Ruzgar Miroglu - Haematology 2 (2024)

All Lectures of Haematology

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Acute Myelogenous Leukemia and AcuteComplications

Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.The underlying pathophysiology in acute myelogenous leukemia consists of a maturational arrest of bone marrow cells in the earliest stages of development. This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to apoptosis, results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.Acute myelogenous leukemia (AML) is more common in men than in women. The prevalence of AML increases with age. The median age of onset is approximately 70 years.

Patients with AML present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both.The most common symptom of anemia is fatigue.And they may also present with fever or history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC).

Diagnosing and Treating MultipleMyeloma

Evaluation ofThrombocytopenia

Thrombocytopenia is the presence of relatively low platelets in blood.In human beings a normal platelet count ranges from 150,000 to 450,000 platelets per 1ml of blood.Often, low platelet levels do not lead to clinical problems rather, they are picked up on a routine full blood count. Occasionally, there may be bruising, particularly purpura in the forearms,petechia (pinpoint hemmorages on skin and mucous membranes) nosebleeds and/or bleeding gums.If the person’s platelet count is between 30,000 and 50,000/mm3, bruising with minor trauma may be expected; if it is between 15,000 and 30,000/mm3, spontaneous bruising will be seen.

Decreased platelet counts can be due to a number of disease processes.

Decreased production

* Vitamin B12 or folic acid deficiency

* Leukemia or myelodysplastic syndrome

* Decreased production of thrombopoietin by the liver in liver failure.

* Sepsis, systemic viral or bacterial infection

* Dengue fever can cause thrombocytopenia by direct infection of bone marrow megakaryocytes as well as immunological shortened platelet survival

* Hereditary syndromes

Fanconi anemia

Bernard-Soulier syndrome, associated with large platelet

Alport syndrome

Increased destruction

* Idiopathic thrombocytopenic purpura (ITP)

* Paroxysmal nocturnal hemoglobinuria (PNH)

* Neonatal alloimmune thrombocytopenia

* Hypersplenism

* HIV-associated thrombocytopenia

Thrombotic ThrombocytopenicPurpura

Thrombotic Thrombocytopenic Purpura is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses to form in small blood vessels throughout the body.Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. Microthrombi formation in the blood vessels lead to Intravascular hemolysis,schistocyte formation and Reduced blood flow due to thrombosis and cellular injury results in end organ damage.

Classically, the following five features are indicative of TTP

* Fluctuating Neurologic symptoms such as hallucinations, bizarre behavior, altered mental status, stroke or headaches

* Kidney failure

* Fever

* Thrombocytopenia leading to bruising or purpura

* Microangiopathic hemolytic anemia

Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia is seen, and therapy is started.Current therapy is based on support and plasmapheresis to reduce circulating antibodies against ADAMTS13 and replenish blood levels of the enzyme.

Disseminated IntravascularCoagulation(DIC)

Disseminated intravascular coagulation (DIC) is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of microthrombi inside the blood vessels throughout the body.As the microthrombi consume coagulation proteins and platelets, normal coagulation is disrupted and abnormal bleeding occurs from the skin , the gastrointestinal tract, the respiratory tract and surgical wounds.

In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding. One critical mediator of DIC is the release of tissue factor. TF binds with coagulation factors that then triggers the extrinsic pathway which subsequently triggers the intrinsic pathway of coagulation.Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in excess amounts of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage.

Definitive diagnosis of DIC depends on the result ofThrombocytopenia,Prolongation of prothrombin time and activated partial thromboplastin time,A low fibrinogen concentration and Increased levels of fibrin degradation products.

Thalassaemia

Thalassaemia is a inherited autosomal recessive hemoglobinopathy. There are different types of thalassaemia.Haemoglobin is made out of two ‘alpha chains’ and two ‘beta chains’ which are put together to make the haemoglobin molecule.In thalassaemia, defect of either the alpha chains or the beta chains.The main types of thalassaemia are called alpha thalassaemia and beta thalassaemia.Each type of thalassaemia has several sub types.The mildest types are called thalassaemia trait. The more severe beta types are beta thalassaemia major and beta thalassaemia intermedia.The more severe alpha forms are Hb Barts and Hb H disease.

Hb H disease is due to having three missing alpha haemoglobin genes.It usually causes a mild but persistent anaemia. Sometimes Hb H causes more symptoms and is similar to beta thalassaemia intermedia (explained below). Some people with Hb H disease need blood transfusions.

Hb Barts is the most severe form of alpha thalassaemia, where all the alpha haemoglobin genes are abnormal or missing. It occurs if a baby inherits two alpha zero thalassaemia genes. In this condition, no normal haemoglobin can be made, even before birth. It is the most serious form of thalassaemia – so serious that the baby will usually die in the uterus from severe anaemia.

Beta thalassemia major or Cooley’s anemia results if both alleles have thalassemia mutations. This is a severe microcytic, hypochromic anemia. If Untreated, it causes anemia, splenomegaly, and severe bone deformities. It progresses to death before age twenty. Treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation.

In Beta thalassemia minor only one beta globin allele bears a mutation. This is a mild microcytic anemia. Detection usually involves measuring the mean corpuscular volume and increased fraction of Hemoglobin A2 and a decreased fraction of Hemoglobin A.

MyelodysplasticSyndromes

Myelodysplastic syndromes (MDS) are a collection of hematological conditions united by ineffective production of myeloid blood cells and risk of transformation to acute myeloid leukemia (AML). Myelodysplastic syndromes has been found in humans, cats and dogs. Anemia requiring chronic blood transfusion is frequently present.
Myelodysplastic syndromes are bone marrow stem cell disorders resulting in disorderly and ineffective hematopoiesis (blood production) manifested by irreversible quantitative and qualitative defects in hematopoietic (blood-forming) cells. In a majority of cases, the course of disease is chronic with gradually worsening cytopenias due to progressive bone marrow failure. Approximately one-third of patients with MDS progress to AML within months to a few years.There is no cure for myelodysplastic syndromes. Treatment for myelodysplastic syndromes usually focuses on reducing or preventing complications of the disease and of treatments. In certain cases, myelodysplastic syndromes are treated with a bone marrow transplant, which may help prolong life.

HEMOLYTIC UREMICSYNDROME

HEMOLYTIC UREMIC SYNDROME(HUS) is part of microangiopathic hemolytic anemia that encompass Thrombotic thrombocytopenic purpura (TTP) and HUS. The classic childhood case of HUS occurs after bloody diarrhea caused by a strain of E. coli that expresses Shiga-like toxin or EHEC (Enterohemorrhagic E. coli). HUS follows an influenza-like or gastrointestinal (GI) prodrome with bleeding manifestations, severe oliguria, hematuria, a microangiopathic hemolytic anemia, and occatinally prominent neurologic changes.The typical pathophysiology involves the shiga-toxin binding to proteins on the surface of glomerular endothelium and inactivating a metalloproteinase ADAMTS13.Once the ADAMTS13 is disabled multimers of vWF form and initiate platelet activation and cause microthrombi formation. In contrast with typical DIC , coagulation factors are not consumed in HUS and the coagulation screen, fibrinogen level, and assays for fibrin degradation products such as “D-Dimers”, are generally normal despite the thrombocytopenia.

BloodTransfusion

Blood transfusion is the process of transferring blood or blood products from one person into the circulatory system of another. It can be life-saving in some situations, such as massive hemorrhages due to trauma, or can be used to replace blood loss in surgery. Blood transfusions may also be used to treat a severe anaemia or thrombocytopenia caused by hematological diseases. People suffering from Thalassemia,hemophilia or sickle-cell disease may require frequent blood transfusions.Early transfusions used whole blood, but modern medical practice commonly uses only components of the blood.

Donated blood is usually subjected to processing after it is collected, to make it suitable for use in specific patient populations.These are include:

Component separation

Leukoreduction(Leukodepletion) is the removal of WBC from the blood product by filtration. Leukoreduced blood is less likely to cause alloimmunization (development of antibodies against specific blood types),and less likely to cause febrile transfusion reactions.

CHRONIC MYELOPROLIFERATIVEDISORDERS

The myeloproliferative diseases(MPD) are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia.There are four main myeloproliferative diseases, which can be further categorized by the presence of the Philadelphia chromosome:

Philadelphia Chromosome “positive” -Chronic myelogenous leukemia (CML)

Philadelphia Chromosome “negative” – Polycythemia vera (PV),Essential thrombocytosis(ET),Myelofibrosis (MF)

All MPDs arise from precursors of the myeloid lineage in the bone marrow.Depending on the type of the MPD, diagnostic tests may include red cell mass determination,bone marrow aspirate and trephine biopsy,oxygen saturation and carboxyhaemoglobin level,neutrophil alkaline phosphatase level, vitamin B12 and serum urate.

Author:Márcia Datz MD, Pediatrician

Introduction

Anemia is a commonly encountered clinical condition that is caused by an acquired or hereditary abnormality of red blood cells (RBC) or its precursors, or may be a manifestation of an nonhematologic disorder.

Definition

Anemia is defined as a decrease in the circulating RBC mass and a corresponding decrease in the oxygen-carrying capacity of the blood.
Normal values of the hemogram:

----------------------------------------------------------TEST WOMEN MEN ---------------------------------------------------------- Ht (%) 36-48 40-52----------------------------------------------------------Hg (g/dl) 12-16 13,5-17,7----------------------------------------------------------Hem 4,0-5,4 4,5-6,0----------------------------------------------------------VCM 80-100 80-100----------------------------------------------------------

A decrease in any of this values (Ht, Hg, Hem) is called anemia. They can be altered by the plasmatic volumes.Diference between women and men values are due to androgen hormones.

Signs and Symptoms

The clinical manifestations vary with the age, degree and rapidity of onset, presence of subjacent illness and other factors. Mild anemia are often assymptomatic. The main symptoms are exercise dyspnea, fatigue, palpitation, pica (consumption of substances such as ice, starch or clay, frequently found in iron deficiency anemia), syncope (particularly following exercise) and bounding pulse. Dizziness, headache, syncope, tinnitus or vertigo, irritability, difficulty sleeping or concentrating are more frequent in severe chronic anemia.

Common signs are pallor (color of skin, palms, oral and conjunctival mucous membrane and nail beds), tachycardia, ejection sistolic murmur, mild peripheral edema and venous hums and wide pulse pressure. In old people, angina pectoris can be an important clinical manifestation. Females commonly develop abnormal menstruation, both amenorrhea and increased bleeding.Males can develop decrease in libido and impotence.

Cardiovascular Adaptations in Anemia

The main consequence of anemia is tissue hypoxia. If anemia has developed rapidly, there may not be adequate time for compensatory adjustments to take place, so there is a sudden marked contraction of intravascular volume, resulting in postural hypotension, fall in cardiac output, shunting of blood from skin to central organs, sweating, restlessness, thirst and air hunger. If anemia has slowly instalation, many adaptations occur for the oxygen mantainance, such as increasing of plasmatic volume and right shift of the oxygen-hemoglobin dissociation curve.

History and Physical Examination

In the hystory is important to ask about duration and time of onset, other subjacent illness, associated symptoms related with one specific etiology, family history, hemotransfusion, blood loss and drug exposure.Physical findings can inclue jaundice, splenic enlargement, neurologic symptoms (loss of vibration sensibility, abnormal march), tongue atrophy, lynphadenopathy, evidence of blood in feces or vomit, leg ulcers, petechiae and myriad signs of primary diseases that may cause a secondary anemia.

Basic Laboratory Exams

• Complete blood count (with reticulocyte count, platelet count, mean cellular volume-VCM- and diferencial leukocyte count).
• Peripheral blood smear can confirm size and color of RBC, variation in red cell size (anisocytosis) or shape (poikilocytosis).Particularly important in evaluating a patient with hemolysis.
• Serum ferritin level, serum iron and total iron binding capability (TIBC).
  OBS: Bone marrow aspiration is useful and critical in the workup of any unexplained anemia, specially in underproductions anemia.

  Initial Evaluation of Anemia

  The first exam to see after detecting the anemia is count of reticulocyte.If it is increased, it means anemia with increased red blood cell loss or destruction.If it is decreased, means anemia associated with decreased red blood cell production.

  Cause	Reticulocyte Number(normal:50.000-100.000/ml)
  Bone Marrow Failure	Low or Normal
  Hemolysis or Acute Blood Loss	High

  Then, if the diagnostic is bone marrow failure, it is important to classifie anemia based on mean cellular volume (VCM).It can be microcytic, normocytic and macrocytic, with low, normal or high VCM, respectively).

  Normocytic Anemias

  • Chronic disease anemia
  • Iron deficiency
  • Secundary anemias (hepatic, renal or endocrine disorders)
  • Primary bone marrow disorders (aplasia, myelodisplasia, myelofibrose,
    hematologic and solid tumors, HIV infection, granulomas)

  Microcytic Anemias

  • Iron Deficiency
  • Chronic Disease Anemia
  • Thalassemia

  Macrocytic Anemias

  • Megaloblastic anemias ( folic acid and cobalamin deficiency and congenital disorders )
  • Alcoholism
  • Drugs
  • Liver diseases
  • Primary bone marrow disorder
  • Hypothyroidism
  • Splenectomy
  • High VCM by artefacts

  Anemias due to Decreased RBC Production

  RBC indexes	Marrow	Additional lab tests	Diagnosis
  Hipochromic microcytic (Low VCM)	No iron	Low Fe, High TIBC	Iron Deficiency
  	+ iron	High HbA2 or High HbF	beta-Thalassemia
  	Ring sideroblasts	Low HbA2	Sideroblastic anemia
  Macrocytic Hyperchromic( High VCM)	Megaloblastic	Low Serum B12	Vitamin B12 deficiency
  		Achlorhydria	Pernicious anemia
  Normocytic, normochromic	normal	Low Serum folate	Folic acid deficiency
  		Low Fe and TIBC	Anemia of chronic inflammation
  		High Crestinine	Anemia of uremia
  		Abnormal liver function tests	Anemia of liver disease
  		Low T4	Anemia of myxedema
  Normoblasts, Teardrops
  	Aplastic	Pancytopenia	Aplastic anemia
  	Fibrosis	Alkaline Phosphatase	Myeloid Metaplasia
  	Infiltrated: tumor, lymphoma, etc.	High leukocyte count	Myelophtisic

  If the number of reticulocytes is high (hemolysis), it’s important to confirm the presence and assess the magnitude of hemolysis, asking for serum unconjugated bilirrubin (increased), haptoglobin (decreased), urine hemosiderin (present), urine hemoglobin (present) and serum lactate dehydrogenase (increased).

  Hemolytic Anemia

  Blood Smear	Additional Lab Tests	Diagnosis
  Schistocytes, Helmet Cells	Positive Coombs test	Traumatic hemolytic anemiaImmunohemolytic anemia
  Spherocytes	High Osmotic Fragility	Hereditary spherocytosis
  Spur Cells	Abnormal LFT+ sucrose lysis	Spur cell anemia, Paroxysmal nocturnal hemoglobinuria
  Sickle cell	+ sickle prep.	Sickle cell syndromes
  Target cell	Abnormal Hb eletrophoresis	HbC, D, etc...
  Heinz bodies	Abnormal Hb eletropheresis Low G6PD	Congenital Heinz body hemolytic anemiaG6PD deficiency