A Rare Case of Addison's Disease Presenting With Intermittent Pancytopenia and Cardiac Tamponade.

OBJECTIVE: To report the first case, to our knowledge, of intermittent pancytopenia and cardiac tamponade occurring together in association with Autoimmune Addison's Disease (AAD). METHODS: A 21 year-old woman presented on three different occasions with multiple complaints. Her evaluation was significant for intermittent pancytopenia (white blood cell, 1.3-3.0 × 103/µL [normal 4.5-11 × 103]; hemoglobin, 8.8-9.6 g/dL [11-16]; and platelets, 102-117 × 103/µL [150-400 × 103/µL]) and pericardial effusion with cardiac tamponade. Further investigation including a morning serum cortisol level of 0.6 µg/dL (5.27-22.45 µg/dL), adrenocorticotropic hormone level of 1027 pg/mL (normal 6-50 pg/mL), and positive 21-hydroxylase antibodies confirmed the diagnosis of primary adrenal insufficiency due to AAD. Treatment with steroids resulted in prompt hemodynamic recovery with normalization of all blood cell lines. RESULTS: The diagnosis of AAD is often delayed or overlooked. Pancytopenia occurring in AAD is most likely due to either marrow suppression in the setting of acute illness and exacerbated by hypoadrenalism or possibly an autoimmune-mediated marrow reaction. Pericarditis with cardiac tamponade has been described in AAD occurring in the setting of polyglandular autoimmune syndrome type II. The pathogenesis involves autoimmune inflammation of the pericardium, which precipitates an acute inflammatory reaction and rapid fluid accumulation. CONCLUSION: Pericarditis with cardiac tamponade and intermittent neutropenia may be rare manifestations of an Addisonian crisis.

Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥70 mg/dL despite maximal-tolerated LDL-cholesterol-lowering therapy.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors, Praluent (alirocumab [ALI]) and Repatha (evolocumab [EVO]) have been approved as adjuncts to the standard-of-care maximal-tolerated dose (MTD) of low-density lipoprotein cholesterol (LDLC)-lowering therapy (LLT), statin therapy, in heterozygous (HeFH) (ALI or EVO) or homozygous (EVO) familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient (both). Since LDLC lowering has been revolutionized by ALI and EVO, specialty pharmaceutical pricing models will be applied to a mass market. METHODS: We applied US Food and Drug Administration (FDA) and insurance eligibility criteria for ALI and EVO to 1090 hypercholesterolemic patients serially referred over 3 years who then received ≥2 months maximal-tolerated dose of standard-of-care LDL cholesterol-lowering therapy (MTDLLT) with follow-up LDLC ≥70 mg/dL. MTDLLT did not include ALI or EVO, which had not been commercially approved before completion of this study. RESULTS: Of the 1090 patients, 140 (13%) had HeFH by clinical diagnostic criteria and/or CVD with LDLC >100 mg/dL despite ≥2 months on MTDLLT, meeting FDA insurance criteria for ALI or EVO therapy. Another 51 (5%) patients were statin intolerant, without HeFH or CVD. CONCLUSION: If 13% of patients with HeFH-CVD and LDLC >100 mg/dL despite MTDLLT are eligible for ALI or EVO, then specialty pharmaceutical pricing models (~$14,300/year) might be used in an estimated 10 million HeFH-CVD patients. Whether the health care savings arising from the anticipated reduction of CVD events by ALI or EVO justify their costs in populations with HeFH-CVD and LDLC >100 mg/dL despite MTDLLT remains to be determined.

Progressively Worsening Premature Coronary Artery Disease: Adding Anticoagulation Stabilizes-Reverses Clinical Symptomatic Disease Progression in Thrombophilic-Atherothrombotic Patients: A Pilot Study.

In 35 patients with 116 severe premature cardiovascular disease (CVD) events (median age: 48 years), 14 having worsening CVD despite maximal intervention, we evaluated thrombophilia and speculated that anticoagulation might arrest-reverse progressive thrombophilic-atherothrombotic CVD. Thrombophilia-hypofibrinolysis in the 35 patients was compared to 110 patients with venous thromboembolism (VTE) without CVD and to 110 healthy normal controls. Efficacy-safety of anticoagulation was prospectively assessed in 14 of the 35 patients whose CVD worsened over 2 years despite maximal medical-surgical intervention. At entry on maximally tolerated lipid-lowering therapy, median low-density lipoprotein was 88 mg/dL. Measures of thrombophilia-hypofibrinolysis in the 35 cases differed from 110 VTE controls only for the lupus anticoagulant, present in 6 (21%) of 28 cases versus 4 (4%) of 91 VTE controls ( P = .01), and for high anticardiolipin antibodies (ACLAs) immunoglobulin G, 5 (14%) of 35 cases versus 4 of 108 VTE controls (4%), P = .04. The 14 patients who were anticoagulated differed from 110 VTE controls only for the lupus anticoagulant, 38% versus 4%, P = .001, and for high lipoprotein (a), 46% versus 17%, P = .028, respectively. The 14 patients with atherothrombosis having inexorably worsening CAD despite maximal medical-surgical therapy were anticoagulated for 6.5 years (median), with clinical CVD progression arrested in 12 (86%), and all 12 became asymptomatic. In the 35 patients with premature CVD, thrombophilia was pervasive, comparable to or more severe than in VTE controls without CVD. When CVD progressively worsens despite maximal intervention, thrombophilia and atherosclerosis (atherothrombosis) are commonly concurrent, and the downhill course of CVD may be arrested-stabilized by anticoagulation.

Thrombophilia in Klinefelter Syndrome With Deep Venous Thrombosis, Pulmonary Embolism, and Mesenteric Artery Thrombosis on Testosterone Therapy: A Pilot Study.

We compared thrombophilia and hypofibrinolysis in 6 men with Klinefelter syndrome (KS), without previously known familial thrombophilia, who had sustained deep venous thrombosis (DVT)-pulmonary emboli (PE) or mesenteric artery thrombosis on testosterone replacement therapy (TRT). After the diagnosis of KS, TRT had been started in the 6 men at ages 11, 12, 13, 13, 19, and 48 years. After starting TRT, DVT-PE or mesenteric artery thrombosis was developed in 6 months, 1, 11, 11, 12, and 49 years. Of the 6 men, 4 had high (>150%) factor VIII (177%, 192%, 263%, and 293%), 3 had high (>150%) factor XI (165%, 181%, and 193%), 1 was heterozygous for the factor V Leiden mutation, and 1 was heterozygous for the G20210A prothrombin gene mutation. None of the 6 men had a precipitating event before their DVT-PE. We speculate that the previously known increased rate of DVT-PE and other thrombi in KS reflects an interaction between prothrombotic, long-term TRT with previously undiagnosed familial thrombophilia. Thrombophilia screening in men with KS before starting TRT would identify a cohort at increased risk for subsequent DVT-PE, providing an optimally informed estimate of the risk/benefit ratio of TRT.

Associations between Serum 25-hydroxyvitamin D and Lipids, Lipoprotein Cholesterols, and Homocysteine.

BACKGROUND: Serum 25(OH) vitamin D levels are inversely associated with cardiovascular disease (CVD) mortality, mediated in part by independent positive relationships with high-density lipoprotein cholesterol (HDLC) and inverse relationships with low-density lipoprotein cholesterol (LDLC), triglyceride, and homocysteine. AIMS: In this study, we assessed relationships between fasting serum vitamin D and lipids, lipoprotein cholesterols, and homocysteine. MATERIALS AND METHODS: We studied 1534 patients sequentially referred to our center from 2007 to 2016. Fasting serum total 25(OH) vitamin D, plasma cholesterol, triglyceride, HDLC, LDLC, and homocysteine were measured. Stepwise regression models were used with total cholesterol, triglyceride, HDLC, LDLC, and homocysteine as dependent variables and explanatory variables age, race, gender, body mass index (BMI), and serum vitamin D levels. Relationships between quintiles of serum vitamin D and triglycerides, HDLC, LDLC, and homocysteine were assessed after covariance adjusting for age, race, gender, and BMI. RESULTS: Fasting serum vitamin D was positively correlated with age, HDLC, and White race, and was inversely correlated with BMI, total and LDL cholesterol, triglyceride, and fasting serum homocysteine (P ≤ 0.0001 for all). Serum vitamin D was a significant independent inverse explanatory variable for total cholesterol, triglyceride, and LDL cholesterol, and accounted for the largest amount of variance in serum total cholesterol (partial R (2) =3.6%), triglyceride (partial R (2) =3.1%), and LDLC (partial R (2) =2.9%) (P < 0.0001 for all). Serum vitamin D was a significant positive explanatory variable for HDLC (partial R (2) = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R (2) = 6.0-12.6%). CONCLUSIONS: In hyperlipidemic patients, serum vitamin D was a significant independent inverse determinant of total cholesterol, LDLC, triglyceride, and homocysteine, and a significant independent positive determinant of HDLC. Thus, serum vitamin D might be protective against CVD.

Retinal vascular occlusion: a window to diagnosis of familial and acquired thrombophilia and hypofibrinolysis, with important ramifications for pregnancy outcomes.

AIM: Our specific aim was to document the pathoetiologic importance of thrombophilia among females presenting with severe ischemic retinal vein (RVO) or retinal artery (RAO) occlusion, without typical risk factors, and to emphasize that the ophthalmologists' diagnosis of thrombophilia has important diagnostic and therapeutic downstream ramifications for nonocular thrombosis, including reproductive outcomes. METHODS: We evaluated familial and acquired thrombophilia in 60 females with RVO (central RVO, n=52; branch RVO, n=8) and 16 with RAO (central RAO, n=11; branch RAO, n=5). They were referred by retinologists, without typical risk factors for RVO/RAO and/or severe ocular ischemic presentation. We focused on extraocular thrombotic events, particularly pregnancy complications, including unexplained spontaneous abortion, pre-eclampsia-eclampsia. Thrombophilia measurements in the 76 females were compared with 62 healthy normal females without ocular vascular occlusions (OVOs). RESULTS: The 76 females with OVO were more likely than 62 normal female controls to have high homocysteine (24% vs 0%, P<0.0001), high anticardiolipin antibody (immunoglobulin M, 17% vs 3%, P=0.012), high (>150%) factor VIII (42% vs 11%, P<0.0001), and high (>150%) factor XI (22% vs 4%, P=0.004). Of the 76 females, 26 (34%) had ≥1 spontaneous abortion; 17 (22%) had ≥2 spontaneous abortions and/or pre-eclampsia-eclampsia. Compared to 62 healthy female controls, these 17 females with pregnancy complications had high homocysteine (29% vs 0%, P=0.0003), high anticardiolipin antibody immunoglobulin M (24% vs 3%, P=0.02), high factor VIII (38% vs 11%, P=0.02), and were marginally more likely to be heterozygous for the factor V Leiden mutation (19% vs 3%, P=0.058). CONCLUSION: In females lacking typical risk factors for retinal vascular occlusion or severely ischemic presentation, by diagnosing thrombophilia as an etiology for OVO, the ophthalmologist opens a window to family screening and preventive therapy, with particular relevance to pregnancy outcomes and venous thromboembolism.

Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant.

BACKGROUND: When exogenous testosterone or treatments to elevate testosterone (human chorionic gonadotropin [HCG] or Clomid) are prescribed for men who have antecedent thrombophilia, deep venous thrombosis and pulmonary embolism often occur and may recur despite adequate anticoagulation if testosterone therapy is continued. CASE PRESENTATION: A 55-year-old white male was referred to us because of 4 thrombotic events, 3 despite adequate anticoagulation over a 5-year period. We assessed interactions between thrombophilia, exogenous testosterone therapy, and recurrent thrombosis. In 2009, despite low-normal serum testosterone 334 ng/dL (lower normal limit [LNL] 300 ng/dL), he was given testosterone (TT) cypionate (50 mg/week) and human chorionic gonadotropin (HCG; 500 units/week) for presumed hypogonadism. Ten months later, with supranormal serum T (1385 ng/dL, upper normal limit [UNL] 827 ng/dL) and estradiol (E2) 45 pg/mL (UNL 41 pg/mL), he had a pulmonary embolus (PE) and was then anticoagulated for 2 years (enoxaparin, then warfarin). Four years later, on TT-HCG, he had his first deep venous thrombosis (DVT). TT was stopped and HCG continued; he was anticoagulated (enoxaparin, then warfarin, then apixaban, then fondaparinux). One year after his first DVT, on HCG, still on fondaparinux, he had a second DVT (5/315), was anticoagulated (enoxaparin + warfarin), with a Greenfield filter placed, but 8 days later had a second PE. Thrombophilia testing revealed the lupus anticoagulant. After stopping HCG, and maintained on warfarin, he has been free of further DVT-PE for 9 months. CONCLUSION: When DVT-PE occur on TT or HCG, in the presence of thrombophilia, TT-HCG should be stopped, lest DVT-PE reoccur despite concurrent anticoagulation.

Pharmacoeconomics of PCSK9 inhibitors in 103 hypercholesterolemic patients referred for diagnosis and treatment to a cholesterol treatment center.

BACKGROUND: PCSK9 inhibitor therapy has been approved by the FDA as an adjunct to diet-maximal tolerated cholesterol lowering drug therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) with suboptimal LDL cholesterol (LDLC) lowering despite maximal diet-drug therapy. With an estimated ~24million of US hypercholesterolemic patients potentially eligible for PCSK9 inhibitors, costing ~ $14,300/patient/year, it is important to assess health-care savings arising from PCSK9 inhibitors vs ASCVD cost. METHODS: In 103 patients with HeFH, and/or ASCVD and/or suboptimal LDLC lowering despite maximally tolerated diet-drug therapy, we assessed pharmacoeconomics of PCSK9 inhibitor therapy with lowering of LDLC. For HeFH diagnosis, we applied Simon Broome's or WHO Dutch Lipid Criteria (score >8). Estimates of direct and indirect costs for ASCVD events were calculated using American Heart Association (AHA), U.S. DHHS, Healthcare Bluebook, and BMC Health Services Research databases. We used the ACC/AHA 10-year ASCVD risk calculator to estimate 10-year ASCVD risk and estimated corresponding direct and indirect costs. Assuming a 50 % reduction in ASCVD events on PCSK9 inhibitors, we calculated direct and indirect health-care savings. RESULTS: We started 103 patients (58 [56 %] women and 45 [44 %] men), on either alirocumab (62 %) or evolocumab (38 %), median age 63, BMI 29.0, and LDLC 149 mg/dl. Of the 103 patients, 28 had both HeFH and ASCVD, 33 with only ASCVD, 33 with only HeFH, and 9 had neither. Of the 103 patients, 61 had a first ASCVD event at median age 55 and on best tolerated cholesterol-lowering therapy median LDLC was 137 mg/dl. In these 61 patients, total direct costs attributable to ASCVD were $8,904,361 ($4,328,623 direct, $4,575,738 indirect), the median 10-year risk of a new CVD event was calculated to be 13.1 % with total cost $1,654,758. Assuming a 50 % reduction in ASCVD events on PCSK9 inhibitors in our 61 patients, $4,452,180 would have been saved in the past; and future 10-year savings would be $1,123,345. CONCLUSION: In the 61 CVD patients, net costs/patient/year were estimated to be $7,000 in the past, with future 10-year intervention net costs/patient/year being $12,459, both below the $50,000/year quality adjusted life-year gained by PCSK9 inhibitor therapy.

Venous Thromboembolism After Knee Arthroscopy in Undiagnosed Familial Thrombophilia.

Venous thromboembolism is uncommon after knee arthroscopy, and there are no guidelines for thromboprophylaxis in elective routine knee arthroscopy. Preoperative evaluation of common thrombophilias should provide guidance for postarthroscopy thromboprophylaxis in otherwise healthy patients who are at high risk for venous thromboembolism. This study assessed 10 patients with venous thromboembolism after total hip or knee arthroplasty. Patients were assessed if venous thromboembolism occurred within 6 months after knee arthroscopy (n=10) or total hip or knee arthroplasty (n=21). This study assessed gene mutations (factor V Leiden, prothrombin G20210A, plasminogen activator inhibitor, methylenetetrahydrofolate reductase) and serologic thrombophilias (high levels of factors VIII and XI, homocysteine, anticardiolipin immunoglobulin G and immunoglobulin M antibodies, and lupus anticoagulant; low antigenic protein C, S, and free S; and antithrombin III deficiency). The same coagulation data were obtained for normal subjects (n=110). The major thrombophilias in the arthroscopy group were factor V Leiden heterozygosity (40%), high factor VIII level (50%), and high homocysteine (30%). The respective values in control subjects were 2% (P=.0004), 7% (P=.0011), and 5% (P=.02). When the arthroscopy group was compared with the 21 patients who had venous thromboembolism after total hip or knee arthroplasty, the sole difference was factor V Leiden heterozygosity, which was 40% vs 0%, respectively (P=.007). Although venous thromboembolism after knee arthroscopy is uncommon, to identify high-risk patients and guide postoperative thromboprophylaxis, the authors suggest routine preoperative measurement of 3 common familial thrombophilias: factor V Leiden, factor VIII, and homocysteine. [Orthopedics. 2016; 39(6):e1052-e1057.].

Safety of 50,000-100,000 Units of Vitamin D3/Week in Vitamin D-Deficient, Hypercholesterolemic Patients with Reversible Statin Intolerance.

BACKGROUND: Vitamin D deficiency (<32 ng/mL) is a reversible cause of statin-intolerance, usually requiring vitamin D3 (50,000-100,000 IU/week) to normalize serum D, allowing reinstitution of statins. Longitudinal safety assessment of serum vitamin D, calcium, and estimated glomerular filtration rate (eGFR) is important. AIMS: Prospectively assess the safety-efficacy of vitamin D3 therapy. MATERIALS AND METHODS: In 282 statin-intolerant hypercholesterolemic patients for 6 months and in 112 of the 282 patients for 12 months, with low-entry serum vitamin D (<32 ng/mL), we assessed safety-efficacy of vitamin D3 therapy (50,000-100,000 IU/week). RESULTS: On mean (66,600 IU) and median (50,000 IU) of vitamin D3/week in 282 patients at 6 months, serum vitamin D rose from pretreatment (21-median) to 46 ng/mL (P < 0.0001), and became high (>100 ng/mL) but not toxic (>150 ng/mL) in 4 patients (1.4%). Median serum calcium was unchanged from entry (9.60 mg/dL) to 9.60 at 6 months (P = .36), with no trend of change (P = .16). Median eGFR was unchanged from entry (84 mL/min/1.73) to 83 at 6 months (P = .57), with no trend of change (P = .59). On vitamin D3 71,700 (mean) and 50,000 IU/week (median) at 12 months in 112 patients, serum vitamin D rose from pretreatment (21-median) to 51 ng/mL (P < 0.0001), and became high (>100 but <150 ng/mL) in 1 (0.9%) at 12 months. Median serum calcium was unchanged from entry (9.60 mg/dL) to 9.60 mg/dL and 9.60 mg/dL at 6 months and 12 months, respectively; P > 0.3. eGFR did not change from 79 mL/min/1.73 at entry to 74 mL/min/1.73 and 77 mL/min/1.73 at 6 months and 12 months, P > 0.3. There was no trend in the change in serum calcium (P > 0.5 for 6 months and 12 months), and no change of eGFR for 6 months and 12 months, P > 0.15. CONCLUSIONS: Vitamin D3 therapy (50,000-100,000 IU/week) was safe and effective when given for 12 months to reverse statin intolerance in patients with vitamin D deficiency. Serum vitamin D rarely exceeded 100 ng/mL, never reached toxic levels, and there were no significant change in serum calcium or eGFR.

Hospitalization for pulmonary embolism associated with antecedent testosterone or estrogen therapy in patients found to have familial and acquired thrombophilia.

BACKGROUND: In patients hospitalized over a 4 year period for pulmonary embolism (PE), we assessed relationships of testosterone (TT) and estrogen therapy (ET) anteceding PE in patients found to have familial-acquired thrombophilia. METHODS: From 2011 through 2014, 347 patients were hospitalized in Cincinnati Mercy Hospitals with PE. Retrospective chart review was used to identify patients receiving TT or ET before PE; coagulation studies were done prospectively if necessary. RESULTS: Preceding hospitalization for PE, 8 of 154 men (5 %) used TT, and 24 of 193 women (12 %) used ET. The median number of months from the initiation of TT or ET to development of PE was 7 months in men and 18 months in women. Of the 6 men having coagulation measures, all had ≥ 1 thrombophilia, and of the 18 women having measures of coagulation, 16 had ≥ 1 thrombophilia. The sensitivity of a previous history of thrombosis to predict PE was low, 25 % (2/8 men), 4 % (1/24 women). CONCLUSIONS: Of 154 men hospitalized for PE, 8 (5 %) used TT, and of 193 women, 24 (12 %) used ET. Our data suggests that PE is an important complication of TT in men and ET in women, in part reflecting an interaction between familial and acquired thrombophilia and exogenous hormone use.

Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥ 70 mg/dl despite maximal tolerated cholesterol lowering therapy.

BACKGROUND: LDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient. METHODS: We applied FDA and insurance eligibility criteria for PCSK9 inhibitor use in 734 hypercholesterolemic patients serially referred over 3 years who then received ≥ 2 months maximally tolerated LDLC lowering therapy with follow up LDLC ≥ 70 mg/dl, and in 50 patients approved by insurance for PCSK9 inhibitors. We documented the percentage of patients with HeFH and/or CVD who met FDA and insurance criteria for PCSK9 inhibitor therapy using LDLC goal-based guidelines. RESULTS: Of 734 patients with LDLC ≥ 70 mg/dl after ≥ 2 months maximally tolerated LDLC lowering therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy. Another 66 (9%) patients were statin intolerant, without HeFH or CVD. Of the 50 patients whose PCSK9 inhibitor therapy was approved for insurance coverage, 45 (90%) had LDLC > 100 mg/dl after ≥ 2 months on maximally tolerated LDLC lowering therapy. Seventeen of these 50 patients (34%) had HeFH without CVD (LDLC on treatment 180 ± 50 mg/dl), 15 (30%) had CVD without HeFH (LDLC on treatment 124 ± 26 mg/dl), 14 (28%) had both HeFH and CVD (LDLC on treatment 190 ± 53 mg/dl), and 4 (8%) had neither HeFH nor CVD (LCLC 142 ± 11 mg/dl). CONCLUSION: Of 734 patients referred for LDLC reduction, with LDLC ≥ 70 mg/dl after ≥ 2 months on maximally tolerated therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy as an adjunct to diet-maximally tolerated cholesterol lowering therapy in HeFH or CVD. If 30% of patients with high LDLC and HeFH-CVD are eligible for PCSK9 inhibitors, then specialty pharmaceutical pricing models (~$14,300/year) will collide with tens of millions of HeFH-CVD patients. We speculate that if there was a 50 % reduction in CVD, then there would be savings of $245 billion, in the middle of the range of estimated PCSK9 inhibitor costs of $185-342 billion. Whether the health care savings arising from the anticipated reduction of CVD events by PCSK9 inhibitors justify their extraordinary costs in broad population use remains to be determined.