Cancer Treatment Today » Coagulation

When and how to test for Factor V Leiden mutation – pro

M Levin, MD — Sun, 02 Sep 2012 13:11:46 +0000

The two situations that bring about testing for Factor V Leiden are when an individual presents with a clotting complication, such as Deep Venous Thrombosis(DVT), or when a family history brings him or her for a consultation. American College of Medical Genetics offered a guideline in 2007. There is a consensus that testing should be performed in at least the following circumstances (these are
the same general recommendations for testing for any thrombophilia):
􀁺 Age <50, any venous thrombosis.
􀁺 Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins).
􀁺 Recurrent venous thrombosis.
􀁺 Venous thrombosis and a strong family history of thrombotic disease.
􀁺 Venous thrombosis in pregnant women or women taking oral contraceptives.
􀁺 Relatives of individuals with venous thrombosis under age 50.
􀁺 Myocardial infarction in female smokers under age 50.
Testing may also be considered in the following situations:
􀁺 Venous thrombosis, age >50, except when active malignancy is present.
􀁺 Relatives of individuals known to have factor V Leiden. Knowledge that they have factor V Leiden may
influence management of pregnancy and may be a factor in decision-making regarding oral
contraceptive use.
􀁺 Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption,
intrauterine fetal growth retardation, or stillbirth.

Knowledge of factor V Leiden carrier status may influence management of future pregnancies. Most laboratories screen ‘at risk’ patients with either a snake venom (e.g. dilute Russell’s viper venom time) based test or an aPTT based test. In both methods, the time it takes for blood to clot is shortened in the presence of the factor V Leiden mutation. This is done by running two tests simultaneously, one test is run in the presence of activated protein C (APC) and the other, in the absence. A ratio is determined based on the two tests and the results signify to the laboratory whether APC is working or not. These are quick, three minute, automated tests that most hospital laboratories can easily perform.

On the other hand, when family history brings a patient to a workup, only the specific mutation analysis test should be performed. The mutation (a 1691G→A substitution) removes a cleavage site of the restriction endonuclease MnlI, so PCR, treatment with MnlI, and then DNA electrophoresis will give a diagnosis.

For patients who are suspected to have the Factor V Leiden mutation, the recommended tests is the direct mutation analysis. If positive, only testing for prothrombin 20210A is recommended.

Wayne W. Grody et al, American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing Genetics in Medicine (2001) 3, 139–148

Herskovits AZ, Lemire SJ, Longtine J, Dorfman DM (November 2008). “Comparison of Russell viper venom-based and activated partial thromboplastin time-based screening assays for resistance to activated protein C”. American Journal of Clinical Pathology 130 (5): 796–804.

Segers K, Dahlbäck B, Nicolaes GA (September 2007). “Coagulation factor V and thrombophilia: background and mechanisms”. Thrombosis and Haemostasis 98 (3): 530–42.

http://www.acmg.net/StaticContent/StaticPages/Factor_V.pdf

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Rituxan and Campath for coagulation inhibitors – pro

M Levin, MD — Mon, 27 Aug 2012 17:42:16 +0000

In general, acquired pan-inhibitors represent a rare and difficult to treat problem, with serious consequences for the patient. Most experience is in the setting of hemophilia. The optimal therapeutic strategy for inhibitor eradication is not yet been defined and is based on immunosupression. The immunosuppressive regimen most
have included corticosteroid therapy alone or in combination with cyclophosphamide.
The response rate reported in the literature is variable: corticosteroids 42-70%, corticosteroids + cyclophosphamide 50-84%. A retrospective
registry in the UK showed no difference in inhibitor eradication or disease-free survival between these two therapies. Recent reports have shown promising results
with Rituxan. A recent literature review based on uncontrolled studies or case reports suggests remission obtained in 79% of patients (N=43)
and no reported cases of opportunistic infections. At present this drug is recommended as second line therapy if cyclophosphamide and/or corticosteroids have failed or were contraindicated.

Recently, a combination of two immunosupressives was reported as a case series of low-dose rituximab plus alemtuzumab in patients with steroid-refractory autoimmune hemolytic anemia and immune thrombocytopenic purpura. There were 22 patients and 19 were assessable. Treatment with 10 mg of alemtuzumab subcutaneously on days 1 to 3, plus 100 mg of rituximab intravenously weekly in 4 doses, was administered. The overall response rate was 100%, with complete response in 58%. The median response duration was 46 weeks (range, 16-89 weeks). Median follow-up was 70 weeks (range, 37-104 weeks). Most toxicity was grade 1 fever related to the first dose. Six patients developed infections. The authros concluded that the combination of rituximab and alemtuzumab is feasible and has an acceptable safety profile and remarkable clinical activity in this group of patients.

http://www.thd.org.tr/html/36thd/Francesco_Baudo.pdf

Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Levesque H, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009;94:566-75.

David Gómez-Almaguer, et al, Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias Blood 2010 116:4783-4785

Celebrex for hemophilia – pro

M Levin, MD — Mon, 27 Aug 2012 17:40:32 +0000

Individuals with bleeding disorders may require analgesics like do other patients. This includes individuals with hemophilia and joint pain associated with acute hemorrhages or chronic hemophilic arthropathy, as well as women with a bleeding disorder (e.g. von Willebrand disease) who suffer menorrhagia and menstrual pain. Although COX-2 inhibitors are not associated with platelet dysfunction in vitro, there are anecdotal reports that use of these drugs has caused clinically significant bleeding in some individuals with bleeding disorders. Whether similar risks exist with other NSAIDS, such as ibuprofen or naproxen, and whether these risks apply to individuals with bleeding disorders is not yet established.

For these reasons, caution is advised with the use of COX-2 agents (e.g. celecoxib) in individuals with bleeding disorders. Whenever possible, alernative anlgesics should be used. The National Hemophilia Foundatoion and Candadian Hemophila Foundation both recommend coution in using it. I quote: ”
1.Caution is advised with use of COX-2 inhibitors in individuals with bleeding disorders. The potential risks of gastrointestinal bleeding, heart attack, and strokes should be weighed against the potential benefits.

2. Individuals sensitive to sulfa should be aware that the COX-2 inhibitor, celecoxib (Celebrex®), contains sulfa groups which may precipitate allergic reactions.

3. Research should be conducted to determine whether alternative COX-2 inhibitors not currently available, such as refecoxib (Vioxx) which does not contain sulfa, can be safely used in lower doses in individuals with bleeding disorders.

4. Special attention should be paid to the use of COX-2 inhibitors in children, in whom thromboembolic risks remain to be assessed”.

Although Celbrex has less effect on platelets thatn traditonal nonsteroidals, it remains unexplored and I did not find studies of it in hemophila. It is not supported by guidelines.

http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=176