Acquired Haemolytic anaemia

Acquired Haemolytic Anaemia Immune 1.Autoimmune *warm Ab *cold Ab 2.Alloimmune *Transfusion rn *HDN Non Immune 1.Mechanical *March haemoglobinuria *Prosthetic heart valves 2.MAHA 3.Infections *Malaria *Clostridium welchii 4.Burns 5.Drugs *Dapsone 6.PNH

18 year old girl C/O - fever, yellow discolouration of eyes and abdominal pain – 2 weeks O/E – Pale ++, Icteric +, Spleen – 1cm 1. How would you confirm haemolysis? 2. What are the possible causes?

Warm autoimmune haemolytic anaemia Antibodies optimally active at IgG Antibodies optimally active at IgG Causes Causes*Idiopathic*secondarySLECLLLymphomas Drugs- Methyl dopa

Warm autoimmune haemolytic anaemia cont. Pathogenesis IgG antibodies are present on the red cells, some of them also bind complement(C3) IgG antibodies are present on the red cells, some of them also bind complement(C3) Red cells are destroyed mainly in the RE system (preferentially spleen) Red cells are destroyed mainly in the RE system (preferentially spleen)

Warm autoimmune haemolytic anaemia cont. Clinical features Haemolytic anaemia Haemolytic anaemia Jaundice Jaundice Splenomegaly SplenomegalyInvestigations Reticulocytosis Reticulocytosis Spherocytes Spherocytes Increased serum bilirubin Increased serum bilirubin Positive direct coomb test Positive direct coomb test

Warm autoimmune haemolytic anaemia cont. Treatment Corticosteroids Corticosteroids Splenectomy Splenectomy Immunosuppresives- Azathioprine Immunosuppresives- Azathioprine Folic acid Folic acid Treat underlying cause Treat underlying cause

Cold autoimmune haemolytic anaemia Auto antibodies (IgM) that react best at temp. <37 0 (0-4 0 ) Auto antibodies (IgM) that react best at temp. <37 0 (0-4 0 )Causes *Idiopathic (CHAD) *secondaryMycoplasma Infectious mononucleosis LymphomaSLE

Cold autoimmune haemolytic anaemia cont. Investigations Anaemia with Anaemia with red cell agglutinates red cell agglutinates Macrocytosis Macrocytosis Reticulocytosis Reticulocytosis Positive direct coomb test Positive direct coomb test Features of IV haemolysis Features of IV haemolysis RBC – 1.1x10 12 /l RBC – 1.1x10 12 /l HB - 6.2g/dl HB - 6.2g/dl MCV – 112fl MCV – 112fl

Cold autoimmune haemolytic anaemia cont. Clinical features Some have acute IV haemolysis & Hburia in cold weather but maintain a normal Hb in warm weather Some have acute IV haemolysis & Hburia in cold weather but maintain a normal Hb in warm weather Others have a compensated chronic haemolysis with a mild to moderate reduction of Hb. Others have a compensated chronic haemolysis with a mild to moderate reduction of Hb. Acrocyanosis, Raynauds phenomenon due to agglutinates. Acrocyanosis, Raynauds phenomenon due to agglutinates. Spleen may not be enlarged Spleen may not be enlarged

Cold autoimmune haemolytic anaemia cont. Investigations Anaemia with red cell agglutinates Anaemia with red cell agglutinates Macrocytosis Macrocytosis Reticulocytosis Reticulocytosis Positive direct coomb test Positive direct coomb test Features of IV haemolysis Features of IV haemolysis

Cold autoimmune haemolytic anaemia cont. Treatment Avoid cold Avoid cold May need blood transfusions May need blood transfusions Rituximab (monoclonal anti CD20) Rituximab (monoclonal anti CD20) Chlorambucil Chlorambucil Plasmapheresis has been used Plasmapheresis has been used Corticosteroids and splenectomy are rarely of any benefit Corticosteroids and splenectomy are rarely of any benefit

Allo immune

ABO & Rh incompatibilty Haemolytic transfusion reactions may be immediate or delayed. Haemolytic transfusion reactions may be immediate or delayed. Immediate life threatening reactions associated with massive IV haemolysis is seen with complement activating antibodies of IgM & IgG classes(ABO antibodies) Immediate life threatening reactions associated with massive IV haemolysis is seen with complement activating antibodies of IgM & IgG classes(ABO antibodies) Severity of the reaction depends on the recipient’s titre of antibody Severity of the reaction depends on the recipient’s titre of antibody

ABO & Rh incompatibilty cont. Extra vascular haemolytic transfusion reactions are seen with the immune antibodies( IgG, unable to bind complement). Extra vascular haemolytic transfusion reactions are seen with the immune antibodies( IgG, unable to bind complement). The only feature may be unexplained anaemia with jaundice The only feature may be unexplained anaemia with jaundice

Non immune causes of haemolysis Mechanical causes of haemolysis Red cells may be injured by excess physical trauma as they circulate through the vascular system. Red cells may be injured by excess physical trauma as they circulate through the vascular system.

Mechanical haemolytic anaemia Cardiac – Occasional complication of open heart surgical procedures eg. valve prostheses. In severe cases marked anaemia with intravascular haemolysis. Cardiac – Occasional complication of open heart surgical procedures eg. valve prostheses. In severe cases marked anaemia with intravascular haemolysis. March haemoglobinuria – Hbnaemia & Hburia following strenuous exercise in healthy young adult males. March haemoglobinuria – Hbnaemia & Hburia following strenuous exercise in healthy young adult males. Traumatic effect on the blood within vessels of sole. Traumatic effect on the blood within vessels of sole. soldiers, athletes, karatekas. soldiers, athletes, karatekas.

Microangiopathic haemolytic anaemia Mechanical haemolytic anaemia in which the red cell fragmentation is due to contact between red cells & abnormal intima of partly thrombosed, narrowed, or necrotic small vessels. Mechanical haemolytic anaemia in which the red cell fragmentation is due to contact between red cells & abnormal intima of partly thrombosed, narrowed, or necrotic small vessels.

Microangiopathic haemolytic anaemia With associated thrombocytopaenia With associated thrombocytopaenia 1.Disseminated intravascular coagulation 1.Disseminated intravascular coagulation 2.Haemolytic uraemic syndrome 3.Thrombotic thrombocytopaenic purpura 4. HELLP syndrome

DIC Widespread intra vascular coagulation induced by pro coagulants (that overcome the natural anti coagulant mechanisms), resulting in the formation of thrombin. Widespread intra vascular coagulation induced by pro coagulants (that overcome the natural anti coagulant mechanisms), resulting in the formation of thrombin. These pro coagulants may be produced in the blood or introduced from out side the circulatory system eg- snake venom These pro coagulants may be produced in the blood or introduced from out side the circulatory system eg- snake venom This results in- This results in- Formation of micro thrombi Ischemia Formation of micro thrombi Ischemia Consumption of platelets & Consumption of platelets & clotting factors Bleeding clotting factors Bleeding

DIC cont. Causes Causes*Trauma*Cancers*Bacteraemia *Severe Haemorrhage *Obstetric & surgical events

DIC cont. Investigations Fragmented red cells Fragmented red cells Low platelet count Low platelet count Prolongation of PT, aPTT, TT, Low fibrinogen Prolongation of PT, aPTT, TT, Low fibrinogen Elevated FDP, D dimers Elevated FDP, D dimers

HUS-TTP Initially described as two distinct entities but thereafter thought to be two ends of the same spectrum. ? Two distinct entities Initially described as two distinct entities but thereafter thought to be two ends of the same spectrum. ? Two distinct entities Formation of platelet thrombi (hyaline thrombi) in terminal arterioles & capillaries. Formation of platelet thrombi (hyaline thrombi) in terminal arterioles & capillaries. Microangiopathic haemolytic anaemia with Thrombocytopaenia Microangiopathic haemolytic anaemia with Thrombocytopaenia

HUS-TTP Clinical features Fever Fever Neurological symptoms Neurological symptoms Renal failure Renal failure+ MAHA MAHA Thrombocytopenia Thrombocytopenia Coagulation screen – NORMAL Coagulation screen – NORMAL LDH - high LDH - high

Causes of HUS E.Coli o157 toxin E.Coli o157 toxin Shigella dysenteriae Shigella dysenteriae

TTP Pathogenesis Pathogenesis Presence of abnormal vwf (platelet adhesion) Presence of abnormal vwf (platelet adhesion) Deficiency of vwf cleaving proteases ADAMTS-13 Deficiency of vwf cleaving proteases ADAMTS-13 Increase in vwf activity, platelet aggregation Increase in vwf activity, platelet aggregation Microthrombi formation Microthrombi formation

Causes of TTP Inherited deficiency of ADAMTS 13 Inherited deficiency of ADAMTS 13 Present in neonatal periodPresent in neonatal period Acquired deficiency of ADAMTS 13 Acquired deficiency of ADAMTS 13 Drugs- clopidogrel, ticlopidine, ciclosporineDrugs- clopidogrel, ticlopidine, ciclosporine Post transplantPost transplant PregnancyPregnancy SLESLE

TTPTreatment Plasma exchange Plasma exchange FFP/CPP FFP/CPP Steroids / immunosuppresion Steroids / immunosuppresion Platelets not given Platelets not given Rituximab Rituximab

HELLP syndrome HELLP syndrome occurs in approximately 0.2 to 0.6 % of all pregnancies. HELLP syndrome occurs in approximately 0.2 to 0.6 % of all pregnancies. Pre eclampsia occurs in 5 to 7 % percent of pregnancies. Pre eclampsia occurs in 5 to 7 % percent of pregnancies. Superimposed HELLP syndrome develops in 4 to 12 percent of women with pre eclampsia or eclampsia. Superimposed HELLP syndrome develops in 4 to 12 percent of women with pre eclampsia or eclampsia.

HELLP The pathogenesis of HELLP is not well understood. The pathogenesis of HELLP is not well understood. Findings are attributed to abnormal vascular tone, vasospasm and coagulation defects. Findings are attributed to abnormal vascular tone, vasospasm and coagulation defects. No common precipitating factor has been found. No common precipitating factor has been found. Some insult that leads to microvascular endothelial damage and intravascular platelet activation. Some insult that leads to microvascular endothelial damage and intravascular platelet activation. Platelet activation, causing vasospasm, platelet agglutination and aggregation, and further endothelial damage. Platelet activation, causing vasospasm, platelet agglutination and aggregation, and further endothelial damage. Fibrin forms networks in the small bld vsl. Fibrin forms networks in the small bld vsl. Liver appears to be the main site of this process Liver appears to be the main site of this process This cascade is only terminated with delivery. This cascade is only terminated with delivery.

HELLP MAHA. MAHA. Elevated liver enzyme levels are thought to be secondary to obstruction of hepatic blood flow by fibrin deposits in the sinusoids. Elevated liver enzyme levels are thought to be secondary to obstruction of hepatic blood flow by fibrin deposits in the sinusoids. This obstruction leads to periportal necrosis and, in severe cases, intrahepatic haemorrhage, subcapsular hematoma or hepatic rupture. This obstruction leads to periportal necrosis and, in severe cases, intrahepatic haemorrhage, subcapsular hematoma or hepatic rupture. The thrombocytopenia has been attributed to increased consumption and/or destruction of platelets. The thrombocytopenia has been attributed to increased consumption and/or destruction of platelets.

HELLP PT, APTT, Fbrinogen usually normal PT, APTT, Fbrinogen usually normal DIC is also seen in about 20% of all women with HELLP syndrome DIC is also seen in about 20% of all women with HELLP syndrome Fibrinogen <3g/l in this setting suspect DIC Fibrinogen <3g/l in this setting suspect DIC

Infections Malaria – anaemia is often only mild Malaria – anaemia is often only mild *can be severe esp.with falciparum infections *Blackwater fever rare but serious complication, seen in endemic areas & in those who have seen in endemic areas & in those who have repeated attacks. Pptd by antimalarial drugs. repeated attacks. Pptd by antimalarial drugs. *Diagnosis by demonstrating the parasite. *Antigen tests *Antigen tests

Infections Clostridium welchii – due to direct action of toxin Clostridium welchii – due to direct action of toxin *mostly post abortal or puerperal infections *Intra vascular spherocytic anaemia, retic count not very high not very high

Drugs Due to direct toxic effects in normal subjects Due to direct toxic effects in normal subjects*Sulphasalazine Haemolysis in subjects with metabolic abnormality G6PD def Haemolysis in subjects with metabolic abnormality G6PD def *Primaquine, Nitrofurantoin Due to a immune mechanism Due to a immune mechanism *Quinine, Penicillin, Sulphonamides Toxins – Snake bite Toxins – Snake bite

Paroxysmal Nocturnal Haemoglobinuria Acquired chronic intra vascular haemolysis Acquired chronic intra vascular haemolysis May have thrombosis and pancytopenia May have thrombosis and pancytopenia Nonmalignant clonal expansion of one or several hematopoietic stem cells that have acquired a somatic mutation of PIGA Affected stem cells are deficient in glycosyl phosphatidylinositol–anchored proteins (GPI-APs)

Urine haemosiderin Urine haemosiderin HAM test HAM test Flow cytometry for GPI –AP Flow cytometry for GPI –AP LDH LDH Transfusion Transfusion Iron replacement Iron replacement

14 year old boy C/O - fever, yellow discolouration of eyes and abdominal pain – 2 weeks O/E – Pale ++, Icteric +, Spleen – 1cm What are the first line investigations?