microangiopathic haemolytic anaemias

8/13/2019 Microangiopathic Haemolytic Anaemias

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MICROANGIOPATHIC HAEMOLYTIC ANAEMIA

HELLP SYNDROME

HAEMOGLOBIN SYNTHESIS DISORDERS

Submitted by: DR.ASFANDYAR SHAH ROGHANI

M Phil. Haematology

IBMS KMU

Submitted to:Dr.NAZISH FAROOQ

Course work: 750

Date:30th

DEC2013


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TABLE OF CONTENTS:

MAHA ....................................................................................................................... 3HELLP SYNDROME...7HB SYNTHESIS DISORDERS..11REFERENCES.18


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MICROANGIOPATHIC HAEMOLYTIC ANAEMIAS(MAHA)

Microangiopathic haemolytic anaemia (MAHA) is a condition in which intravascular

haemolysis with fragmentation of red cells is caused by their destruction in an abnormal

microcircula-tion. Proof of microangiopathy may be lacking in those not subjected to a

post - mortem, and MAHA should be considered a clinical syndrome. The three main

pathological lesions that give rise to MAHA are deposition of fi brin strands, often

associated with DIC; platelet adherence and aggregation; and vascu-litis. The vessel

abnormalities may be generalized or confi ned to particular sites or organs. In most

cases, the haemolysis is of less consequence than the underlying cause of the microangio-pathy, but the fragmentation of red cells may be important in pointing to the diagnosis.

Some of the disorders producing MAHA are discussed here

Microangiopathic haemolytic anaemia and malignant disease

Fragmentation of red cells with chronic intravascular haemoly-sis may occur in

malignant disease. Clinically significant anaemia may occur, especially when there is

invasion of the tumour into a large blood vessel (as in haemangiopericytoma), but more

commonly the haemolysis is trivial or well compen-sated. The fragmentation may

simply be noted on the blood film. A blood fi lm that shows evidence of MAHA together

with leucoerythroblastic changes is virtually diagnostic of malignant disease with

secondary deposits in the bone marrow


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In acute leukaemia, particularly but not exclusively promy-elocytic (M3), there may be

intense intravascular coagulation that may be accompanied by MAHA. The coagulation

changes dominate the clinical picture.

Microangiopathic haemolytic anaemia and infection

Infections, particularly septicaemia, may provoke intravascular coagulation and

MAHA. Generally, the coagulation changes and septic shock overshadow the mild

fragmentation but, occasionally, infections produce a chronic state of partially

compensated intravascular haemolysis and marked red cell fragmentation. Haemolytic


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uraemic syndrome may be precipi-tated by infection, particularly Escherichia

coli0157. Haemolytic uraemic syndrome is discussed in Chapter 44 .

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is an acute syndrome characterized by fever,

neurological signs, haemolytic anaemia with fragmented red cells and

thrombocytopenia. The diagnosis is made on the basis of the clinical presentation and

evidence for haemolytic anaemia with fragmented red cells and throm-bocytopenia.

Bilirubin is elevated, as is serum LDH, indicating intravascular haemolysis. LDH is a

useful marker for measuring the activity of the microangiopathic process, as is the

persist-ence of red cell fragments in the blood film. It may take up to 1 week for allfragments to be removed from the circulation after the haemolytic process stops. The

destruction of red cells occurs at the site of intravascular occlusions; at post - mortem,

platelet and fibrin plugs are found in capillaries

March haemoglobinuria

Haemoglobinuria following running has been documented for about 100 years. Its

origin is mechanical, with destruction of red cells occurring in the feet. It can be cured

by wearing soft shoes or running on soft ground. The disorder may arise in joggers and

is benign except that it may lead to extensive invasive investigations unless recognized.

The blood film does not show any red cell fragmentation or consistent abnormality.

Occasionally, haemoglobinuria after running is accompanied by nausea, abdominal

cramps and aching legs, and enthusiastic athletes with this condition may exhibit mild

splenomegaly and jaundice.

Presentation and investigations:

Varying degree of anaemia most severe in DIC, TTP/HUS and HELLP. Often associated with decreased platelets.


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Blood film

RBC fragmentation, stomatocytes and spherocytes. Reticulocytosis often very marked.

Signs of underlying disease should be sought

Treatment

Diagnose and treat underlying disease. Give folic acid and iron supplements if deficient.


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HELLP SYNDROME

HELLP syndrome is a life-threatening pregnancy complication usually considered to be a

variant of preeclampsia. Both conditions usually occur during the later stages of pregnancy,

or sometimes after childbirth.

HELLP syndrome was named by Dr. Louis Weinstein in 1982 after its characteristics:

H(hemolysis, which is the breaking down of red blood cells),

EL(elevated liver enzymes)

LP(low platelet count).

A suspicion of HELLP syndrome can be frustrating to the physician when all requirements

for its certain diagnosis are not apparent. In some patients who are developing HELLP

syndrome the primary preeclampsia indicators of high blood pressure and protein in the urine

may not be present, and its symptoms can be mistaken for gastritis, flu, acute hepatitis, gall

bladder disease, or other conditions. While some of these other conditions may also be

present, there is no evidence they are related.

Early diagnosis is critical because the morbidity and mortality rates associated with the

syndrome have been reported to be as high as 25%. As a result, patient awareness of HELLP

syndrome, and how it relates to preeclampsia, is helpful to ensure optimal and timely medical

care for mother and baby.

Symptoms of HELLP Syndrome

The physical symptoms of HELLP Syndrome may seem at first like preeclampsia. Symptoms

reported by the pregnant woman developing HELLP syndrome may include one or all of the

following:

headache nausea/vomiting/indigestion with pain after eating


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epigastric (abdominal) or substernal (chest) tenderness and right upper quadrant pain(from liver distention)

shoulder pain or pain when breathing deeply bleeding visual disturbances swelling

Signs to look for include:

high blood pressure protein in the urine

The most common reasons for the mother to become critically ill or die are liver rupture or

stroke (cerebral edema or cerebral hemorrhage). These can usually be prevented when caught

in time. If you or someone you know has any of these symptoms, please see a health care

provider immediately.

Most often, the definitive treatment for women with HELLP Syndrome is delivery of the

baby. Transfusion of some form of blood product (red cells, platelets, plasma) is often

needed. Corticosteroids can be used to improve fetal lung maturation in the very preterm

pregnancy; the University of Mississippi MFM group have reported

beneficial maternaleffects to slow disease progression, to improve laboratory parameters, to

lessen liver and central nervous system morbidity, and to shorten hospitalization.

Who is at risk of getting HELLP syndrome?

Among pregnant women in the United States, 5 - 8% develop preeclampsia; 15% of those

women develop evidence of HELLP syndrome (15-20% of those with severe preeclampsia),

meaning as many as 48,000 women per year will develop HELLP syndrome in the US. There

is still some difference of opinion among experts as to what lab values constitute HELLP

syndrome, so these estimates are approximate and also reflect the higher end of the spectrum.

These numbers will vary with attention to the mother's care. If preeclampsia is diagnosed

early and the baby is delivered, HELLP syndrome may not develop. The rate of HELLP and


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the mortality will then be lower than stated. If the diagnosis of preeclampsia was delayed or it

was managed too conservatively, a woman's likelihood of developing HELLP syndrome is

even higher.

What can I do to prevent HELLP syndrome?

Unfortunately at this time, there is no way to prevent this illness. The best thing to do is:

Get yourself in the best physical shape before getting pregnant Have regular prenatal visits Inform your care providers about any previous high-risk pregnancies or family history

of HELLP syndrome, preeclampsia, etc.

Understand the warning signs and do not delay reporting them to your healthcareprovider, including trusting yourself when "something just doesn't feel right"

3 Classifications of HELLP

The severity of HELLP syndrome is measured according to the blood platelet count of the

mother and divided into three categories, according to a system termed "the Mississippi

classification."

Class I (severe thrombocytopenia): platelets under 50,000/mm3 Class II (moderate thrombocytopenia): platelets between 50,000 and 100,000/mm3 Class III (AST > 40 IU/L, mild thrombocytopenia): platelets between 100,000 and

150,000/mm3

Babies Born from Mothers with HELLP Syndrome

If the baby weighs over 1000 grams (approx. 2 lbs.), at birth, his or her survival rate and

length of hospital stay is similar to non-HELLP babies of comparable sizes, and there doesn't

seem to be many long-term adverse outcome.

If the baby weighs less than 1000 grams at delivery, the news is not as good. Several studies

have suggested longer hospital stays and more chance of needing ventilator care.


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Unfortunately, right now doctors can't predict the scope of the medical problems that these

small babies encounter.

How likely is the baby to die from HELLP Syndrome? In developed countries, the stillbirth

rate (in utero death of the baby after 20 weeks of gestation) is 51/1,000 a rate higher than

both severe preeclampsia and eclampsia. Overall perinatal mortality from HELLP Syndrome

(stillbirth plus neonatal death) ranges from 7.7 to 60%. Most of these deaths are attributed to

abruption of the placenta (placenta prematurely separating from the uterus), placental failure

with intrauterine asphyxia (fetus not getting enough oxygen), and extreme prematurity.

Risk of Getting HELLP in Future Pregnancies

Women with a history of HELLP syndrome are at increased risk of all forms of preeclampsia

in subsequent pregnancies. The rate of preeclampsia in subsequent pregnancies ranges from

16 - 52%, with higher rates if the onset of HELLP syndrome was in the second trimester. The

rate of recurrent HELLP syndrome ranges from 2 - 19% depending upon the patient

population studied.

Treatment

The only effective treatment is prompt delivery of the baby. Several medications have been

investigated for the treatment of HELLP syndrome, but evidence is conflicting as to

whethermagnesium sulfate decreases the risk of seizures and progress to eclampsia.

TheDIC is treated withfresh frozen plasma to replenish the coagulation proteins, and

theanemia may requireblood transfusion. In mild

cases,corticosteroids andantihypertensives (labetalol,hydralazine,nifedipine) may be

sufficient. Intravenous fluids are generally required. Hepatic hemorrhage can be treated with

embolization as well if life-threatening bleeding ensues.

The University of Mississippi standard protocol for HELLP includes

corticosteroids. However, a 2009 review found "no conclusive evidence" supporting

corticosteroid therapy,and a 2010 systematic reviewby theCochrane Collaboration also

found "no clear evidence of any effect of corticosteroids on substantive clinical outcomes"

either for the mothers or for the newborns
http://en.wikipedia.org/wiki/Magnesium_sulfatehttp://en.wikipedia.org/wiki/Disseminated_intravascular_coagulationhttp://en.wikipedia.org/wiki/Fresh_frozen_plasmahttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Blood_transfusionhttp://en.wikipedia.org/wiki/Corticosteroidhttp://en.wikipedia.org/wiki/Antihypertensivehttp://en.wikipedia.org/wiki/Labetalolhttp://en.wikipedia.org/wiki/Hydralazinehttp://en.wikipedia.org/wiki/Nifedipinehttp://en.wikipedia.org/wiki/Systematic_reviewhttp://en.wikipedia.org/wiki/Cochrane_Collaborationhttp://en.wikipedia.org/wiki/Cochrane_Collaborationhttp://en.wikipedia.org/wiki/Systematic_reviewhttp://en.wikipedia.org/wiki/Nifedipinehttp://en.wikipedia.org/wiki/Hydralazinehttp://en.wikipedia.org/wiki/Labetalolhttp://en.wikipedia.org/wiki/Antihypertensivehttp://en.wikipedia.org/wiki/Corticosteroidhttp://en.wikipedia.org/wiki/Blood_transfusionhttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Fresh_frozen_plasmahttp://en.wikipedia.org/wiki/Disseminated_intravascular_coagulationhttp://en.wikipedia.org/wiki/Magnesium_sulfate


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PORPHYRIAS-HB SYNTHESIS DISORDERS

Description

Group of seven predominantly inherited metabolic disorders, caused by deficiencies ofenzymes of the heme biosynthetic pathway

Symptoms result from accumulation of precursors in heme biosynthesis Clinically characterized by cutaneous and/or acute neuropsychiatric symptoms; such as

severe abdominal pain

Cutaneous porphyrias affect the skin causing cutaneous photosensitivity, which can be severe Acute neuropsychiatric porphyrias affect the nervous system and can be life-threatening, but

attacks can be aborted by early administration of hemin

Latency is common, and some carriers only become symptomatic after exposure toprecipitating factors such as alcohol or certain drugs

When a patient is diagnosed with porphyria, the whole family must be screened so thatprecipitating factors can be avoided in anyone found to be a carrier

Synonyms

Delta-aminolevulinic aciduria ALAD porphyria Swedish porphyria Pyrroloporphyria Intermittent acute porphyria Gunther disease Porphyria variegata South African porphyria

Protocoproporphyria Royal malady Protoporphyria Erythrohepatic protoporphyria Toxic porphyria

Immediate action

Acute symptoms may need immediate hospitalization


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If an elevated urine porphobilinogen is detected, send a 24-h specimen for quantitation andadditional tests

Intravenous glucose for mild acute porphyria is appropriate; intravenous hemin therapyshould be instituted soon after and as soon as it is available

Key points

A group of metabolic disorders that present with gastrointestinal, neuropsychiatric, and skinsymptoms; can be divided into acute and non-acute porphyrias

Diagnosis of acute neuropsychiatric porphyrias is supported by the finding of elevated urineporphobilinogen on a single void urine specimen

Intravenous hemin treatment is the therapy of choice for acute neuropsychiatric porphyriasalong with glucose, intravenous fluids, and elimination of any precipitating factors

Background

Cardinal features

A group of inherited metabolic disorders that are caused by a partial or nearly completedeficiency of enzymes of the heme biosynthetic pathway

Symptoms result from accumulation of precursors in heme biosynthesis Seven different kinds of porphyria have been distinguished, representing discrete deficiencies

of each of the seven enzymes beyond the first and rate-limiting step of the pathway

Dysfunction of each specific enzyme causes a unique pattern of abnormally elevated levels ofporphyrins and/or their precursors to accumulate in tissues, and to be excreted in urine and

stool

Clinical presentation depends on associated enzyme and mode of inheritance, and is ofteninfluenced by metabolic and environmental factors

Clinically characterized by cutaneous or acute neuropsychiatric symptoms and syndromes, orboth

Cutaneous manifestation is typically cutaneous photosensitivity, which can be severe Acute neuropsychiatric manifestations are most typically abdominal pain, constipation,

dysesthesia, muscular paralysis, and respiratory failure (which can be fatal); attacks can be

aborted by early administration of hemin

Latency is common and there can be asymptomatic or minimally symptomatic carriers


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Some carriers only become symptomatic after exposure to an additional agent or factorcapable of inducing disease expression

Classification (from most to least common type):

Porphyria cutanea tarda (includes hepatoerythropoietic porphyria, a very rare type ofporphyria associated with hemolytic anemia)

Acute intermittent porphyria Erythropoietic protoporphyria Variegate porphyria Hereditary coproporphyria Congenital erythropoietic porphyria Aminolevulinic acid dehydratase deficiency

Can also be categorized as:

Hepatic porphyrias (delta-aminolevulinic acid dehydratase deficiency porphyria, acuteintermittent porphyria, variegate porphyria, hereditary coproporphyria, porphyria cutanea

tarda), in which the excess porphyrin production occurs in the liver

Erythropoietic porphyrias (erythropoietic protoporphyria, congenital erythropoieticporphyria), in which excess porphyrin production occurs in the bone marrow

Can also be categorized as:

Acute porphyrias (delta-aminolevulinic acid dehydratase deficiency porphyria, acuteintermittent porphyria, variegate porphyria, hereditary coproporphyria), which typically cause

neuropsychiatric problems, often manifesting as a severe abdominal pain and are associated

with excess production and excretion in urine of porphobilinogen and delta-aminolevulinic

acid

Nonacute porphyrias (porphyria cutanea tarda, congenital erythropoietic porphyria,erythropoietic protoporphyria), in which porphobilinogen and delta-aminolevulinic acid are

not produced in excess

Can also be categorized according to their mode of inheritance:

Autosomal dominant (acute intermittent porphyria, variegate porphyria, hereditarycoproporphyria, porphyria cutanea tarda (20% of cases are autosomal dominant),

erythropoietic protoporphyria)


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Autosomal recessive (delta-aminolevulinic acid dehydratase deficiency porphyria, congenitalerythropoietic porphyria)

Causes

Common causes

The inherited mutant gene encodes the specific enzyme deficiency (in order of sequence of

enzymes in the heme biosynthetic pathway):

Delta-aminolevulinic acid dehydratase deficiency causes delta-aminolevulinic aciddehydratase deficiency porphyria

Porphobilinogen deaminase deficiency causes acute intermittent porphyria Uroporphyrinogen III synthase deficiency causes congenital erythropoietic porphyria Uroporphyrinogen decarboxylase deficiency (UROD) causes the familial type (approx. 20%

of cases) and sporadic type (80%) of porphyria cutanea tarda

Coproporphyrinogen oxidase deficiency causes hereditary coproporphyria Protoporphyrinogen oxidase deficiency causes variegate porphyria Ferrochelatase deficiency causes erythropoietic protoporphyria

The two autosomal recessive porphyrias, congenital erythropoietic porphyria and delta-

aminolevulinic acid dehydratase deficiency porphyria are very rare; for each there is little or

no production of normal enzyme.

The other five porphyrias are mainly inherited in an autosomal dominant manner, although

more complex patterns of inheritance are possible.

Signature feature for each is low clinical penetrance Inheritance of one copy of a mutant gene decreases enzyme activity by 50%, which is

sufficient for normal cellular metabolism

Clinical presentation requires additional factors (genetic or environmental) that affect theheme pathway

These factors either increase the normal demand for heme production, cause a decrease inenzyme activity, or are a combination of these effects

Porphyria cutanea tarda

Further variation is seen in porphyria cutanea tarda, the most common porphyria worldwide,

and many risk factors precipitate the disease.


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There are three clinically indistinguishable subtypes:

Type 1 (sporadic, no family history of porphyria) accounts for 80% of cases. UROD activity

is inhibited (inactivated) only in the liver. Although sporadic cases do not have mutation in

the UROD gene, there is association with mutations in the hemochromatosis (HFE) gene and

other, as yet unknown, genetic causes. The disease is precipitated by various risk factors:

Hepatitis C infection Alcohol Oral estrogens Hexachlorobenzene and tetrachloridibenzo-p-dioxin Hepatic tumors

Type 2 (familial, autosomal dominant) accounts for 20% of cases, and is caused by inherited

mutations in the UROD gene.

Distinguished from sporadic cases by measuring erythrocyte UROD activity or by molecularanalysis

Coinheritance of UROD mutation and either homozygous or heterozygous HFE C282Y andH63D mutations result in earlier onset of symptoms

Manifestation of disease requires precipitating factors, such as chronic exposure to alcohol,hepatotropic viruses, excess iron intake or storage, and oral estrogen use

Additional modifying genetic loci are implicated in the disease processType 3 (familial, very rare), results from other inherited mutations in the UROD gene.

Contributory or predisposing factors

All porphyrias:

Liver disease Hepatitis C Infection Heavy alcohol use Major surgery

Acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, delta-

aminolevulinic acid dehydratase deficiency porphyria:
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Drugs: estrogen and progesterone from contraception and hormone replacement therapies(although may be beneficial in some patients in prevention of cyclic menstrual attacks);

danazol; griseofulvin; rifampin, sulfonamides, chloramphenicol and primidone; diclofenac;

phenobarbital, carbamazepine, valproic acid, clonazepam, chlordiazepoxide and

meprobamate; imipramine; chlorpropamide and metoclopramide; methyldopa and

glutethimide; ergotamine; pyrazinamide; carisoprodol; ethchlorvynol; and pentazocine,

mephenytoin, succinimides, and pyrazolones

Steroids: endogenous steroid hormones, sex steroid preparations Menstrual cycle: in presence of high levels of progesterone Pregnancy Fasting Emotional and physical stress Substance abuse: particularly marijuana, ecstasy, amphetamines, and cocaine Tobacco

Porphyria cutanea tarda:

Drugs: nonsteroidal anti-inflammatory drugs, sulfonylureas, busulfan Estrogens, especially from oral contraceptives Iron supplements

Epidemiology

Incidence and prevalence

Prevalence

Porphyria cutanea tarda: 10 cases per 100,000 of population, including both inherited andsporadic types

Acute intermittent porphyria, erythropoietic protoporphyria, variegate porphyria: 1-10 casesper 100,000 of population

Hereditary coproporphyria:


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Erythropoietic protoporphyria: older childhood Acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, delta-

aminolevulinic acid dehydratase deficiency porphyria: young adult

Porphyria cutanea tarda: typically after the fourth decadeGender

Erythropoietic protoporphyria, congenital erythropoietic porphyria: males and femalesequally affected

Porphyria cutanea tarda: generally more common in males; however, female incidence isincreasing in association with oral contraceptive and alcohol use

Acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, delta-aminolevulinic acid dehydratase deficiency porphyria: more common in females

Race

More common in Caucasians than African-Americans or Asians.

Genetics

The seven porphyrias form a group of inherited metabolic disorders, with the most commonbeing porphyria cutanea tarda

The majority (80%) of patients have the sporadic (type 1) form of porphyria cutanea tarda, inwhich UROD deficiency is restricted to the liver

Familial (type 2) porphyria cutanea tarda accounts for approx. 20%, and may bedistinguished from the sporadic cases by measuring erythrocyte UROD activity or by

molecular analysis of the UROD gene

Four additional porphyrias (acute intermittent porphyria, variegate porphyria, hereditarycoproporphyria, and erythropoietic protoporphyria) are mainly inherited in an autosomal

dominant manner, although more complex patterns of inheritance are seen in some families

The two autosomal recessive porphyrias, congenital erythropoietic porphyria and delta-aminolevulinic acid dehydratase deficiency porphyria, are very rare

A number of disease-specific mutations have been identified in each of the genes that encode

the enzymes that are deficient in the porphyrias.

Gene testing identifies mutations in 90% or more of affected individuals with the variousinherited forms of porphyria

Additional modifier genes, such as the HFE gene for hemochromatosis, are associated withsome forms of porphyria, in particular porphyria cutanea tarda


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Family screening and genetic counseling are important aspects of management for each of the

porphyrias, and requires referral to a genetic specialist.

microangiopathic haemolytic anaemias

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