Cytopenias

Question 1

ITP

Answer 1

Description

ITP is a diagnosis of exclusion. It is defined as isolated thrombocytopenia (platelet count <100,000/microL) without anemia or leukopenia and without another apparent cause of the thrombocytopenia

also called idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura) is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults.

Severe ITP – Severe ITP refers to ITP with bleeding symptoms sufficient to require treatment; this typically occurs when platelet counts are below 20,000/microL.

Antibody production

Antibody production — Antibody production in ITP appears to be driven by CD4-positive helper T cells reacting to platelet surface glycoproteins, possibly involving CD40:CD40L co-stimulation [32-34]. Splenic macrophages appear to be the major antigen-presenting cells.

Classification

●Primary ITP – Primary ITP is acquired immune thrombocytopenia due to autoimmune mechanisms leading to platelet destruction and platelet underproduction that is not triggered by an apparent associated condition.

●Secondary ITP – Secondary ITP is ITP associated with another condition

• Chronic lymphocytic leukemia (CLL)
• Systemic lupus erythematosus (SLE)
• Antiphospholipid syndrome (APS)
• Common variable immune deficiency (CVID)
• Autoimmune lymphoproliferative syndrome (ALPS)
• Selective IgA deficiency
• Measles, mumps, and rubella (MMR) vaccination
• Helicobacter pylori infection
• HIV infection
• Hepatitis C virus (HCV) infection
• Cytomegalovirus (CMV) infection
• Varicella zoster virus (VZV) infection

●Drug-induced immune thrombocytopenia – Drug-induced immune thrombocytopenia (DITP) is thrombocytopenia due to drug-dependent platelet antibodies that cause platelet destruction.

Timeframe

• Newly diagnosed – Up to three months since diagnosis
• Persistent – Three to 12 months since diagnosis
• Chronic – More than 12 months since diagnosis

Exam:

●Petechiae – Petechiae are flat, red, discrete lesions that do not blanch under pressure. often legs

●Purpura – Purpura refers to a lesion caused by coalescence of petechiae.

●Epistaxis

●Severe hemorrhage (ICH, GIT, menstrual, haematuria)

Ix:

Thrombocytopenia, criteria for ITP is a platelet count <100,000/microL

Antiplatelet antibodies are not demonstrable in close to 50 percent of patients with ITP, low sensitivity, hence we don’t use assays for ITP

Blood film

ITP is not characterized by abnormal platelet morphology (eg, lack of granules, uniform populations of large or small platelets). If present, abnormal platelet morphology should prompt consideration of a hereditary platelet disorder.

●Immature white blood cells may suggest infection or leukemia

●Schistocytes may suggest a microangiopathic process such as thrombotic thrombocytopenic purpura (TTP)

●Prolonged clotting times may suggest liver disease or disseminated intravascular coagulation (DIC)

Management

do not use transfused platelet count in individuals with a stable platelet count above 20,000/microL unless there are other comorbidities or medications that increase bleeding risk.

“first-line” to refer to glucocorticoids, intravenous immune globulin (IVIG), and anti-D immune globulin (also called Rho[D] immune globulin) because they are generally used for initial treatment of newly diagnosed patients. Historically, second-line therapy meant splenectomy. However, rituximab and thrombopoietin receptor agonists are useful second-line agents.

Question 2

drug-induced thrombocytopenia

Answer 2

caused by accelerated platelet (and rarely, megakaryocyte) destruction from drug-dependent, platelet-reactive antibodies [1-3]. In almost all cases, drug-dependent antiplatelet antibodies bind non-covalently to specific platelet antigens via their Fab regions.

drop in platelet count occurs within two weeks of exposure to the drug.

hrombocytopenia in DITP is often severe, with a nadir platelet count <20,000/microL

Question 3

HIT

Answer 3

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (eg, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in a small percentage of patients exposed, regardless of the dose, schedule, or route of administration.

HIT results from an autoantibody directed against endogenous platelet factor 4 (PF4) in complex with heparin. This antibody activates platelets and can cause catastrophic arterial and venous thrombosis. Untreated HIT has a mortality rate as high as 20 percent; although with improved recognition and early intervention, mortality rates have been reported as below 2 percent.

• HIT type I (HIT I) is a mild, transient drop in platelet count that typically occurs within the first two days of heparin exposure. The platelet count typically returns to normal with continued heparin administration
• HIT type II (HIT II) is a clinically significant syndrome due to antibodies to platelet factor 4 (PF4) complexed to heparin, referred to as “HIT antibodies” or “PF4/heparin antibodies

Heparin-induced antibodies (HIA) – Some patients produce antibodies that react in laboratory assays for HIT but do not cause thrombocytopenia or thrombosis. These antibodies can occur in patients exposed to heparin

The mean nadir platelet count is approximately 60,000/microL. Platelet counts below 20,000/microL are rare

HIT typically occurs 5 to 10 days after the initiation of heparin. Early onset of HIT (ie, thrombocytopenia within the first 24 hours of exposure) may be seen if the patient has been exposed to heparin in the previous one to three months and has circulating HIT antibodies

Delayed-onset HIT is a well-described condition in which thrombocytopenia and/or thrombosis occur after heparin has been withdrawn;

Thrombosis — Thrombosis occurs in up to 50 percent of individuals with HIT who are not treated with a non-heparin anticoagulant,

• can cause skin necrosis, limb gangrene, organ ischemia/infarct

Stop heparin for a presumptive diagnosis of HIT

Warfarin can be used for anticoagulation once stable anticoagulation with another non-heparin agent has been established and an adequate platelet count has been attained (eg, >150,000/microL).

Bivalirudin — Bivalirudin (Angiomax, previously called Hirulog), a parenteral direct thrombin inhibitor and hirudin analog, has been successfully used in patients with HIT,

Question 4

Aplastic anaemia

Answer 4

Description:

• immune-mediated pancytopenia and hypocellular bone marrow (bone marrow failure - hypoplasia/aplasia)

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Pathophys:

• When the HSC pool falls below a critical mass, the conflicting demands of self-renewal and differentiation can lead to pancytopenia.
• Pathophysiologic processes that lead to loss of HSCs and cause aplastic anaemia include:

●Autoimmune mechanisms (SLE, GVHD, eosinophilic fasciitis)

●Direct injury to HSCs (eg, by drugs, chemotherapy agents, immunosuppressants, chemicals, irradiation)

●Viral infection (e.g. EBV, HIV)

●Clonal and genetic disorders (fanconi anaemia, myelodysplastic syndrome, dyskeratosis congenita)

● miscellaneous (pregnancy, anorexia nervosa, Paroxysmal nocturnal hemoglobinuria)

Presentation:

• recurrent infections (bacterial, invasive fungal) due to neutropenia
• mucosal hemorrhage or menorrhagia due to thrombocytopenia
• fatigue and cardiopulmonary findings associated with progressive anemia

Labs:

• neutropenia (ANC <0.5), thrombocytopenia (plts <20), anemia, reticulocytopenia (retic’s <20)
• Bone marrow aspirate and biopsy: profoundly hypocellular (<25% residual cells) with a decrease in all elements; the marrow space is composed mostly of fat cells and marrow stroma.

Differentials:

• Megaloblastic anemia (eg, pernicious anemia, malnutrition) can cause profound pancytopenia and bone marrow hypoplasia, due to B12/folate deficiency. Characterised by hypersegmented neutrophils and macro-ovalocytes on the peripheral blood smear and megaloblastic changes in the bone marrow examination
• Infiltrative BM disorders (e.g. primary myelofibrosis, MDS, AML, lymphoma, multiple myeloma), or invasive infections (tuberculosis, fungi)
• BM suppression that is reversible (due to chemotherapy etc)
• Hypersplenism/splenomegaly due to cirrhosis, portal vein thrombus, BM infiltration)

Management:

Begin treatment when patient is transfusion dependent (6-10units) and at risk of iron overload; when neutropenic (ANC <0.5)

• Medically fit patients can be considered for allogeneic HCT, thymoglobulin, cyclosporine
• medically unfit: considered for eltrombopag (bone marrow stimulating agent)
• frail patients: supportive care (transfusions), iron chelation thereapy (deferasirox), prophylaxis against PJP, fungal, viral (valacyclovir), bacterial (mouthwash), vaccinations

Question 5

Haemolytic anaemia

Answer 5

Description:

• premature destruction of RBCs

Causes:

Intrinsic (intracorpuscular defects) - the defect resides within the RBC itself, affecting the Hb structure, function, RBC volume, redox potential. Most of these causes are extravascular and inherited.

• Enzyme deficiencies (eg, deficiencies of G6PD, pyruvate kinase, glucose-phosphate isomerase, 5’ nucleotidase)
• Hemoglobinopathies (eg, sickle cell disease, thalassemias, unstable hemoglobins)
• Membrane defects (eg, hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis)

Extrinsic (extracorpuscular defects) - the defect resides external to the RBC itself, leading to premature loss, membrane damage, change in Hb solubility. Most of these causes are extravascular.

• Liver disease
• Hypersplenism
• Infections (eg, Bartonella, Babesia, malaria)
• Oxidant agents (eg, dapsone, nitrites, aniline dyes)
• Other agents (eg, lead, copper, snake and spider bites)
• Autoimmune hemolytic anemia (warm- or cold-reacting, drugs). Reticuloendothelial macrophages progressively phagocytize small pieces of RBC membrane that are opsonized with autoantibodies.
• Intravenous immune globulin infusion
• Intravascular causes: DIC

Intravascular: within circulation. Elevated free serum hemoglobin, elevated urinary hemoglobin/hemosiderin, low haptoglobin. The serum and urine may be pink or darker brown. Free Hb may induce AKI, DIC, thrombosis.

• Microangiopathic hemolytic anemia (eg, TTP, HUS, aortic stenosis, prosthetic valve leak)
• Transfusion reactions (eg, ABO incompatibility): acute or delayed transfusion reactions
• Infection (eg, clostridial sepsis, severe malaria)
• Paroxysmal cold hemoglobinuria; cold agglutinin disease (on occasion)
• Paroxysmal nocturnal hemoglobinuria
• Following intravenous infusion of anti-RhD immune globulin
• Following intravenous infusion with hypotonic solutions
• Snake bites
• Exposure to compounds with high oxidant potential (eg, copper poisoning, Wilson disease)

Extravascular: via the reticuloendothelial macrophages and monocytes of the liver spleen, bone marrow and lymph nodes. Refer to intrinsic and extrinsic causes

Immune mediated:

• most of these causes are extravascular
• positive DAT (direct Coombs), positive indirect Coombs (antibody screen)
• causes: AIHA, drug-induced hemolysis, and hemolytic transfusion reactions. Less-common causes of immune hemolysis include paroxysmal cold hemoglobinuria and cold agglutinin disease

Inherited:

• most of these causes are intracorpuscular/intrinsic
• •Alpha thalassemia
• •Beta thalassemia
• •Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• •Hereditary spherocytosis (HS)
• •Hereditary elliptocytosis (HE)
• •Hereditary stomatocytosis (HSt)
• •Hereditary xerocytosis (HX)
• •Pyruvate kinase (PK) deficiency
• •Sickle cell disease
• •Unstable hemoglobin variants

Drug-induced:

• •Drug-induced immune hemolysis
• •Drug-induced hemolysis associated with G6PD deficiency
• •Drug-induced thrombotic microangiopathy (DITMA)

Other/miscellaneous common causes of haemolytic anaemia:

• Clostridial sepsis
• •Mechanical hemolysis from aortic stenosis or prosthetic heart valve
• •Mechanical hemolysis from marching or bongo drumming
• •Osmotic lysis from hypotonic infusion
• •Paroxysmal nocturnal hemoglobinuria (PNH)
• •RBC parasite (eg, malaria, Babesia)
• •Snake bite
• •Thrombotic microangiopathy (TMA) such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS)

RBC physiology:

• The rate of RBC turnover is the reciprocal of RBC survival (the higher the rate of turnover, the lower the survival)
• Reticulocytosis requires adequate iron and vitamins (B12, folate) for RBC production, along with a normally-functioning bone marrow and adequate erythropoietin production.
• when free haemoglobin is released into circulation in the case of intravascular haemolysis, it becomes bound to haptoglobin. The hemoglobin-haptoglobin complex is rapidly removed by the liver, leading to a reduction in plasma haptoglobin, often to undetectable levels
• Biliverdin produced from RBC destruction is immediately reduced to unconjugated bilirubin by the enzyme biliverdin reductase and is released into the plasma.

Diagnosis:

• increased reticulocyte count not explained by recent bleeding or recent correction of iron/nutrient deficiency
• evidence of RBC destruction: elevated LDH and bilirubin; elevated urinary haemosiderin; decreased haptoglobin; peripheral blood smear showing spherocytes

Management:

• Folic acid supplementation: Chronic hemolysis leads to folate deficiency due to compensatory RBC production. Administration of folic acid (1 mg/day PO) is reasonable as long as hemolysis persists. This may not be necessary given routine folate supplementation of grains and other foods in most countries, but it is unlikely to be harmful.