Approach to patient

with cytopenias

H. Atilla Özkan, MD
Neutropenia
Definition

 Neutrophil count less than 1.5x109/L

 Severity is important
 1.0x109/L
 0.5x109/L
Clinical manifestations

 Systemic illness
 Mostly asymptomatic
 >1.0x109/L
 Neutropenia of short duration
 Pnumonia
 Pharyngitis
 Infection of skin
Abnormalities in the bone
marrow compartment
 Bone marrow injury
 Drugs and cytotoxic agents
 Radiation
 Chemicals
 Benzene, nitrous oxide, DDT, dinitrophenol
 Immunologically mediated
 Rheumatic disorers
Abnormalities in the bone
marrow compartment
 Bone marrow injury
 Bone marrow replacement (infitrative dis.)
 Malignancies
 Fibrosis
 Inherited neutropenia syndromes
 Cyclic neutropenia, severe congenital
neutropenia, Shwachman-Diamond syndrome
Maturation defects

 Acquaired
 Folic acid deficiency
 Vitamin B12 deficiency
 Clonal disorders
 Myelodysplastic syndromes
 Paroxysmal nocturnal hemoglobinuria
Abnormalities in the
extravascular compartment
 Increased utilization
 Severe bacterial, fungal, viral, or rickettsial
infection
Drugs that cause
neutropenia
 Antiarrhytmics
 Tocainide, procainamide, propranolol, quinidine
 Antibiotics
 Chloramphenicol, penicillins, sulfonamides,
rifampin, vancomycin, isoniazid, gancyclovir
 Antimalarials
 Dapsone, quinine, pyrimethamine
 Anticonvulsants
 Phenytoin, carbamazepine
Drugs that cause
neutropenia
 Hypoglycemic agents
 Tolbutamide, chlorpropamide
 Antihistaminics
 Cimetidine, brompheniramine, tripelennamine
 Antihypertensives
 Methyldopa, captopril
 Anti-inflammatory agents
 Ibuprofen, gold salts, indomethacin
Drugs that cause
neutropenia
 Antithyroid agents
 Prophylthiouracil, methimazol, thiouracil
 Diuretics
 Hydrochlorothiazide, chlorthalidone
 Phenothiazines
 Chlorpromazine, prochlorperazine
 Cytotoxic agents
 Immunosuppressive agents
Diagnosis

 Complete blood count

 Pheripheral blood smear
 Fever!!!
 Patient with fever and severe neutropenia
Diagnosis

 Drug and toxin

 Chronicity of neutropenia
 Recurrent infections
 Underlying disease
 Vitamin B12 and folic acid levels
 Examination of bone marrow
Thrombocytopenia
 Definition
 Normal platelet count: 150,000-
450,000/microL. Thrombocytopenia is
decreased platelet count below normal.
 Surgical bleeding usually does not occur
until the platelet count is less than 50,000,
and spontaneous bleeding does not occur
until the platelet count is less than 10,000-
20,000.
Platelets
 Platelets are produced in bone
marrow from Megakaryocytes
 An estimated 1000-5000
platelets are produced from
each Megakaryocyte
 In normal adults platelet
production is ~35,000-
50,000/microL of whole blood
per day. This value can be
increased 8-fold during times
of increased demand
 Clinical picture
 Regardless of cause, severe thrombocytopenia results
in a typical pattern of bleeding:
 multiple petechiae in the skin, often most evident on
the lower legs;
 scattered small ecchymoses at sites of minor trauma;
 mucosal bleeding (epistaxis, bleeding in the GI and
GU tracts, vaginal bleeding); and
 excessive bleeding after surgery. Heavy GI bleeding
and bleeding into the CNS may be life threatening.
Clinical picture

 However, thrombocytopenia does not cause

massive bleeding into tissues (eg, deep
visceral hematomas or hemarthroses), which is
characteristic of bleeding secondary to
coagulation disorders
Etiology
Thrombocytopenia may be due to :
1. Idiopathic (Immune) thrombocytopenic purpura.
2. Other immunologic causes : HIV , collagen
vascular diseases (as SLE), lymphoproliferative
disorders, drugs.
3. Heparin induced.
4. Non immunologic : Splenomegaly, Gram
negative sepsis, ARDS.
5. Thrombotic thrombocytopenic purpura-
Hemolytic uremic syndrome
Etiology

Also, aetiology can be classified as follows

according to the mechanism:
 Decreased platelet production

 Increased platelet destruction

 Dilutional Thrombocytopenia

 Splenomegaly or splenic sequestration

Decreased Platelet Production
Usually some offense that causes bone marrow
suppression or damage:
 Viral illness
 HIV (direct damage to Megakaryocytes)
 Chemo-or radiation therapy
 Congenital or acquired bone marrow aplasia or
hypoplasia
 Vitamin B12 or Folate deficiency
Increased Platelet Destruction
 Idiopathic (Immune) Thrombocytopenic
Purpura
 Alloimmune destruction; Posttransfusion,
Post-transplantation
 Disseminated Intravascular Coagulation
 Thrombotic Thrombocytopenic Purpura
 Antiphospholipid Antibody Syndrome
 Certain drugs; Heparin, quinidine, valproate
Splenic Sequestration

 Normally, ~1/3 of platelets are sequestered in the

spleen in any given time
 In extreme splenomegaly, up to 90% of platelets can
be trapped in the spleen
 Cirrhosis, portal HTN, splenomegaly can all present
with apparent thrombocytopenia
Drugs causing
thrombocytopenia
 Many drugs can cause thrombocytopenia.
 Some drugs like anticancer drugs and
valproic acid causes dose dependent
decrease in the number of platelets by
myelosuppression.
 Drugs may also cause thrombocytopenia by
immunological mechanisms.
Drugs causing
thrombocytopenia
 Quinine and Quinidine group
 Heparin : Both the Regular unfractionated heparin and LMWH
 Gold salts
 Antimicrobials
 Antimony containing drugs as Stibophen and Sodium stibogluconate
 Cephalosporins as Cephamandazole, Ceftazidime , Cephalothin .
 Penicillins : Ampicillin, Apalcillin , Methicillin, Meziocillin, Penicillin , Piperacillin.
 Sulpha group : Sulfamethoxazole, Sulfamethoxypyridazine, Sulfisoxazole
 Ciprofloxacin - Clarithromycin
 Fluconazole - Fusidic acid
 Gentamicin - Nilidixic acid
 Pentamidine - Rifampin
 Suramin - Vancomycin
Drugs causing
thrombocytopenia
 Anti-inflammatory drugs
 Salicylates , Diclofenac , Fenoprofen , Ibuprofen , Indomethacin,

Meclofenamate, Mefanamic acid , Naproxen , Oxyphebutazone,

Phenylbutazone , Piroxicam , Sulindac , Tolmetin .

 Cardiac medications and diuretics

 Digoxin , Digitoxin , Amiodarone, Procainamide, Alprenolol ,

Oxprenolol , Captopril , Diazoxide , Alpha-methyldopa,

Acetazolamide , Chlorothiazide , Chlorthalidone , Furosemide ,
Hydrochlorothiazide , Sprinolactone .
Drugs causing
thrombocytopenia
 Benzodiazepines as Diazepam
 Anti-epileptic drugs as Carbamazepine , Phenytoin, Valproic acid.
 H2-antagonists as Cimetidine , Ranitidine .
 Sulfonylurea drugs as Chlorpropamid , Glibenclamide.
 Iodinated contrast agents
 Retinoids as Isotretinoin , Etretinate .
 Anti-histamines as Antazoline, Chlorpheniramine
 Illicite drugs as Cocaine , Heroin .
 Antidepressants as Amitriptyline, Desipramine , Doxepin, Imipramine, Mianserine .
 Miscellaneous drugs:Tamoxifen ,Actinomycin-D, Aminoglutethimide, Danazole,
Desferrioxamine, Levamizole, Lidocaine ,Morphine, Papaverine, Ticlodipine
 History
 A thorough drug history must be taken to rule
out exposure to drugs known to increase platelet
destruction in sensitive patients.
 For example, up to 5% of patients receiving
heparin may develop thrombocytopenia, which
may occur even with very low dose heparin (eg,
used in flushes to keep IV or arterial lines open).
History
 The history may elicit symptoms suggestive of underlying
immunologic disease (eg, arthralgia, Raynaud's phenomenon,
unexplained fever);
 Signs and symptoms suggestive of thrombotic thrombocytopenic
purpura-hemolytic-uremic syndrome (TTP-HUS);
 Blood transfusion within 10 days, which may suggest
posttransfusion purpura;
 Significant alcohol consumption, which may suggest alcohol-
induced thrombocytopenia.
 Thrombocytopenia, usually mild, occurs in about 5% of pregnant
women at term.
 Patients with HIV commonly have thrombocytopenia, which may be
clinically indistinguishable from idiopathic thrombocytopenic
purpura (ITP).
Findings on physical
examination are also important
for diagnosis
Fever may be present in thrombocytopenia secondary to
(1)
infection or active SLE and in TTP-HUS, but is absent in ITP
and in drug-related thrombocytopenias.
(2) The spleen is not enlarged in thrombocytopenias caused by
increased platelet destruction (eg, ITP, drug-related immune
thrombocytopenias), but it is palpably enlarged in most
thrombocytopenias secondary to splenic sequestration of
platelets or secondary to a lymphoma or a myeloproliferative
disorder.
(3) Other physical signs of chronic liver disease are important
to document: eg, spider angiomas, jaundice, and palmar
erythema.
(4) Near-term pregnancy is a common cause of
thrombocytopenia.
Laboratory
 The peripheral blood cell count is key to establishing the presence and severity of
thrombocytopenia, and examination of the smear provides etiologic clues.
 Screening tests of hemostasis will be normal unless the thrombocytopenia is associated
with another condition affecting hemostasis (eg, liver disease, disseminated intravascular
coagulation).
 Bone marrow aspiration may be indicated if abnormalities other than thrombocytopenia
are noted on the peripheral blood smear. It provides information on the number and
appearance of megakaryocytes and confirms the presence or absence of disease causing
marrow failure (eg, myelodysplasia).
 Measurement of antiplatelet antibodies is not clinically useful.
 Tests for HIV antibody should be performed in patients whose history or examination
provides evidence of risk for HIV infection.
 Treatment
Treatment of thrombocytopenia varies with its cause and severity.
 The cause should be rapidly sought and identified and corrected when
possible (eg, discontinuing heparin in heparin-induced thrombocytopenia).
 Platelet transfusions should be used prophylactically with discretion
because they may lose their effectiveness with repeated use owing to the
development of platelet alloantibodies.
 If thrombocytopenia is caused by increased platelet consumption, platelet
transfusions should be reserved for management of life-threatening or CNS
bleeding.
 If thrombocytopenia is caused by marrow failure, platelet transfusions are
reserved for management of active bleeding or severe thrombocytopenia (eg,
platelet count <10,000/µL).
Immune
thrombocytopenia
Definition
 This is a disease in which antibodies to platelets are produced by
one’s immune system. These antibodies adhere to the platelets
and cause them to be destroyed, often in the spleen.
 Sometimes it is possible to identify specific diseases or drugs
that cause the condition. Often, however, there is no obvious
reason. In these instances the term immune or idiopathic is used.
 The disease may be seen at any age but is more common in
children and younger adults.
 Immune thrombocytopenia in
adults
There are a number of differences:

1. It is much more likely to be caused by a drug or an underlying

disease, such as lupus. Sometimes that disease may not be
obvious until later.
2. More often, the disease does not get better and is therefore
chronic.
3. The disease is more frequently relapsing.
4. It often does not respond as well to treatment as in children.
Treatment
 Steroids: Prednisolon 1mg/kg
 Gammaglobulin can be used, but it will not cause improvement
in as high a percentage of patients as it does in children.
 Splenectomy helps in 50 to 75 percent of patients; however,
there is no good way to predict, before the surgery, who will
benefit.
 Rituximab (anti CD 20 monoclonal ab)
 Some chemotherapy drugs, such as Cylophosphamide, Imuran
and Vincristine, as well as male hormones (androgens) have
worked in cases that do not respond with other treatment.
 Occasionally nothing works very well, and the platelet counts
stays down. Fortunately, even with very low counts, most people
escape serious bleeding problems.