Hemolytic anemia |

HEMOLYTIC ANEMIA

Bhagyavardhan Singh

Post graduate resident, department of medicine, LHMC

Hemolytic anemias are disorders characterized by a shortened lifespan of mature red blood cells (RBCs) in the peripheral blood where the rate of RBC destruction exceeds the capacity of bone marrow erythropoiesis to sustain normal levels of hemoglobin and hematocrit.

According to the cause, hemolysis can take place within the vasculature (intravascular hemolysis) or in the liver or spleen (extravascular hemolysis).

Hemolytic anemia can be intrinsic (intracorpuscular) due to defect of the red cell membrane or a red cell constituent (hemoglobin structure or enzyme machinery). Alternatively, hemolytic anemia can be extrinsic (extracorpuscular) due to acquired abnormality that attacks the RBC’s membrane (immune, infectious, toxic)

Autoimmune hemolytic anemia (AIHA) is a rare acquired autoimmune disease in which autoantibodies directed against autologous RBCs’ membrane antigens lead to their accelerated destruction. The presence of RBCs bound autoantibodies is demonstrated by a positive direct antiglobulin test (DAT) that is essential for diagnosis. AIHA is classified into warm or cold AIHA according to the temperature at which autoantibodies bind optimally to RBCs.

The disease may be primary, drug induced and associated with various viral infections such as mycoplasma, EBV, CMV, HIV, HCV, Parvo virus B19. AIHA might be first presentation of underlying hematogenous malignancies such as CLL, Multiple Myeloma, lymphoproliferative disorders and connective tissue disorders (SLE, RA, Scleroderma), immunodeficiencies, solid tumors, or transplants.

Rituximab and glucocorticoids are effective in warm AIHA. Splenectomy is indicated for patients who are refractory to medical therapy. C1-INH BERINERT, sirolimus, bortezomib, fostamatinib, bruton tyrosin kinase inhibitor, these newer agents have shown efficacy in treating warm AIHA. Rituximab combined with bendamustin/fludarabine has shown higher rate of complete remission in case of primary CAD. C1s inhibitor BIVV009 (sutimlimab) that is now entering phase 3 studies for CAD.

In an adult with an acquired DAT-negative intravascular hemolytic anemia, Paroxysmal nocturnal hemoglobinuria (PNH) should be suspected. It is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. PNH is a consequence of deficiency of the glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leading to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. Somatic mutations in phosphatidylinositol glycan class A (PIGA) gene is responsible for GPI anchor protein deficiency. It is diagnosed by flow cytometry

Eculizumab/Ravulizumab, a monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. These agents modify the natural history of PNH but has no effect on underlying disease process (i.e. on the PIGA mutant). Only cure for PNH is by allogenic hematopoietic stem cell transplantation.

Inherited defects of membrane protiens of RBC leads to alteration in shape resulting in premature destruction, seen clinically as hemolytic anemia. Hereditary spherocytosis, elliptocytosis, pyropoikilocytosis are the important ones among erythrocyte membrane disorders. In transfusion-dependent patients’ genetic diagnosis of deficient membrane protein should be considered before proceeding to the irreversible treatment of splenectomy.

G6PD deficiency is the most commen erythrocyte enzyme defect leading to hemolytic anemia which occurs due to stress imposed by infection, ingestion of oxidative drugs [dapson, primaquine, ciprofloxacin, cotrimoxazole, rasburicase ]and fava beans. Diagnosis is by quantitative assay or a screening test confirmation of the diagnosis by DNA analysis. Avoiding triggering factors, gene therapy and bone marrow transplantation are the treatment options.

When RBCs are forced through partial vascular occlusion or over abnormal vascular surfaces, it leads to their fragmentation and hemolysis. Thrombotic microangiopathy is term used for combination of MAHA and thrombocytopenia. It’s various causes are HUS, TTP, APLA, HELLP syndrome, DIC and disseminated malignancies. TTP is due to partial vascular obstruction caused by platelet aggregates in systemic microvasculature while HUS is caused by platelet fibrin thrombi in renal microvasculature. . TTP is characterized by severe deficiency of the von Willebrand cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). An ADAMTS13 activity level of less than 10% supports the diagnosis of TTP. treatment of acute TTP includes plasma exchange and corticosteroids. Rituximab can be used when TTP refractory to plasma exchange, splenectomy is the last resort if refractory to both PEX and immunosuppressive therapy. CAPLACUZIMAB [antiVWFdimeric nanobody] is the newer agent prooved to be efficacious in treatment of TTP.

HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. In strong clinical suspicion of TTP and HUS, first we evaluate ADAMTS13 activity and EHEC test, if we found <10% activity then diagnosis of TTP is confirmed, if there is >10% activity atypical HUS is considered while IF EHEC test positive, diagnosis of STEC-HUS is confirmed. Eculizumab is the first line therapy for atypical HUS in place of PEX. Steroids and rituximab can be given for atypical HUS caused by autoantibodies to complement factor H.

REFERENCES

American society of hematology update
William’s hematology, 10^thedition
Goldman-Cecil medicine, 26^thedition