Thrombotic thrombocytopenic purpura (TTP) is most frequently seen in previously healthy women in their third and fourth decades of life, with a significant predilection toward black women [1]. However, two main types are described in literature - hereditary, in which symptoms appear soon after birth; and autoimmune, a far more common entity affecting adolescents and adults demarcated by the presence of anti-ADAMTS13 IgG antibodies [1]. The trigger of TTP and its symptoms is still unknown, but microvascular thrombosis and microangiopathic hemolysis, two main pathological features of TTP, lead to a sudden onset of life-threatening hemolytic anemia, thrombocytopenia (due to excessive consumption of platelets), and neurological symptoms [1] [2]. Headaches, confusion, syncope, ataxia, visual symptoms due to retinal hemorrhage, focal deficits (hemiparesis, slurred speech, paresthesias, aphasia), seizures or even coma have all been reported in TTP, and they may even precede initial hematologic changes [2] [3]. Renal damage can manifest as hematuria and proteinuria, while the pulmonary or hepatic injury is rarely reported [2]. Although the course may range from rapid deterioration within a few days to a slowly progressive onset for weeks or months [2], a prodromal period consisting of nonspecific symptoms - abdominal and chest pain, arrhythmia, fever, and malaise can often mislead the physician and delay the diagnosis [2]. Furthermore, 30-60% of patients develop relapses, most frequently during the first month after the initial episode, but the period between symptom reoccurrence may range from days to even years [2]. Infection, diarrhea, pregnancy, and surgery have been proposed as triggering events, but their association is yet to be established [2].

• Easy Bruising

  The patient denied bleeding from the gums, easy bruising, and rashes. The patient did not admit to illicit or prescription drug use. [academic.oup.com]

• Anemia

  Additional findings include anemia, elevated reticulocyte count, and negative Coombs test. [symptoma.com]

  Mon, 08/07/2017 - 5:00am Back to Basics: Thrombotic Thrombocytopenic Purpura (TTP) Classic Pentad (rarely all present) : Fever Microangiopathic hemolytic anemia Thrombocytopenia Renal pathology CNS abnormalities Risk Factors: pregnancy, infection (HIV [emdaily.cooperhealth.org]

  CASE REPORT: We present the case of a 23-year-old female with TTP, diagnosed by the presence of the neurological symptoms, microangiopathic hemolytic anemia and severe thrombocytopenia (platelets 4000/μL). [ncbi.nlm.nih.gov]

• Fever

  It is well known for Chikungunya fever to present as myriad of skin rash along with usual joint pain and fever, but probably this is the first case report of Chikungunya fever presenting as severe life threatening thrombotic microangiopathy, thrombotic [ncbi.nlm.nih.gov]

  Presentation There may be a prodrome resembling a flu-like illness, including fever, fatigue and generalised malaise and arthralgias. [patient.info]

  Although the course may range from rapid deterioration within a few days to a slowly progressive onset for weeks or months, a prodromal period consisting of nonspecific symptoms - abdominal and chest pain, arrhythmia, fever, and malaise can often mislead [symptoma.com]

  TTP symptoms: “Nasty Fever Ruined My Tubes” → N – Neurological symptoms, F – Fever, R – Renal function impairment, M – Microangiopathic hemolytic anemia, T – Thrombocytopenia References: [7] [1] [8] Diagnostics Differential diagnoses The differential [amboss.com]

• Fatigue

  Abstract We report a female patient presenting with headache, fatigue, ecchymoses and recent, excessive vaginal bleeding. Prompt review of the peripheral blood smear showed evidence of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. [ncbi.nlm.nih.gov]

  Presentation There may be a prodrome resembling a flu-like illness, including fever, fatigue and generalised malaise and arthralgias. [patient.info]

  dyspnea ;, and pallor Jaundice Impaired renal function Hematuria, proteinuria Oliguria, anuria The typical patient is a previously healthy adult presenting with mental status changes, fever, petechiae, fatigue, and pallor. [amboss.com]

  Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. [jitc.biomedcentral.com]

  Hemolytic anemia can lead to paleness, yellowing of the eyes and skin ( jaundice ), fatigue, shortness of breath, and a rapid heart rate. [1] [2] [3] Acquired TTP usually begins in adulthood, but can affect children. [rarediseases.info.nih.gov]

• Weakness

  An 18-year-old second-trimester primigravida presented with a history of fifteen days of intense weakness, followed by diarrhea over the past six days. [ncbi.nlm.nih.gov]

  Anemia typically causes weakness and fatigue. Thrombocytopenia often causes purpura or bleeding. Manifestations of ischemia develop with varying severity in multiple organs. [msdmanuals.com]

• Malaise

  Although the course may range from rapid deterioration within a few days to a slowly progressive onset for weeks or months, a prodromal period consisting of nonspecific symptoms - abdominal and chest pain, arrhythmia, fever, and malaise can often mislead [symptoma.com]

  Other side-effects include malaise and muscle and joint pains. Cyclophosphamide Cyclophosphamide is an immunosuppressive drug which is most commonly used in cancer treatment. [netdoctor.co.uk]

  Presentation There may be a prodrome resembling a flu-like illness, including fever, fatigue and generalised malaise and arthralgias. [patient.info]

  Other symptoms include: malaise fever headaches diarrhea confusion difficulty speaking transient paralysis numbness bleeding into the skin or mucus membrane changes in consciousness fatigue heart rate over 100 beats per minute pallor purplish spots in [schmidtlaw.com]

• Nausea

  An 83-year-old woman who complained of dizziness and nausea visited our hospital. An electrocardiogram showed ST-segment elevation in multiple leads and an echocardiogram showed severe hypokinesis of the anteroseptal wall of the left ventricle. [ncbi.nlm.nih.gov]

  […] and widespread organ injury associated with cerebral (headache, confusion, altered consciousness, coma, seizures, hemiparesis and visual disturbances), cardiac (arrhythmia, infarction, congestive heart failure and cardiac arrest) and gastrointestinal (nausea [orpha.net]

  Case Presentation A 51-year-old African-American female presented to the emergency department with a 3-week history of abdominal pain associated with nausea, vomiting, and diarrhea. [academic.oup.com]

  The first three cycles of this treatment were well-tolerated, other than some mild nausea. Her only medications were bupropion, omeprazole and ondansetron as needed. [healio.com]

  CASE REPORT: A 34 year old African American male presented to the emergency department (ED) having experienced nausea, vomiting and diarrhoea for two days. He denied haematochezia, meleana or sick contacts at home. [bjmp.org]

• Vomiting

  Seven days after surgery, our patient started to vomit, developed melena, and was admitted to our pediatric intensive care unit (PICU) with clinical presentation of shock. Gastroscopy revealed H. pylori positive hemorrhagic gastritis. [ncbi.nlm.nih.gov]

  […] widespread organ injury associated with cerebral (headache, confusion, altered consciousness, coma, seizures, hemiparesis and visual disturbances), cardiac (arrhythmia, infarction, congestive heart failure and cardiac arrest) and gastrointestinal (nausea, vomiting [orpha.net]

  Case Presentation A 51-year-old African-American female presented to the emergency department with a 3-week history of abdominal pain associated with nausea, vomiting, and diarrhea. [academic.oup.com]

• Hypertension

  Malignant hypertension is a medical emergency with an incidence of 1% in hypertensive patients. [bjmp.org]

  Malignant hypertension is the clinical syndrome of severe elevations in blood pressure and funduscopic hypertensive retinopathy, including bilateral flame-shaped hemorrhage and papilledema. [ncbi.nlm.nih.gov]

  Hypertension was defined as systolic and diastolic blood pressure over 95th centile for the age and height. [doi.org]

  but usually no pre-existing hypertension HUS and TTP are usually considered part of clinical spectrum, in which disease manifestations depend on distribution of microangiopathy (but see Arch Pathol Lab Med 2003;127:834 ) HUS : fibrin / red cell rich [pathologyoutlines.com]

  Severe hypertension. Neurological problems as above. Splenomegaly. Investigations [ 2 ] Blood smear shows fragmented erythrocytes, ie schistocytes. This is consistent with haemolysis. [patient.info]

• Tachycardia

  Upon admission, her physical examination was remarkable for mild tachycardia and subtle scleral icterus. Initial laboratory data revealed a mild hyperbilirubinemia and transaminase elevations (see table 1). [healio.com]

  The remaining patients from both groups all experienced minor complications, including nausea, hypotension, tachycardia, tachypnoea, dizziness, chills or oedema. [doi.org]

• Blurred Vision

  He complained of blurred vision without photophobia, headache and mild chest discomfort. His past medical history was unremarkable. The patient did not have any significant family history. [bjmp.org]

  vision, mild ataxia, and minor mental status changes. [bloodadvances.org]

• Purpura

  Thrombotic thrombocytopenic purpura. Dis Mon. 2014;60(10):500-4. 3. Crawley JT, Scully MA. Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013(1):292-9. 4. [degruyter.com]

  Thrombotic thrombocytopenic purpura (TTP) is most frequently seen in previously healthy women in their third and fourth decades of life, with a significant predilection toward black women. [symptoma.com]

  Annu Rev Pathol 3: 249-277 Tsai HM (2010) Pathophysiology of thrombotic thrombocytopenic purpura. [omicsonline.org]

  […] thrombotic thrombocytopenic purpura (TTP). [aruplab.com]

  Gómez-Almaguer, Thrombotic thrombocytopenic purpura, Medicina Universitaria, 17, 69, (234), (2015). [doi.org]

• Kidney Failure

  Congenital thrombotic thrombocytopenic purpura (TTP) may not be recognized until organ failure related to the microvascular thrombosis occurs. Kidney failure may be the initial presenting clinical feature. [ncbi.nlm.nih.gov]

  Thrombotic thrombocytopenic purpura Pathology Type Blood coagulation disorder Cause(s) Cancer, Bone marrow transplant, Pregnancy, Hormone replacement therapy for Menopause, certain medications Symptoms Change in behavior, stroke, headache, kidney failure [house.wikia.com]

  Complications may include: Kidney failure Low platelet count (thrombocytopenia) Low red blood cell count (caused by the premature breakdown of red blood cells) Nervous system problems Severe bleeding (hemorrhage) Stroke Call your health care provider [nlm.nih.gov]

  Other manifestations may include alterations in level of consciousness and sometime kidney failure. [msdmanuals.com]

• Oliguria

  Renal anomalies may be mild in acquired TTP but oliguria, anuria, hemoglobinuria and acute renal insufficiency have been reported. Fever occurs in less than 50% of patients. [orpha.net]

  A 21-year-old Asian male presented with fever, myalgia, oliguria and dyspnoea where he was managed as for leptospirosis complicated with pulmonary haemorrhages and acute renal failure. [ncbi.nlm.nih.gov]

  […] dizziness Low platelet count ( i .e. thrombocytopenia ) Petechiae, purpura Mucosal bleeding Prolonged bleeding after minor cuts Microangiopathic hemolytic anemia Fatigue, dyspnea ;, and pallor Jaundice Impaired renal function Hematuria, proteinuria Oliguria [amboss.com]

  (also called verocytotoxin because it damages Vero cells in culture) Main cause of childhood acute renal failure Usually infants and young children, may occur at any age Symptoms : sudden onset of influenza, bleeding (hematemesis or melena), severe oliguria [pathologyoutlines.com]

  Oliguria, volume overload, and loop diuretics. Crit Care Med. 2008; 36(4, Suppl) S172-S178 61 Pape L, Ahlenstiel T, Kreuzer M et al. [doi.org]

• Cloudy Urine

  A urinalysis showed cloudy urine positive for protein and blood. A computed tomography (CT) scan showed fullness and stranding around the pancreatic head, suggestive of acute pancreatitis ( Image 2 ). [academic.oup.com]

• Seizure

  Headaches, confusion, syncope, ataxia, visual symptoms due to retinal hemorrhage, focal deficits (hemiparesis, slurred speech, paresthesias, aphasia), seizures or even coma have all been reported in TTP, and they may even precede initial hematologic changes [symptoma.com]

  Etiologies and risk factors for seizures Focal or generalized seizures occurred in approximately 20% of TTP patients observed. 99 Seizures can be associated with TTP for several reasons: Vascular damage in cortical regions, creating a seizure focus or [epilepsy.com]

  This article illustrates that in patients with HIV-TTP who do not respond to plasma infusion, early escalation to plasma exchange may help avoid life-threatening complications such as seizures and even death. [ncbi.nlm.nih.gov]

  […] activation CLINICAL FEATURES Classic pentad (FAT R/N) fever anaemia (microangiopathic haemolytic anaemia) thrombocytopenia renal problems (88% have renal problems, 15% haematuria) – more likely in HUS than TTP neurological problems (headaches, confusion, seizures [lifeinthefastlane.com]

• Headache

  Headaches, confusion, syncope, ataxia, visual symptoms due to retinal hemorrhage, focal deficits (hemiparesis, slurred speech, paresthesias, aphasia), seizures or even coma have all been reported in TTP, and they may even precede initial hematologic changes [symptoma.com]

  Abstract We report a female patient presenting with headache, fatigue, ecchymoses and recent, excessive vaginal bleeding. Prompt review of the peripheral blood smear showed evidence of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. [ncbi.nlm.nih.gov]

  Complications may include neurological problems (such as personality changes, headaches, confusion, and slurred speech), fever, abnormal kidney function, abdominal pain, and heart problems. [rarediseases.info.nih.gov]

  Thrombotic thrombocytopenic purpura Pathology Type Blood coagulation disorder Cause(s) Cancer, Bone marrow transplant, Pregnancy, Hormone replacement therapy for Menopause, certain medications Symptoms Change in behavior, stroke, headache, kidney failure [house.wikia.com]

  Disseminated microvascular thrombosis leads to consumptive peripheral thrombocytopenia, MAHA and widespread organ injury associated with cerebral (headache, confusion, altered consciousness, coma, seizures, hemiparesis and visual disturbances), cardiac [orpha.net]

• Confusion

  Headaches, confusion, syncope, ataxia, visual symptoms due to retinal hemorrhage, focal deficits (hemiparesis, slurred speech, paresthesias, aphasia), seizures or even coma have all been reported in TTP, and they may even precede initial hematologic changes [symptoma.com]

  Complications may include neurological problems (such as personality changes, headaches, confusion, and slurred speech), fever, abnormal kidney function, abdominal pain, and heart problems. [rarediseases.info.nih.gov]

  In two male sons, this mutation caused a severe (< 3%) deficiency of ADAMTS-13 activity and antigen level, associated with periodic thrombocytopenia, haemolytic anaemia and mild mental confusion. [ncbi.nlm.nih.gov]

• Altered Mental Status

  mental status, and acute kidney injury. [ncbi.nlm.nih.gov]

  The pentad of clinical findings consists of : Fever Neurological signs and symptoms Altered mental status ;, delirium Seizure, focal defects, stroke Headache, dizziness Low platelet count ( i .e. thrombocytopenia ) Petechiae, purpura Mucosal bleeding [amboss.com]

  On the morning of her evaluation, she complained of subjective fevers, altered mental status, and worsening fatigue. Physical examination was remarkable for a petechial rash over the chest and bilateral upper extremities. [jitc.biomedcentral.com]

• Cognitive Impairment

  Cognitive impairment seemed to be a consequence of depression, almost independently of number and severity of TTP episodes. © 2017 AABB. [ncbi.nlm.nih.gov]

  Increased rates of cognitive impairment ( 47 47. Kennedy AS, Lewis QF, Scott JG, Kremer Hovinga JA, Lämmle B, Terrell DR, et al. Cognitive deficits after recovery from thrombotic thrombocytopenic purpura. Transfusion. 2009;49:1092-101. [acphospitalist.org]

  However, modest cognitive impairment has been observed in some patients. Relapses occur in about one third of patients, often within the first year after the initial episode. [oncologynurseadvisor.com]

  Our estimated current prevalence of patients in remission is 19 per 1 000 000, similar to the estimated 13 patients per 1 000 000 in France. 20 These patients are at risk not only for relapse, but also for hypertension, depression, minor cognitive impairment [bloodadvances.org]

  Depression and cognitive impairment following recovery from thrombotic thrombocytopenic purpura. Am J Hematol 2015 ;90: 709 - 714 10. Kennedy AS, Lewis QF, Scott JG, et al. Cognitive deficits after recovery from thrombotic thrombocytopenic purpura. [doi.org]

Initial workup should include a complete blood count (CBC) and a peripheral blood smear, as thrombocytopenia and the presence of schistocytes are considered to be the hallmarks of TTP, respectively [3] [4] [5]. In fact, a very high schistocyte count has been proposed as one of the most specific signs of TTP, having in mind that they appear in various other conditions (disseminated intravascular coagulation, sepsis, etc.) but in much lower numbers [4]. Additional findings include anemia, elevated reticulocyte count, and negative Coombs test. Liver and kidney function (aspartate and alanine aminotransferases, blood urea nitrogen and creatinine), as well as assessment of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, fibrinogen, and D-dimer) and lactate dehydrogenase (LDH) should be performed, while 10-50% of patients have high titers of antinuclear (ANA) antibodies [3]. Genetic tests to confirm ADAMTS13 levels in circulation are not widely available, but its activity should be evaluated if possible [2]. In virtually all cases, a very low functional activity (<10% of normal) is observed. TTP can also be confirmed by detection of anti-ADAMTS13 IgG antibodies in plasma and by looking at the size of vWF multimers through vWF collagen binding (vWF:CB) assays [4] [6]. Ultra large vWF multimers, depending on the stage of TTP, can be present in remission, or can be completely absent during active disease [2] [3] [6].

• Schistocytosis

  Clinical course consists of relapsing acute events triggered mostly by infections, associated icterus and hyperbilirubinemia, severe hemolytic anemia with schistocytosis and a negative Coombs test, severe thrombocytopenia, and sometimes symptoms related [ncbi.nlm.nih.gov]

  Patients with hematologic abnormalities including hemolysis, schistocytosis, and thrombocytopenia warrant evaluation for vitamin B 12 deficiency. [consultant360.com]

  This finding may be extremely important for the clinician, as lack of classic and an impressive degree of schistocytosis may delay the important initiation of therapy. [journals.lww.com]

• Hemoglobin Decreased

  He was found to have a platelet level of 153,000/mm, hemoglobin decreased from 9.2 to 6.2 g/dL, creatinine raised from 1.0 to 2.4 mg/dL, and the peripheral smear showed schistocytes. [ncbi.nlm.nih.gov]

  The platelet count declined to 6000/mm 3, while the hemoglobin decreased to 10 mg/dL with a peripheral blood smear demonstrating moderate schistocytes; LDH concomitantly rose to 1979 IU/L. [journals.lww.com]

• Decreased Platelet Count

  The large vWF proteins promote platelet activation and aggregation, leading to the formation of platelet thrombi. 7 Besides platelet consumption and harshly decreased platelet counts, this has 2 main consequences: MAHA and ischemic end-organ damage due [academic.oup.com]

  In patients with an episode of refractory TTP, addition of rituximab to PEX and corticosteroids increases platelet counts in >80% of patients and may decrease the time required to achieve a platelet count response. [doi.org]

• Neutrophilia

  […] enterohemorrhagic E.coli 0157) (classically HUS) drugs (calcineurin antagonists, clopidogrel, cyclosporin, ticlopidine) pregnancy SLE graft versus host disease HIV-1 connective tissue disorders malignancy INVESTIGATIONS FBC anaemia thrombocytopenia variable neutrophilia [lifeinthefastlane.com]

• Haptoglobin Decreased

  (decreased or absent), and lactate dehydrogenase (increased). [acphospitalist.org]

(aTTP) in combination with the standard treatment of plasma exchange and immunosuppression. [bestpractice.bmj.com]

Without treatment the mortality is 90%; however, this can be greatly reduced with prompt treatment with plasma exchange. [patient.info]

Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. [doi.org]

Prognosis The prognosis depends primarily on prompt initiation of treatment. Timely treatment can prevent acute complications ( AKI, coma, and death), as well as progression to chronic renal failure. [amboss.com]

A subgroup of (young) patients presenting with a mild nephropathy and not requiring dialysis has a good prognosis, however. [adc.bmj.com]

TTP is a rare complication of pregnancy with a poor prognosis and high fetal mortality, especially when it occurs during the first trimester. Recent data have supported that effective treatment of TTP is plasma therapy. [ncbi.nlm.nih.gov]

Takaaki Hato and Yoshiyuki Kurata, Epidemiology, Autoimmune Thrombocytopenia, 10.1007/978-981-10-4142-6_4, (41-49), (2017). M. Patient, P. Fuseau and C. [doi.org]

The patient was a 28 year-old man with clinical and epidemiological diagnosis of arboviruses infections who developed thrombocytopenia and anemia, after which oral corticosteroid therapy was started. [ncbi.nlm.nih.gov]

Epidemiology References: [1] [2] Epidemiological data refers to the US, unless otherwise specified. Etiology Pathophysiology TTP is a thrombotic microangiopathy, a condition in which microthrombi form and occlude the microvasculature ;. [amboss.com]

Summary Epidemiology The annual incidence estimates range from 1/250,000 to 1/1,000,000. The incidence in the U.K. is estimated at 1/166,000. Acquired TTP accounts for approximately 95% of all TTP cases. [orpha.net]

The emphasis in this review is the pathophysiology of familial and acquired idiopathic TTP. [ncbi.nlm.nih.gov]

In addition, monitoring ADAMTS13 has the potential to identify patients who are at risk of relapse in time for preventive therapy. © 2017 by The American Society of Hematology. [ncbi.nlm.nih.gov]

References: [9] [10] Prevention Tertiary prevention following TTP Follow-up monitoring of platelet count and LDH Initiation of PEX if either indicates a relapse of TTP [amboss.com]

1. Scully M, Thomas M, Underwood M, et al. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood. 2014;124(2):211-219.
2. Tsai HM. Current Concepts in Thrombotic Thrombocytopenic Purpura. Annu Rev Med. 2006;57:419-436.
3. Tsai HM. Thrombotic Thrombocytopenic Purpura. A Thrombotic Disorder Caused by ADAMTS13 Deficiency. Hematol Oncol Clin North Am. 2007;21(4):609-v.
4. Lämmle B, Kremer Hovinga JA, Alberio L. Thrombotic thrombocytopenic purpura. J Thromb Haemost. 2005;3(8):1663-1675.
5. Burns ER, Lou Y, Pathak A. Morphologic diagnosis of thrombotic thrombocytopenic purpura. Am J Hematol. 2004;75(1):18-21.
6. Casonato A, Fabris F, Pontara E, et al. Diagnosis and follow-up of thrombotic thrombocytopenic purpura by means of von Willebrand factor collagen binding assay. Clin Appl Thromb Hemost. 2006;12(3):296-304.