Haemorrhagic and Haemolytic of Newborn Diseases

Haemorrhagic & Haemolytic Disease in Newborn

• Presenter: Muhammad Naqib BajuriAzizah MajidNoor Azwa SulaimanNoor Afifah Abd Rahman

Normal Haemostasis

5 main components:1) Coagulation factors- activated when released of Tissue

Factor (TF) by vessel injury2) Coagulation inhibitors- to prevent widespread coagulation3) Fibrinolysis- limits fibrin deposition4) Platelets- aggregate at sites of vessel injury to form primary

haemostatic plug5) Blood vessels- intact vascular endothelium secretes PGI2

and NO which promote vasodilation & inhibit plt aggregation. Damaged endothelium releases TF & procoagulants (collagen & vWF).

Endpoint of coagulation cascade is generation of thrombin.

Abnormal bleeding

Acquired disorders

• Vit. K def.• Liver disease• Thrombocytopenia:

immune, DIC

Inherited

• Haemophilia A• Haemophilia B• Von Willebrand

disease (vWD)

Acquired disorders of coagulation

Secondary toi. Vit K def.ii. Liver diseaseiii. ITP ( immune thrombocytopenia)iv. DIC ( disseminated intravascular coagulation)

1) Vit. K deficiency

• Essential for production of active forms of factors II, VII, IX, X and anticoagulants such as protein C & S

• Def d/t– Inadequate intake– Malabsorption ( coeliac dz, cystic fibrosis,

obstructive jaundice)– Vit K antagonists (eg. Warfarin)

PathogenesisNon-functional proteins called PIVKA (proteins

formed in vit. K absence)

Conversion of PIVKA to biologically active forms

with carboxylation of glutamic acid

Vit K converted to vit K epoxide which cycled

back to reduced form by reductases

Gamma-carboxylated glutamic acid binds Ca

ions which forms a complex with platelet

phospholipid

2) Liver Disease

• Biliary obstruction impaired vit K absorption l/t decrease synthesis FII,FVII,FIX and X.

• Severe hepatocellular dz, reduced FV, fibrinogen & plasminogen activator.

• Dysfunctional fibrinogen (dysfibrinogenaemia)• Low thrombopoietin production l/t

thrombocytopenia• Hypersplenism associated with portal HTN l/t

thrombocytopenia

• Disseminated intravascular coagulation (DIC) related to release of thromboplastins from damaged liver l/t low conc. of antithrombin, protein C, impaired removal activated clotting factors & increase fibrinolytic activity.

3) Immune Thrombocytopenia (ITP)

• Commonest cause of thrombocytopenia in childhood

• Incidence of 4 per 100 000 children per year• Caused by antiplt IgG autoantibodies• Approx. 75% follows vaccination or infect.

such as chickenpox• Associated with SLE, HIV, CLL, Hodgkin’s dz or

autoimmune haemolytic anemia

Clinical features

• Children ages of 2-10 years old• Onsets 1-2 weeks after viral infection• Petechiae• Purpura• Superficial bruising• Epistaxis• Intracranial bleeding (rare)

4)Disseminated Intravascular Coagulation (DIC)

• Coagulation pathway activation l/t diffuse fibrin deposition in microvasculature and consumption of coagulation factors & plts.

• Commonest causes are severe sepsis or shock d/t circulatory collapse (in meningococcal septicaemia or extensive tissue damage from trauma or burns.

PathogenesisIncreased activity of tissue factor release

from damaged tissues on tumour cells

Triggered by entry of procoagulant material

into circulation eg. Severe trauma, liver

disease

Initiated by widespread endothelial damage & collagen exposure eg.

Severe burns

Deposition of fibrin in microcirculation,

intravascular thrombin formation

Intense fibrinolysis stimulated by thrombi

on vascular walls

Combined action of thrombin & plasmin cause depletion of fibrinogen and all coagulation factors

Bleeding probs d/t thrombocytopenia

caused by consumption of plts

Clinical Features

• Bleeding• Generalized bleeding in GIT, oropharynx, into

lungs, urogenital tract and vaginal bleeding particularly severe

• Skin lesions• Renal failure• Gangrene of toes• Cerebral ischaemia

Inherited diseases

1) Haemophilia• Commonest severe inhereted: haemophilia A

& haemophilia B• X-linked recessive inheritance• In haemophilia A, there is FVIII deficiency• 1 in 5000 male births• Haemophilia B (FIX def.)• 1 in 30 000 male births

Clinical features

• Bleeding episodes most freq. in joints & m/s• Crippling arthritis (recurrent spontaneous bleeding into

joints and m/s)• Painful haemarthroses and m/s haematomas l/t

progressive joint deformity & disability• Intracranial haemorrhage• Bleeding post-circumsition• Prolonged oozing from heel stick & venepuncture sites• Spontaneous haematuria & GI haemorrhage• Haemophilic pseudotumours

4) Von Willibrand disease (vWD)

• Has 2 major roles:– Facilitates plt adhesion to damaged endothelium– Acts as carrier protein for FVIII:C

• Results from either qualitative or quantitaive def. of vWD

• l/t defective plt plug formation and def. of FVIII:C• Many different mutations in vWF gene and many types

of vWD• Inheritance usually autosomal dominant• Commonest subtype, type I (60-80%)

Classification

Type IQuantitative partial def

Type IIFunctional abnormality

Type IIIComplete def

Clinical features

• Bruising• Prolonged, excessive bleeding after surgery• Epistaxis & menorrhagia (mucosal bleeding)• Haematomas & haemarthroses (uncommon)

Hemorrhagic disease of newbornDiagnosis

InvestigationTreatment

Management

Azizah Majid HBA 10027653

Notes

• Vitamin K represents a group of lipophilic and hydrophobic vitamins. The term vitamin K originated from koagulations-vitamin in German

• Vitamin K is a necessary cofactor for γ-glutamyl carboxylase, the enzyme required for posttranslational carboxylation of prothrombin, FVII, FIX, and FX, and proteins C, S, and Z.

Abstract on Haemorrhagic disease in newborn and older infants: a study in hospitalized children in Kelantan, Malaysia.

Retrospective study: epidemiology, CF, lab findings,

treatment and outcome of haemorrhagic disease in 42

Kelantanese infants- Hospital Universiti Sains Malaysia during a

2-year period (1987-1988).

Classical haemorrhagic disease of the newborn was the

commonest presentation (48%), followed by early onset (29%) and late onset (24%) disease.

Home deliveries accounted for 81% of the affected infants.

Most of these babies were not given vitamin K at birth in

contrast to those delivered in hospitals.

Commonest presenting CF: pallor, jaundice, umbilical cord

bleeding, tense fontanelle, convulsions & hepatomegaly.

All the infants had prolonged prothrombin and partial

thromboplastin times which were corrected by

administration of vitamin K.

Subdural haemorrhage was the commonest form of intracranial

haemorrhage, followed by subarachnoid haemorrhage.

The overall case fatality rate: 14%. The results of this

study :emphasize the value of vitamin K prophylaxis in the

newborn.

DDx of neonatal haemorrhagic disorder

Neonatal Thrombocytopenia

Platelet Abnormalities

Vitamin K Deficiency Bleeding

Inherited Coagulation

DisordersLiver Disease

Diagnosis

• The diagnostic criteria for vitamin K deficiency bleeding include:

• Prolonged prothrombin time (PT)/Elevated international normalized ratio (INR) (gold standard)

• Prolonged activated partial thromboplastin time (aPTT)• Fibrinogen levels and a platelet count within in normal range for

newborns

• The diagnosis is confirmed if the INR normalizes after administration of vitamin K and the bleeding is stopped.

Why It Is Done

• The prothrombin time (PT) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation ( INR is a calculation made to standardize prothrombin time. INR is based on the ratio of the patient's prothrombin time and the normal mean prothrombin time)

• PT measures factors I (fibrinogen), II (thrombin), V, VII, and X.

• It is used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway

• Blood clotting factors: blood to clot (coagulation). • Prothrombin, or factor II, made by the liver. Vitamin K is needed to make it & other

clotting factors.

The prothrombin time can be prolonged as a result of deficiencies in vitamin K, warfarin therapy, malabsorption, or lack of intestinal colonization by bacteria (such as in newborns). In addition, poor factor VII synthesis (due to liver disease) or increased consumption (in disseminated intravascular coagulation) may prolong the PT.

Tests and Exams

• Significant bleeding in neonates should prompt clinical evaluation.

• ‘Initial empirical therapy consists of platelet and/or factor supplementation, which is often administered while diagnostic studies are under way’

• Laboratory evaluation of the hemorrhage in newborns should include

Sepsis evaluation determination of the ( Blood clotting tests) platelet

count, PT, aPTT, TT, and fibrinogen concentration.

Cont..

IMAGING STUDIES• Ultrasound-intracranial bleeding

– rare and usually associated with other causes of bleeding, particularly thrombocytopenia

• MRI – exposes the neonate to no radiation – becoming the preferred way to study the brain because tissue

damage can be better defined.

Cont..

PROCEDURES• If the cause of bleeding is not straight forward, the

caregiver may need to perform other procedures like endoscopic retrograde cholangiopancreatography [ERCP] to rule out hepatobiliary diseases.

HISTOLOGIC FINDINGS• If liver biopsy is indicated, histopathology with and

without special stains or biochemical analyses may be helpful to rule out hepatitis, biliary atresia, tumors, and inherited metabolic diseases of the liver.

Cont…

• Genotype analysis(GA) : Congenital vitamin K deficiency is an autosomal recessive disorder that occurs because of mutations in the genes encoding γ-glutamyl carboxylase or vitamin K2,3–epoxide reductase complex. Neonates with this disorder often have severe bleeding, including IntraCranial Haemorrhage. GA to confirm the defect.

Tx & Management

• Vitamin K :for prevention of & tx of vit. K deficiency bleeding (VKDB). Other coagulation factors are rarely needed.

• Severe bleeding: use of fresh frozen plasma.

• No other drugs or treatments are acceptable substitutes for prompt vitamin K dosing.

• Subcutaneous administration of vit. K is preferred over the intramuscular (IM) route in symptomatic infants.

Cont…

SURGICAL CARE• Normally, vitamin K deficiency bleeding infants

do not require surgical care but in rare cases, an infant may need neurosurgical evaluation and treatment.

• Other conditions, such as those associated with short bowel syndrome and hepatobiliary disease may require surgical evaluation

Potential Complications

• Bleeding inside the skull (intracranial hemorrhage), with possible brain damage

• Death • Severe bleeding

Prevention

• Many newborns- deficient in vit. K, whether measured in cord blood or indirectly by measuring the levels of vitamin K–dependent coagulation proteins. Recommends giving every baby a shot of vitamin K immediately after birth. This practice has helped prevent the condition.

• The early onset form of the disease may be prevented by giving vitamin K shots to pregnant women who take anti-seizure medications.(mechanisms by which anticonvulsant drug l/t vit. K deficiency bleeding in neonates :not clearly understood)

• Most infants born to well-nourished mothers have adequate vitamin stores at birth

– Vitamin K is naturally produced by intestinal bacteria which newborn’s lack resulting in the deficiency

– Suppression of intestinal bacteria by various antibiotics is responsible for this deficiency

– Infants receive Vitamin K either orally or intramuscularly

Prognosis (Outlook)

• The outlook tends to be worse for babies with late onset hemorrhagic disease than other forms. There is a higher rate of bleeding inside the skull (intracranial hemorrhage) associated with the late onset condition.

• There is no upper limit to vitamin K because of its low toxicity– Infants 0-6 months = 2 µg– Infants 7-12 months = 2.5 µg– Children 1-3 years = 30 µg– Children 4-8 years = 55 µg– Children 9-13 years = 60 µg– Adolescents 14-18 years = 75 µg

RECOMMENDED VALUE

HAEMOLYTIC DISEASE IN NEWBORN

• Haemolytic anemia is characterised by reduced red cell lifespan due to increased red cell destruction in the circulation (intravascular haemolysis) or liver/spleen (extravascular haemolysis)

• In haemolysis, red cell survival may be reduced to a few days but bone marrow production can increase about 8-fold, so haemolysis only lead to anemia when bone marrow is no longer able to compensate for the premature destruction of red cells

Common causes

• RhD incompatibility• ABO incompatibility

Rare causes

• Maternal autoimmune disease such as autoimmune hemolytic anemia or systemic lupus erythematosus: maternal antibodies enter fetal circulation and result in fetal or infant erythrocyte destruction

• Minor blood group antigen incompatibility (Kell, Duffy, M, S)• Drug-induced hemolysis such as from penicillin or acyclovir• Infection such as from cytomegalovirus, toxoplasmosis, syphilis, or

sepsis• Disseminated intravascular coagulation• Hereditary erythrocyte disorders such as hereditary

spherocytosis/elliptocytosis, thalassemia, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency

• Metabolic abnormalities such as acidosis or galactosemia• Angiopathic hemolysis such as cavernous hemangioma, large

vessel thrombi, renal artery stenosis, or severe coarctation of the aorta

ISOIMMUNIZATION

Rh diseaseABO incompatibility

1. Rh disease• Rhesus disease is a condition which affects an unborn baby when its

mother’s immune system generates antibodies which attack the baby’s red blood cells.

• Prevalence of genotype varies with the population. Rh negative individuals comprise 15% of Caucasians, 5.5% of African Americans, and <1% of Asians.

• For Rh (D) disease to develop in an unborn baby, two conditions must be met. – a woman with the Rhesus-negative blood type is pregnant with a baby who

has Rhesus-positive blood. – the pregnant woman must have previously been exposed to Rhesus-positive

blood. This second condition must be met in order for the woman’s immune system to generate antibodies to the Rhesus-positive blood cells of the baby.

• Rhesus disease only affects the baby. It will not cause any symptoms for the mother.

• In the unborn baby, they may become anemic which can be measured by Doppler ultrasound (blood thinner and flow quickly)

• In the newborn baby this may cause:– Anemia with/without jaundice– increased breathing rate – poor muscle tone – poor feeding

• Wont always have obvious symptoms when they are born. Symptoms can develop up to three months afterwards.

• If rhesus disease causes severe anemia in the fetus, it can also cause:– fetal heart failure – fluid retention – swelling (oedema) – Stillbirth

• In newborn baby:– Kernictus (deafness, blindness, brain damage, learning

difficulties, death)

Investigation…

• Maternal– Kleihauer-Betke / flow cytometry• Can confirm that fetal blood has pass into maternal

circulation• Estimate the amount of fetal blood has passed into

maternal circulation

– Indirect Coombs test• Screen blood from antenatal women for IgG ab that

may pass through the placenta and cause HDN

• Unborn baby– Doppler ultrasound– Fetal blood sampling (FBS)

• Newborn baby – Direct Coombs test

• Evidence of anti-D ab that have cross placenta

– FBC• Hb level and platelet count

– Bilirubin

Treatments…

• Unborn baby– Intrauterine blood transfusion (IUT)

• Newborn baby– Phototherapy– Exchange transfusion– Intravenous immunoglobulin (IVIG)

• Prevent destruction of RBC

Preventions…

• All non-sensitized Rh D-negative women should be given anti-D immunoglobulin at 28 and 34 weeks of gestation to reduce risk of sensitization from fetomaternal haemorrhage.

• At birth, if the baby is Rh –ve, no further treatment needed. • • If baby is Rh +ve, prophylactic anti-D should be administered

within 72h of delivery.

2. ABO Incompatibility

• ABO incompatibility is the most common cause of hemolytic disease of the newborn.

• Approximately 15% of live births are at risk, but manifestations of disease develop in only 0.3-2.2%.

2. ABO Incompatibility

• With maternal blood types A and B, isoimmunization does not occur because the naturally occurring antibodies (anti-A and -B) are IgM, not IgG.

• In type O mothers, the antibodies are predominantly IgG, cross the placenta and can cause hemolysis in the fetus.

• The association of a type A or B fetus with a type O mother occurs in ~15% of pregnancies. However, HDN occurs in only 3%, is severe in only 1%, and <1:1,000 require exchange transfusion.

• Unlike Rh, ABO disease can occur in first pregnancies, because anti-A and anti-B antibodies are found early in life from exposure to A- or B-like antigens present in many foods and bacteria.

• Clinical presentation: generally less severe than with Rh disease.

• Diagnosis and investigation are same as Rh disease.

• Treatment are by phototherapy and exchange transfusion.

• There is no effective prevention against ABO incompatibility reaction.

Differential diagnosis

• Hemorrhage in the newborn• Failure of erythrocyte production in the

newborn• Conjugated hyperbilirubinemia

AUTOIMMUNE HEMOLYTIC ANEMIA

anemia secondary to premature destruction of red blood cells (RBCs) caused by the binding of autoantibodies and/or complement to RBCs

ISOIMMUNE VS AUTOIMMUNE• The most important immune hemolytic

disorder in pediatric practice is hemolytic disease of the newborn (erythroblastosis fetalis), caused by transplacental transfer of maternal antibody active against the RBCs of the fetus, that is, isoimmune hemolytic anemia

• Various other immune hemolytic anemias are autoimmune

Pathogenesis

• abnormal antibodies are directed against RBC membrane antigens, but the pathogenesis of antibody induction is uncertain.

• The autoantibody may be produced as an inappropriate immune response to an RBC antigen or to another antigenic epitope similar to an RBC antigen, known as molecular mimicry.

• Alternatively, an infectious agent may alter the RBC membrane so that it becomes “foreign” or antigenic to the host. The antibodies usually react to epitopes (antigens) that are “public” or common to all human RBCs, such as Rh proteins.

AIHA

• caused by autoantibody-induced hemolysis (the premature destruction of circulating red blood cells); – usually idiopathic,– SECONDARY, associated with 1. infection, 2. lymphoproliferative disorders, 3. autoimmune diseases4. drugs

CLASSIFICATION • Based on etiology:

– Warm antibody mediated: immunoglobulin (Ig) G (often idiopathic or associated with leukemia, lymphoma, thymoma, myeloma, viral infections, and collagen-vascular disease)

– Cold antibody mediated: IgM and complement in majority of cases (often idiopathic; at times associated with infections, lymphoma, or cold agglutinin disease)

– Drug induced: three major mechanisms: 1. Antibody directed against Rh complex (e.g., methyldopa)2. Antibody directed against RBC-drug complex (hapten induced; e.g.,

penicillin)3. Antibody directed against complex formed by drug and plasma

proteins; the drug-plasma protein-antibody complex causes destruction of RBCs (innocent bystander; e.g., quinidine)

warm autoantibody

immunoglobin G (IgG) attacks red blood cells

(RBCs); patients are usually over age 50;

typically treated with corticosteroids and

therapies for underlying diseases

cold

chronic cold agglutinin disease: cold-activated immunoglobin M (IgM) and complement (C3d) coat RBCs and trigger hemolysis; patients usually over age 50; sometimes resolves with cold avoidance; rarely progresses to renal failure

Paroxysmal cold hemoglobinuria (PCH): rare disease induced most often by postviral Donath-Landsteiner autoantibody at cold temperatures in children; often acute and severe, though usually short-lived and self-limited; rarely progresses to renal failure, frank lymphoma, or death

CAUSES

Warm AIHA

• Idiopathic: warm autoantibody IgG, its complement (C3d), or both, coat the red cell membrane and at 37°C induce phagocytosis

• Secondary: warm antibodies produced by – lymphoproliferative disorders (e.g. non-Hodgkin's

lymphoma, chronic lymphocytic leukemia (CLL); – collagen vascular/autoimmune diseases

(e.g. systemic lupus erythematosus (SLE)– HIV infection

Cold agglutinin disease

• Idiopathic: the IgM autoantibody has an affinity for RBCs at cold temperatures (0ºC-18ºC); at warmer temperatures (37ºC, or 98.6ºF), when the two have no particular affinity, the IgM antibody can come off the RBC, but the remaining complement sticks. Hemolysis occurs as the liver and spleen remove complement-coated RBCs

• Secondary: cold autoantibodies produced by – infections such as Epstein-Barr virus, Mycoplasma

pneumoniae, and infectious mononucleosis– lymphoproliferative disorders, such as non-Hodgkin's

lymphoma and chronic lymphocytic leukemia (CLL)

Paroxysmal cold hemoglobinuria

• Idiopathic: Donath-Landsteiner autoantibody• Secondary: viral infections (particularly in

children and young adults), which produce the Donath-Landsteiner antibody

Predisposing factors

• B-cell malignancy (produces hemolysis-inducing autoantibodies)

• Family or personal history of autoimmune disease (produces hemolysis-inducing autoantibodies)

• Viral infection in children (produces the Donath-Landsteiner autoantibody, which induces PCH)

• Cold temperature (induces IgM activation in cold agglutinin disease)

Symptoms

Common for all AIHA:• Fatigue, dyspnea, malaise• Light-headedness or dizziness• Feeling hot and cold, or shivering (fever)• Abdominal/back pain• Occasionally abdominal fullness due to

splenomegaly• Jaundice and dark urine

Specific for cold agglutinin disease:• Episodes of jaundice and dark urine• Acrocyanosis of hands, feet, earlobes, and/or

tip of nose• Exposure to cold will precipitate symptoms

Specific for paroxysmal cold hemoglobinuria:• Paroxysms of hemoglobinuria on exposure to

cold

Signs

Common for all AIHA:• Low hematocrit (<40% in males; <37% in females)• Pallor• Tachycardia, palpitations of the heart, and soft systolic murmurs• Jaundice, usually mild• Dark urine• Reticulocytosis• Palpable spleen/splenomegaly, especially if chronic (often secondary to B-cell

malignancy)• Fever, secondary to underlying malignancy or infection• Weight loss, secondary to underlying malignancy• Secondary rash/petechiae/ecchymoses• Congestive heart failure (occasionally)

Specific for warm autoimmune hemolytic anemia:• Positive direct Coombs test previously reported in patient

referred for transfusion

Specific for chronic cold agglutinin disease:• Skin findings include cool tips of the hands, feet, earlobes,

and/or nose• Splenomegaly is common• Hemoglobinuria at cold temperatures in some patients

Specific for paroxysmal cold hemoglobinuria:• Severe anemia• Hemoglobinuria• Hemoglobinemia• Renal failure

Investigation tests

In the differential diagnosis of AIHA, first determine whether there is anemia, then whether there is hemolysis.

Order of tests• CBC with reticulocyte count• Peripheral blood smear• Urine dipstick for blood• Liver function tests for bilirubin• Liver function tests for serum lactate dehydrogenase (LDH)• Haptoglobin• Direct Coombs test• Cold agglutinin titer• Donath-Landsteiner autoantibody

Test Finding

CBC with reticulocyte count hemoglobin and hematocrit vary in AIHA, but typically are low; the reticulocyte count, typically elevated in AIHA, is the hallmark indicator of red cell destruction

Liver function tests for bilirubin and serum lactate dehydrogenase (LDH)

bilirubin and LDH are breakdown products of hemoglobin; elevated levels provide additional evidence of RBC destruction

Haptoglobin binds in plasma with free hemoglobin when RBCs are destroyed; depressed haptoglobin provides additional evidence of hemolysis

Urine dipstick for blood may be helpful to diagnose intravascular hemolysis by detecting hemoglobinuriaIf tests point to hemolytic anemia, then conduct further tests to determine whether the HA is caused by the hallmark autoantibodies of AIHA. Finally, if tests point to AIHA, prepare further tests to determine which specific autoantibody (IgG, IgM, or IgA) and/or complement is responsible for hemolysis (i.e. which specific AIHA is afflicting the patient).

Peripheral blood smear critical to the diagnosis of any anemia, it shows the number and morphology of different cell lines, and provides the visual evidence of hemolysis. In all warm AIHAs, macrophages transform disc shape of healthy RBCs to telltale spherocytes. Classically, reticulocytosis and nucleated red blood cells are also apparent. Examination of white blood cells and platelets provides clues to diagnosing hematologic or malignant disorders that sometimes coexist with AIHA. RBC aggregation on the smear suggests the diagnosis of cold AIHA

Direct Coombs test positive test indicates presence of autoantibodies (attached to RBCs); if positive, prepare an antibody eluate and examine the specificity for known RBC antigensIndirect Coombs test: positive test indicates the presence of autoantibodies (not attached to the RBCs)Thermal amplitude of the cold agglutinin indicates whether the antibody can bind RBC at physiologically relevant temperatures

Donath-Landsteiner autoantibody

If paroxysmal cold hemoglobinuria is suspected, confirm diagnosis with test for hallmark Donath-Landsteiner autoantibody

Cold agglutinin titer useful if suspect cold agglutinin disease, in which titer usually is very high (from >1000 to >1:105). Titer does not predict severity of disease

Urine hemosiderin staining the urine with Prussian blue or other iron stain can indicate whether there is hemosiderin present in the urine. If positive, this indicates possible hemolysis; however, other conditions of iron overload may also result in increased hemosiderin

Summary

Warm AIHA

• Direct Coombs test is positive for immunoglobulin G (IgG), complement (C3d), or both

• Spherocytes present on the peripheral blood smear• Phagocytized RBCs are typically sequestered in the

spleen• Most patients quickly respond to corticosteroids,

though the disorder is chronic and often relapsing• Refractory cases require prolonged

immunosuppression or may undergo splenectomy; life-threatening cases may require transfusion

Chronic cold agglutinin disease• Positive direct Coombs test rarely detects cold-reactive IgM, but always

detects C3d bound to RBC membrane• RBC aggregates seen on peripheral blood smear• Typically, cold agglutinin titer is very high• Idiopathic form of disease is frequently recurrent condition and often

responds to cold avoidance; exacerbations are intermittent• Critical to explore diagnosis of B-cell lymphoma, which will determine

therapy• Corticosteroids are usually not helpful• Splenectomy is rarely beneficial (unless splenic lymphoma) because RBCs

destroyed primarily by C3d activation are sequestered in the liver, not spleen

• In presence of B-cell neoplasm, chemotherapy or immunotherapy may help• Exposure to cold can prompt sudden drop in hematocrit and induce renal

failure

Paroxysmal cold hemoglobinuria• Diagnosis generally relies on clinical presentation; routine tests do not pick

up pathological Donath-Landsteiner autoantibody• Most often appears postviral in children and young adults• Symptoms may include fever, chills, abdominal distress, nausea, leg/back

pain• Signs may include jaundice and hemoglobinuria• IgG detected in serum• Direct Coombs test is usually negative for pathological IgG and

complement• Indirect Coombs test is negative• Diagnosis is confirmed with test for hallmark Donath-Landsteiner

autoantibody• Often acute and severe, but usually short-lived and self-limited• Treatment includes: cold avoidance; supportive care; transfusions to

alleviate symptoms; corticosteroids rarely useful• In rare cases can progress to renal failure

RED CELL ENZYME DISORDER

G6PD deficiency

• G6PD– Rate-limiting enzyme in the pentose phosphate

pathway – Essential for preventing oxidative damage to red

cells• Def – susceptible to oxidant-induced haemolysis– X-linked, predominantly affect males

• Kids with G6PD deficiency typically do not show any symptoms of the disorder until their red blood cells are exposed to certain triggers.

• Clinical features:– Sudden rise of body temperature and yellow coloring of skin

and mucous membrane. – Dark yellow-orange urine. – Pallor, fatigue, general deterioration of physical conditions. – Heavy, fast breathing. – Weak, rapid pulse.

• Once the trigger is removed or resolved, the symptoms of G6PD deficiency usually disappear fairly quickly, typically within a few weeks.

Investigations…

• Bilirubin level (high)• Complete blood count, including red blood cell

count• Hemoglobin – blood (low)• Haptoglobin level (low)• Methemoglobin reduction test• Reticulocyte count (high)• Blood film (concentrated and fragmented cells,

‘bite’ cells and ‘blister’ cells)

Management…

• Medicines to treat an infection, if present

• Stopping any drugs that are causing red blood cell destruction

• Transfusions, in some cases