Warfarin necrosis

Warfarin necrosis is acquired protein C deficiency due to treatment with warfarin. In the initial stages of warfarin action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to paradoxical activation of coagulation and necrosis of skin areas.

Source = Wikipedia (article on protein C).

The FAB (old) classification of MDS, from Wikipedia

MDS is classified according to bone marrow findings:

• RA = refractive anaemia
  Myeloblasts less than 5%.
  Sideroblasts less than 15%.
  Pathology mostly confined to erythroid precursors.
• RARS = RA with ringed sideroblasts
  Myeloblasts less than 5%.
  Sideroblasts more than 15%.
• RAEB = RA with excess blasts
  Myeloblasts 5-20%.
• RAEBt = RAEB in transformation
  Myeloblasts 21-30% (more than 30% blasts = AML, by definition).
  
• CMML = chronic myelomonocytic leukaemia
  5-20% blasts + monocytes > 1000x10⁹cells/µL.

In the newer WHO classification CMML is no longer considered a MDS, but an overlap between MDS and MPD.

AIHAs = DAT+

This post is about autoimmune haemolytic anaemias.

AIHAs = antibody production against self RBCs.
AIHAs are characterised by a positive DAT (direct antiglobulin test), a.k.a. the Coombs' test.

Differential diagnosis of spherocytes = hereditary spherocytosis or haemolytic anaemia. Distinguish with DAT.

AIHAs are divided into 'warm' and 'cold' types, depending on whether the antibody reacts more strongly with RBCs at 37 or at 4 degrees Celsius.

Warm AIHAs

The most common antibody is IgG, though sometimes IgA and IgG with complement is found. The IgGs attach to RBCs, leaving their Fc portion exposed. The Fc region is recognized and grabbed onto by Fc receptors found on monocytes and macrophages in the spleen (RES). These cells will pick off portions of the RBC membrane, almost like they are taking a bite. The loss of membrane causes the red blood cells to become spherocytes to maintaim the same volume. Spherocytes are not as flexible as normal RBCs, and will be singled out for destruction in the red pulp of the spleen as well as other portions of the RES. The RBCs trapped in the spleen cause the spleen to enlarge, leading to the splenomegaly often seen in these patients. (Wikipedia)

IgG is a monomer, so there is no RBC agglutination in warm AIHA.

Lab findings are typical of an extravascular haemolytic anaemia with spherocytosis in the peripheral blood. DAT is positive as a result of IgG, IgG with complement or IgA on the cells. The antibodies both on the cell surface and free in serum are best detected at 37 degrees.

Rx:

1. Remove the underlying cause e.g. methyldopa.
2. Corticosteroids - start with prednisolone 60mg/d and taper. Those with predominantly IgG on cells do best whereas those with complement often respond poorly, both to steroids and splenomegaly.
3. Splenectomy if steroids fail to maintain satisfactory Hb level.
4. Immunosuppression when everything else fails, e.g. azathioprine, cyclophosphamide.
5. Monoclonal antibodies - anti-CD20 (rituximab) and anti-CD52 (Campath-1H).
6. Folic acid.
7. Blood transfusion if anaemia severe and causing symptoms. The blood should be the least incompatible and if the specificity of the autoantibody is known, donor blood is chosen that lacks the relevant antigen(s). The patients readily make alloantibodies against donor cells.
8. High-dose Ig has been used but with less success than in ITP.

Cold AIHAs
The antibody attaches to RBCs mainly in the peripheral circulation where the blood temperature is cooler.

The antibody is usually IgM (a polymer) and binds to RBCs best at 4 degrees.

IgM antibodies are highly efficient at fixing complement and both intravascular and extravascular haemolysis can occur. (Incomplete)

Haemolytic anaemias - a vital introduction

The breakdown of haemoglobin from red cells liberates:

• Iron for recirculation via plasma transferrin to marrow erythroblasts.
• Protoporphyrin --> Bilirubin --> Glucoronides --> Stercobilinogen & stercobilin. Stercobilin and stercobilinogen are partly reabsorbed and excreted in urine as urobilin and urobilinogen.
• Globin chains --> amino acids.

Haptoglobins are proteins present in plasma that bind Hb. The Hb-haptoglobin complex is removed from plasma via the RES.

RBCs are normally removed from blood by extravascular haemolysis; intravascular haemolysis plays no part.

Clinical features:

• Pallor of mucous membranes.
• Mild fluctuating jaundice and splenomegaly.
• There is no bilirubin in the urine but the urine may turn dark on standing due to excess urobilinogen.
• Pigment (bilirubin) gallstones.
• Some patients (esp with sickle cell disease) develop ulcers around the ankle.
• Aplastic crises may occur, usually precipitated by parvovirus infection which 'switches off' erythropoiesis, characterised by a sudden increase in anaemia and drop in reticulocyte count.
• Rarely, folate deficiency may cause an aplastic crisis in which the BM is megaloblastic.
  

Hereditary haemolytic anaemias are the result of intrinsic RBC defects; acquired haemolytic anaemias are usually the result of extracorpuscular change. The exception is paroxysmal nocturnal haemoglobinuria (PNH) - it is an acquired defect AND the RBCs have an intrinsic defect.

Lab findings:

1. Features of increased RBC breakdown:
   a) Serum bilirubin raised, uncongugated and bound to albumin.
   b) Urine urobilinogen increased
   c) Faecal stercobilinogen increased.
   d) Serum haptoglobins absent because they become saturated with Hb and the complex removed by the RES.
   
   
2. Features of increased RBC production:
   a) Reticulocytosis (--> MCV increased; polychromasia)
   b) BM erythroid hyperplasia. The normal BM myeloid:erythroid ratio of 2:1 to 12:1 is reduced to 1:1 or reversed.
   
   
3. Damaged RBCs:
   a) Morphology, e.g. microspherocytes, elliptocytes, fragments.
   b) Osmotic fragility, autohaemolysis, etc.
   c) RBC survival shortened as shown by 51Cr labelling with study of the sites of destruction. This test is now not widely available.
   

Classification of haemolytic anaemias:

• Hereditary:
  - Membrane: Hereditary spherocytosis, hereditary elliptocytosis.
  - Metabolism: G6PD deficiency, pyruvate kinase deficiency.
  - Haemoglobin abnormalities.
  
  
• Acquired:
  - Autoimmune: Warm antibody type, cold antibody type.
  - Alloimmune: Haemolytic transfusion reactions, haemolytic disease of the newborn, allografts esp BM transplantation.
  - Chemical and physical agents - drugs and burns.
  - Red cell fragmentation syndrome.
  - March haemoglobinuria.
  - Infections: malaria, clostridia.
  - Secondary: Liver and renal disease.
  - Paroxysmal nocturnal haemoglobinuria.

Intravascular haemolysis:
Free Hb is released which rapidly saturates plasma haptoglobins --> The excess free Hb is filtered by the glomerulus. If the rate of haemolysis saturates the renal tubular reabsorptive capacity, free Hb enters the urine and, as iron is released, the renal tubules become loaded with haemosiderin.

Methaemalbimun and haemopexin are also formed from the process of intravascular haemolysis.

Causes of intravascular haemolysis:

• Mismatched blood transfusion (usually ABO)
• G6PD deficiency with oxidant stress
• Red cell fragmentation syndromes
• Some autoimmune haemolytic anaemias
• Some drug- and infection-induced haemolytic anaemias
• PNH
• March haemoglobinuria
• Unstable haemoglobin

Lab features of intravascular hamolysis:

• Hb-aemia and Hb-uria
• Haemosiderinuria (iron storage protein in the spun deposit of urine).
• Methaemalbuminaemia (detected spectrophotometrically by Schumm's test).
  

Source: Essential Haematology page 61