scholarly journals Late Endocrine Effects after Stem Cell Transplant in a Young Girl with Griscelli Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Shana R. Mencher ◽  
William V. Tamborlane ◽  
Anisha D. Patel
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Growth Parameters ◽  
Alkylating Agents ◽  
Growth Failure ◽  
Ovarian Failure ◽  
Premature Menopause ◽  
Cell Transplant ◽  
Griscelli Syndrome ◽  
History Of

Background. Griscelli syndrome (GS) is a rare disorder characterized by partial albinism and silver hair with alteration in genes necessary for melanin transport. Type 2 GS is fatal due to severe immunodeficiency without curative stem cell transplant (SCT). Late endocrinopathies are quite common in other disorders after SCT. These complications have not been reported in GS. Case Presentation. A 7-year-old female presented for growth failure with a history of GS status post curative SCT and consequently developed graft-versus-host disease (GvHD). She also had a history of eosinophilic enterocolitis, for which she was taking supraphysiologic glucocorticoids for the past year. She presented with severe short stature along with mild hyperthyroxinemia with subsequent diagnosis of Graves’ disease, which was treated with methimazole. GH therapy was commenced due to persistent growth failure, with a robust increase in growth parameters. She started spontaneous puberty; however, initial biochemical evaluation revealed hypergonadotropic hypogonadism with undetectable anti-Mullerian hormone (AMH) consistent with low ovarian reserve and premature ovarian failure. Discussion. Growth failure was multifactorial due to her inflammatory condition and poor weight gain from multiple underlying illnesses, including hyperthyroidism, as well as chronic supraphysiologic glucocorticoid use. Although hypothyroidism is more commonly seen after SCT, rare cases of hyperthyroidism have been reported. In addition to SCTs, GvHD and GS have been associated with autoimmune conditions. It is important to monitor pubertal progression as the majority of those treated with alkylating agents prior to SCT have pubertal and ovarian failure and remain at risk for premature menopause.

scholarly journals SAT-078 Griscelli Syndrome and Late Endocrine Effects After Stem Cell Transplant

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Shana Mencher ◽  
Anisha D Patel ◽  
William V Tamborlane
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Late Onset ◽  
Conditioning Regimen ◽  
Growth Failure ◽  
Growth Parameter ◽  
Underlying Disease ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Griscelli Syndrome

Abstract BACKGROUND: This a unique case of late-onset endocrinopathies after stem cell transplant in a girl with Griscelli syndrome. Griscelli syndrome is a rare disorder characterized by partial albinism, silver hair and immune failure with alteration in genes necessary for melanin transport, which is curative by stem cell transplant. Although late endocrinopathies are quite common in other disorders after stem cell transplant, these complications have not been reported in Griscelli syndrome. CLINICAL CASE: A 7-year old female who received a stem cell transplant as a toddler and subsequently developed graft-versus-host-disease (GvHD) at 2 years of age presented for evaluation of growth failure. Patient had severe short stature along with mild hyperthyroxinemia with subsequent diagnosis of Graves’ disease which was treated with methimazole. Although hypothyroidism is more commonly seen after stem cell transplant, rare cases of hyperthyroidism have been reported. Despite normal GH and IGF-1 levels, GH therapy was commenced due to persistent growth failure. She showed a robust increase in growth parameter from -6 to -2 SD below the mean. She started spontaneous puberty, however, biochemical evaluation showed hypergonadotropic hypogonadism with undetectable anti-mullerian hormone (AMH) which is consistent with low ovarian reserve most likely related to total body irradiation prior to stem cell transplant. CONCLUSION: Our patient demonstrates that growth failure, thyroid disease and ovarian dysfunction can be complications of stem cell transplants in young children with Griscelli syndrome. This can be a result of the underlying disease leading to transplant, conditioning regimen prior to transplant or complications thereafter. GvHD may also be a risk factor for future autoimmune endocrine complications in this syndrome and in other syndromes treated with stem cell transplant. REFERENCES: (1) Griscelli C, Prunieras M. Pigment dilution and immunodeficiency: a new syndrome. Int J Dermatol. 1978;10:788–91. (2) Sağ E, Gönç N, Alikaşifoğlu A, et al. Hyperthyroidism after allogeneic hematopoietic stem cell transplantation: A Report of Four Cases. J Clin Res Pediatr Endocrinol. 2015;4:349–54.

Weekly Cyclophosphamide and Alternate Day Prednisone: An Effective, Convenient and Well Tolerated Treatment for Relapsed Multiple Myeloma Following Autologous Stem Cell Transplant.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4917-4917
Author(s):  
A. Keith Stewart ◽  
Young Trieu ◽  
Suzanne Trudel ◽  
Greg Pond ◽  
Joseph Mikhael ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Median Time ◽  
Stem Cell Transplant ◽  
Alkylating Agents ◽  
Progression Free Survival ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Protein Reduction

Abstract Alkylating agents remain among the most potent therapies available for treatment of Multiple Myeloma (MM). Their use prior to, or following, autologous stem cell transplant (ASCT) is, however, compromised by concerns about stem cell quality and by myelosuppression limiting effective dose delivered. To address this concern we have studied a combination of cyclophosphamide 500 mg p.o. once weekly and prednisone 100 mg p.o. on alternate days in 66 patients requiring salvage therapy post-ASCT. Dose reductions were allowed for toxicity beginning at cycle 2. On an intent to treat basis, 66 patients received this regimen, however, 7 of these patients were not fully evaluable for response due to non-secretory disease. Of the 59 patients evaluable for response, the median time from transplant to treatment was 26.4 months (range, 6.0 to 66.6). The median time from post-transplant relapse to start of cyclophosphamide and prednisone (C/P) therapy was 1.4 months. The median number of therapies from time of diagnosis to C/P initiation was 2 (range, 1.0 to 5.0). At the date of analysis, treatment with C/P is ongoing in 12 (20.3%) patients, with a median duration of 3.6 months (range, 1.9 to 11.6). The 47 patients who have completed C/P therapy were treated for a median time of 5.5 months (range, 0.5 to 21.7). The reason for discontinuation among these 47 patients included disease progression (42.6% of patients discontinued), plateau disease (21.3%), receiving a second transplant (17.0%), toxicity (10.6%), or switched to another regimen (8.5%). A partial response (>50% protein reduction) was obtained in 37.3% of patients, 18.6% attained minimal response (25–50% protein reduction), 33.8% patients stable disease, while 10.2% patients had progressed on treatment. The estimated median (95% CI) months of progression-free survival after start of C/P treatment is 14.9 (8.7, 21.7). Twenty-three (38.9%) of patients have relapsed after C/P treatment, a median (range) of 8.7 (0.5–65.7) months after start of C/P treatment. At 6 months 74.3% (95% C.I. 61.9% – 89.1%) of patients were progression-free with 28% (95% CI: 16.1–49.2%) progression free at two years. At time of analysis, 44 (74.6%) patients are still alive, with a median follow up of 10.6 months (range, 1.2 to 65.7) since the start of C/P therapy. Fifteen patients have died at a median 13.0 months (range, 1.4 to 61.7) since the time of C/P initiation. The median overall survival (95% C.I.) is estimated to be 35.9 months (24.2, NA). These results demonstrate that the combination of oral cyclophosphamide and prednisone is an effective (56% MR or PR), very well tolerated (10% discontinued due to toxicity) and convenient treatment as salvage MM therapy post-ASCT. The relative lack of myelosuppression allows for re-collection of stem cells and salvage transplant while retaining other active second line agents for later relapse. This regimen thus compares favorably with recent salvage therapeutics introduced in MM and is now being studied in combination with these newer active agents and in induction therapy.

Single-Agent Lenalidomide for Patients with Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma Who Had Received Prior Stem Cell Transplant.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2699-2699
Author(s):  
Julie M. Vose ◽  
Thomas Habermann ◽  
Myron S Czuczman ◽  
Pier Luigi Zinzani ◽  
Craig B. Reeder ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Prior History ◽  
Cell Transplant ◽  
Phase 2 ◽  
Two Phase ◽  
Phase Ii Studies ◽  
History Of

Abstract Abstract 2699 Poster Board II-675 Introduction: High-dose chemotherapy with autologous stem cell transplant (SCT) is a standard treatment option for younger patients with aggressive non-Hodgkin's lymphomas (a-NHL) who fail to respond, or relapse after initial therapy. For patients who relapse after SCT there are few effective treatment options and prognosis remains poor (Vose et al Blood. 80(8):2142–8, 1992). A second SCT was shown to achieve only marginal responses and at an increased risk of toxic death (Lenain et al Hematol J. 5(5):403–9, 2004). Therefore, new approaches are needed for treatment of patients in this poor prognostic group. Lenalidomide (Revlimid®) is an immunomodulatory agent that has shown clinical activity in treatment of several B-cell malignancies. Two phase 2 studies of lenalidomide monotherapy in patients with relapsed or refractory (R/R) a-NHL were conducted in the US (NHL-002; Wiernik et al JCO 26:4952–7, 2008) and internationally (CC-5013 NHL-003). In an extended follow-up of the NHL-002 study, the overall response rate (ORR) was 35%, which included 12% of patients with a complete response (CR), and a median duration of response (DR) lasting 10.4 months (Wiernik et al 2008 EHA. Abst: 764). Comparable efficacy was observed in the larger confirmatory, phase 2, NHL-003 study of lenalidomide in a similar patient population. The goal of this analysis was to learn the ORR and DR to lenalidomide in patients with a prior SCT. Methods: Patient data from both phase II studies were pooled for this report. Eligibility for both studies was similar – patients with R/R a-NHL, which included diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), and follicular lymphoma grade III (FL-III), with measurable disease (≥ 2 cm), and ≥ 1 prior treatment regimen. Patients received oral lenalidomide 25 mg once daily on days 1–21 of a 28-day cycle. Protocol defined treatment continued for up to 52 wks in NHL-002, or until disease progression in NHL-003. Primary endpoint was ORR; secondary endpoints included DR, progression-free survival (PFS), and safety. Results: 87 patients with a prior SCT (14 patients from NHL-002; 73 patients from NHL-003) were included in this analysis. Median age of patients was 61 yrs (range, 23–76), with a median of 4 prior therapies (range, 2–12). The ORR to lenalidomide was 39% (34/87), with 13% (11/87) CR/CRu and 26% (23/87) partial response (PR). Median PFS for all 87 patients was 3.8 months (95% CI, 2.6, 5.6) and the DR for 34 responders was 9.7 months (95% CI, 4.2, 16.3). Responses occurred in 15 of 52 patients (29% ORR; 10% CR/CRu) with DLBCL, 12 of 19 patients with MCL (63% ORR; 26% CR/CRu), and in 6 of 10 patients with TL (60% ORR; 10% CR/CRu). The table summarizes responses for patients who did not have a transplant, for those who had a SCT anytime prior to lenalidomide; as the last therapy prior to lenalidomide; and not as last therapy prior to lenalidomide. Most common grade 3 or 4 adverse events were neutropenia (44%), thrombocytopenia (33%), and anemia (9%). Eighteen (20.6%) patients discontinued treatment due to adverse events. Patients with a prior history of SCT appeared to have a significantly higher rate of thrombocytopenia, all grades (51% v 30%; P = 0.001), and grades 3 or 4 (33% v 16%; P = 0.002). Patients with a prior SCT were also more likely to experience a dose reduction/interruption due to thrombocytopenia compared with those without a prior SCT (25% v 14%; P = 0.027). Conclusions: Based on a pooled dataset from two phase II studies, oral lenalidomide monotherapy appears to be a well tolerated and active therapy resulting in durable responses in patients with R/R a-NHL who had a prior SCT. Furthermore, the potential of achieving a response to lenalidomide appears to be independent of prior history of SCT. Disclosures: Vose: Celgene: Research Funding. Off Label Use: Lenalidomide for the treatment of relapsed/refractory aggressive non-Hodgkin's lymphoma. . Czuczman:Celgene: Research Funding. Zinzani:Celgene: Research Funding. Tuscano:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pietronigro:Celgene: Employment, Equity Ownership. Ervin-Haynes:Celgene: Employment. Witzig:Celgene: Research Funding.

scholarly journals The Incidence and Associated Risk Factors in Central Venous Catheter Associated Infectious Complications within the Autologous Stem Cell Transplant Population of Eastern Health

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-31
Author(s):  
Tom Dunne ◽  
David M. Jones
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Incidence Rate ◽  
Infectious Complication ◽  
Stem Cell Transplant ◽  
Infectious Complications ◽  
Eastern Health ◽  
Cell Transplant ◽  
Factors Associated ◽  
History Of

Background: Central venous catheters (CVCs) carry a risk of infectious complication with associated morbidity and mortality. Hematologic malignancies are a known independent risk factor for these complications. Patients undergoing hematopoietic stem cell transplant (HSCT) are at increased infectious risk with an incidence of 24.7-31.3%. Proposed contributors to this risk are the underlying malignancy, extended neutropenia, and increased requirement for blood products. Existing cohort studies of HSCT patients have been unable to identifying consistent, modifiable risk factors to target with infection prevention and control initiatives. This single-centre retrospective cohort study examines an autologous stem cell transplant population to identifying risk factors associated with CVCs. Objectives:To determine the incidence and incidence rate per 1000 catheter-days within the autologous HSCT program at Eastern HealthTo identify protective and risk factors associated with CVCs in HSCT patientsDescribe the causative agents in CVC infectious complication identified by blood and catheter-tip culture results Methods: Charts of all adult patients with hematologic malignancy who underwent HSCT with CVC placement at Eastern Health between January 1, 2014 and March 1, 2020 were examined to determine which patients experienced any of a catheter-related bloodstream, tunneled-line or exit site infectious complication as defined by the Public Health Agency of Canada's surveillance definitions. Risk factors assessed included patient factors (age, malignancy, history of bacteremia, fungemia or radiation therapy), immunosuppressive factors (lines of chemotherapy, total 90 day corticosteroid burden, erythropoietin use, days to polymorphonuclear cells >500/µL), and CVC factors (line type, insertion site, antibiotic prophylaxis, heparin impregnation, training level of radiologist, days indwelling, thrombotic complication. Additional data captured included 90-day mortality, whether the CVC was terminated and the causative organism identified by blood or catheter-tip culture. Preliminary Results: The incidence of total infectious complications was 56.2% with an incidence of catheter-related bloodstream infection (CR-BSI) of 22.9%. The incidence rate for total infectious complications was 6.51 per 1000-catheter days, with a CR-BSI infectious rate of 2.65. Both incidence and incidence rate were below results found in other centres. In univariate analysis found single-line of chemotherapy (HR 0.114, p=0.001), use of Permacath (HR 0.03, p=0.002), right internal jugular placement (HR 0.048, p=0.006) to be protective for infectious complication. Multivariate analysis identified a history of bacteremia (OR 763.1, p=0.039) and total days CVC indwelling (OR 0.94, p=0.011) to be associated with CVC infectious complication. Conclusion: Modifiable risk factors associated with CVC infectious complication are choice of device and placement site. Risk factors such as multiple lines of previous chemotherapy or history of bloodstream infection signal need to increased observation for infection. Disclosures No relevant conflicts of interest to declare.

scholarly journals Early Detection of Vulvovaginal Graft-Versus-Host Disease: An Integrative Review

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Payton L. Ten Hagen, DNP, APRN, FNP-C ◽  
Christi Bowe, MSN, APRN, ANP-C ◽  
Joyce E. Dains, DrPH, JD, APRN, FNP-BC, FNAP, FAANP
Keyword(s):  
Stem Cell ◽  
Early Identification ◽  
Stem Cell Transplant ◽  
Small Sample ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Female Patients ◽  
Presenting Symptoms ◽  
History Of

Introduction: Vulvovaginal graft-vs.-host disease (VVGvHD) is a condition caused by a T-cell mounted immune response after allogeneic hematopoietic stem cell transplant (alloHSCT), which can lead to sclerotic changes of the external genital organs. A common complication of alloHSCT, VVGvHD is underreported and underdiagnosed in female patients. Without detection and treatment, VVGvHD can progress to complete obliteration of the vaginal canal requiring surgical intervention in severe cases. Design: This review summarizes findings to assist providers in detecting and treating VVGvHD. It utilized PubMed, Scopus, and CINAHL databases. Inclusion criteria consisted of female patients, a history of stem cell transplantation, and a history of VVGvHD. Studies not published in English and dated more than 15 years were excluded. After the evaluation of 333 articles, 10 were included based on relevance and applicability. Limitations of this review included small sample sizes, retrospective nature of articles, and lack of randomized control trials. Findings: Early identification of VVGvHD requires identifying the rate of occurrence and risk factor profile, recognizing the presenting symptoms, improving VVGvHD assessment techniques, ascertaining when to biopsy, and establishing clinically targeted surveillance programs. Conclusion: For female patients who have undergone alloHSCT, targeted surveillance for early identification of VVGvHD results in earlier treatment initiation. Subsequently, this can improve sexual health, partner relationships, and quality of life in patients after stem cell transplant.

Safety of Liposomal Cytarabine Prophylaxis in Pediatric Bone Marrow Transplant (BMT) Recipients with Acute Leukemia (AL) and Non Hodgkin Lymphoma (NHL) At High Risk of CNS Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4249-4249
Author(s):  
Jessica Hochberg ◽  
Deirdre Duffy ◽  
Lauren Harrison ◽  
Erin Morris ◽  
Mitchell S. Cairo
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Liposomal Cytarabine ◽  
Matched Unrelated Donor ◽  
Cns Relapse ◽  
History Of ◽  
Grade Ii

Abstract Abstract 4249 BACKGROUND: Liposomal Cytarabine is a derivative of cytarabine designed for intrathecal or intraomaya treatment of leukemia/lymphomatous meningitis (LLM). This formulation allows for sustained release with prolonged therapeutic concentration and drug exposure of 8 to 14 days in children and adults, respectively. Adult trials have shown liposomal cytarabine 50mg to be both safe and effective in the treatment of LLM (Glantz et al, JCO 1999). Bomgaars et al. investigated the use of liposomal cytarabine in children in a phase I dose escalation trial and demonstrated the maximal tolerated dose to be 35mg and that it was safe, well tolerated and effective (Bomgaars et al., JCO 2004). Comparisons of liposomal cytarabine use with conventional methotrexate prophylaxis suggest an improved quality adjusted survival benefit for patients where any possible additional toxicities are out measured by prolonged overall survival (Cole et al, Cancer 2003). However, there remains a paucity of data on the use of liposomal cytarabine prophylaxis to prevent LLM in pediatric patients, particularly in pediatric allogeneic stem cell (AlloSCT) recipients. Review of the literature reveals conflicting data concerning the efficacy of intrathecal chemoprophylaxis in children with leukemia/lymphoma after hematopoietic stem cell transplant. Recent multicenter trials suggest no statistically significant difference in the incidence of isolated or mixed CNS relapses between children receiving standard post-SCT intrathecal prophylaxis versus those that received no prophylaxis (Rubin et al., BMT 2011). This highlights the need to explore alternative chemoprophylaxis strategies in these high risk patients so that significant progress can be achieved. OBJECTIVE: We report on the safety and tolerability of liposomal cytarabine prior to and following allogeneic or autologous stem cell transplant in pediatric BMT recipients with AL and NHL. METHODS: Pediatric stem cell recipients with a history of AL or NHL and high risk of CNS disease received liposomal cytarabine 35mg (<21yr) or 50mg (>21yr) via lumbar puncture or omaya resevoir pre conditioning and approximately every 3months for 1–2yrs post stem cell transplant. No other intrathecal prophylaxis was administered. Patients received dexamethasone (0.15mg/kg/dose BID) concomitantly × 5days. Eight patients received a 9/10 or 10/10 matched unrelated donor transplant, 1 patient received an 8/10 matched unrelated donor. There were 9 matched related donor transplants and 3 autologous transplants. Twelve patients received a TBI (1200 cGy) based myeloablative conditioning regimen. Seven patients received an additional CNS boost of up to 1200 cGy during conditioning. All allogeneic SCT recipients received GVHD prophylaxis as previously described (Oswunko/Cairo, BBMT 2004; Bhatia et al, BBMT 2009) with tacrolimus and MMF. RESULTS: To date there have been 21 patients: (12 ALL, 2 AML, 3 Burkitt, 3 DLBCL and 1 T-LL). At the time of transplant, 7 patients were CR1/PR1, 10 patients CR2 and 4 patients CR3. Among all patients, they have received a total of 46 doses (median=1, range 1–12). Median age: 12yr (range 6–22). Mean follow up: 517 days (median= 294days). Eight of 21 patients had a history of CNS AL/NHL involvement prior to AlloSCT. No patients had evidence of LLM at the time of AlloSCT. Two patients experienced Grade II-III headache. Grade II-III vomiting was also noted in 2 additional patients. Head CT scans that were done at the time of symptom occurrence were negative for any evidence of hydrocephalus, hemorrhage, infarct or inflammation in all patients. Patients were treated with supportive therapy and had complete resolution of symptoms. Seven patients developed relapsed systemic disease, but none relapsed in the CNS. An additional 3 patients are deceased secondary to multi organ failure and 2 patients from overwhelming infection. However, none of the above patients had CNS AL/NHL at time of death. CONCLUSION: These preliminary results suggest that prophylactic liposomal cytarabine is tolerable and effective in pediatric AlloSCT and AutoSCT recipients at risk for CNS relapse. Larger studies are needed in the future to compare this to other CNS prophylaxis regimens post auto or AlloSCT. In addition, trials are in development to investigate the combination of intraomaya Rituximab followed by liposomal Cytarabine in children with recurrent/refractory CNS CD20+ AL/NHL. Disclosures: No relevant conflicts of interest to declare.

Pneumococcal induced thrombotic thrombocytopenic purpura with features of purpura fulminans

2021 ◽  
Vol 14 (1) ◽  
pp. e235580 ◽  
Author(s):  
Laura Frances Walsh ◽  
Jacqueline E Sherbuk ◽  
Brian Wispelwey
Keyword(s):  
Stem Cell ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Stem Cell Transplant ◽  
Pneumococcal Infection ◽  
Purpura Fulminans ◽  
Altered Mental Status ◽  
Cell Transplant ◽  
Thrombocytopenic Purpura ◽  
History Of ◽  
Immunoglobulin Levels

A 42-year-old woman with a history of acute myeloid leukaemia status postallogeneic stem cell transplant presented with fevers, altered mental status, pulmonary infiltrates and septic shock that further progressed to thrombocytopenia and purpura fulminans. Laboratory studies were consistent with a diagnosis of thrombotic thrombocytopenic purpura (TTP). Blood cultures grew Streptococcus pneumoniae. On chart review, our patient had a history of low immunoglobulin levels following stem cell transplant, which may have predisposed her to pneumococcal infection. The patient responded to therapy with ceftriaxone, plasma exchange, rituximab and caplacizumab. This is the fourth-documented case of pneumococcal induced TTP and, to the best of our knowledge, the first-describing pneumococcal induced TTP with purpura fulminans. We conclude that patients with TTP should be evaluated for infectious aetiologies and empiric antibiotics should be considered. Clinicians should be aware of the possibility for TTP to lead to purpura fulminans.

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