Men Should Receive Lifelong Anticoagulation Following Unprovoked DVT or PE

The current standard of care is to treat subjects who have a provoked venous thromboembolism (VTE-either DVT or PE) with anticoagulation for 3 months. In those who have an unprovoked VTE (no history of leg fracture, leg in cast, immobility for > 3 days, major surgery within 3 months or diagnosed cancer) for 6 months. However, many subjects in this latter group have "catch-up" thromboembolism once anticoagulation is stopped.

Two observations should prompt a change in current practice.

Firstly, several studies, particularly two papers published in 2008 and 2016 from Canada, have shown that men run a far higher risk of recurrent DVT/PE over a follow up period of around 5 years after stopping anticoagulation following an index event. (7.6% annually in men v 2.8% in women). The average risk of repeat VTE in the first year is around 10% when both genders are combined. In the second year, this falls to 5%. Subsequently, the risk remains constant at around 3% per year. Over 8 years, the cumulative risk of recurrent VTE across both genders is ~30%. For men, this risk is higher at around 40%.

Women are not completely safe, however. Among women, using a risk stratifier called HERDOO2 (explained soon), women with 0 or 1 risk factors had a very low risk of recurrent VTE after stopping anticogulation, while women with 2 or more risk factors, had a risk of recurrent VTE only slightly lower than men (approximately 1% annually in low risk women and 6% in high risk women).

HERDOO2 includes HER-Hyperpigmentation, pretibial Edema, and Redness, all indicators of post thrombotic syndrome measured at ~6 months after the index DVT or PE in either leg. D is serum D-Dimer of >250 ug/ml, measured while on anticoagulation, the first O is Obesity (BMI>30) and the 2nd O is for Old age (>65 years).

HERDOO2 should only be used to risk stratify women. All men are at a higher risk of recurrent VTE.

Across all risk groups, continuing anticoagulation reduces the risk of a repeat VTE episode by around 80%.

What about mortality benefit? In low risk women, the risk of dying from major haemorrhage while on anticoagulation is around the same as the risk of dying from recurrent VTE if anticoagulation is stopped after 6 months. However, in men and high risk women, continuing anticoagulation reduces the risk of death from repeat VTE from 1.4% over 8 years to less than 0.3%. The risk of dying from a major bleed while on anticoagulation over the same period is 1.1%.

The second observation comes from two recent papers that show that in subjects receiving newer oral anticoagulants (NOACs), maintenance treatment with low dose NOAC (10 mg with rivaroxaban or 2.5 mg BD with apixaban daily) has the same benefit in terms of VTE prevention as maintenance with full dose NOAC (20 mg of rivaroxaban or 5 mg BD of apixaban daily) with similar or lower risk of bleeding as placebo (in the first study) or aspirin (in the second study), although the risk of bleeding in general was low across all treatment groups. All subjects received full dose NOAC for the first 6-12 months after the index VTE.

There is thus a strong case for maintaining men and high risk women with unprovoked VTE on lifelong low dose apixaban or rivaroxaban after an initial 6-month period of full dose anticoagulation. Current practice needs to change.

References.
1. Rodger MA, Scarvelis D, Kahn SR, et al. Long-term risk of venous thrombosis after stopping anticoagulants for a first unprovoked event: a multi-national cohort. Thromb Res 2016;143:152-158
2. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708
3. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. DOI: 10.1056/NEJMoa1700518

Non-Intuitive Medicine: Using Anti-D to Treat ITP

Most people are aware of the consequences of Rhesus incompatibility. It's usually the 2nd pregnancy. The mother is Rhesus negative. The father is Rhesus positive and has the D antigen. The foetus inherits the D antigen from the father. The mother's immune system mounts an attack on the D iso-antigens in the child's blood, resulting in haemolysis, sometimes ending fatally in erythroblastosis foetalis.

Now countenance this. Would you consider infusing a patient known to be Rhesus positive with pre-formed antibodies to the Rhesus(D) antigen, deliberately risking haemolysis?

No, I thought not.

Yet, that is exactly what happens in in subjects with severe Idiopathic Thrombocytopenic Purpura (ITP) who have life threatening haemorrhage. If the patient is D+, he/she is infused with anti-D containing immunoglobulin. IgG antibodies to the D antigen agglutinate the subjects' RBCs. Macrophages, mainly in the spleen, recognise the Fc portion of the anti-D immunoglobulins to bind to the D antigen on RBC and take them up actively. In so doing, the reticulo-endothelial system becomes saturated with millions of antibody-agglutinated RBC and is no longer free to bind to and destroy the platelets.

Medicine in reverse.

Of course, a better known agent for treating ITP is intravenous immunoglobulin (IVIG). It was from observing the small incidence of haemolysis in subjects receiving IVIG that the idea of using anti-D arose. Anti-D has a number of advantages over IVIG. These include a substantially shorter infusion time, markedly smaller infusion volume, longer duration of response demonstrated in HIV-infected patients with ITP, lower cost, and exposure to 1/100th as many donors per dose. Increased platelet count is seen in 70-80% of patients receiving anti-D. The dose is 50-75 ug/kg. It is licensed for this purpose in the USA but not in Europe, where plasmapheresis and romiplostim (thrombopoetin agonist) are used in addition to IVIG for treating major bleeding (intracranial or gastrointestinal) in severe ITP.

Anti-D is not without its dangers with such usage. Approximately 1 in 1000 patients develop severe transfusion reactions, with extravascular haemolysis, and increased risk of DIC and acute renal failure. This has resulted in a Black Box warning being issued by the FDA for such usage. However, in most patients, the degree of haemolysis is mild, with Hb dropping by 0.5-2g within a week, and recovering by 3 weeks.

Understandably, anti-D should not be used in those with pre-existing haemolysis, in those with a positive Coomb's test or those with renal impairment. It is ineffective in those who have had a splenectomy. Some haematologists never use anti-D despite its advantages, and prefer IVIG instead.

IgG anti-D does not bind complement. There is therefore no intravascular haemolysis. Haptoglobin and haemopexin do not fall.

References:

1. Despotovic JM, Lambert MP, Herman JH et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy. Transfusion 2012;52:1125-6.