HEMOGLOBINURIA 111

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HEMOGLOBINURIA:

HEMOGLOBINURIA BY SHASHIDHAR PATIL

Heamoglobinuria:

Heamoglobinuria H emoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in high concentrations in the urine. The condition is often associated with hemolytic anemia, in which red blood cells are destroyed, thereby increasing levels of free plasma hemoglobin . The excess hemoglobin is filtered by the kidneys, which release it into the urine, giving urine a red colour .

Classification of Hemolytic anemias I. Red cell abnormality (Intracorpuscular factors) A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) B. Acquired 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH) :

Classification of Hemolytic anemias I. Red cell abnormality (Intracorpuscular factors) A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) B. Acquired 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria ( PNH)

II. Extracorpuscular factors A. Immune hemolytic anemias 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood B. Nonimmune hemolytic anemias 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), venons 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves 4. Hypersplenism:

II. Extracorpuscular factors A. Immune hemolytic anemias 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood B. Nonimmune hemolytic anemias 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), venons 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves 4. Hypersplenism

Metabolic Defect:

Metabolic Defect G6PD deficiency Hexose monophosphate shunt Most common RBC enzyme defect, >50 variants X-linked Low glutathione due to low NADPH Oxidative lysis, Heinz bodies, spherocytic Primaquine, fava beans Pyruvate kinase deficiency Glycolysis Low RBC ATP level Non-spherocytic B12 and folate deficiency Macrocytic HJ bodies Hemoglobinopathies Poikilocytosis Abnormal Hb

Extracorpuscular Factors:

Extracorpuscular Factors Antibodies Autoimmune Isoimmune Drugs, antibiotics Fresh water Abnormal plasma lipids Acanthocytosis Venom Snake Spider Bee

Extracorpuscular Factors:

Extracorpuscular Factors Trauma DIC Hemolytic uremic syndrome (HUS) TTP Angiopathy Heat Heart valves “March” hemoglobinuira Microorganisms Malaria Babesia Clostridium Gram negative endotoxin

Mechanisms of hemolysis: - intravascular - extravascular :

Mechanisms of hemolysis: - intravascular - extravascular

Intravascular hemolysis : - red cells destruction occurs in vascular space - clinical states associated with Intravascular hemolysis: acute hemolytic transfusion reactions severe and extensive burns paroxysmal nocturnal hemoglobinuria severe microangiopathic hemolysis physical trauma bacterial infections and parasitic infections (sepsis) :

In t ravascular hemolysis : - red cells destruction occurs in vascular space - clinical states associated with Intravascular hemolysis: acute hemolytic transfusion reactions severe and extensive burns paroxysmal nocturnal hemoglobinuria severe microangiopathic hemolysis physical trauma bacterial infections and parasitic infections (sepsis)

Intravascular hemolysis : - laboratory signs of intravascular hemolysis: indirect hyperbilirubinemia erythroid hyperplasia hemoglobinemia methemoalbuminemia hemoglobinuria absence or reduced of free serum haptoglobin hemosiderynuria :

In t ravascular hemolysis : - laboratory signs of intravascular hemolysis : indirect hyperbilirubinemia erythroid hyperplasia hemoglobinemia methemoalbuminemia hemoglobinuria absence or reduced of free serum haptoglobin hemosiderynuria

Extravascular hemolysis : - red cells destruction occurs in reticuloendothelial system - clinical states associated with extravascular hemolysis : autoimmune hemolysis delayed hemolytic transfusion reactions hemoglobinopathies hereditary spherocytosis hypersplenism hemolysis with liver disease - laboratory signs of extravascular hemolysis: indirect hyperbilirubinemia increased excretion of bilirubin by bile erythroid hyperplasia hemosiderosis:

Extravascular hemolysis : - red cells destruction occurs in reticuloendothelial system - clinical states associated with extravascular hemolysis : autoimmune hemolysis delayed hemolytic transfusion reactions hemoglobinopathies hereditary spherocytosis hypersplenism hemolysis with liver disease - laboratory signs of extravascular hemolysis: indirect hyperbilirubinemia increased excretion of bilirubin by bile erythroid hyperplasia hemosiderosis

Paroxysmal Nocturnal Hemoglobinuria:

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria (PNH):

Paroxysmal Nocturnal Hemoglobinuria (PNH) PNH is an acquired chronic hemolytic anemia which arises from a somatic mutation in a hematopoietic stem cell. Most hematopoitic cell lines may be affected by the intrinsic membrane defect. This defect renders the red cells highly susceptible to complement mediated lysis resulting in the characteristic hemolysis.

History:

History Investigator Year Contribution Gull 1866 Described nocturnal and paroxysmal nature of “intermittent haematinuria” in a young tanner. Strubing 1882 Distinguished PNH from paroxysmal cold haemoglobinuria and march haemoglobinuria. Attributed the problem to the red cells. van den Burgh 1911 Red cells lysed in acidified serum. Suggested a role for complement. Enneking 1928 Coined the name “paroxysmal nocturnal haemoglobinuria”. Marchiafava 1928- Described perpetual hemosiderinemia in absence of and Micheli 1931 hemolysis. Their names became eponymous for PNH in Europe. Ham 1937- Identified the role of complement in lysis of PNH red 1939 cells. Developed the acidified serum test, also called the Ham test, which is still used to diagnose PNH. Demonstrated that only a portion of PNH red cells are abnormally sensitive to complement. Davitz 1986 Suggests defect in membrane protein anchoring system responsible Hall & Rosse 1996 Flow cytometry for the diagnosis of PNH

Epidemiology:

Epidemiology Rare disease - frequency unknown thought to be on the same order as aplastic anemia (2-6 per million) Median age at diagnosis ~ 35 yrs PNH reported at extremes of age Female:Male ratio = 1.2:1.0 No increased risk of PNH in patient relatives Median Survival after diagnosis ~ 10-15 yrs

Paroxysmal Nocturnal Hemoglobinuria:

Paroxysmal Nocturnal Hemoglobinuria Caused from a defect in the production of GPI protein anchors on the surface of all blood cells produced by the PNH bone marrow stem cells This is an acquired mutation of PIG-A, a gene on the X chromosome important in making GPI protein anchors. Only blood cells have the defect. Defect makes the red cells in particular susceptible to destruction by the complement system.

PNH:

PNH There are 2 main ways to attach proteins to the surface of cells-either through transmembrane attachments or GPI-anchors. Many proteins are attached to the surface by GPI anchors. PIG-A gene is vital to the production of GPI anchors. In PNH, you have a mutation in PIG-A so that it has reduced activity or no activity at all.

Pathogenesis - The Defect:

Pathogenesis - The Defect Defect - Somatic mutation of PIG-A gene (phosphatidylinositol glycan complementation group A) located on the X chromosome in a clone of a hematopoietic stem cell >100 mutations in PIG - A gene known in PNH The mutations (mostly deletions or insertions) generally result in stop codons - yielding truncated proteins which may be non or partially functional - explains heterogeneity seen in PNH

Pathogenesis - The Defect:

PIG - A gene codes for 60 kDa protein glycosyltransferase which effects the first step in the synthesis of the glycolipid GPI anchor (glycosylphosphatidylinositol). Results in clones lacking GPI anchor - in turn, attached proteins Pathogenesis - The Defect GPI Anchor PIG - A protein

Pathogenesis - The Defect GPI Anchor deficiency:

PNH blood cells deficient in GPI anchor lack membrane proteins linked via the anchor Membrane proteins w/o anchor degraded in ER Severity & size of deficiency - variable - clinical/diagnostic implications GPI anchor highly conserved in all eukaryotic cells Variant surface proteins of Trypanosomes - GPI linked Shed by cleavage of GPI anchor - immune system avoid Swapping GPI linked proteins - CD55 complement resistance - Schistosoma mansoni In Humans signal transduction, co-receptors advantage to this type of anchor? Pathogenesis - The Defect GPI Anchor deficiency

Proteins anchored by GPI Anchor and:

Proteins anchored by GPI Anchor and Surface Proteins Missing on PNH Blood Cells Antigen Expression Pattern Enzymes Acetylcholinesterase (AchE) Red blood cells Ecto-5'-nucleotidase (CD73) Some B- and T-lymphocytes Neutrophil alkaline phosphatase(NAP) Neutrophils ADP-rybosyl transferase Some T-lymphs, Neutrophils Adhesion molecules Blast-I/CD48 Lymphocytes Lymphocyte function- associated antigen-3(LFA-3 or CD58) All blood cells CD66b Neutrophils Complement regulating surface proteins Decay accelerating factor (DAF or CD55) All blood cells Homologous restriction factor, Membrance inhibitor of reactive lysis All blood cells (MIRL or CD59)

PowerPoint Presentation:

Surface Proteins Missing on PNH Blood Cells Antigen Expression Pattern Receptors Fc-  receptor III (Fc  Rlll or CD16) Neutrophils, NK-cells, macrophages, some T-lymphocytes Monocyte differentiation antigen Monocytes, macrophages (CD14) Urokinase-type Plasminogen Monocytes, granulocytes Activator Receptor (u-PAR, CD87) Blood group antigens Comer antigens (DAF) Red blood cells Yt antigens (AchE) Red blood cells Holley Gregory antigen Red blood cells John Milton Hagen antigen (JMH) Red blood cells, lymphocytes Dombrock reside Red blood cells Neutrophil antigens NB1/NB2 Neutrophils

PowerPoint Presentation:

Surface Proteins Missing on PNH Blood Cells Antigen Expression Pattern Other surface proteins of unknown functions CAMPATH-1 antigen (CDw52) Lymphocytes, monocytes CD24 B-lymphocytes, Neutrophils, eosinophils p5O-80 Neutrophils GP500 Platelets GPI75 Platelets

Pathogenesis - Functional consequences of lack of GPI linked proteins:

Pathogenesis - Functional consequences of lack of GPI linked proteins In vivo function of many of these membrane proteins not fully understood However, CD55 and CD59 functions are well known CD55 (decay accelerating factor) inhibits the formation or destabilizes complement C3 convertase (C4bC2a) CD59 (membrane inhibitor of reactive lysis, protectin, homologous restriction factor) Protects the membrane from attack by the C5-C9 complex Inherited absences of both proteins in humans have been described Most inherited deficiencies of CD55 - no distinct clinical hemolytic syndrome Inherited absence of CD59 - produces a clinical disease similar to PNH with hemolysis and recurrent thrombotic events

PowerPoint Presentation:

Mechanism for hemolysis in PNH via lack of CD59 (CD59) (CD59)

Pathogenesis - Clonal evolution and cellular selection:

Pathogenesis - Clonal evolution and cellular selection Expansion of abnormal hematopoietic stem cell required for PNH disease expression Theories for expansion Blood cells lacking GPI-linked proteins have intrinsic ability to grow abnormally fast In vitro growth studies demonstrate that there are no differences in growth between normal progenitors and PNH phenotype progenitors In vivo - mice deficient for PIG -A gene also demonstrates no growth advantage to repopulation of BM. Additional environmental factors exert selective pressure in favor of expansion of GPI anchor deficient blood cells PNH hematopoitic cells perferentially engraft SCID mice compared to phenotypically hematopoitic cells Close association with AA - PNH hematopoitic cells cells may be more resistant to the IS than normal hematopoitic cells. Evidence in AA is that the decrease in hematopoitic cells is due to increased apoptosis via cytotoxic T cells by direct cell contact or cytokines (escape via deficiency in GPI linked protein???)

PowerPoint Presentation:

Normal Hematopoietic Cells Membrane lipid bilayer Transmembrane protein CD55 CD59 GPI anchors

PNH:

PNH PNH red cells are deficient in all GPI anchored protein, but 2 are important in protecting red cells from destruction: CD55 (DAF) and CD59 (MIRL). Without these proteins, red cells don’t have their normal protection against the complement system. In PNH, you have uncontrolled, complement mediated hemolysis (destruction of red cells). This happens all the time, and is accelerated when you have an event that activates the complement system (infection).

How do you get PNH?:

How do you get PNH? This is an acquired disease. We think PIG-A mutations can happen spontaneously, but unless the environment is supportive of those mutations they never develop into PNH. In a bone marrow under attack or failing, PIG-A mutations have an advantage-they survive the attack better (for some reason). Therefore, the PNH cells have an advantage and can expand to become a significant portion of the bone marrow cells.

PowerPoint Presentation:

Two-Step Model of Developing PNH Normal Bone Marrow Normal bone marrow with normal HSC’s and rare PNH mutant HSC’s MARROW INJURY Step I. Clonal Selection Step II. Clonal Dominance Bone marrow damage (likely immune mediated) selects for clones. After selection, expansion of PIG-A mutant HSC’s varies depending on other characteristics of the affected cells. These other characteristics may be determined by genetic (mutational), epigenetic (nonmutational), or environmental factors.

How do we know PNH cells have an advantage?:

How do we know PNH cells have an advantage? PNH is found in diseases where the bone marrow is under attack or damaged: Aplastic anemia (up to 60% of patients with aplastic anemia have a detectable PNH clone). Myelodysplastic syndrome (MDS)-up to 20% of patients with MDS have an identifiable PNH clone Other immune-mediated diseases: ITP Blood cancers: leukemias-both chronic and acute Why the PNH cells have an advantage is unknown. Why the PNH cells expand to produce more blood cells is unknown.

How do you get PNH?:

How do you get PNH? Patients with PNH often have a history of aplastic anemia or other bone marrow injury PNH can come on later, after they have recovered from the initial bone marrow insult. You can have a little or a lot of PNH cells, and that can effect how the disease impacts the health of the patient.

PowerPoint Presentation:

Who Should be Tested for PNH? Patients with unexplained hemolytic anemia Patients with bone marrow failure, including aplastic anemia and MDS Patients with hemoglobinuria Patients with unusual/repetitive thrombosis, and arterial thrombosis otherwise unexplained. Patients with episodic swallowing problems or abdominal pain of unclear etiology with associated hemolysis

PNH symptoms:

PNH symptoms FATIGUE Anemia Decreased stamina Shortness of breath Abdominal pain Back pain Difficulty swallowing Chest pain Erectile dysfunction Decreased libido or interest in intimacy Headaches Swelling related to blood clots Increased risk for infections Increased risk for bleeding Depression, frustration, feeling lack of control over life Weight changes, body changes

PowerPoint Presentation:

Signs and Symptoms # of Px (%) Symptoms of anemia 28 (35) Hemoglobinuria 21 (26) Hemorrhagic signs and symptoms 14 (18) Aplastic anemia 10 (13) Gastrointestinal symptoms 8 (10) Hemolytic anemia and jaundice 7 (9) Iron-deficiency anemia 5 (6) Thrombosis or embolism 5 (6) Infections 4 (5) Neurologic signs and symptoms 3 (4) Presenting features in 80 patients with PNH Dacie and Lewis, 1972

Clinical Features:

Clinical Features Major symptoms (Hemolysis, Cytopenia, and tendency to thrombosis) chronic hemolysis with acute exacerbations (hallmark) most patient at some stage only 1/3 exhibit hemolysis at diagnosis Recurrent attacks of intravascular hemolysis are usually associated with; hemoglobinuria abdominal pain dysphagia

Clinical Features:

cytopenia (varying severity) isolated subclinical thrombocytopenia classical severe aplastic anemia tendency to thrombosis venous thrombosis (40%) of patients, main cause of morbidity Variable expression of above often causes considerable delay in the diagnosis Major cause of death venous thrombosis complications from progressive pancytopenia Clinical Features

Clinical Features - Long term:

25% of PNH patients survive >25 years - one half of these go on to spontaneous remission Remission patients hematological values revert to normal no PHN rbcs or granulocytes detected PNH lymphocytes - still detected but no clinical consequence Higher incidence of acute leukemia (6%) “preleukemic condition” most likely bone marrow failure not PNH Clinical Features - Long term

Clinical Features - Relationship to aplastic anemia (AA):

AA described as pancytopenia with nonfunctioning bone marrow. Cytopenia in one or all cell lineages also common to PNH High percentage of patients with AA develop clinical PNH or have lab evidence of PNH abnormality at some point (52 %) Supports the theory that bone marrow failure supports the abnormal PNH cells Clinical Features - Relationship to aplastic anemia (AA)

Natural History of PNH:

Natural History of PNH Long term study of 80 patients with PNH seen at one institution between 1940 and 1970 Results median age at diagnosis: 42 (16-75) median survival: 10 years 28% survived more than 25 years 39% had one or more episodes of venous thrombosis 12 experienced spontaneous clinical recovery leukemia did not develop in any of the patients Hillmen et al, NEJM, 1995

Laboratory Evaluation of PNH:

Laboratory Evaluation of PNH Acidified Serum Test (Ham Test 1939) Acidified serum activates alternative complement pathway resulting in lysis of patient’s rbcs May be positive in congenitial dyserythropoietic anemia Still in use today Sucrose Hemolysis Test (1970) 10% sucrose provides low ionic strength which promotes complement binding resulting in lysis of patient’s rbcs May be positive in megaloblastic anemia, autoimmune hemolytic anemia, others Less specific than Ham test

Laboratory Evaluation of PNH:

PNH Diagnosis by Flow Cytometry (1986) Considered method of choice for diagnosis of PNH (1996) Detects actual PNH clones lacking GPI anchored proteins More sensitive and specific than Ham and sucrose hemolysis test Laboratory Evaluation of PNH

PNH Diagnosis by Flow Cytometry:

PNH Diagnosis by Flow Cytometry Antigen Cell Lineage Function CD14 monocytes LPS receptor, MDF CD16 neutrophils Fc  III receptor CD24 neutrophils B-cell differentiation marker CD55 all lineages DAF CD58 all lineages possible adhesion CD59 all lineages MIRL, HRF, protectin CD66b neutrophils CEA-related glycoprotein Of the long list of GPI anchored protein, monoclonal antibodies to the following antigens have been used in the diagnosis of PNH The most useful Abs are to CD14, 16, 55, 59, and 66. Are all required? Probably not - more studies needed

PNH Diagnosis by Flow Cytometry:

Antigen expression is generally categorized into three antigen density groups type I Normal Ag expression type II Intermediate Ag expression type III No Ag expression Patient samples that demonstrate cell populations with diminished or absent GPI-linked proteins (Type II or III cells) with multiple antibodies are considered to be consistent with PNH . Should examine multiple lineages ( ie granulocytes & monocytes) PNH Diagnosis by Flow Cytometry

PNH Diagnosis by Flow Cytometry:

PNH Diagnosis by Flow Cytometry Examples of variable GPI linked CD59 expression on granulocytes on four PNH patients

PNH Diagnosis by Flow Cytometry:

PNH Diagnosis by Flow Cytometry Example of variable expression of several GPI linked Ags on several lineages From Purdue Cytometry CD-ROM vol3 97

PNH Diagnosis by Flow Cytometry:

Flow Cytometry is method of choice but only supportive for/against diagnosis More studies are needed to better define whether the type (I, II, or III), cell lineage, and size of the circulating clone can provide additional prognostic information. Theoretically - should be very valuable PNH Diagnosis by Flow Cytometry

PNH Complications:

PNH Complications Bone marrow failure-all the blood counts are low, bone marrow is not producing cells as it should be. Clots! Infections-either related to disease or complications of treatment (prednisone, eculizumab ) Bleeding-either from low blood counts or blood thinners for treatment/prevention of clots Risk of blood transfusions-the blood product pool is extremely safe at this time Cardiopulmonary issues related to nitric oxide scavenging by free hemoglobin-can cause high pressure in the lung system (pulmonary hypertension) that can damage the heart. Some can be reversed by eculizumab . Pregnancy

Implications of Living with PNH:

Implications of Living with PNH Quality of life issues Financial impacts Ability to work Costs of treatments/medical care Unpredictability Fear of complications Am I going to clot (again)? Burden of treatments Blood transfusions Eculizumab Bone marrow transplantation

Therapy:

Therapy Bone Marrow Transplantation Only curative treatment chronic condition (possiblity of spontaneous remission) - BMT should be avoided Immunosuppressive therapy Antilymphocyte globulin &/or cyclosporine A Does not alter proportion of PNH hemopoiesis Steroids - experimental - controlled studies ?? Growth Factors Some improvement no evidence that normal clones respond better than PNH clones

PNH: Management Guidelines:

PNH: Management Guidelines Luzzato, ASH, 2001

What are the treatments? Cures?:

What are the treatments? Cures? Treatment options depend on certain factors What is the clone size? How does the marrow function? What are all the blood counts? Clot risk Short-term vs. long-term treatment Blood transfusions and pulse prednisone often used in short-term Long-term-vitamin replacement, low-dose prednisone, eculizumab, bone marrow transplant Cures? Yes, with bone marrow transplant Control? Yes.

Eculizumab:

Eculizumab First/only drug targeted to PNH Monoclonal antibody against complement protein 5 (C5). Binds this protein and halts the rest of the complement cascade. “Protects” PNH cells from destruction by halting the complement cascade. Very effective at reducing hemolysis, reducing transfusion needs, improving QOL. Early evidence suggests it may reduce clots.

Eculizumab-Pro’s and Con’s:

Eculizumab-Pro’s and Con’s Pro’s Very effective at reducing hemolysis Well tolerated Improvements in QOL, reduction in transfusions proven Reduction in burden of disease Infusion weekly X5, then every 2 weeks Probable reduction in clots Con’s Expensive Infusion weekly X5, then every 2 weeks Infection risk: meningococcal meningitis Burden of treatment Plan for lifetime therapy Does not improve other blood counts

Eculizumab in Pregnancy:

Eculizumab in Pregnancy Pregnancy in PNH is very risky for both the mother and fetus, due to risk of clotting, infection, and fetal loss. Is eculizumab safe in pregnancy? Could this help reduce the risks of pregnancy? Report of 7 pregnancies in patients that received eculizumab at some point during pregnancy.

Outcomes in Pregnancy with Eculizumab:

Outcomes in Pregnancy with Eculizumab Patient Clone size Use in pregnancy Complications in pregnancy Outcomes 1 70% Up to 5 weeks No Elective termination 2 93% Up to 5 weeks No Healthy baby 3 96% Up to 14 weeks Post-partum fever Healthy baby 4 88% Up to 4 weeks No Healthy baby 5 99% All of pregnancy Hemolysis-breakthough Healthy baby 6 98% From week 27 Post-partum hemorrhage Healthy baby twins at 35 wks 7 98% All of pregnancy Pre-eclampsia Healthy baby at 28 wks

Bone Marrow Transplant for PNH:

Bone Marrow Transplant for PNH This is very effective at curing PNH Risks include toxicity from the transplant and graft vs. host disease (GVHD) In patients with aplastic anemia or MDS/leukemia and PNH transplant is driven by other disease Transplantation continues to improve over time, in particular transplants from unrelated donors

PowerPoint Presentation:

Matched sibling 10 year survival 65% All transplants 10 year survival 56% From Italian group, 26 transplants for PNH 1988-2006

Treatment Options:

Treatment Options Classical PNH High clone size (>50%) Risk of clot highest Bone marrow functions well and tries to keep up (high reticulocyte count) May or may not need red cell transfusions Treatments Folic acid 3-5 mg per day Iron supplements Prophylactic coumadin? Transfusions as needed Eculizumab Bone marrow transplant Prednisone

Treatment Options:

Treatment Options PNH/Aplastic Anemia In addition to anemia, have low platelet count and/or low white count Bone marrow production is deficient Clone size may be large or small Clotting risk may be less (still increased compared to baseline) Treatments Immunosuppression (cyclosporine, ATG) Danazol (marrow stimulator) Folic acid and iron less important, but need to make sure adequate Erythropoietin supplementation Bone marrow transplant Prednisone Eculizumab (?)

Hemoglobinuria and ARF:

Hemoglobinuria and ARF It is one of the complications of hemoglobinuria - Pigment Nephropathy Pathophysiology: Hypovolemia and renal ischemia Direct hemoglobin nephrotoxicity Tubular obstruction Hemolysis(DIC-glomerular fibrin deposit) Risk factors: Older age, hypotension,dehydration and severe acidosis with low urinary ph

Myglobinuria v/s Hemoglobinuria:

Myglobinuria v/s Hemoglobinuria SL No Factors Myoglobinuria Hemoglobinuria 1 Urine colour Brown Reddish Brown 2 Serum colour Clear Pink 3 Orthotoludine test Positive Positive 4 Muscle pain Present Absent 5 CPK levels Normal/Absent 6 Serum Haptaglobin Normal Decreased

March hemoglobinuria:

March hemoglobinuria March hemoglobinuria , also known as march hematuria , occurs when blood is seen in the urine after strenuous exercise, particularly affecting the feet (such as running on a hard road or Kendo) and hands (e.g. Conga or Candombe drumming). The word "march" is in reference to the condition arising in soldiers who have been marching for long periods

PowerPoint Presentation:

The repetitive nature of these types of activities cause mechanical trauma to the red blood cells causing hemolysis The situation usually lasts for a day or two. No specific medication is required. This hematuria is usually unnoticed by common man, and is figured out usually by one's who've had a history with hematuria. Usually March hematuria isn't life threatening.

Paroxysmal Cold Haemoglobinuria :

Paroxysmal Cold Haemoglobinuria Paroxysmal cold haemoglobinuria (PCH) is an autoimmune haemolytic anaemia , caused by cold-reacting immunoglobulins . It primarily affects children and tends to cause quite severe, but transient, disease. The usual trigger for the formation of the cold-reacting polyclonal immunoglobulin G ( IgG ) autoantibodies is an episode of infection. The episode usually, but not always, follows a period of exposure to cold. It is usually a transient postinfectious or postvaccination problem that resolves, but it may cause significant morbidity . The degree of haemolysis is variable but may lead to an acute onset of intravascular haemolysis and haemoglobinuria .

Pathogensis:

Pathogensis Cross-reactivity (between antibodies formed against microbial antigens and the red-cell membrane P-antigen) induces intravascular haemolysis through complement activation. The antibodies detectable in the blood of those who suffer from PCH are known as ' Donath -Landsteiner antibodies'.

Epidemiology:

Epidemiology It is a very rare illness; there are no reliable population-incidence figures, but it is believed to be responsible for about 40% of all autoimmune haemolytic anaemias that affect children (lower percentage for adults ). Autoimmune haemolytic anaemias are, however, very rare, with an annual incidence of <1 per 100,000 population . Although the vast majority of cases occur in children, adults may rarely be affected . The acute, transient form of paroxysmal cold haemoglobinuria (by far the most usual modern presentation) is much more common in children than in adults.

Causative illnesses:

Causative illnesses Viral infections - measles, mumps, adenovirus, chickenpox, influenza A, cytomegalovirus,Epstein -Barr virus. Bacterial infections - Haemophilus influenzae , Mycoplasma pneumoniae and Treponema pallidum (a chronic recurrent form is associated with secondary, tertiary or congenital syphilis). Postvaccination syndrome - particularly measles vaccine. Rarely, when it affects adults, it may be precipitated by an underlying neoplasm. Very rare chronic idiopathic/primary autoimmune disease form (usually seen in adults).

Presentation:

Presentation There is often a history consistent with antecedent respiratory or other acute viral/bacterial infection Jaundice and the passage of dark urine - red or reddy -brown - strongly suggest the diagnosis Vasomotor occlusion causes urticaria after cold exposure, paraesthesiae of the hands and feet, peripheral cyanosis , Raynaud's phenomenon and peripheral infarction with gangrene . Anaemia may cause parents to notice their child's pallor, or it may lead to tiredness, exertional dyspnoea and poor feeding in babies/infants. Oliguria or anuria may be a presenting feature.

Signs:

Signs There may be an urticarial rash or an exanthem due to precipitating viral illness . In the acute phase there will be a high fever, often >40°C. Pallor and tachycardia are likely to be present and the abdomen should be examined for evidence of hepatosplenomegaly (possible underlying neoplasm). Lymph node areas should be examined and the chest checked for evidence of current infection. .

Differential diagnosis:

Differential diagnosis Warm antibody-induced autoimmune haemolytic anaemia /drug-induced haemolysis . Cold agglutinin disease (the other major cryopathic haemolytic syndrome; it affects adults and tends to cause mild or subclinical illness). Autoimmune lymphoproliferative syndrome (ALPS). Lymphoproliferative disorders. Non-Hodgkin's lymphoma . Systemic lupus erythematosus . Renal disorders in children causing haematuria . Paroxysmal nocturnal haemoglobinuria . Severe malaria . Syphilis.

Investigations:

Investigations Urinalysis : haemoglobinuria will be present to varying degrees at presentation; examine the urine for colour and dipstick for haemoglobin , proteinuria may also occur . Full blood count : may show acute anaemic picture, ranging from mild to severe. Usually normochromic, normocytic pattern. May appear as macrocytic anaemia during acute haemolytic phase. Blood film : shows spherocytes , polychromasia , nucleated red cells, and occasionally neutrophil-mediated erythrophagocytosis . Biochemistry : indirect bilirubin , lactate dehydrogenase (LDH) and plasma haemoglobin are elevated due to haemolysis .

Autoantibody detection:

Autoantibody detection A specialist indirect IgG antiglobulin test performed at low temperature may detect anti-P Donath -Landsteiner antibodies . The Donath -Landsteiner bithermic haemolytic test is not very sensitive but quite specific, especially if utilising the cells of a patient with paroxysmal nocturnal haemoglobinuria . The patient's red blood cells are incubated with serum and complement at a low temperature and then at body temperature; the presence of haemolysis indicates a positive test . Direct Coombs' test : is negative.

Treatment:

Treatment Keep the patient warm with extremities covered during the acute phase of the illness . Blood transfusion should be given washed, warmed and in packed-cell format. If active bacterial infection is suspected then treat with appropriate intravenous antibiotics . Renal complications such as acute tubular necrosis may occur Close attention must be paid to fluid status and consideration given to alkalinisation of urine. Steroids are occasionally used but there is no good evidence for their effectiveness.

PowerPoint Presentation:

The syndrome may recur and patients should be advised to avoid cold exposure during this time . Folic acid intake through diet or supplementation may be a useful and presumably harmless, cheap adjunct during/after acute haemolytic disease in children. In the rare chronic (usually adult) forms, ongoing folate supplementation is advised

Complications:

Complications Severe, acute anaemia Organ failure due to anaemia , e.g. cardiac arrest or respiratory failure . Acute renal failure . Death due to acute haemolytic crisis may occur, but is unusual.

PowerPoint Presentation:

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