Hematology summary

Index
1. 2. 3. 4. 5. Anemia Lymphoma TTP DIC Myeloproliferative disorders

Anemia

Index = Reticulocyte index

IDA

A 29-year-old female has become increasingly lethargic for the past 6 months. She complains from SOB, fatigue and tachycardia. She reported a heavy menstrual cycle and denied any previous history of melena or hematemesis . On physical examination she was afebrile.

1.
2.

Identify the condition?

Iron deficiency anemia Blood loss from the menstrual cycle . Other causes of IDA include: Poor intake Increased demand (growth and pregnancy) Decreased absorption (small bowel disease or after gastrectomy) Anemia of chronic disease (could be normochromic normocytic also) Thalassaemia. Sideroplastic anemia. (Prussian blue iron stain of the bone marrow shows ringed sideroblasts, which are nucleated red blood cell precursors with perinuclear rings of iron-laden mitochondria. Look to this figure)

Causes:

3.

DDx? other causes of Hypochromic Microcytic anemia:

4.

Clinical Presention:
In acute blood loss (hypovolemia) Hypotension Decreased organ perfusion Chronic onset vary with the Age Adequacy of blood supply to critical organs. Moderate anemia is associated with Fatigue, loss of stamina Breathlessness Tachycardia Pale skin & mucous membranes Decreased epithelial iron Brittle hair & nail Atrophic glossitis Angular stomatitis Rarely seen Paterson-Brown-Kelly syndrome (Pharyngeal webs causing dysphagia) Koilonychia (Spoon-shaped nail)

5. Investigation:
Blood count: low Hb & low MCV Blood film ; microcytic, hypochromic, with anisocytosis & poikilocytosis. Serum ferritin (reflect iron stores) is low Serum iron is low Total iron binding capacity (TIBC) is high resulting in a transferrin saturation < 19% Serum soluble transferring receptor: increase in IDA. Bone marrow examination is only necessary in complicated cases and shows erythroid hyperplasia and absence of iron.

Micocytic Hypochromic Anisocytosis and poikilocytosis

6. Management
Find and treat the underlying cause. Oral iron Parenteral iron
Rarely necessary Pts are intolerant Poor response to oral iron (severe malabsorption)

Thalassaemia and Sideroblastic anemia: Accumulation of iron Increases serum iron and ferritin Low TIBC

Megaloblastic Anemia
A 26 years old male presented to your clinic complaining from Anorexia , weight loss and diarrhea. Taking history revealed that he is vegan and alcoholic. Physical examination shows glossitis , angular stomatitis , slight skin brusining and parasthesia in the tip of his fingers. Past medical hx reveals recurrent URTI during the last 6 months.

1. Identify the condition:

Megaloblastic anemia due to B12 deficiency

2. Causes:
Low dietary intake: Vegans Impaired absorption:
Stomach : Pernicious anemia / Gastrectomy Small bowel : Ileal disorder or resection / celiac disease / tropical sprue /Bacterial overgrowth.

Congenital transcoblamine II deficiency (rare).

3. DDx:
Megaloblastic : B12 deficiency or Folate Deficiency. Normoblastic : Myelodysplasia , hemolysis (inc, retics). Other defect of DNA synthesis , e.g. chemotherapy.

4.

Clinical presentation Symptoms of anemia (previously mentioned). Mild jaundice. Anorexia , Weight loss , diarrhea or constipation Glossitis (red sore tongue). Polyneuropathy caused by symmetrical damage to the periephral nerve. Subacute combined degeneration of the spinal cord.pts are presented with progressive weakness , ataxia and paraplegia. Optic atrophy may cause dementia and visual disturbances. Thrombocytopenia & leucopoenia.
Glossitis: Pernicious anemia.

Glossitis: Folic acid deficiency

5. Investigation:
Blood count: severe cases leucopoenia and thrombocytopenia. Blood film : Macrocytic anemia with hypersegmented neutrophil nuclei serum B12: Low Red cell folate may be reduced. Serum billirubin may be increased. BM examination shows a hypercellular BM with megaloblastic changes.

Hypersegmented neutrophils

Hypercellular BM with megaloblastic changes

6. Management:
B12 deficiency:
IM vitamin B12. Oral B12 (dietary deficiency)

Folic acid deficiency:

Oral folic acid (higher doses in malabsorption).

Undetermined megaloblastic anemia: folic acid alone may aggravate the neuropathy of B12 deficiency, so give both

Thalassemia

Prominent Maxilla

Target cells Bull's-eye appearance X ray shows: Hair like in the periphery of skull, which indicate BM hypertrophy.

1.

Identify the condition: Thalassemia. 2. Cause: Inherited disorders Impaired synthesis of one or more of the polypeptide chains of globin. 3. DDx: Other causes for microcytic hypochromic RBC's. 4. Clinical picture: Vary from hematologic abnormality severe and fatal anemia. In B thalassemia major Severe anemia presents in the 1st year of life FTT Recurrent infection. Prominent maxilla, frontal & parietal bones (Hypertrophy BM). Hepatosplenomegaly.

5. Investigation: (Homozygous disease) Blood count: raised reticulocyte count Blood film: hypochromic, microcytic anemia , nucleated red cells in the periephral circulation. 6. Diagnosis: Hb electrophoresis, which shows Increase in Hb F. Absent or markedly reduced Hb A. 7. Management: Homozygous pt : blood transfusion. Some cases :BM transplantation.

Normal

IDA

Low Hb Low MCV (microcytic) Low MCH (hypochromic) High RDW (poikilocytosis)

Megaloblastic Anemia
Markedly increased MCV Mildly increased Blood loss Hemolytic anemia

MICROANGIOPATHIC HEMOLYTIC ANEMIA(MAHA)

Low RBC Low HCT High RDW Blood film: Schistocytes (fragmented RBC)

SPHEROCYTOSIS
Small & rounded RBC (not biconcave), so increased Hb content. High MCHC DDx: Autoimmune hemolytic anemia

Severe anemia who underwent transfusion

Low RBC High MCV (inc. retics) High MCH HIGH RDW

Dual populations of RBCs

Lymphoma
HD & NDL

Epidemiology of lymphomas
5th most frequently diagnosed cancer overall for both males and females males > females Mechanisms
Genetic alterations Infection Antigen stimulation Immunosuppression cyclosprine

incidence
NHL increasing over time
B-cell (70%) T-cell (30%)

Hodgkin lymphoma stable

Hodgkins disease
More common in
Males Caucasian

Late 20th & >45y. Spread by contiguous Etiology:

Viral infection: EBV, HIV

WHO classification 1. Nodular lymphocyte predominant HL (5%)

Cervical & inguinal involvement Frequent relapse Good prognosis, rarely fetal

Pathology
Reed-Sternberg cells Lymphocytes, histiocytes, neutrophila & eosinphils.

2.

Classical HD
Nodular sclerosis Lymphocytes Rich Mixed cellularity Lymphocytes depleted

A possible model of pathogenesis

transforming event(s) EBV? loss of apoptosis

cytokines

germinal centre B cell

RS cell

inflammatory response

Classical HD
Nodular sclerosis HD:
Most common type More in females Associated with
Mediastinal mass Hilar lymphadenopathy Neck

Lymphocytes Rich
Uncommon Good Prognosis (stage I, II)

Mixed cellularity:
More in older people 2nd most frequent Prognosis fair (stage III)

Lymphocytes depleted
Rare Poor prognosis (stage III, IV)

Good prognosis (stage I,II) Histology

Fibrosis Lacunar cells

RS cell and variants

classic RS cell
(mixed cellularity)

lacunar cell
(nodular sclerosis)

popcorn cell
(lymphocyte predominance)

Reed-Sternberg cell
Reed-Sternberg cells may be found in: NHL Benign illnesses Carcinoma

 Lymphadenopathy, 4% have limited diseases below the diaphragm

Non-tender (painless) Firm, rubbery

Clinical

B symptoms associated with poor prognosis and advanced disease.

Fever > 38C Drenching night sweats Weight loss (>10%)

Rarely the patients may present with

Auto immune thrombocytopenia Auto immune hemolytic anemia

Hepatosplenomegaly Thromboembolic disease Viral > bacterial infection

Anorexia, fatigue Purities Alcohol induced pain Contiguous involvement

Cough SOB

LN biopsy is the definitive diagnosis RS cells CT scan for staging Gallium scan to asses the response of treatment

Investigations
1.

Laboratory tests
CBC Anemia Lymphocytopenia (replacement of LN structure) Neutrophilia, eosinophilia Thrombocytosis or thrombocytopenia. LFT may be abnormal Chlestatic pattern, non caseating granuloma Live involvement with HD LDH may be elevated due to Disease activity Organ involvement ESR, Serum ferritin, and B2 micro globulin are elevated in patients with advanced disease.

2. CXR Mediastinal widening 3. CT scan Intrathoracic nodes (70%) For staging 4. BM aspirate Advanced disease Anemia, high ESR. B symptoms, Stage IV 5. PET Staging & disease activity

DDx
Lymphadenopathy

Eosinophilia
Lymphoma Vasculitis Parasitic infection Allergic reaction

Lymphoma TB Brucellosis Metastatic carcinoma Sarcoidosis

Site, size & shape Colour Temp. & tenderness Consistency Mobility Relations

Hx:

Elevated LDH:
Lymphoma Acute leukemia Hemolytic anemia

Mediastinal lymphoma
Staging: 1. History 2. PE
LN Spleen Liver

3. Blood studies 4. Imaging studies

Stage III LN regions on both side of the diaphragm. 1. Stage I Localized involvement of extra Single LN region lymphatic organ Single extra lymphatic organ Spleen involvement 2. Stage II 4. Stage IV 2 or more LN regions on the Diffuse involvement of 1 or same side of the diaphragm more extra lymphatic organs Localized involvement of the LN enlargement extra lymphatic organ. Liver or BM involvement is always considered Stage I Stage II Stage III Stage IV stage IV

Staging

3.

A. B. E. X.

Absence of B symptoms Presence of B symptoms Extra nodal site by local extension Bulky disease: mediastinal widening >1/3 at T6-7 >10 cm in any single dimension.

1. Radiotherapy Early stage I, II without B symptoms 2. Chemotherapy Stage B 3. Combined modality treatment Early staged some poor prognostic factors. Massive mediastinal involvement. 4. BM transplantation Chemotherapy side effects: Cyclophosphamide: hemorrhagic cystitis Anthracyclines: cardiomyopathies Bleomyocin: pulmonary fibrosis Vinca alkaloids: neuropathies BM suppression (long period) Infertility

Treatment
Radiation side effects: Mouth
Stomatitis Oral thrush

Thyroid
Hypothyroidism

Lung
Radiation pneumonitis Pulmonary fibrosis

Cardiac disease Pelvic irradiation

Infertility

2nd malignancies
Sarcomas, lung, skin cancer

Risk factors
immunosuppression or immunodeficiency Ionizing radiation Infectious agents CT disease Family Hx of lymphoma

NHL
Clinical manifestations Asymptomatic Systemic B symptoms: Fever Night sweats Weight loss Anorexia Pruritis Local manifestations Lymphadenopathy Splenomegaly most common any tissue potentially can be infiltrated

Complication:
CNS infiltration BM failure Immune hemolysis or thrombocytopenia Bulky disease, compression of structures as spinal cord, ureters pleural/pericardial effusions Ascites

Clinical features Adenopathry Extra nodal CNS Thyroid Mediastinal Lung Abdominal masses Testes BM especially with indolent low grade lymphomas. Skin (esp. T cells: Mycosis fungoides Sezary syndrome Renal failure (tumor lysis syndrome)

Lab investigations
CBC leukaemic phase of lymphoma LDH ESR, B2 micro globulin IG LFT KFT Diagnosis Tissue biopsy Flowcytometry Cytogenetics Radiological
CT MRI Gallium scan

Staging is not useful.

Lymphoma classification
(based on 2001 WHO)
1. B-cell neoplasms (70%)
Precursor B-cell neoplasms (2 types) Mature B-cell neoplasms (19) B-cell proliferations of uncertain malignant potential (2)

2. T-cell (30%) & NK-cell neoplasms

Precursor T-cell neoplasms (3) Mature T-cell and NK-cell neoplasms (14) T-cell proliferation of uncertain malignant potential (1)

3. Hodgkin lymphoma
Classical Hodgkin lymphomas (4) Nodular lymphocyte predominant Hodgkin lymphoma (1)

Neoplasms of lymphoid origin, typically causing lymphadenopathy Clonal expansions of cells at certain developmental stages

A practical way to think of lymphoma

Category Survival of untreated patients Years Curability To treat or not to treat

Non-Hodgkin lymphoma

Indolent

Generally not curable

Generally defer Rx if asymptomatic

Aggressive

Months

Curable in some
Curable in some Curable in most

Treat

Very aggressive Hodgkin lymphoma All types

Weeks

Treat

Months to years

Treat

B-cell development
stem cell lymphoid precursor progenitor-B

CLL MCL

memory B-cell mature naive B-cell germinal center B-cell

MZL CLL MM

LBL, ALL

pre-B immature B-cell

DLBCL, FL, BL, HL

plasma cell

Follicular lymphoma
Most common type of indolent lymphoma 20% of B cell lymphoma Often asymptomatic Associated with BCL-2 gene rearrangement [t(14;18)] Cell of origin: germinal center B-cell Not curable (some exceptions) Treatment
Asymptomatic (watch-and-wait) Symptomatic: chemotherapy

Death due to

Transformation to aggressive lymphoma Therapy

Diffuse large B-cell lymphoma

Most common type of aggressive lymphoma Usually symptomatic Extranodal involvement is common Cell of origin: germinal center B-cell Treatment should be offered curable in ~ 40%

Chronic lymphoid leukaemias

Most common type of leukaemia in elderly M:F 2:1 Majority asymtomatic Etiology: 1. Genetic factors : familial cases, west 2. Immunological factors : Inherited and acquired immunodeficiency are often associated with CLL, and other LPD Clonal disease of mature lymphocytes Peripheral blood shows: Persistent lymphocytosis Small mature lymphocytes B symptoms are rare Pulmonary leukaemic infiltrate are common BM infiltration CD5 positive ,weak expression of SIg Richter syndrome (5%) Transformation to large cell lymphoma Clinical features: Fever Weight loss Increased localized or generalized lymphadenopathy.

Trisomy

BM

Clinical Manifestations
25% symptomatic A Symmetrical enlargement of LN
Mobile Non tender Mainly involving the supraclavicular, axillary & inguinal region. Obstructive manifestations

Splenomegaly (50%). Immunodeficiency (recurrent infections as Herpes Zoster) Hypogammaglobulinaemia Bacterial infections (e.g. S.pneumonia, S.aureus, H.infleunzae, Pneumocystis Carinii) Hypervicosity due to increase lymphocytes count.

Immunologic abnormalities : Decreased gamma globulins Impaired granulocytes function Impaired T cell function Coombs positive hemolytic anemia (10%) Immune thrombocytopenia (5%) Rarely immune neutropenia & pure red cell aplasia Increased incidence of secondary malignancy e.g. skin cancer

Poor prognostic factors : Lymp. count> 50x 10/l Lymp. doubling time < 12 months Prolymphocytes >10% BM histology diffuse type Cytogenetics Trisomy 12 Age > 70 years Sex male High level of B2 micro globulins Anaemia & thrombocytopenia due to BM infiltration

Management
Usually indolent 1. Persistent or progressive symptoms ( fever, night sweats, weight loss) 2. lymphadenopathy causing mechanical obstruction or cosmetic deformities 3. Progressive enlargement of LNs, spleen & liver. 4. Stge III,IV 5. Immune hemolytic anemia or thrombocytopenia 6. Rapid lymphocytes doubling time.

Multiple myeloma
Less common than NHL >15% of BM is plasma cells Plasma cell function: Igs production Osteoclast activation Lytic bone lesion Hyper-Ca RF
Clinical features: BM faliure Elevated Igs Hypercalcemia RF Bone disesase Lytic lesions Dec. bone density Hyperviscosity syndrome Recurrent infections Amyloidosis Heavy proteinuria (NS) Malabsorption Large tongue Splenomegaly Bleeding tendency

Diagnosis: BM biopsy (inc. plasma cells) Serum protein electrophoresis (monclonal bands) Skeletal survey (lytic lesions & hyper-Ca) Quantitative Igs Hyperviscosity syndrome: Due to increase in Cells (polycythemia & leukemia) Proteins Multiple myeloma (IgA & IgG3) Waldenstrom macroglobulinemia (IgM) Lymphadenopathy Splenomegaly

THROMBOCYTOPENIA

Petechiae Investigations: plt. count

Hematoma

Purpura

Ecchymosis If normal PT & PTT Trombocytopenia

Thrombocytopenia
Plt < 150 x 109/L May be caused by: 1. Decreased platelet production BM infiltration (malignancy, myelofibrosis, gauchers disease) Aplastic anemia/Paroxysmal nocturnal hemoglobinuria Viral infection (HIV, CMV, hepatitis) Chemo-/Radiotherapy Alcohol (direct toxicity, folate deficiency) Folate & Vitamin B12 deficiency Myelodysplastic syndrome Congenital thrombocytopenias (Fanconis anemia, TAR, WiskottAldrich syndrome) 2. Increased platelet destruction Immune: ITP Drug-induced (quinidine, heparin-HIT) Malaria-associated Non-immune: TMA DIC Inflammatory platelet activation (malignancy, sepsis) 3. Platelet sequestration Normally 30% of platelets reside in the spleen Splenomegaly of any etiology ( infection, storage disease, malignancy, congestion) may produce pancytopenia, a syndrome termed Hypersplenism.

Hypersplenism (signs) 1. Splenomegaly 2. Pancytopenia 3. Normal/hyperplastic BM 4. Respond to splenctomy Causes: Hemolytic anemia Portal HTN Leukemia Lymphoma

Splenomegaly Infections Inflammation (SLE, RA & sarcoidosis) Haemtological Portal HTN Miscellaneous
Storage disease Neoplasia Amyloidosis

Low plt. & splenomegaly, not:

ITP Aplastic anemia

ITP
Incidence 1:10,000 Peak incidence: 3-5y ( M/F 1:1) 20-30y ( M/F 1:3) Chronic, insidious disease Caused by auto-antibodies, which bind to platelets IIb/IIIa glycoprotein receptor Antibody-coated plt. cleared from circulation by spleen.

Primary ITP Secondary:

SLE Lymphoproliferative disorders (esp. CLL & Hodgkins disease) GVHD Myasthenia Gravis Viral infection (HIV..)

ITP in Adults
Sx:
Easy bruising of several mon. Petechiae/purpura (esp. over dependent parts) Mucosal bleeding Epistaxis Hematuria Melena Heavy menses Internal bleeding (rare) No Splenomegaly Lymphadenopathy

Laboratory results
Thrombocytopenia Normal WBC Normal coagulation studies Peripheral smear Large platelets BM examination: Inc. megakaryocyte count NormalErythroid & myeloid development.

Diagnosis of Primary ITP is by exclusion. Isolated thrombocytopenia DDx:

Secondary ITP Hypersplenism Drug-induced thrombocytopenia TMA Pseudothrombocytopenia

Treatment
1. 2. Steroids prednisone: Impaired clearance of antibodycoated platelets by RES Inhibition of antibody production Increased platelet production Stabilization of vessel wall IVIg & Anti-D Ig Not achieve cure Emergencies Preparation for splenectomy Management of patients resistant to other therapeutic.
3.

Splenectomy
Steroid-dependent Steroid-resistant

Failing splenectomy: 4. Look for accessory spleen 5. Immunosuppression

Vincristine Azathioprine Cyclophosphamide

6. Danazole (weak androgen) 7. Cyclosporin A 8. Rithuximab (Mabthera) Emergency treatment 9. Platelet transfusion 10. IV steroids 11. IVIg 12. Anti-fibrinolytic agents 13. Emergency splenectomy

ITP in Pregnancy
Incidence: 1-2/1000 deliveries Chronic ITP often exacerbates during pregnancy Plt > 30,000 suffice for delivery > 50,000 are required CS Antibodies ( IgG ) cross the placenta and may cause severe thrombocytopenia in the fetus
DDx of thrombocytopenia in pregnancy: Gestational (4% 3rd trimester) usually Plt>75,000) ITP Preeclampsia (incl. HELLP syndrome) Von Willebrand disease (type IIb) Treatment of ITP in pregnancy: Steroids IVIg Splenectomy (should be avoided unless necessary) Immunosuppressive drugs are contraindicated

Thrombotic Microangiopathies (TMA)

Incidence: 3,5:10,000 F/M 3:2 Peak incidence: 3rd decade Mortality 100% without treatment 15% with treatment
1. Primary (abs against ADAMTS13) Thrombotic Thrombocytopenic Purpura-TTP 2. Secondary (enzyme is depressed) Verotoxin associated (Hemolytic Uremic Syndrome-HUS) Malignancy and chemotherapy associated HIV associated BM transplantation (BMT) associated Drug associated Pregnancy associated Autoimmune associated Neuraminidase-associated 3. Hereditary (enzyme deficiency) Upshaw schulman syndrome

Thrombotic Thrombocytopenic Purpura

Classical Pentade of Findings:
1. Microangiopathic hemolytic anemia (sin qua non of the disease) 2. Thrombocytopenia - may be quite severe (<20,000); bleeding at presentation is common 3. Neurological impairment (fluctuating, headache, confusion, convulsions, coma) 4. Renal failure (hematuria, proteinuria, azotemia) 5. Fever
- LDH is constantly elevated; - Coagulation tests are normal

Pathogenesis: Initiating factors are unknown Endothelial wall damage Inducing platelet aggregation Production of ultra-large multimers of vWF supporting platelet aggregation (most imp.)

UL-vWF multimers are normally cleaved by a vWFcleaving protease, encoded on chromosome 9 Familial TTP, congenital deficiency of the enzyme Acquired TTP, its activity is inhibited by neutralizing antibodies (autoimmunity)

Other factors involved: Increased endothelial production & release of platelet-activating proteins (calpain) Impaired endothelial production & increased degradation of prostacyclin Anti-endothelial cell antibodies Apoptosis of endothelial cells with predilection to renal & cerebral vasculature) Factor V Leiden (microthrombosis)

Treatment: Plasmapheresis 90% response within 3 weeks 30% relapse months to years after initial episode Splenectomy (for refractory disease) Steroids (effective only in conjunction with apheresis) Anti-platelet agents (aspirin, clopidogrel) Platelet transfusions are CONTRAINDICATED bcz abs

Hemolytic-Uremic Syndrome
Induced by infection with verotoxin-producing E.Coli (esp. 0157:H7) Shigella Causing Endothelial damage Secondary platelet activation Formation of thrombi in renal microvasculature Incidence: highest <5 y.
The patients present with sudden onset Abdominal pain & diarrhea 10-30% progress to develop HUS: Oliguria Mild thrombocytopenia Microangiopathic anemia Fever & neurologic manifestations (rare)

Treatment
selflimited Long-term renal abnormalities (50%) Plasmapheresis is not effective in preventing renal damage Supportive (dialysis) Antibiotics increase the risk of disease progression

TMA - malignancy and chemotherapy associated

Disseminated malignant neoplasms Esp. adenocarcinomas of GIT No effective treatment exists The survival is measured in weeks (unless responds to treatment)

TMA caused by chemotherapeutic agents Especially Mitomycin C Responds to plasmapheresis in 2050%; Mortality is >50% in 2 months

TMA HIV associated

20% of AIDS patients develop TTP Pathogenesis Endothelial damage by
Opportunistic infections Drugs HIV itself

TMA BMT associated

Develops in 5% of bone marrow recipients May be caused by
Irradiation Cyclosporin A

Plasmapheresis is beneficial Prognosis is generally poor (about 1 year)

GVHD Prognosis depends on the severity of the disease Plasmapheresis is indicated, but its benefit is unclear

TMA - other
Drug-associated (quinine, ticlopidine, clopidogrel) Pregnancy-associated (10% of TTP; chronic disease can be exacerbated by pregnancy) Autoimmune disease-associated Neuraminidase-associated (enzyme secreted by Streptococci)

DISSEMINATED INTRAVASCULAR COAGULATION

Clinical picture Bleeding from any where, spontonous. 5-10 % microthrombotic lesions
Gangrene of fingers, toes, renal arteriols. PATHOGENESIS: DIC occurs when the compensatory mechanisms of haemostasis have been overcome. The triggering mechanisms: 1. Entry of tissue thromboplastin into the blood stream, following extensive tissue trauma, malignant disease, massive blood transfusion. 2. Direct activation of factor X or prothrombin (Factor II) by snake venoms. 3. Severe vascular endothelial injury in patient with gram negative septicaemia. 4. Direct platelets activation

Pathophysiology of DIC
PATHOPHYSIOLOGIC EVENTS
underlying disorder depletion of clotting factors prolonged PT, PTT thromboctyopenia (consumption) hemorrhage depletion of physiologic anticoagulants decreased fibrinogen generalized intravascular fibrin deposition microangiopathic hemolytic anemia thrombosis/infarction increased FDP and D-dimer

LABORATORY MANIFESTATIONS

CLINICAL MANIFESTATIONS

tissue factor release

activation of extrinsic pathway of coagulation (systemic thrombin generation)

activation of fibrinolytic system (systemic plasmin generation)

Cause
Acute
Shock Sepsis Allergic reactions Mismatched transfusion Obstetrical problems Trauma Burns Extracorporeal circulation Acidosis Purpura fulminans Decreases in both coagulants & anticoagulants Severity may relate to levels of anticoagulants

Subacute/Chronic
Acute leukemia Carcinomas Hemangiomata Aortic aneurysms ???? liver disease

Diagnosis
Thrompocytopenia Prolongation of PT & aPTT Low Fibrinogen Fibrin split products D-dimer RBC fragmentation Other tests Low level of Anti thrombin III Low level of protein C Thrombin/ Anti thrombin III complex

Treatment
Depends on primary manifestation Thrombosis - Anticoagulant therapy Heparin Bleeding - Replacement therapy Cryoprecipitate - Fibrinogen Fresh frozen plasma - Other factors Platelets Primary treatment TREAT UNDERLYING DISEASE

Thrombocytopenia
Pseudo?
(Perform smear)

True?

Fragmented RBCs

No need to work up Low WBC/Hb MCV-N MCV

TMA?
WBC, Hb PT/PTT Physical examination Splenomegaly Normal

High WBC

PTT

Leukemia?

DIC? Hypersplenism?
(look for cause)

Vitamin B12 deficiency? MDS?

(consider bone marrow aspiration)

ITP?

Myeloproliferative disorders

 Chronic Clonal disorders of hemopoietic stem cells Over-production of all cell lines, with usually one line in particular Fibrosis is a secondary event Acute Myeloid Leukemia may occur Splenomegaly is the major physical sign Include 1. Chronic myeloid leukemia 2. Polycythemia (Rubra) Vera (PRV, PV)

3. (Primary) Essential Thrombocythemia

4. Myelofibrosis (with Myeloid Metaplasia), Agnogenic Myeloid Metaplasia (MF,MMM, AMM)

Chronic Myeloid leukaemia CML

Proliferation of all haematopoietic lineages, predominantly in the granulocytic cell line, without the loss of their capacity to differentiate. Occurs 30 to 80 y. More common in males The aetiology is unknown. Blood film: All stages of maturations Majority are myelocytes & neutrophils In CLL, majority are lymphocytes

Clinical features
Asymptomatic (25%) Anorexia, Wt loss, lassitude, night sweats Splenomegaly Anaemia, pallor, dyspnoea, tachycardia Bruising, epistaxis, menorrhagia Gout, renal impairment
Cytogenetic and molecular aspects: 1. Philadelphia chr. 2. Reciprocal translocation between chromosome 9 & 22 in region called BCR carried ABL oncogene. Management 1. Curative treatment: Allogeneic BM transplant, but it is still not completely curable. 2. Control treatment: Imatinib, inhibit BCR-ABL activity but it is very expensive 3000 JD\month Hydroxyurea & interferon.

Natural Hx
1. A chronic phase (85%) Duration 3-4 years Splenomegaly Leukocytosis Easily controlled The major goal of treatment is to control symptoms and complications resulting from
Anemia Thrombocytopenia Leukocytosis Splenomegaly

Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase,

2. Accelerated phase Emergence of a discrete blast cell population blast < 20% Left shift 3. Blast phase >30% blasts Promyelocytes in peripheral blood or marrow. Normal marrow erythropoiesis Megakaryopoiesis reduced. Disease transformed into AML (70%) ALL (30%)

Chronic phase

Accelerated phase

Blast phase

Case presentation
A 49yr old teacher, saw her physician because of fatigue for about six months. Physical exam Showed little except for pallor, normal temperature, and massive splenomegaly. Blood tests were ordered to investigate possible anaemia. Laboratory results indicated a high white count consistent with Chronic Myeloid Leukaemia.

Essential Thrombocythemia
Constitutive production of thrombopoietin by liver raised level of dysfunctional circulating platelets Plt. > 600 at least 2 months Diagnosis by exclude reactive causes Clinical Thrombosis Erythromelagia painful big toe CVA TIA Stroke Bleeding Management Aspirin (thrombosis) Hydroxyurea

WBC x 109/L Hb g/L MCV fl Platelets x 109/L Neuts x 109/L Lymphs x 109/L Monos x 109/L Eos x 109/L Basos x 109/L

10.0 156 85 1560 7.0 2.0 0.8 0.1 0.1

[4-11] [140-180] [80-100] [150-450] [2-7.5] [1.5-4] [0.2-0.8] [0-0.7] [0-0.1]

Blood film: many large and abnormal platelets

Polycythemia Rubra Vera (PRV)

Excessive production of all myeloid cell lines, predominantly red cells. PRV masked by IDA. Clinical features Increase in whole blood viscosity causes
Vascular occlusion Ischemia

Headaches, Itch Thrombosis, TIA, stroke Splenomegaly

Secondary PRV

Diagnosis
1. Raised red cell mass (PCV) Males PCV>51% Females PCV >48% 2. Normal plasma volume level 3. Normal or low erythropoietin 4. O2% >92% 5. Splenomegaly & central cyanosis

Hypoxia due to Chronic lung diseases, Congenital heart disease VSD Renal cell carcinoma which leads to increase erythropoietin synthesis, Diuretics therapy (reduction in plasma volume) Smokers

WBC x 109/L Hb g/L HCt MCV fl Platelets x 109/L Neuts x 109/L Lymphs x 109/L 2.0 Monos x 109/L Eos x 109/L Basos x 109/L

18.0 200 0.62 75

14.6 [1.5-4] 0.8 [0.2-0.8] 0.1 [0-0.7] 0.5 [0-0.1]

[4-11] [140-180] [.42-.51] [80-100] 850 [150-450] [2-7.5]

Management 1. Phlebotomy venesection to decrease viscosity, repeated every 5-7 days till hematocrit become less than 0.45 2. low-dose aspirin (controversial) - 80 mg/day 3. Hydroxyurea if necessary 4. Do not treat with iron

Blood film: Microcytosis Large and abnormal platelets

Myelofibrosis (MF)
Characterized by BM fibrosis Clinical: Extramedullay haematopoiesis BM failure Leukoerythroblastic blood picture Splenomegaly BM failure Diagnosis 9/L WBC x 10 2.4 [4-11] Typical blood picture Hb g/L 88 [140-180] Splenomegaly MCV fl 85 [80-100] Dry aspirate Platelets x 109/L 60 [150-450] Fibrosis on trephine Neuts x 109/L 1.0 [2-7.5] biopsy Absence of other cause Lymphs x 109/L 1.0 [1.5-4] Monos x 109/L 0.2 [0.2-0.8] Treatment: Supportive care Eos x 109/L 0.1 [0-0.7] Splenectomy if Basos x 109/L 0.1 [0-0.1]

necessary

Blood film: A few nucleated red cells Myelocytes (leukoerythroblastic) Tear-drop (poikilocytes)

Case 1
50 year female patient presented to ER, complaining of painful big toethis is a CBC for her: WBC x 109/L 10.0 [4-11] Hb g/L 156 [140-180] MCV fl 85 [80-100] Platelets x 109/L 1560 [150-450] Neuts x 109/L 7.0 [2-7.5] Lymphs x 109/L 2.0 [1.5-4] Monos x 109/L 0.8 [0.2-0.8] Eos x 109/L 0.1 [0-0.7] Basos x 109/L 0.1 [0-0.1] DDx: Essential thrombocytothemia Secondary:
Chronic Myeloid Leukaemia Post splenectomy Malignancy Inflammatory diseases (eg.rhumatoid) Bleeding Anaemia

Clinical Erythromelagia Peripheral Vascular occlusion Transient Ischemic Attack (TIA) Stroke Bleeding (esp. surgical) PE Splenomegaly

63 smoker male patient presented to a clinic complaining of headache, & this is a CBC for him: WBC x 109/L 18.0 [4-11] Hb g/L 200 [140-180] HCt 0.62 [.42-.51] MCV fl 75 [80-100] Platelets x 109/L 850 [150-450] Neuts x 109/L 14.6 [2-7.5] Lymphs x 109/L 2.0 [1.5-4] Monos x 109/L 0.8 [0.2-0.8] Eos x 109/L 0.1 [0-0.7] Basos x 109/L 0.5 [0-0.1] DDx: Primary: Polycythemia (Rubra) Vera Secondary: Smoking, COPD Diuretics Cyanotic heart disease, PCKD Renal cell carcinoma

Case2
PE & investigation: PCV Plasma volume Erythropoietin level Oxygen saturation US for spleen, liver & kidney Diagnosis Polycythemia (Rubra) Vera (PRV) Clinical: Headaches Itch particularly after a hot bath Vascular occlusion Thrombosis in unusual sites TIA Stroke Splenomegaly

Case 3
70 year male patient presented to you has massive splenomegaly, history of pallor with malaise..this is a CBC for him: WBC x 109/L 2.4 [4-11] Hb g/L 88 [140-180] MCV fl 85 [80-100] Platelets x 109/L 60 [150-450] Neuts x 109/L 1.0 [2-7.5] Lymphs x 109/L 1.0 [1.5-4] Monos x 109/L 0.2 [0.2-0.8] Eos x 109/L 0.1 [0-0.7] Basos x 109/L 0.1 [0-0.1] DDx: Leukaemia, lymphoma Metastatic cancer Chronic infections TB, radiation Glaucomatous disorders Autoimmune disorders Myelofibrosis Blood film: Tear-drop cell (pathognomic) Leukoerythroblastic Diagnosis: Myelofibrosis Compesation: Extra medullary haematopoiesis Hepatosplenomegaly

Case 4
Chronic myeloid leukaemia Increased WBCs Normal or high RBCs Increased platlets With basophilia & eosinophilia Philadelphia chromosome t(9:22) & BCR-ABL gene Blood film: All stages of maturations Majority are myelocytes & neutrophils Diagnosis CBC Splenomegaly BM