Prosthetic Valve Haemolysis

Prosthetic valve haemolysis is intravascular red cell destruction caused by abnormal flow across a prosthetic valve or by a paravalvular leak. It causes anaemia, jaundice, iron deficiency and, in severe cases, heart failure and renal injury.

Mild compensated haemolysis is common after mechanical valve replacement. Clinically significant anaemia is uncommon and points to a paravalvular leak or to valve dysfunction, particularly obstruction, endocarditis or dehiscence.

Mechanical valves are the usual source. Haemolysis from bioprostheses is rare and nearly always is caused by a paravalvular leak. Older caged ball and tilting disc designs, small prostheses and mitral position carry more risk.

Causes of haemolysis that are unrelated to the valve must be excluded: autoimmune haemolytic anaemia, G6PD deficiency, thrombotic microangiopathy, sickle cell disease, malaria and drugs.

Pathophysiology.

High shear stress from regurgitant jets (paravalvular leak or transvalvular), high velocity flow across a small orifice, or contact with the valve or sewing ring fragments red cells.

Free haemoglobin binds haptoglobin, which is then depleted. Excess haemoglobin appears in urine as haemoglobinuria and haemosiderinuria, which depletes iron stores and causes iron deficiency despite haemolysis.

Free haemoglobin scavenges nitric oxide, which can cause vasoconstriction, pulmonary hypertension and renal injury. Anaemia also worsens heart failure, which in turn reduces cardiac output and increases jet velocity.

Fatigue, pallor, exertional dyspnoea, angina, jaundice, dark urine and worsening heart failure. A new regurgitant murmur suggests paravalvular leak, and an absent or muffled prosthetic click suggests valve dysfunction. Splenomegaly and pigment gallstones occur in chronic cases.

Fever, embolic phenomena or a new murmur point to endocarditis as the cause.

• Full blood count with reticulocyte count (raised), haemoglobin, and blood film for schistocytes (fragmented red cells).
• LDH (usually over 2 times the upper limit of normal), haptoglobin (low or undetectable), indirect bilirubin (raised), plasma free haemoglobin, urine haemosiderin, and a negative direct antiglobulin test.
• Ferritin, transferrin saturation, vitamin B12 and folate (folate is consumed in chronic haemolysis).
• Creatinine and urine analysis for pigment nephropathy.
• Transthoracic and transoesophageal echocardiography (including three dimensional) for paravalvular leak location, size and circumference, prosthetic leaflet motion, gradients and ventricular function. Cardiac CT where necessary.
• Blood cultures to exclude endocarditis. Tests to exclude other causes: G6PD assay (after the acute episode), ADAMTS13 activity when thrombocytopenia is present, malaria film where relevant, and sickle screening.

Differential diagnosis.

• Autoimmune haemolytic anaemia and drug induced haemolysis.
• Thrombotic thrombocytopenic purpura and other microangiopathy.
• G6PD deficiency, sickle cell disease and malaria.
• Iron deficiency or blood loss from anticoagulation, ineffective erythropoiesis and chronic kidney disease.

Treat the cause. A paravalvular leak with haemolysis is treated by closure, or by valve replacement when the leak cannot be closed. Obstruction needs the treatment for valve thrombosis or pannus. Endocarditis needs the full antibiotic and surgical treatment.

Supportive treatment for compensated or moderate haemolysis.

• Folic acid 5 mg orally once daily, long term while haemolysis persists; no renal adjustment.
• Iron replacement when ferritin is under 100 microgram/L or transferrin saturation is under 20%: ferrous sulphate 200 mg (65 mg elemental iron) orally once daily or on alternate days, with a vitamin C source, for at least 3 months and until stores are replete, checking ferritin and haemoglobin at 4 weeks. For intolerance, poor response or heart failure: ferric derisomaltose 20 mg/kg (maximum 1000 mg) intravenously as a single infusion over at least 20 minutes, or ferric carboxymaltose 500 to 1000 mg intravenously by weight and haemoglobin (maximum 1000 mg in a single dose); check phosphate after repeated doses.
• Beta blocker (for example metoprolol succinate 25 to 100 mg orally once daily, with a heart rate target of 60 to 70 beats/min where tolerated) to lower shear stress; the evidence is limited.
• Avoid unnecessary transfusion. Transfuse (leucocyte depleted units) when haemoglobin is under 7 g/dL, or under 8 g/dL with cardiovascular disease or symptoms, and give one unit at a time with reassessment.
• Erythropoiesis stimulating agent for persistent anaemia despite iron and folate in patients awaiting intervention (for example epoetin alfa 50 to 100 units/kg subcutaneously three times weekly, titrated to a haemoglobin of 10 to 11 g/dL; maximum haemoglobin 12 g/dL); monitor blood pressure and thrombotic risk, and ensure anticoagulation is therapeutic. Dose and agent are set with haematology.
• Maintain hydration, and monitor creatinine in significant intravascular haemolysis.
• Do not reduce the INR target to limit haemolysis.

Intervention.

• Indications: anaemia needing repeated transfusion, haemoglobin falling under 8 g/dL despite supportive treatment, heart failure from the leak, or progressive valve dysfunction.
• Transcatheter paravalvular leak closure with vascular plug or septal occluder devices in suitable anatomy (mitral and aortic); technical success is about 70 to 90%, and haemolysis improves in most patients when the leak is closed. Redo surgery (re-suture of the sewing ring or valve re-replacement) is used for large or multiple leaks, dehiscence, infection or failed closure.
• Decision by a heart team with imaging and interventional experience.

Monitoring. Haemoglobin, reticulocytes, LDH, bilirubin and ferritin every 4 to 12 weeks initially, then every 3 to 6 months when stable; creatinine and urine at the same intervals; echocardiography yearly or when haemolysis worsens.

Referral and escalation. Refer all patients with significant haemolysis to a heart team and haematology. Urgent referral for haemoglobin under 8 g/dL or a fall of 2 g/dL or more, new heart failure, fever (possible endocarditis), acute kidney injury or dark urine.

Special groups.

• Pregnancy: anaemia and haemolysis add to cardiac risk. Folic acid 5 mg daily and iron are continued; intravenous iron is used from the second trimester; erythropoiesis stimulating agents are used with specialist input.
• Kidney impairment: pigment nephropathy risk; adjust epoetin dose and monitor haemoglobin; avoid nephrotoxins.
• Children: weight based iron and folate dosing; early referral for closure or replacement.
• Region specific: malaria, hookworm, G6PD deficiency and sickle cell disease are frequent alternative or additional causes of anaemia and must be excluded before attributing anaemia to the valve.