Clinical Pentad Research Articles

BRASH Syndrome: A Case Report and Literature Review

BRASH syndrome is a newly coined diagnosis consisting of the clinical pentad of bradycardia, renal failure, atrioventricular (AV) nodal blockade, shock, and hyperkalemia. It is a rare syndrome with just under 50 reported cases. This case report and literature review present a case of BRASH syndrome, refractory to pharmaceutical measures, and subsequent literature review to assess treatment decisions and overall outcomes. The consensus from the literature supports the use of advanced interventions in most cases, including transcutaneous or transvenous pacing, hemodialysis, and adrenergic support. The early recognition and initiation of treatment in this patient demographic are paramount to reducing possible multi-system organ damage and mortality. This case report and literature review aim to improve patient outcomes and help further elucidate a protocol for treating BRASH syndrome.

Caplacizumab As Step-up Therapy in Refractory TTP Utilizing Adamts-13 Activity and Evidence of End-Organ Damage

Background: Thrombotic Thrombocytopenic Purpura (TTP) is a form of microangiopathic hemolytic anemia that is classically characterized by the clinical pentad of fever, hemolytic anemia, thrombocytopenia, renal dysfunction, and neurologic dysfunction. The pathophysiology of acquired TTP is marked by autoantibody formation against ADAMSTS13, an enzyme responsible for breaking down von Willebrand Factor (vWF) multimers. Standard therapy for TTP includes both replenishing functional ADAMTS-13 and immune-modulation with plasma-exchange and steroids/rituximab, respectively. A novel therapy addresses the microvascular thrombosis hallmark of end-organ damage in TTP. Caplacizumab, a humanized immune globulin that inhibits vWF interaction with platelets, achieved its primary endpoint of faster time to platelet normalization than placebo in the Stage 3 HERCULES trial when given up-front with additional standard therapies. Case Summary: A previously health 26-year-old G3P2 female presented to the ED at 38 weeks gestation with fatigue and confusion. She was found to have a platelet count of 5,000 per microliter, hematocrit of 18.6%, lactate dehydrogenase (LDH) of 1,750 IU/L, and haptoglobin of 11mg/dL. Peripheral blood smear was remarkable for evidence of microangiopathic hemolytic anemia. She had a normal serum creatinine. She was diagnosed clinically with TTP and subsequently underwent emergent caesarian section. She was started on plasma exchange given her ADAMTS13 activity of 6% and features of severe TTP. Her neurological status and platelets initially responded well to plasmapheresis (PE) at 1x volume alone; however, on Day 6 her platelets decreased from 97,000 to 15,000 per microliter. This prompted initiation of both steroids, weekly rituximab and increasing PE to 1.5 x. She continued to be refractory and acutely declined on Day 7, during which she developed worsening headaches followed by seizure, renal failure with proteinuria, uncontrolled hypertension and increasing hemolysis. She required ICU admission and one session of hemodialysis. Despite increasing PE, steroids and rituxan, the patient's inhibitor peaked to 142 U/ml with an ADAMTS-13 activity of 0% on Day 9. PE was increased to 1.5 x volume twice daily. Caplacizumab was obtained and initiated on Day 10. Her platelets on Day 11 were at their nadir of 4,000 per microliter, with an inhibitor of 93.9 and an ADAMTS-13 activity of 0%. She remained in the ICU, where her mental status, renal function improved gradually. She was found with a reticulocyte index of 1.29, for which she was treated with Vitamin B-12 for a methylmalonic acid level of 798 nmol/L (range 87-318 nmol/L) and a low normal level of vitamin B-12. PE was stopped on Day 22 after confirming her platelet level remained >150,000 per microliter for more than three days. Her course was further complicated by aspiration, parainfluenza 3, MSSA bacteremia, and E Coli UTI, for which she received antibiotics and supportive treatment. She completed four cycles of rituximab on Day 27, and was discharged to home with a steroid taper and an additional 21 days of caplacizumab. She was readmitted three times during those 21 days for hemiplegic migraines. She achieved remission with normal complete blood count and ADAMTS13 >109% with an inhibitor 3 on Day 54, after which she was administered her last dose of caplacizumab on Day 56. Discussion: We detail the clinical and treatment course in our patient with severe, acquired TTP from pregnancy. Our timing of caplacizumab administration differed from that in the HERCULES Trial. Rather than administering caplacizumab at the onset of diagnosis, we utilized markers of end-organ damage, ADAMTS13 activity and inhibitor level to gauge the trajectory of the disease process before administering additional therapies. This may represent an alternative approach to treating aTTP in a post-caesarian patient given concern for risk of bleeding and lack of trial data that adequately captures the bleeding risk of this sub-population. Lastly, we describe reticulocytopenia and Vitamin B12 deficiency in this patient complicating her recovery from TTP. The etiology of her B12 deficiency is still unclear ( anti-parietal antibody titer <1:120). Figure Disclosures No relevant conflicts of interest to declare.

AN UNUSUAL PRESENTATION OF THROMBOTIC THROMBOCYTOPENIC PURPURA FOLLOWING HEPATITIS A INFECTION: A CASE REPORT

Introduction: Thrombotic Thrombocytopenic Purpura (TTP) is a fulminant thromboticmicroangiopathy often manifested as clinical pentad of fever, thrombocytopenia, haemolytic anemia, renal failure and neurological abnormalities. ADAMTS13 deficiency has been noted as causative factor however secondary TTP/HUS preceded by various insult is also noted. Insults like burn, malignancy, viral infections and sepsis has been associated with TTP/HUS. Association of TTP/HUS with hepatitis A infection is rare and not reported.
 Case Summary: 27 years old male was admitted with acute onset fever, drowsiness, decreased urine output and icterus. Physical examination was unremarkable except icterus. He was found to have IgM positive for hepatitis A along with evidence of microangiopathic haemolytic anemia. He was diagnosed to have Hepatitis A along with TTP/HUS and plasmapheresis was started. He improved dramatically after it. No recurrence of TTP/HUS was noted on follow up.
 Conclusion: We present an interesting case of Hepatitis A as a possible trigger for Thrombotic thrombocytopenic purpura. Any haemolytic microangiopathy in hepatitis A should be carefully looked for a possibility of TTP.
 Keywords: Thrombotic thrombocytopenic purpura, Hepatitis A, TTP/HUS, HAV

Non Secretory Multiple Myeloma With HCV Infection: A Rare Case Entity

Multiple Myeloma is a neoplasm of B cell lineage characterized by excessive proliferation of abnormal plasma cells. It is characterized by a clinical pentad of 1) anemia, 2) a monoclonal protein in the serum or the urine or both, 3) bone leisons and or bone pain, 4) hypercalcemia>11.5g/dl and 5) renal insufficiency. Non secretory multiple myeloma is a rare variant of the classic form of multiple myeloma and accounts for 1% to 5 % of all cases of multiple myeloma. The clinical presentation and radiographic findings of non-secretory multiple myeloma and multiple myeloma are the same. The diagnosis of multiple myeloma requires the demonstration of monoclonal gammopathy in the serum or urine. In non-secretory multiple myeloma, however no such gammopathy can be demonstrated, making the diagnosis more difficult. We describe a 60 year old woman who initially presented with back pain which when further investigated by complete blood count revealed hemoglobin of 13g/dl, Total Leukocyte Count of 10,890 and platelet count of 1.5 lac/cmm. Viral markers revealed HCV positive. Hypercalcemia with a serum calcium level of 12.5g/dl was also demonstrated. MRI revealed multiple lytic bony lesions. No monoclonal gammopathy was found in the serum or urine and bone marrow biopsy showed marked plasmacytosis of > 45%. We present a case of Non Secretory multiple myeloma because of its illusive nature and rare entity.

Utilization Of ADAMTS13 Testing In Suspected Thrombotic Thrombocytopenic Purpura (TTP)

IntroductionThrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening condition, characterized by thrombotic microangiopathy (TMA) that results in microangiopathic hemolytic anemia (MAHA), thrombocytopenia and clinical symptoms including altered mental status, renal impairment and fever. Diagnosing TTP in acute setting continues to be a challenge, since the clinical pentad is not consistently present in TTP, making it difficult to differentiate from other conditions with TMA. The initial clinical decision for plasma exchange (PEX) is supported if there are MAHA and thrombocytopenia without a clear alternative cause. Acquired autoimmune deficiency of ADAMTS13 is known to cause idiopathic TTP and forms a basis for success of PEX in many patients by replenishing ADAMTS13 in addition to immunosuppressive therapy. However, low levels of ADAMTS13 alone are known to be neither sufficiently sensitive nor specific for diagnosis of TTP in acute setting. The aims of this retrospective study were to evaluate: (i) the utilization of ADAMTS13 testing in suspected TTP; (ii) the utilization of PEX in patients with TTP diagnosis; (iii) the association of low ADAMTS13 activity with early mortality in TTP; and (iv) the incidence of ADAMTS13 deficiency in non-TTP diagnoses. MethodsAfter IRB approval, we identified 49 adult patients at a single tertiary medical center, who had ADAMTS13 testing between 2005 and June 2013 for suspected TTP. We searched the final diagnosis, either TTP or non-TTP. The results of ADAMTS13 testing and use of PEX were reviewed in the TTP and non-TTP patients. We identified the final diagnosis of the non-TTP patients. We assessed association of severely low ADAMTS13 activity (<10%) with early mortality defined as death within 3 months of diagnosis in patients with TTP diagnosis. ResultsOf the 49 patients who had ADAMTS13 testing 18 (37%) were male. The median age was 51years (range 20-81). All patients with TTP had PEX except one who could not initiate PEX due to early death. Twenty-five of the 30 patients (83%) with TTP had low ADAMTS13 activity and 17 of the 30 patients (57%) had severe deficiency (<10%). Five of the 30 patients with TTP suffered early mortality. The relative risk of death among TTP patients with severely low ADAMTS13 activity (<10%) was 1.15 (95% CI 0.22-5.90) compared to TTP patients with low to normal ADAMTS13 activity. Nineteen of the 49 patients who had ADAMTS13 testing subsequently had non-TTP diagnosis. Eight of these 19 patients with non-TTP diagnoses were found to have low ADAMTS13 activity: two patients with DIC secondary to sepsis; two patients with thrombocytopenia associated with primary presentation of hemophagocytic lymphohistiocytosis (HLH); one patient each with malignancy associated with TMA, vasculitis due to autoimmune disease, hematopoietic stem cell transplantation associated TMA and sepsis with renal failure; None of the eight patients with non-TTP diagnosis had severe deficiency. Four patients with non-TTP diagnosis underwent PEX and all had normal ADAMTS13 activity. Three of the 4 patients were subsequently diagnosed with drug induced TMA after oral opioid injection and one with hemolytic uremic syndrome. ConclusionsPatients with a strong suspicion of TTP should be treated with PEX. ADAMTS13 activity is found to be relatively specific for TTP, being supportive of the clinical diagnosis in majority of cases. There was no statistically significant correlation between death and severely low ADAMTS13 activity in the cohort of TTP patients studied. ADAMTS13 activity can be low in a variety of non-TTP conditions. Its utility in diagnosis and prognosis of non-TTP conditions, especially HLH, needs further evaluation. Disclosures:No relevant conflicts of interest to declare.

A new ocular phenotype associated with an unexpected but known systemic disorder and mutation: novel use of genomic diagnostics and exome sequencing

We identified a 28-year-old cognitively normal patient with severe visual loss, absent electrical signals from the photoreceptors by electroretinogram (ERG) and nystagmus due to Leber congenital amaurosis (LCA), associated with...

Safety and Efficacy of Mycophenolate Mofetil in Relapsing Acquired Thrombotic Thrombocytopenic Purpura: Could It Prevent Further Relapse?.

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a life threatening condition requiring rapid diagnosis and treatment. Plasma exchange (PEX) is the mainstay of treatment. Various forms of immunosuppression (IS) have been used which include steroids, cyclosporine, cyclophosphamide, vincristine and rituximab. The percentage of patients relapsing is unclear. There is a suggestion that up to half of the patients with severe acquired deficiency of von Willebrand factor -cleaving protease (vWF-CP) activity relapse within a year. There are no reports of the use of mycophenolate mofetil (MMF) in acquired TTP. We describe three patients with acquired TTP, treated with MMF at relapse, with the intention to prevent further relapse.Methods: The 3 patients presented with acute acquired TTP. They all had at least 3 of the clinical pentad of fever, microangiopathic haemolytic anaemia, thrombocytopenia, neurological and renal impairment plus a vWF-CP level of < 2% at initial presentation. All of them underwent PEX until remission (platelet count of >150 x 109/L for at least 2 consecutive days with resolution of neurological and renal signs). MMF was introduced at remission after relapse at a dose of 500mg BD, post PEX, increasing upto a maximum dose of 750 mg BD. MMF was introduced at 4th relapse for patient A, 2nd relapse for patient B and 1st relapse for patient C.Results: All 3 patients were females. The ages at presentation were 63, 72 and 46 years. At presentation, the haemoglobin was 6.0, 8.7 and 6.7 g/dL and platelet count was 19, 36 and 21 x 109 /L respectively. Patient A relapsed eight times at day (d) 9, d20, d53, d89, d198, d209, d221 and d231. She was treated with PEX in conjunction with steroids and vincristine, cyclosporine, cyclophosphamide and rituximab for the first 3 relapses respectively. During the third relapse the patient's condition deteriorated and she became unconcious requiring ventilation. MRI brain showed multiple small foci consistent with vascular disease. She recovered, but relapsed again despite cyclophosphamide and rituximab. After the 4th relapse on d102, MMF was started reaching a maximum dose of 750mg BD. She had regular full blood counts checked. At d187 she was found to be neutropenic and the MMF was stopped. She relapsed in 11 days and was recommenced on MMF at 500mg bd after PEX. MMF was continued at the dose of 750mg BD after the 7th and 8th relapse. Despite full dose MMF, she relapsed and was treated with PEX and a further course of rituximab was given at the 8th relapse. Patient B had received 500mg of methyl prednisolone on ITU with PEX at initial presentation. MMF (500mg BD) was commenced at remission after second relapse (d23) after undergoing plasma exchange. Patient C was commenced on MMF (500mg BD) after first relapse (d36). All 3 are in remission and continue on MMF at a follow up of 12, 2 and 4 months respectively since last relapse. MMF was tolerated very well except for transient neutropenia (patient A) and transient diarrhoea (patient C).Conclusion: MMF appears to be safe in patients with relapsed TTP who received multiple lines of treatment. Due to the small size of this case series it is unclear whether MMF is efficacious in reducing the risk of relapse in TTP; a formal longer study may be warranted.

Additional Environmental and/or Genetic Factors Are Required to Trigger TTP in ADAMTS13-Deficient Mice.

Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening systemic illness characterized by the formation of platelet-rich thrombi in the microcirculation and the clinical pentad of fever, hemolytic anemia, thrombocytopenia, neurological symptoms, and renal dysfunction. TTP is associated with ultra-large von Willebrand Factor multimers (UL-VWF) in the circulation due to deficiency of the ADAMTS13 metalloprotease. ADAMTS13 gene mutations account for most if not all cases of familial TTP, and autoantibodies to ADAMTS13 underlie most cases of acquired TTP. To further explore the pathogenesis of TTP in vivo, ADAMTS13 deficient mice were generated by gene targeting to remove exons 1–6 which encode most of the protease domain of ADAMTS13. Although the resulting homozygous null mice (Adamts13−/−) have lost all specific VWF-cleaving protease activity (< 1% of control), embryonic development is normal, and the null mice are born at the expected Mendelian frequency. Analysis of baseline hematologic parameters and peripheral blood smears revealed no difference between Adamts13−/− mice and wild-type littermates, with no evidence for thrombocytopenia or microangiopathic hemolytic anemia. Pathologic survey of multiple tissues revealed only normal histology and no evidence for platelet or VWF-rich thrombi in the vasculature. Despite the absence of VWF-cleaving protease activity, plasma from wild-type and ADAMTS13-deficient mice exhibited identical VWF multimer size distributions. However, VWF multimers from both wild-type and Adamts13−/− mice were observed to be considerably larger than those from normal human plasma, and equivalent in size to UL-VWF seen in plasma from familial TTP patients. Challenge of Adamts13−/− mice by injection with endotoxin, and genetic crosses to mice with markedly elevated VWF levels (CASA/Rk), failed to induce findings consistent with TTP. However, treatment with verotoxin-2 (a bacterial endothelial toxin important in the pathogenesis of the hemolytic uremic syndrome), caused thrombocytopenia in 6 of 11 Adamts13−/− mice (vs. 3 of 11 wild-type controls, p < 0.07) and mortality at 6 days in 9 of 11 Adamts13−/− mice (vs. 6 of 11 controls, p < 0.02). Examination of peripheral blood from one of the Adamts13−/− mice at 8 days following verotoxin administration demonstrated marked microangiopathic changes. In conclusion, mice with targeted disruption of the Adamts13 gene do not develop TTP spontaneously, suggesting the requirement for additional environmental triggers or genetic modifiers. Though some humans with congenital ADAMTS13 deficiency have been reported to remain asymptomatic for many years, the increased size of the baseline VWF multimer distribution in mice may indicate a higher threshold for VWF-ADAMTS13 interaction which may be protective for TTP. Our results also suggest that microbial-derived toxins, or other sources of endothelial injury, may be one of the key environmental triggers responsible for the lack of spontaneous TTP findings in the ADAMTS13-deficient mice, and possibly for the intermittent symptoms seen in humans.

Thrombotic thrombocytopenic purpura (TTP) presenting as pancreatitis

Thrombotic thrombocytopenic purpura (TTP) is a rare clinical entity. It is a multi-systemic disorder characterized by a clinical pentad of thrombocytopenia, microangiopathic hemolytic anemia, diffuse and nonfocal neurologic symptoms, decreased renal function, and fever. Abdominal pain is an uncommon presenting symptom for TTP. Pancreatitis may occur from TTP or, in a few cases, may trigger TTP. The clinical diagnosis of TTP is generally difficult because there are many varied clinical presentations and the full expression of the pentad may be prolonged. However, once the diagnosis is suspected or confirmed, immediate plasmapherseis with plasma exchange must be performed to reduce the severe morbidity from neurologic disability.

The neuronal ceroid-lipofuscinoses

The neuronal ceroid lipofuscinoses (NCL) are a relatively frequent group of progressive neurodegenerative disorders in children with similar, but not identical, clinical and morphological features, entailing different clinical groups, some of which have been found to represent different genetic entities, ie, infantile (INCL) or CLN1, late-infantile (LINCL) or CLN2, juvenile (JNCL) or CLN3, and a Finnish variant of LINCL or CLN5. Within the clinical pentad are included seizures, motor disturbances, visual impairment, dementia, and familial occurrence in an autosomal-recessive fashion. The ultrastructure of accruing lipopigments is diagnostically required to recognize an individual patient's NCL by showing granular lipopigments in INCL, curvilinear profiles (with or without fingerprint profiles) in LINCL and fingerprint profiles (with or without curvilinear profiles) in JNCL. Identification of genes for INCL and JNCL, together with electron microscopy in LINCL, allows safe prenatal diagnosis which is still impossible by biochemical techniques, unlike other lysosomal disorders. However, both cause and pathogenesis of the individual forms of NCL are still unknown, and therapy is gravely insufficient.

Acute Suppurative Cholangitis

Acute suppurative cholangitis is characterized by obstruction, inflammation, and pyogenic infection of the biliary tract associated with the clinical pentad of fever (and chills), jaundice, pain, shock, and central nervous system depression. The disease occurs most commonly in the elderly who have a history of calculous biliary tract disease. The disease represents a true surgical emergency. Appropriate antibiotic therapy and immediate surgical decompression of the biliary tract are essential and carry a mortality rate of approximately 33 per cent. Nonoperative management is uniformly fatal. If inadequately treated or untreated, the disease follows a fulminant course of progressive systemic sepsis, hepatic abscess formation, and heptic failure leading ultimately to death. Acute suppurative cholangitis, the most serious sequela of calculous biliary tract disease, is preventable by early elective surgical treatment for benign biliary tract disease.

Self-limited TTP-like Syndrome After Bee Sting

THROMBOTIC thrombocytopenic purpura (TTP) is a complex, poorly understood syndrome diagnosed in patients with evidence of microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurological disease, and fever. The prognosis is poor. Occasionally patients survive after a variety of therapeutic maneuvers. We describe a patient who had the clinical pentad of the TTP syndrome following anaphylaxis secondary to a bee sting. She recovered completely without therapy. <h3>Report of a Case</h3> A 44-year-old woman was admitted to the hospital with complaints of anorexia, fatigue, jaundice, and severe retro-orbital headache. Seventy-two hours before admission, she was stung on the lower lip by a honeybee. She had previously been given Hymenopteran-whole-body-extract desensitization injections, but had stopped receiving them two years earlier. Because of three previous anaphylactic reactions from Hymenoptera stings, the patient had been taught to administer epinephrine hydrochloride subcutaneously to herself. Minutes after the sting in the present case, the patient lost consciousness and

Thrombotic thrombocytopenic purpura. Survival following treatment with aspirin, dipyridamole, and prednisone.

A 14-year-old boy had the clinical pentad of thrombotic thrombocytopenic purpura (TTP) consisting of fever, thrombocytopenia, hemolytic anemia, transient neurological symptoms, and renal involvement. Remission was achieved with treatment consisting of aspirin (1.2 gm/day), dipyridamole (600 mg/day), and prednisone (60 mg/day). At the time of this writing the patient has been in remission for a period of 18 months. This favorable response suggests that steroids combined with inhibitors of platelet function may be of benefit in patients with TTP. (JAMA228:1141-1143, 1974)

Thrombotic Thrombocytopenic Purpura

A 14-year-old boy had the clinical pentad of thrombotic thrombocytopenic purpura (TTP) consisting of fever, thrombocytopenia, hemolytic anemia, transient neurological symptoms, and renal involvement. Remission was achieved with treatment consisting of aspirin (1.2 gm/day), dipyridamole (600 mg/day), and prednisone (60 mg/day). At the time of this writing the patient has been in remission for a period of 18 months. This favorable response suggests that steroids combined with inhibitors of platelet function may be of benefit in patients with TTP. (<i>JAMA</i>228:1141-1143, 1974)

ACUTE OBSTRUCTIVE CHOLANGITIS.

ACUTE obstructive cholangitis is a clinical syndrome characterized by right upper abdominal pain, jaundice, chills with fever (Charcot's triad), central nervous system signs such as lethargy, disorientation, or coma, combined with septic shock. Reynolds and Dargan in 1959 emphasized this clinical pentad as a distinct entity which if untreated results in a high mortality rate.1An awareness of this syndrome leading to early recognition and prompt surgery will offer the best opportunity for survival. Acute inflammation of the biliary tree has been recognized since Charcot's original description in 1877.2Osler in 1890 stressed that Charcot's fever was irregular and of short duration.3In 1899 in necropsy studies Rogers recognized the role of surgical intervention in acute suppurative cholangitis.4He unsuccessfully performed surgical decompression of the common duct by utilizing a glass tube on a patient with this disease. In 1940 Cutler and Zollinger stressed the need