1. 1. 1. QUESTION

      Case report for TTP editing PhD level writing grammar and punctuation

       

      Atypical Presentation of TTP

       

      Emily Kassar B.S., Asia Filatov M.D/Ph.Dc PGY1, Oladipo Cole M.D. PGY1

      Introduction:

      Thrombocytopenic Purpura (TTP) is a rare hematologic disorder causing widespread clotting, resulting in low platelets. The disease results from a deficiency of the a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMST13) protease, which results in excessive multimers of the Von Willebrand Factor (VWF) protein-platelet complex attached to vascular endothelium (Sadler, 2015). The classic pentad known as FATRN –  fever, microangiopathic hemolytic anemia (MAHA), thrombocytopenia, renal abnormalities, and neurologic symptoms –  represents the disease in its most severe form (Williams, Marques, 2016). Neurologic symptoms are most commonly headache and confusion but in rare cases can present as seizures and focal deficits (Williams, Marques, 2016). In the following case, we will examine a patient who presented to her primary care physician with a complaint of upper respiratory symptoms along with nausea, vomiting, diarrhea, and abdominal pain. During her visit, she began to exhibit an expressive aphasia and was sent to the ER for a stroke workup.
      Case Presentation:

      A pleasant 31-year-old female with no significant past medical history presented to the emergency department with garbled speech that began just prior to arrival. In the days prior, she experienced viral upper respiratory symptoms as well as nausea, vomiting, diarrhea and fatigue. Of note, she is an elementary school teacher who is frequently exposed to contractible illness. Due to the persistence of her symptoms, she saw her primary care physician. During the visit, she began to exhibit garbled speech and was sent to the ER where a stroke workup was initiated. Upon arrival her altered speech was still present, which included statements such as “I ate Benadryl for breakfast”. She also complained of paresthesias.

      In the ED, a CT head was obtained which was negative for acute intracranial findings. She was febrile with a temperature of 38.1 deg C. The possibility of initiating TPA for acute ischemic stroke was discussed, however complete blood count (CBC) was returned with a hemoglobin of 6.6, an MCV of 93 and a platelet count of 4000. As the patient had neurologic symptoms with anemia and thrombocytopenia in the setting of viral illness, TTP and Hemolytic Uremic Syndrome (HUS) were included in the differential diagnosis. She was admitted to the ICU and further workup was initiated. A peripheral smear was performed and showed schistocytes. Lactate dehydrogenase (LDH) was elevated at 1154 and Haptoglobin was decreased at <8, indicative of intravascular hemolysis (Williams, Marques, 2016). An ADAMST13 level was ordered. Since this test takes several days to return, her plasmic score was assessed, which uses several variables including platelet count, MCV and INR to calculate the probability of severe ADAMST13 deficiency (Li et. al., 2017). Her score was 6, indicating a high risk of severe ADAMST13 deficiency (Li et. al., 2017). See figure 1

      Figure 1: Components Plasmic score and patient data

      Component	Our patient	Point (0-1)
      Platelet Count <30 x10 9 per L	4 X 109  per L	1
      Hemolysis (indirect bilirubin >2 mg/dL, uncorrected reticulocyte count >2.5%, or undetectable haptoglobin)	Uncorrected reticulocyte 20.4%, haptoglobin >8	1
      No active cancer in the previous year	No active cancer in previous year	1
      No history of solid organ or stem cell transplant	No history of solid organ or stem cell transplant	1
      MCV <90	MCV 93	0
      INR <1.5	INR 1.1	1
      Creatinine <2.0 mg/dL	0.8	1
      Total: 6

       

      Hematology was consulted. On her second day in the ICU, she received 4 units of fresh frozen plasma, 2 units of packed red blood cells and 2 courses of plasmapheresis. Her aphasia and paresthesias began to improve. Magnetic Resonance Angiography (MRA) was negative for embolic event, ruling out ischemic stroke. An infectious workup which included HIV, stool shiga toxin, mycoplasma and EBV was negative. Her ANA was within normal limits, excluding rheumatologic causes. EEG was performed to determine risk of seizures and need to initiate anticonvulsive therapy and was found to be negative. She continued to receive daily courses of plasmapheresis as well as steroids. Her ADAMST13 returned at less than 5%, confirming TTP, and the decision to start Rituxan was made. She received weekly therapy with a total of 4 treatments during her hospital stay. Plasmapheresis was performed daily, excluding the days that she received Rituxan. Her platelets steadily climbed. Neurology and Hematology continued to follow the patient. After a 36-day hospital admission she was discharged with platelets just over 200,000 and a hemoglobin of 10.2. She was placed on daily prednisone and instructed to follow up with outpatient hematology, including weekly bloodwork.
      Discussion:

      The pathophysiology of TTP is based on the ADAMST13 protease, which cleaves the Von Willebrand Factor (VWF) multimer. VWF is a protein-platelet complex essential in creating a platelet plug at the endothelium of injured vessels (Sadler, 2015). In the acquired form of the disease, autoantibodies are produced against the ADAMST3 protease, which results in persistent VWF multimers and systemic thromboses. Platelet counts decrease as platelets are consumed, causing thrombocytopenia. Microangiopathic hemolytic anemia (MAHA) in TTP results from shearing forces as red blood cells travel across platelet clumps on vascular endothelium. Microangiopathic hemolytic anemia (MAHA) in TTP results from shearing forces as red blood cells travel across platelet clumps on vascular endothelium, producing fragmented red blood cells known as schistocytes See figure 2.

      Figure 2: Schistocytes on peripheral smear (Scordino, 2016)

       

      Expressive aphasia is an example of neurological manifestation occurring in TTP resulting from brain damage, particularly the areas concerned with language. Consequently, the patient’s speech production is severely damaged, even though his or her intellect might be intact. The usual causes of aphasia are brain injury or stroke that damages one or more areas of the brain dealing with language. In the majority of the cases, neurological symptoms including expressive aphasia occur in the course of thrombotic thrombocytopenic purpura (Sayani & Abrams, 2015). This argument is based on the interaction between the circulating platelets and vascular endothelium that results in profound dysregulation of coagulation. Radiological Computed Tomography (CT) scan of these patients may demonstrate infarcts in specific sections of the brain that correlate with neurological findings including expressive aphasia (Sadler, 2015).

      Research studies have demonstrated incidences of atypical thrombotic thrombocytopenic purpura in patients with strokes. A case involved a middle-aged woman with atypical thrombocytopenic purpura and presented with inability to speak, mild dysarthria and expressive aphasia (Idowu & Reddy, 2013).  The patient showed marked improvement in her neurological status upon receiving seven TPEs. Crum and O’Brien in their research article reported two TTP cases where initial findings majorly comprised of neurological deficits including expressive aphasia, hence causing delays in diagnosis. These neurological deficits were later followed by hematological manifestations (Idowu & Reddy, 2013). A research study has also shown that TTP is commonly associated with abnormal brain neuroimaging and therapeutic plasma exchange was useful in resolving the symptoms (Boattini & Procaccianti, 2013). A case report by Ahmad et al of a thirty-eight-year-old lady who presented with TTP, expressive aphasia and right-sided body weakness also show that these symptoms may commonly occur together (Azmi & Maizuliana, 2017). TTP is a hematologic condition that is described by a pentad of neurological and renal abnormalities, fever, anemia, and thrombocytopenia. Patients with TTP in most cases present with neurological deficits; however, expressive aphasia is rare hence requiring further investigations to ensure effective management.

      The diagnostic test for TTP is an ADAMST13 assay, which expresses ADAMST13 activity as a fraction of normal activity within pooled plasma (Levy, 2005). Because an ADAMST13 assay takes several days to return, a preliminary diagnosis can be made clinically if the patient presents with microangiopathic hemolytic anemia and thrombocytopenia without another known cause and without acute renal failure. If acute renal failure is present, hemolytic uremic syndrome (HUS) is more likely. A plasmic score, as was calculated in our patient, is often used to determine the probability that a severe ADAMST13 protease deficiency is present based on several clinical findings with 1 point assigned to each. In 2018, a study evaluated the success of plasma exchange therapy in patients with low intermediate (0-5) risk scores and high (6-7) risk scores (Li et al., 2017). In the high-risk group, treatment with plasma exchange therapy lead to significantly increased survival (Li et al., 2017). With a plasmic score of 6, our patient was considered high risk, and plasma exchange was conducted prior to the return of an ADAMST13 level.

      TTP is a recognized rare disease according to the National Heart Lung and Blood institute, a center part of the National institute of health. As with many rare diseases, treatment modalities are scarce, but novel studies are underway [6]. Here, we will review the accepted treatment guidelines, in addition to other treatment modalities used in refractory cases as well as novel biologics being studied currently.

      The recognized guideline treatment for TTP is plasmapheresis or plasma exchange (PEX) for acquired TTP or plasma therapy for inherited TTP. For inherited TTP, plasma therapy is instituted to replace the ADAMTS13 enzyme [2,3,4,5,6]. Whereas acquired TTP, where our focus is, PEX is used to remove anti-ADAMTS13 enzyme antibody and to replete the enzyme itself. A once fatal process now has a survival benefit of up to 85% using PEX [4,5]. As soon as a diagnosis is made or suspect TTP, PEX should be initiated at 1.5 x plasma volume exchange for the first procedure and 1.0 x plasma volume exchange for subsequent treatments. This process is performed until platelet concentration reaches normal levels, organ involvement has resolved, and hemolysis have terminated [1,2,3,4,5].

      Steroids are often the mainstay of treating autoimmune disease such as ITP, SLE, and Sjogren to name a few. However, evidence of its effectiveness in treating TTP, is minimal at best. Coppo et. al. evaluated the outcomes in various studies and concluded results where steroids were given in combination with PEX vs PEX alone were equivalent [3,4,5]. Furthermore, it has been observed that relapse occurred more frequent with steroid treatment. Nevertheless, current guidelines recommend the initiation of systemic steroids of 1.5mg/kg/day for 3wks; which is quite reasonable. Some studies even suggest using high dose methylprednisolone (10mg/kg/day for 3 days followed by 2.5mg/kg/day) as an adjunctive treatment with PEX for patient with new onset TTP; achieving a modest 78% remission after 23 days of treat in a small study [5].

      Rituximab is an anti-CD20 monoclonal antibody originally developed to treat B cell malignancies [2,5]. However, several trials have shown its effective properties and high response to treat TTP and has now become the mainstay first-line treatment in both the acute phase and refractory cases (ie, exacerbations or no improvement in clinical features or lack of platelet response within 4 days of PEX) and has led to remission in 1- 4 weeks in patients [2,3,5]. For acute cases, two prospective trials resulted in shorter hospitalization and fewer relapses in patients who do not respond optimally to PEX. As with other treatments, discussed below, targeting the inhibition in the production of anti-ADAMTS13 antibody with 4 infusion at 375mg/m2/wk after PEX, is the goal using rituximab. This therapy quickly reduces peripheral antibody producing B cells, thus causing a rapid and substantial reduction in anti-ADAMTS13 antibody. Remission have been significant within the first year of therapy. These are considerably significant when compared to other modalities of therapies.

      Cyclosporine and vincristine have historically been used in refractory TTP. Both of these agents have been reported to have a steady remission rate in refractory TTP up to 73% and in some instances are being utilized as frontline agents in small subset of patients, when response to PEX is inadequate. Nevertheless, literature and specialists consider these choices as a secondary or salvage therapy after rituximab [1,5]. These two agents have suppressive properties of the anti-ADAMTS13 antibody. However, novel randomized studies have resulted in a more significant response with steroids decreasing the serum concentration of anti-ADAMTS13 antibody; questioning these two agents’ utility in treatment [1,4,5].

      Rare diseases like TTP are on the path of achieving medical breakthroughs, with novel antigen/antibody targeted treatment modalities. Caplacizumab, an inhibitor of VWF-glycoprotein 1b interaction (formerly ALX-0081), may pave the way [3]. The HERCULES trial, a Phase III double blinded placebo-controlled study [http://www.clinicaltrials.gov NCT02553317], is using Caplacizumab showing promising results. Significant results like shorter time to platelet recovery, decrease in ischemic organ dysfunction through inflammatory biomarkers and reduction in the incidence of exacerbations are paving the way to make this drug quite promising [3].

      One concern highlighted by this case is the exclusion criteria for tissue plasminogen activator (TPA) administration in a patient presenting with neurological deficits and a negative head CT. Per the American Heart Association (AHA) and American Stroke Association (ASA) guidelines, the inclusion criteria for initiation of TPA includes a clinical diagnosis of ischemic stroke with neurological deficit, time from symptom onset between 3-4.5 hours and no absolute contraindications. (Jauch et. al., 2013). Per the ASA/AHA, a platelet count of <100k is an absolute contraindication, and a CBC is required as part of immediate testing in a patient with stroke symptoms (Jauch et. al., 2013).

      A retrospective cohort study published in 2015 examined the importance of awaiting the results of a CBC prior to initiating TPA. The study population consisted of patients receiving TPA in both a hospital in China and hospital in the United States, and showed that a significantly shorter door to needle interval was found in the group of patients who received TPA prior to receipt of CBC results. (Dong et al., 2015) Additionally, of the patients who received TPA before CBC was returned, 98.8% of patients had normal results. (Dong et al, 2015) The remaining patient had a platelet count of 88,000 and no adverse event occurred from TPA administration. Applying the results of this study would have been catastrophic in our patient, and raises the following question: if time is of the essence and we cannot wait for a CBC to return, how often would we be causing a negative outcome, most importantly intracranial hemorrhage (ICH)? In a patient with no risk factors for ischemic stroke, including a young age and no significant past medical history, should we be concerned for a hematologic cause and wait for a CBC, even if we risk closing the window for TPA administration?

      Conclusion:

      Thrombotic thrombocytopenic purpura is an autoimmune condition that affects the coagulation system resulting in the formation of microscopic blood clots in any blood vessel such as cerebral arteries. The clinical presentation of TTP occurs due to end-organ damage and reduced blood flow. Neurological manifestations such as expressive aphasia, altered mental status, visual disturbances, seizures, and paresthesia can often be experienced by these patients as a result of cerebral ischemia caused by microscopic clots occurring in cerebral arteries. Patients with TTP can present to the emergency setting in the same manner as an acute stroke with negative CT imaging. This can prompt physicians to treat these patients as an ischemic stroke and administer TPA, which highlights the importance of checking a CBC prior to stroke intervention.

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