Thrombosis Journal - Latest Comments

severe hyperhomocystemia is common in patients with pernicious anemia

Marion Hofmann — 2010-02-11T00:00:00Z

We would like to make an addendum to our case report. In contrast to what we reported, the severity of hyperhomocystenemia (105 μM) in our case is not unusually high for patients with vitamin B12 deficiency caused by pernicious anemia. A large cohort study by Savage and colleagues (ref 1) measured homocysteine in 408 patients with vitamin B12 deficiency, of which 234 (58%) had proven pernicious anemia and 76 (18%) had probable pernicious anemia. This case series accumulated over 21 years and is the largest study in the literature reporting homocysteine determinations in patients with pernicious anemia. In this study, the mean homocysteine level was 89.4 μM (with a range of approximately 18-475 μM) in anemic patients with vitamin B12 deficiency. Unfortunately, the incidence of thrombotic complications was not reported in this large cohort of patients with moderate to severe hyperhomocystenemia.
We apologize for omission of this landmark study. Nevertheless, it does not change our conclusion that severe hyperhomocystenemia needs to be considered in the work-up of acute myocardial infarction not explained by atherosclerotic heart disease.

Reference:
1. Savage D.G, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994 (96): 239-246

Resistance of cancer cell to immune killing

Boguslaw Lipinskii — 2008-06-23T00:00:00Z

I would like to bring to the attention of the authors that in 2000 we published a paper in Medical Hypotheses (54:456-460) proposing a mechanism by which fibrin protects tumor cells against recognition and killing by cellular immune system. This concept is based on decades of previous research on the role of soluble fibrin monomers in degenerative diseases and specifically in cancer. A characteristic feature of of a fibrin coat around the tumor cells is its remarkable resistance to fibrinolytic degradation that normally removes readily any intravascular fibrin deposits. Our recent studies indicate that such a resistance might be due to the presence in fibrin clots of free radical-induced polymerized form of fibrinogen. In addition we have found that sodium selenite prevents the formation of a protective fibrin-fibrinogen protective coat on tumor cells.

Boguslaw Lipinski, Ph.D.

Caution with regard to generalizability of results

David Somerset — 2008-03-06T00:00:00Z

This report provides weak evidence of benefit from anticoagulation during preganncy to women who are homozygous for the MTHFR C677T mutation and have a history of recurrent miscarriage. Of the three succesful outcomes: one mother had a history of two prior miscarriages and one full term pregancy; one had a history of two prior miscarriages only; and one had a history of 6 prior miscarriages and 3 full term pregnancies. Recurrent miscarriage is usually defined as three consecutive pregnancy losses, thus only the last of these patients could fullfil this definition, depending on the chronicity of her losses.

Successful pregancy outcome is observed in 71-76% of women following 2 consecutive miscarriages, and 67-69% of women following 3 consecutive miscarriages (Stirrat (1990) Lancet 15;336(8716):673-5). Thus the observed results in these three women could easily have happened by chance.

Of further concern, the prevalence of the MTHFR 667T/T genotype was reported to be 8% in an unselected newborn population from Wisconsin (Qi et al (2003) Genet Med. 5(6):458-9). Thus it is not uncommon to be homozygous for this mutation. To recommend treatment for a woman with no history of pregancy loss who is MTHFR 667T/T therfore seems over-enthusiastic.

Recombinant activated factor VII for emergency correction of coagulation before major surgery in the elderly.

Giuseppe Lippi — 2008-03-06T00:00:00Z

I read with interest the article of Angelo et al., describing two cases of orally anticoagulated patients over 75 years of age whose prolonged International Normalized Ratios (INRs) were corrected with prothrombin-complex concentrates (PCCs) ahead of surgical treatment of a bleeding ruptured spleen and for emergency surgery of a dissecting aorta (1). It was concluded that in the two presented cases PCC was effective and safe in reversing oral anticoagulation.

A timely reversal treatment of excessive anticoagulation is essential in several clinical circumstances, such as urgent surgery, along with an efficient anti-haemorrhagic prophylaxis to prevent further bleeding. According to available guidelines, current recommendations for emergency anticoagulant reversal mainly apply to adult patients independent of age and include the use of PCC. This strategy is however challenging in the elderly, since many studies reported orally anticoagulated patients mainly <75 years of age who are at lower risk of both, bleeding as well as atherothrombotic complications. In this respect, the article of Angelo et al. is valuable, in that it demonstrates that patients older than 75 years of age might benefit from PCC used for immediate correction of life-threatening INRs without additional risks or relevant side effects. However, it is also to mention that alternative strategies might be devised to overcome this problem besides PCC administration.

Recombinant activated factor VII (rFVIIa) is an hemostatic agent that was originally designed for the treatment of hemorrhage in patients with hemophilia and inhibitors. However, in the last few years rFVIIa has been employed successfully in a broad spectrum of congenital and acquired bleeding conditions and, on the whole, data in the literature suggest a potential role for rFVIIa in the management of bleeding unresponsive to standard therapy (2). Recent clinical evidences demonstrate that low-dose rFVIIa appears to be an effective, rapid reversal modality for major bleeding events in the presence of warfarin and an elevated INR (3-5), which can be efficaciously used also in emergency situations, such as urgent surgery (3). Moreover, due to the good correlation with factor VII clotting activity, a simple INR test can be reliably used for monitoring rFVIIa therapy (6). Preliminary reports indicate that besides its actual high costs, rFVIIa might be a useful and safe, noninvasive therapeutic tool in selected cases also in the elderly (7,8). Although trials with larger numbers of patients are needed to establish the most appropriate doses and timing of rFVIIa, especially in the aged population, and to assess its efficacy and safety in this particular clinical setting, I suggest that administration of rFVIIa might be a valuable prophylactic aid to urgently reverse elevated INRs ahead of surgery, thus preventing life-threatening haemorrhages.

References

1. Angelo M, Gutmann B, Adami M, Zagler B, Zelger A, Pechlaner C, Wiedermann CJ: Emergency correction of coagulation before major surgery in two elderly patients on oral anticoagulation. Thromb J 2007;5:1.

2. Franchini M, Veneri D, Lippi G: The potential role of recombinant activated FVII in the management of critical hemato-oncological bleeding: a systematic review. Bone Marrow Transplant 2007 Apr 9; [Epub ahead of print]

3. Dager WE, King JH, Regalia RC, Williamson D, Gosselin RC, White RH, Tharratt RS, Albertson TE: Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy 2006;26:1091-8.

4. Schulman S, Bijsterveld NR: Anticoagulants and their reversal. Transfus Med Rev 2007;21:37-48.

5. Ingerslev J, Vanek T, Culic S: Use of recombinant factor VIIa for emergency reversal of anticoagulation. J Postgrad Med 2007;53:17-22.

6. Lippi G, Montagnana M, Salvagno GL, Poli G, Franchini M, Guidi GC: Influence of warfarin therapy on activated factor VII clotting activity. Blood Coagul Fibrinolysis 2006;17:221-4.

7. Ali ZS, Al-Shaalan H, Jorgensen J: Successful treatment of massive acute lower gastrointestinal bleeding in diverticular disease of colon, with activated recombinant factor VII (NovoSeven). Blood Coagul Fibrinolysis 2006;17:327-9.

8. Dragani A, Di Bartolomeo E, La Barba G, Cavoni A, Lanzillotta P, Guizzardi G, Davì G: Recombinant activated factor VII therapy in acquired hemophilia of the elderly. Aging Clin Exp Res 2004;16:487-9.

Reactive Oxygen Species, Oxidative - Redox Stress Occur Upstream from Inflammation

Melvin Hayden — 2004-02-26T00:00:00Z

Dr. Altman,

Congratulations on your fine review aricle. I found it to be very informative and extrememly well written!

I think it is exciting that Redox Stress occurs upstream from the inflammatory process and is further induced by the inflammatory process creating a pernicious cycle of damage and dysfunction to the endothelial cell!

I work with Dr. Tyagi of reference 145 and we are quite interested in diabetes and homocysteine.

We think it is also exciting that the induced vasa vasorum acts as a custom delivery system to deliver the accelerated substrates to continue the ongoing inflammatory process within the atherosclerotic proinflammatory and prothrombotic vulnerable plaques. We also feel that diabetes is a vascular disease even before the diagnosis of overt type 2 diabetes.

Cardiovasular Diabetology: Vol 3:1 Feb 2004 Vasa vasorum....

Is type 2 diaabetes a vascular disease Feb 2003

INtimal redox stress.... Sept 2002

We are interested in your thoughts regarding von Willebrand factor in the setting of accelerated atherosclerosis --> atheroscleropathy,metabolic syndrome,and overt type 2 diabetes mellitus in atherothrombosis ?

Again, thank you for a great paper in this exciting field of study!

Sincerely,

M.R. (Pete) Hayden, M.D.

Adjunct Assistant Professor

Department of Family and Community Medicine

University of Missouri

School of Medicine