Thomas G. DeLoughery

Common Mutation in Methylenetetrahydrofolate Reductase Correlation With Homocysteine Metabolism and Late-Onset Vascular Disease

BACKGROUND Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this mutation in many subjects with and without vascular disease and related it to homocysteine and folate levels. METHODS AND RESULTS DNA from 247 older subjects with vascular disease and 594 healthy subjects without vascular disease (in three different control groups) was screened for the MTHFR 677 C-to-T mutation. Within each group, 9% to 17% of the subjects were homozygous for this mutation, and the mutant allele frequency was 31% to 39%. The genotype distributions, homozygote frequencies, and allele frequencies did not differ significantly between the study groups. In the vascular disease subjects, despite significantly lower folate levels in MTHFR homozygotes, there was no significant difference in homocysteine levels among the MTHFR genotype groups. The negative slope of the regression line relating homocysteine and folate was significantly steeper for those with a homozygous MTHFR mutation compared with those without this mutation. CONCLUSIONS Although the thermolabile MTHFR mutation is very common, it does not appear to be a significant genetic risk factor for typical late-onset vascular disease. Because MTHFR homozygotes have increased homocysteine with low folate levels, this mutation may contribute to early-onset or familial vascular disease. The genotype dependence of the folate-homocysteine correlation further suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletion and a better response to folic acid therapy.

Coagulation defects in trauma patients: etiology, recognition, and therapy

Trauma patients have many reasons to have defects in coagulation. These can be caused by the trauma or because of pre-existing disorders. Trauma patients who are at risk for coagulation defects should be screened with the basic tests (aPTT, INR/PT, platelet counts, hematocrit, and fibrinogen), with therapy based on the results. Attention also should be paid to any other correctable factors such as hypothermia. Finally, pre-existing disorders can influence the patients hemostasis greatly and may require specific therapies.

Peripherally inserted central catheter usage patterns and associated symptomatic upper extremity venous thrombosis

OBJECTIVES Peripherally inserted central catheters (PICCs) may be complicated by upper extremity (UE) superficial (SVT) or deep venous thrombosis (DVT). The purpose of this study was to determine current PICC insertion patterns and if any PICC or patient characteristics were associated with venous thrombotic complications. METHODS All UE venous duplex scans during a 12-month period were reviewed, selecting patients with isolated SVT or DVT and PICCs placed ≤30 days. All UE PICC procedures during the same period were identified from an electronic medical record query. PICC-associated DVTs, categorized by insertion site, were compared with all first-time UE PICCs to determine the rate of UE DVT and isolated UE SVT. Technical and clinical variables in patients with PICC-associated UE DVT also were compared with 172 patients who received a PICC without developing DVT (univariable and multivariable analysis). RESULTS We identified 219 isolated UE SVTs and 154 UE DVTs, with 2056 first-time UE PICCs placed during the same period. A PICC was associated with 44 of 219 (20%) isolated UE SVTs and 54 of 154 UE DVTs (35%). The rates of PICC-associated symptomatic UE SVT were 1.9% for basilic, 7.2% for cephalic, and 0% for brachial vein PICCs. The rates of PICC-associated symptomatic UE DVT were 3.1% for basilic, 2.2% for brachial, and 0% for cephalic vein PICCs (χ(2)P < .001). Univariate analysis of technical and patient variables demonstrated that larger PICC diameter, noncephalic insertion, smoking, concurrent malignancy, diabetes, and older age were associated with UE DVT (P < .05). Multivariable analysis showed larger catheter diameter and malignancy were the only variables associated with UE DVT (P < .05). CONCLUSIONS The incidence of symptomatic PICC-associated UE DVT is low, but given the number of PICCs placed each year, they account for up to 35% of all diagnosed UE DVTs. Larger-diameter PICCs and malignancy increase the risk for DVT, and further studies are needed to evaluate the optimal vein of first choice for PICC insertion.

Incidence and Risk Factors for Venous Thromboembolic Disease in Podiatric Surgery

BACKGROUND The Agency for Healthcare Research and Quality ranks prevention of venous thromboembolism (VTE) as a top priority for patient safety; however, no guidelines or population-based research exist to guide management for podiatric surgery patients. The objective of our study was to determine the incidence and risk factors for postprocedure VTE in podiatric surgery. METHODS A 5-year retrospective analysis of patients undergoing podiatric surgery in a large not-for-profit health maintenance organization serving > 485,000 members in the Pacific Northwest from 1999 to 2004. RESULTS We identified 16,804 surgical procedures in 7,264 patients and detected 22 symptomatic postprocedure VTEs. The overall incidence of postprocedure VTE was 0.30%. Three risk factors were significantly and independently associated with VTE in podiatric surgery: prior VTE (incidence, 4.6%; relative risk, 23.0; p < 0.001), use of hormone replacement therapy or oral contraceptives (incidence, 0.55%; relative risk, 4.2; p = 0.01), and obesity (incidence, 0.48%; relative risk, 3.0; p = 0.02). CONCLUSIONS We identified a low overall risk of VTE in podiatric surgery, suggesting that routine prophylaxis is not warranted. However, for patients with a history of VTE, periprocedure prophylaxis is suggested based on the level of risk. For podiatry surgery patients with two or more risk factors for VTE, periprocedure prophylaxis should be considered. Until a prospective study is completed testing recommendations, guidelines and care decisions for podiatric surgery patients will continue to be based on retrospective data, expert consensus, and clinical judgment.

High dose calcitriol may reduce thrombosis in cancer patients

The incidence of venous and arterial thrombosis in a placebo‐controlled randomised trial of DN‐101 (high dose calcitriol) with docetaxel versus docetaxel was compared. Of the 13 thrombotic events observed in the 250 patients enroled in this study, two occurred in DN‐101 and 11 in placebo‐treated patients (P = 0·01). This difference remained significant after adjustment for baseline history of thrombosis, atrial fibrillation and use of anti‐thrombotic agents. In vitro and vitamin D receptor (VDR) knockout mouse studies predict that nanomolar concentrations of calcitriol may act as an antithrombotic agent. We report the first clinical observation that supports this hypothesis in humans.

Bleeding and thrombosis in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) has evolved from being a deadly to a highly curable disease, due totargeted molecular therapy with all‐trans retinoic acid (ATRA). As a result, the incidence of early hemorrhagic deaths for which APL is notorious has reduced to 5–10% as reported in clinical trials. These results are not replicated outside of clinical trials as is evident from recent population‐based registries. High incidence of early hemorrhagic deaths remains the greatest contributor to treatment failure in this otherwise curable leukemia. Additionally, thrombosis is now being increasingly recognized in APL patients and may be associated with ATRA usage. Am. J. Hematol. 87:596–603, 2012.

Phase II study of transdermal estradiol in androgen-independent prostate carcinoma.

Oral estrogen therapy has activity in patients with hormone‐naive and androgen‐independent prostate carcinoma (AIPC), but its utility is limited by the associated risk of thromboembolic toxicity. Parenteral administration may be safer as it avoids “first pass” liver exposure to estrogen. The authors tested the safety and efficacy of transdermal estradiol (TDE), as well as the effect of therapy on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with AIPC.

The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients

BACKGROUND The international normalized ratio (INR) was developed to assess adequacy of Coumadin dosing. Its use has been generalized to guide fresh frozen plasma (FFP) therapy in stable patients. Thrombelastography (TEG) is a whole-blood assay measuring the viscoelastic properties of the clot in near real time. This study hypothesized that INR does not reflect coagulopathy and should not be used to guide FFP therapy in stable trauma and surgical patients. METHODS Prospective observational data were collected from stable trauma and surgical patients (n = 106) who received FFP transfusions. Pretransfusion and posttransfusion blood samples were obtained to assess complete blood count, standard coagulation parameters (INR, partial thromboplastin time, fibrinogen and D-dimer), soluble clotting factors (II, V, VII, VIII, IX, X, XI, XII, proteins C and S) and TEG. Data were analyzed using a Mann-Whitney U-test. Significance was defined as p < 0.05. RESULTS A total of 262 U of FFP were transfused, with 78% of 106 patients receiving two or more units. Despite a reduction in INR, median TEG values remained within normal limits, while clotting factor levels retained adequate function to produce normal clotting before and following FFP transfusion. CONCLUSION The use of FFP in this population did not affect coagulation status in a clinically relevant manner based on TEG values and coagulation factor function. INR is not a predictor of coagulopathy and should not be used to guide coagulation factor replacement in stable trauma and surgical patients. LEVEL OF EVIDENCE Diagnostic study, level III.

Practical aspects of the oral new anticoagulants

After years of only oral vitamin K antagonists, there are new many new antithrombotic agents in development and on entering the marketplace. This review will analyze clinical trial results for these new agents—especially dibigatran, rivaroxaban, and apixiban. Also to be discussed are practical aspects of use of these new agents such monitoring, reversal, and use before procedures. Am. J. Hematol. 2011.

Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine metabolic pathway enzyme, has been associated with increased homocysteine levels and increased risk for premature cardiovascular disease. The purpose of this study was to assess the association between the prevalence of the MTHFR mutation, hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population comprised of three age-balanced groups of patients. The presence of the C677T MTHFR mutation was determined by a direct polymerase chain reaction-based assay performed on blood samples from 136 patients with acute ischemic stroke, 95 patients with atherosclerotic risk factors for stroke (including some with a history of previous stroke or transient ischemic attack), and 52 healthy control subjects. The prevalence of the homozygous C677T mutation was not significantly higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%) or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/-3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have significantly higher homocysteine levels than non-homozygotes. Moderate hyperhomocysteinemia, though common in older patients with ischemic cerebrovascular disease, is not attributable, at least in this patient group, to a higher prevalence of the C677T MTHFR mutation.