence of anti-ADAMTS 13 antibodies (with undetectable ADAMTS13 activity).
  • Patients with a history of TTP:
    • Patients with immune TTP:
      • In women recovered from immune TTP, the precise risk of relapse during pregnancy is unknown.
      • This risk mainly depends on the level of ADAMTS13 activity at pregnancy onset (increased risk if activity remains undetectable).
      • Serial monitoring, at least in each trimester and in the postpartum period, of ADAMTS13 activity in all immune TTP pregnant women is highly recommended.
      • However, its cost-effectiveness remains to be fully assessed. Reported experience is scarce and preemptive strategies in this context are still highly empirical. The patient should be informed that a severe reduction in ADAMTS13 to <20% would be an indication for elective therapy to raise the enzyme level and prevent TTP relapse. She should also be informed of the side effects of potential therapies required: steroids, azathioprine, calcineurin inhibitors, and plasma exchange: these therapies are preferred to rituximab.
    • Patients with hereditary TTP:
      • In hereditary TTP, the risk of relapse in the subsequent pregnancy is 100% in the absence of plasma prophylaxis.
      • Thus, prophylactic plasma infusions should be initiated at about10 weeks of gestation, or immediately after the diagnosis of pregnancy, and continued throughout pregnancy and postpartum.
      • Empirically, a volume of 10 mL/kg to 15 mL/kg plasma every 10 to 21 days is usually recommended. This regimen needs to be adapted to prevent cytopenia and hemolysis.
      • Typically, the volume of plasma and the frequency of administration increase from about 20 weeks of gestation; in the third trimester, therapeutic plasma exchange may be required to prevent fluid overload.
      • Treatment aims to maintain a normal platelet count, to prevent hemolysis, and, ideally, to restore ADAMTS13 activity >20%.
      • Delivery is usually induced at around 37 weeks.
      • Prophylactic plasma infusions in hereditary TTP result in an excellent fetal and maternal prognosis, by limiting placental micro-occlusion arterial thrombosis.
      • Women with hereditary TTP should be informed of the need for early start of prophylactic plasma infusions and for close monitoring with serial growth scans and determination of uterine artery flow. Hereditary TTP is an autosomal-recessive disease and thus the risk of inheritance in the offspring of an affected patient is extremely unlikely, except in consanguineous families.