Prepared by


• Redha Al-Rumaih • Ayman Abdulali • Sadiq Radhi • Ahmad Obidan • Ahmed M. Shammasi • Abdullah Al- Bat'hi Special thanks to Husain Al-Hashim

This note contains what we could catch during the lectures. We tried our best to avoid any mistake that is out of our responsibility if presents. Please contact us if you find mentionable mistake and help modifying this note

Hematology ΙΙ
White blood cells diseases: o Leukocytosis: § Neutrophilia § Eosinophilia § Basophlia § Lymphocytosis § Monocytosis o Leucopenia: § Granulocytopenia (agranulocytosis) § Lymphopenia (infectious mononucleosis) o Tumors: § Leukemia: • Lymphocytic : o Acute o Chronic • Granulocytic: o Acute o Chronic § Multiple myeloma. § Lymphomas: • Hodgkin's lymphoma • Non-Hodgkin's lymphoma Platelet Disorders: o Quantitative: § Thrombocytopenia § Idiopathic thrombocytopenic purpura o Qualitative: § Glanzmann's disease § Brenard-Soulier Syndrome Coagulation disorders: o Inheretid: § Hemophilia § Factor ΙΧ disease (Christens disease) § von Willebrand disease (lupus anticoagulant) o aquired: § vitamin K deficiency. § Hepatocellular failure. § Disseminated intravascular coagulation (DIC) § Deficiency of natural anticoagulants. Myeloprolifirative disorders: o Polycythemia Vera. o Essential Thrombocythemia. o Essential Agogenic Myelofibrosis. o Chronic Granulocytic Leukemia. Blood transfusion: o Packed RBCs. o Platelets o plasma


White blood cell diseases
• • • • • • White blood cells (WBCs) are either: o Granulocytic: Neutrophils, Eosinophils, and basophils o Mononuclear: lymphocytes and monocytes. Variations in WBCs count and morphology indicate certain disease conditions. Normal WBC’s count is 4,000-10,000/µL. Leukocytosis occurs when WBCs count is more than 10,000/µL Leukopenia occurs when WBCs count is less than 4,000/µL Most of the variations in total leukocyte count are due to ↑ or ↓ in neutrophils or lymphocytes because they constitute the majority of WBC’s.

a- Neutrophilia (neutrophil leukocytosis): • Increase neutrophil count. • Neutrophil nucleus has 3-4 lobes. If > 4, hypersegmented neutrophil as in megaloplastic anemia. If < 3, hyposegmented ( hypogranular ) seen in preleukemia • causes: a. Infection by pyogenic bacteria as in pneumonia. NB. Some infections cause neutropenia b. Physiological as in pregnancy and in newborns. c. Acute hemolytic conditions and active bleeding d. Burns (as it causes inflammation) e. Trauma e.g. surgery f. Hepatic amebiasis (amebic hepatitis): the only parasitic condition causing neutrophilia. g. Myeloprolifirative disorders e.g. polycythemia vera, essential thrombocythemia, and myelofibrosis h. Chronic granulocytic leukemia i. Leukemoid reaction: high WBCs count mistaken for leukemia. Total WBCs count Basophils Leukocyte alkaline phosphatase (LAP)* Philadelphia chromosome
* released by neutrophils

Chronic granulocytic leukemia > 100,000/µL ↑ ↓ or absent ++

Leukemoid reaction ≤ 50,000/µL Normal ↑ -

b- Eosinophilia: • Increased eosinophil count . • Eosinophil has golden yellow granules and a nucleus with 2-3 lobes. o Allergy o Parasitic infection: intestinal worms, liver flukes, bilharziasis, onchocerciasis, tinea worms (and all other tape worms) NB. Malaria and ameba don't cause eosinophilia o Certain malignancies e.g. Hodgkin's lymphoma. o Idiopathic e.g. hypereosinophilic syndrome: charectarized by severe weakness and joint pain. Treated by high doses of corticosteroid.


c- Basophilia • Increased basophile count.. • Normaly, basophils present in low level (1-2% of WBC count) • Causes of basophilia: o Chronic granulocytic leukemia o Myeloproliferative disorders. d- Lymphocytosis: • Increased lymphocytes count • Causes: o Viral infection. o Chronic lymphocytic leukemia (occurs in adults but never in children). o Non-Hodgkin's lymphoma. o Whooping cough: in children only (it’s the only acute bacterial infection associated with lymphocytosis. Caused by Bordetella pertussis) • Differentiation between Chronic lymphocytic leukemia and whooping cough is by the clinical pattern: age of the patient and the presence or absence of whoops. e- Monocytosis: • Causes: o TB. o Chronic infections in general. o Viral infection ( slight increase)

a- granulocytopenia( neutropenia): • Agranulocytosis: severe reduction of neutrophil count (< 500/ µL) o Leads to ↓ body defenses → infections → Ulcers in the mouth and throat • Causes of granulocytopenia: o Aplastic anemia. o Drugs: chloramphenicol, analgesics (e.g. phenylbutazone and butazolidin), sulphonamide, hyperthyroidism drugs, rheumatoid arthritis drugs, chemotherapeutic agents. o Infection: typhoid fever, visceral leishmaniasis, and some viral infection (hepatitis). o Acute leukemia (due to infiltration of bone marrow by malignant cells). b- lymphopenia: Causes : o HIV infection ( destruction of CD4 cells) o Hodgkin's lymphoma. o Infectious mononucleosis.


Infecious mobonucleosis ( glandular fever)
• • • Caused by Epstein- Bar virus (EBV) infection which is transmitted by droplet infection and kissing. Affects children and young adults. Patients present with : o Fever, headache, sore throat, feeling ill. o Enlargement of lymph nodes (esp. cervical L.N.s) o Skin rash in the upper abdomen. o Slight enlargement of spleen and/or liver. o Rupture of spleen (as it becomes fragile). Laboratory findings: o Normal Hb level or slight anemia. o Leukocytosis mainly due to lymphocytosis and slight monocytosis. o ↑ level of atypical mononuclear cell : reactive T-cell larger than normal lymphocytes with basophilic cytoplasm and ↓ nuclear/cytoplasmic ratio. They indicate viral infection in general but its high level indicates this infection. o Normal platelet count. But, patients might develop autoantibodies against red blood cells or platelets leading to immune hemolytic anemia or immune thrombocytopenia, respectively. Evan’s syndrome is caused by presence of autoantibodies against both red blood cells and platelets, hence, both immune hemolytic anemia and immune thrombocytopenia result. Detection of infectious mononucleosis : o Paul-Bunnell test (heterophile antibody test) : § Addition of patients serum to sheep red blood cells result in agglutination because it contains antibodies that agglutinate red blood cells of sheep (or other species)(Heterophile antibodies) o Monospot test: similar test that does not require sheep red cells and use strips containing antigen that agglutinate with the same antibodies. Management: o There is no specific treatment. o Patients are managed by analgesics (palliative treatment), resting, and fluids till the body eradicates the virus.

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Definition: Malignant proliferation of bone marrow cells. Classified according to type of cells into lymphocytic or myeloid (granulocytic) leukemia. And each is further classified into acute and chronic. Acute leukemia

a- Acute lymphocytic leukemia (ALL): • Disease of children (3-10 yaers old) but can occur in adults. • Cells of origin are lymphoblasts: immature lymphocytes. • These cells proliferate in bone marrow and involve other organs such as lymph nodes and spleen leading to enlargement of both. • Proliferation of the born marrow suppresses its cells resulting in pancytopenia as the infiltration involves the whole marrow. • Clinical presentation : (indicate failure of the bone marrow) o Anemia, bleeding and recurrent acute infections. o Bone pain by compression of bone nerves by the malignant cells. o Lymphadenopathy. o Splenomegally. Classification of ALL: o FAB* classification: according to morphology of lymphoblasts. L1 Cell size Nuclear/cytoplasmic ratio Cytoplasm Nucleolus Prognosis Small High Scanty Not prominent Best L2 Large heterogeneous Low ↑ Prominent Poor L3 Small Low Basophilic & vacuolated In between L1 & L2 , usually not prominent worst

o Immunophenotyping classification: § According to specific antibodies. Types: o T- cell o B-cell o non B non T o and Null ALL § Nucleotidyl transferase is positive in T-cell and Null ALL types. • Prognostic indicators: 1. Age: patient younger than 3 or older than 10 years have poor prognosis. 2. Gender: females have better prognosis as malignant cell may reach testis in males where chemotherapeutic agents can not reach and destroy them. 3. WBC count: the higher the count the worse is the prognosis. 4. Subtype: see table 5. Organ involvement: i. malignant cells may infiltrate the brain and proliferate leading to ↑ intracranial pressure , poor prognosis.


French Americam British


ii. Liver, spleen and mediastinal lymph node involvement have poor prognosis. 6. Philadelphia chromosomes (described on P.7) are associated with poor prognosis. b- Acute non-lymphocytic leukemia: • Usually disease of adults. • Worse prognosis than ALL. • FAB classification: (M = myeloid) M0 – totally undifferentiated. M1 – differentiated using cytochemistry. M2 – acute myeloblastic leukemia M3 – acute promyelocytic leukemia. M4 – acute myelomonocytic leukemia. M5 – acute monoblastic leukemia M6 – Erythroleukemia (Erythroblastic leukemia) M7 – megakaryoblastic leukemia • M3 – acute promyelocytic leukemia : o Promyelocyte is the stage after myeloblast. o Myelobalsts have fewer granules in addition to Auer rods (glycoprotein material) while promyelocyte have many granules and clusters of Auer rods forming fagots. o As promyeloblast rupture, granules and fagots (procoagulant agents) are released and induce coagulation resulting in disseminated intravascular coagulation (DIC) and depletion of coagulation proteins and platelets leading to severe bleeding. M4 and M5 are characterized by severe gum swelling as the leukemic cells infiltrate the gums. M7 characterized by thrombocytopenia as the malignant cells produce immature platelet. Clinical presentation of Acute non-lymphocytic leukemia in general is similar to that of ALL except that there is no lymphadenopathy, in addition to specific characteristics mentioned above for M 3, M4, and M5. Management: 1. supportive measures: i. Blood transfusion to improve Hb level. ii. Platelet transfusion to restore hemostasis. iii. Rehydration with IV solutions. iv. Blood culture and give antibiotics for detection and treatment of infection. v. Treatment of hyperuricemia (e.g allopurinol) NB. High cell proliferation results in high turnover of nucleoprotein and subsequently hyperurecemia (gout). 2. chemotherapy: including i. Induction of remission. • Usually using more than one chemotherapeutic agent. • Remission: reduce leukocyte count to as much as <1%.

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ii. Maintenance of remission by using fewer drugs for long period of time (6-12 months) or dose spacing (↑ interval between doses) to prevent relapse. iii. CNS prophylaxis: • Chemotherapeutic agents can't cross the blood brain barrier, for that intrathecal methotrexate is used to eradicate leukemic cells in the brain (meninges). Sometimes irradiation of skull is an option, but it has many complications. - The patient is cured if no sign of relapse is observed within 1-2 years after therapy has been stopped. 3. Bone marrow transplantation (in cases of relapse – it has its complications). Chronic leukemia a- Chronic granulocytic (myeloid) leukemia: CGL or CML • Affects adults of 40 years old or above (rarely affects children). • Clinical presentation : o Nocturnal fever and weight loss due to increased metabolic rate by malignant cell proliferation. o Sweating o Abdominal discomfort due to spleen enlargement. o Bone pain. o Gout and gouty arthropathy due to ↑ nucleoproteins turnover and subsequent high uric acid production. o Anemia (common due to occupation of bone marrow by malignant cells) • It is characterized by ↑ proliferation and arrest of maturation of granulocyte precursors resulting in presence of promyelocyte, myelocytes, metamyelocytes and few blast cells in the peripheral blood which are normally not present. Their count reaches 100,000/µL or more. Also there is basophilia. • Bone marrow is hypercellular and shows decrease in count of normal cells like erythrocyte precursors. In early stage of the disease, megakaryocytes might be normal or ↑ but later on they ↓ as well as platelets. • Leukocyte alkaline phosphatase is deficient (reduced or absent). • cytogenetic studies show that more than 99% of patients show Philadelphia chromosomes (prognostic factor), which results from reciprocal translocation of the long arms of chromosomes 9 : 22. This result in the production of excessive amounts of tyrosine kinase that stimulates proliferation of leukemic cells. • Natural history of the disease: o It starts as chronic leukemia that continues for about 40 months. o Then it passes through the transitional period, metamorphosis period, which is characterized by gradual ↑ blast cell count, ↑ spleen size, ↑ cell count and thrombocytopenia. o Then becomes acute leukemia (when blast cells exceed 30%) and patient is going to die. Juvenile CGL: o Differ from that of adults in the following: 7

Hepatomegaly instead of splenomegaly. Lymphadenopathy (not in adults). Thrompocytopenia (normal platelet count in adults (in early stage)). § Skin rash (not in adults). Treatment of CGL : o No curative treatment except bone marrow transplantation. o Chemotherapeutic agents are used to reduce the count of malignant cells and spleen size but do not eradicate malignancy. § Busulfan (myleran): very potent drug, given in milligrams, and needs regular follow up as large doses may lead to death. • If the count is reduced from 100,000 to 15,000, stop drug use. § Hydroxyurea: less toxic, given in grams. o Tyrosine kinase inhibitors e.g. Imatinib (Glevic): very expensive new drug.

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b- Chronic lymphocytic leukemia • Age :60 years, does not occur in children. • Clinical presentation: o Cervical lymphadenopathy. o Anemia (due to long living malignant cells in bone marrow). o Late thrombocytopenia. o Infection (lack of immune competence) • Diagnosis: o In most cases, it is diagnosed incidentally by doing WBC count. • Complications: o Some patients develop auto-immune complications such as immune thrombocytopenia and immune hemolytic anemia (as a result of formation of antibodies against platelets and RBC respectively). o Very rarely, may be complicated by transforming into acute lymphocytic leukemia. • Treatment: o No treatment available, but can be controlled by giving cytotoxic cyclophosphamide and corticosteroid to reduce malignant cell mass. • Patients usually die from infections.


Multiple myeloma(plasma cell malignancy)
• • • Also known as monoclonal gammopathy or paraprotienemia. Usually in old age. Clinical Presentation and pathophysiology: o Bone pain, especially backache. o Pathological fracture: fracture occurs as a result of minor trauma, particularly femur bone. Crushing of the vertebral bodies is also common leading to paraplegia due to compression on the spinal cord. o Hypercalcemia: there is increase in the calcium secondary to increased destruction of bone. o Hyperuricemia: this result from increased turn over of nucleoproteins. o Anemia: due to infiltration of the bone marrow by malignant plasma cells and replacement of haemopoietic tissue. o Thrombosis: as a result from increased blood viscosity by elevated level of paraprotein. o Renal function derangement: which may progress to renal failure (see below). o Skeletal lesion: § Malignant plasma cells proliferate and present in clusters in the bone marrow (normally they present in a small number in the bone marrow). § These malignant cells secrete an osteoclast activating factor (IL-6) which activates osteoclast that resorb the bone. Hence, bone mass is markedly reduced and becomes easily broken due to minor trauma (pathological fracture). § Osteoblastic activity also reduced because these patients usually tend to minimize their movement (due to bone pain) and this reduces mechanical stimulation of osteoblast, resulting in osteoporosis and further fractures. § Skeletal lesions are usually found in the axial bones such as vertebrae, ribs and pelvic bone. § Skeletal survey: this X-ray survey is done to demonstrate punched-out osteolytic lesions of the bone*. o Renal lesions: § Hypercalcemia results from excessive resorption of bone. The released calcium is deposit in many sites including the kidney, which is augmented by increased turn over of proteins. Uric acid also deposits in the kidney (hyperuricemia). § Malignant cells secrete monoclonal immunoglobulins (mainly IgG & sometimes IgA) that are not against any compatible living cell. These immunoglobulins increases blood viscosity and may coat the platelets resulting in bleeding in the patient. § They also deposit in the tubules of the kidney and obstruct them interfering with the normal function of the kidney. § Light chains of the immunoglobulin (Bene Jones protein or myeloma protein) are separated from heavy chains and pass in the urine and also deposit in the kidney.

Remember: in secondary prostatic carcinoma, there is increase of bone formation: osteoblastic lesion.


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Amyloid also deposits extracellularlly (in the connective tissue of the kidney) Thus, renal complications in multiple myeloma patients are common.

Diagnosis: o Pathological fractures (if the patient complains of recurrent pathological fracture, always expect malignancy). o Peripheral blood shows: anemia, rouleaux formation (RBCs sticked to each others) due to high level of Ig, high erythrocyte sedimentation rate (ESR), no plasma cells earlier until late stage of the disease. o These plasma cells have eccentric nucleus with cart-wheel appearance and perinuclear hollow. o Bone marrow of the patient contains high number of mature plasma cells that present in clusters (normally, few plasma cells are found in bone marrow). o Plasmoprotein electrophoresis shows paraprotein band (monoclonal band) which is diagnostic for multiple myeloma. o Skeletal survey shows punched-out ostoelytic lesions of axial bones. Urine: contains Benes Jones protein.

Monoclonal Gammopathy of Undetermined Significant: (MUGS) • Paraprotein band(smallr than that of multiple myloma), as well as high plasma cell count is seen in the following situations: o Old people, above 70 years. o SLE patients. o Lymphomas • These patients should be followed up to prevent development of multiple myeloma. • Differentiation between (MGUS) and multiple myeloma is done by demonstration of β2 microglobulin, which is found only in multiple myeloma and is not found in MGUS. • Treatment of multiple myeloma: o Multiple myeloma is untreatable. o Remission is indused by chemotherapy: cyclophosphamid. o Supportive measures include: § Treatment of hyperuricemia. § Improving renal function. § Control of anemia by blood transfusion. § Treatment of hypercalcemia. § Antibiotics to control infections. § Treatment of dehydration by fluids.


Lymphomas are classified into two main categories: o Hodgkin’s lymphoma o Non-Hodgkin’s lymphoma.

a- Hodgkin’s lymphoma Hodgkin's lymphoma incidence • Age: It affects both young & the old. o it shows bimodal age distribution i.e. it has two peaks: one between 15 and 30 and the second above 50 years. 15 30 50 o age ' years ' • Presentation: o Enlarged lymph nodes: cervical, axillary, & medistinal o Lymph nodes are firm, discrete, and give rubbery feeling on cutting. o Loss of weight, nocturnal fever, and excessive sweating. o Pain in enlarged lymph nodes after alcohol intake.

Diagnosis: o Presence of Reed Sternberg cells: binucleated cell, each nucleus contains a nucleolus giving (owl’s eye appearance). Histological classification: o Normal architecture of the lymph node is destructed due to infiltration by malignant cell. According to histology of lymph node, Hodgkin’s lymphoma is classified into: 1. Lymphocyte predominant: there is excess of lymphocyte together with the ReedSternberg cells and few plasma. This type has good prognosis. 2. Nodular sclerosis: lymph node architecture is destroyed and is divided by broad fibrous tissue bands into nodules (hence, nodular sclerosis). Lymph node tissue is replaced by cellular infiltrate that consists of: Reed Sternberg cells, lacunar cells (ReedSternberg cells found in lacunae), eosnophils, plasma cells, histyocytes, lymphocyte, & neutrophils. This type has very good prognosis. 3. Mixed cellularity: diffuse infiltration by different types of cells including Reed Sternberg cells & fibroblast with no nodule. It has poor prognosis. 4. Lymphocyte depleted: many Reed Sternberg cells are found, some are atypical, with very few lymphocyte. Other cells are also present. This type has the worst prognosis. Treatment: o It is either by chemotherapy, radiation or both depending on the clinical stage of the disease. Clinical staging is as follows: Stage I. One lymph node group is involved above (e.g cervical) or below (e.g inguinal) the diaphragm, i.e. on one side of diaphragm. 11

Stage II. More than one lymph node group is involved on the same side of diaphragm, i.e. either above or below. Stage III. More than one lymph node group on both sides of diaphragm are involved. Stage IV. Lymph node are affected with extra-nodal tissue involvement (e.g lung, liver, and intestine). o Stage I and II are treated by irradiation of the affected lymph node and the adjacent area, to insure that even metastases( if occurs) have been irradiated. o There are two common fields for irradiation. Mantel field and inverted-Y field. Each used as follows: § if the involved lymph node is above diaphragm (e.g cervical) Mantel field is done to irradiate axillary and mediastinal groups in addition to the cervical group. § If it is below diaphragm (e.g inguinal), inverted-Y field is done to insure that both inguinal and para-aortic groups have been irradiated. § Sometimes combination of both fields is perform (total body irradiation). o Stage III and IV is diffuse and thus chemotherapy is used. Chemotherapy protocol used is MOPP: Methotrexate, Oncovin, Procarbazine, and Prednisolone.


• The term hemostasis implies the physiologic processes that prevent and control bleeding. The components that are involved in this process include: o Blood vessel endothelium. o Platelets o Coagulation proteins: Factor I till XIII. o In addition to : § Prostacyclin : secreted by the intact endothelium to prevent platelet aggregation. § von Willebrand factor (vWB factor) which is found in the plasma and the subendothelium and is important for platelet adhesion. § Anti-thrompin III and Protein C: natural anti coagulants § plasminogen activation factor Platelets: o Platelets circulate in the center of the blood vessel (axial stream of blood flow) because they carry an electrical charge( negative) similar to that of endothelium (similar charges repel each other). o Platelets are seen by light microscope as small particles (were thought to be dust particles contaminating the slide during preparation). o By electron microscope, they are oval disc containing light and dense granules: § Light granules contain: • β-thromboglobulin. • Fibronectin • Platelet derived growth factor (PDGF) • vWF • Factor V § Dense granules contain: • ADP • Ca++ • serotonine o Platelets also contain microtubules which transport these contents outside the platelets. Formation of primary hemostatic plug: o If the integrity of the endothelium is lost (due to injury to blood vessels), the platelets become in contact with sub-endothelial connective tissue (has positive electrical charge) due to loss of electrical charge on the endothelium. o When platelets contact with foreign surface it become stimulated. Its surface becomes sticky (to adhere and stick firmly) and its shape becomes amoeboid rather than oval to increase surface area. o Dense granules secrete their content and attract other platelets (by ADP) leading to platelet aggregation till primary hemostatic plug is formed.


o Vasoconstriction is required during this process to reduce blood flow that might wash out the plug during its formation. Serotonin secreted by dense granule induces this vasoconstriction. o Then the coagulation process is activated to secrete fibrin in order to enforce platelet, otherwise platelet will be removed soon after the cessation of vasoconstriction. • Coagulation pathways: o Intrinsic pathway and extrinsic pathway as seen the diagram:

o o o o

o Thrombin (factor IIa) is a very strong proteolytic enzyme that converts fibrinogen into fibrin and at the same time activate factor XIII to XIIIa. o Factor XIIIa stabilizes fibrin (from being dissolved) and act as cement. o After blood vessel injury, both intrinsic and extrinsic pathway are activated: § Platelet aggregation → intrinsic pathway. § Release of tissue factor → extrinsic pathway. • Why coagulation process does not obstruct the entire blood vessel lumen? o Intact endothelium secretes prostacyclin that prevents platelets aggregation and makes this aggregation limited to the injured area. o Protein C and anti-thrompin III are natural anti-coagulant and prevent coagulation process in intact part of blood vessel. Blood vessel repair: o After this temporary repair, permanent repair of the blood vessel is done by endothelial growth that is induced by platelet-derived growth factor (PDGF). o β-thromboglobulin and fibronectin are adhesion molecules that help growing cells to come close to each other. 14

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Platelets disorders
Platelets play an essential role in the hemostasis, particularly in the formation of the primary hemostatic plug. Disorders of platelets could be either quantitative (thrombocytopenia) or qualitative (dysfunction).
Quantitative platelet disorder

Thrombocytopenia (low platelet count) Normally, platelet count is ~ 140,000 – 240,000/µL. Below this range (<140,000), it is diagnosed as thrombocytopenia. If the platelet count is 20,000/µL or less, patient will have spontaneous bleeding and if it is > 20,000/µL, bleeding occurs after a minor trauma. o Causes: either decreased production or increased destruction § Decreased production: (low megakaryocyte) • Aplastic anemia. • Infiltration of bone marrow by malignant cell: as in acute leukemia. • Deficiency of vitamin B12 and folic acid (megaloplastic anemia). • Myelodysplastic syndrome (preleukemia). § Increased destruction: due to production of antibodies against platelet, which could be either primary or secondary: • Primary: idiopathic thrombocytopenic purpra (ITP) see below. • Secondary: in case of: o SLE: these patients need high doses of corticosteroid. Poor compliance (adhesion to treatment) may result is dangerous complication ending with death. o Infectious mononucleosis. o Lymphomas and chronic lymphocytic leukemia. o DIC: as a result of consumption of the platelets. o Young ladies who develop thrombotic thrombocytopenic purpra (TTP).Children develop similar condition called hemolytic urimic syndrome. TTP is treated by plasma exchange. TTP: caused by deficiency of certain enzymes→ microthrombi →obstruction of small vessels→ organ failure. Also microthrombi cause intravascular hemolysis and consume platelets and coagulation factors leading to bleeding. b- Idiopathic thrombocytopenic purpra • Could be acute or chronic (> 6 months). • Majority of patients are children. • Acute disease occurs in children, preceded by flu-like illness then they show purpra hemorrhage. • Adult may also be affected. • Clinical picture: o Bleeding, pertaining to primary hemostasis. 15

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o Purpura: small spots of bleeding (pin-head size) on the skin and mucus membrane. o Ecchymosis: when purpra spots join with each others. o Sub-conjunctival hemorrhage. o Epistaxis (nasal bleeding) o Rarely, may lead to intracranial hemorrhage. NB: purpura is 2-10 mm in diameter, where ecchymosis is > 10 mm in diamtere • Treatment:: o these patients are given the following in order depending on the response: § Corticosteroid in high doses. § Intravenous immunoglobulins, which may reduce the production of the antibodies against platelets. § Splenectomy: removal of the spleen ( where platelets are destroyed) may reduce platelet destruction. § Finally, if the patient does not respond to the mentioned treatments, very potent immunosuppressive drugs (e.g. cyclophosphmide) are used to prevent antibody formation.
Qualitative platelet disorder

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Glanzmann's disease (thrombasthenia) : Inherited autosomal recessive platelet functional disorder. Common in Iraqi gauche, Jordan as well as in gulf area. Characterized by bleeding : epistaxis, GI bleeding, mucous membrane bleeding and purpura. • Caused by deficiency of glycoprotein ΙΙ b and ΙΙΙ a which act as receptors. • Diagnosed from birth as bleeding continues after cutting the umbilical cord for long time. • Patients should not undergo surgery unless they receive platelet transfusion before, during and after surgery. • Lab finding: o Normal platelet count . o Negative platelet aggregation test ( see below) o Failure of clot retraction test.: § Normally blood clots on a glass tube then the clot retracts. o Prolonged bleeding time. • Treatment: o Blood (platelet) transfusion. o Contraceptive pills are used in females to prevent postpartum hemorrhage. Also, the uterus may be removed to decrease blood loss. b- Brenard-Soulier Syndrome: • Autosomal recessive syndrom, less common than Glanzmann's disease. • Lab findings: o Defective platelet function. o Slight thrombocytopenia. o Giant platelets. o No response to von Willebrand factor • Platelet aggregation test differentiates between Glanzmann's disease and Brenard-Soulier Syndrome : 16

o This test is performed using many agents: § Platelets of Glanzmann's disease aggregate with Ristocerin but not with ADP (adenine diphosphate) ,epinephrine or collagen while the opposite occurs in the platelets of Brenard-Soulier Syndrome.

Coagulation Disorders
Coagulation factors are synthesized in the liver. Synthesis of factors II, VII, IX, and X require vitamin K. Diseases of coagulation factor could be inherited or acquired. Generally, in cases of coagulation disorder, bleeding occurs mainly in muscles, joints, and intestine.

Inherited disorders
The most important disorders are factor VIII and factor IX disorder. Hemophilia is the term used to describe factor VIII disorder. Sometimes, factor XIII disorder is so-called hemophilia A, while factor IX disorder (or Christmas disease) is called hemophilia B. Hemophilia • • Factor VIII is a complex molecule consisting of: o Factor VIII clotting activity. o von Willebrand factor (vWF). Hemophiliac patients require medical team consisting of hematologist, psychologist , orthopedic and others as the disease has its impact on many aspects of patients health. Pattern of inheritance: o For factor VIII clotting activity, it is x-linked recessive. Thus, males are mostly affected (disorder of males), while females are almost carriers. o For vWF, it is an autosomal recessive. Clinical Presentation: o Patients usually present with bleeding tendency during childhood. o This bleeding ranges from mild, moderate to severe depending on the degree of the inheritance. o Sites of hemorrhage include: muscles and joints and rarely intracranial hemorrhage. Clinical history: o It is a very important contributor for diagnosis. o Gender: patients are usually males. o Family history: ask about any similar history of bleeding in the maternal uncles and other children in the family suffering from similar symptoms. o History of circumsetion: some patient may present with severe hemorrhage after circumsetion. This bleeding may continue until death. Classification: o Severe: bleeding occurs spontaneously. o Moderate: bleeding after slight trauma. o Mild: patient bleeds excessively when exposed to surgery of severe trauma. 17

Diagnosis : by screening of coagulation factor o There are two tests used for screening of coagulation factor deficiency. 1. Prothrombin time: test for • Extrinsic pathway factor VII. • Common pathway: X, V, II, and I. § Normal prothrombin time: 10-14 sec. § Prolonged prothrombin time (>14 sec.) indicate deficiency in these factor. 2. Activated partial thromboplastin time (APTT): test for • Intrinsic pathway: factors VII, IX, XI, and XII. • Common pathway: factors X, V, II, and I. § Normal time: 28-40 sec. o If both test are positive (prolonged)→ deficiency in one of the common pathway factors. Rarely, there is deficiency in two factors of both pathways together. o Correction tests are used to identify the deficient factor using certain reagents, each identify specific factor. o factor VIII and IX are the most common factor to be deficient causing coagulation disorders. For that correction test are done to detect their deficiency first using the following two reagents ( each used separately) : 1. Adsorbed plasma: it is normal plasma without factor IX (but contains factor VIII). Equal volumes of patient’s plasma and adsorbed plasma are added. If APTT (which is previously prolonged) is corrected, this indicates factor VIII deficiency. If factor VIII is normal, APTT will be prolonged due to increase in the plasma volume (after addition of adsorbed plasma). 2. Aged serum: it contains factor IX but not factor VIII. If added to the serum of the patient and the APTT is corrected, this indicate factor IX deficiency. o Extent of deficiency: § The extent of factor deficiency ( factor VIII in hemophilia and factor IX in Christmas disease) is done to determine whether the disease is mild, moderate, or severe. This is done by Factor Assay : • Severe: < 1% of the factor • Moderate: 1-5% • Mild: 5-25%. • Patient with 25% or more can survive normally.

Treatment: 1. Fresh Frozen Plasma (FFP): o Plasma that is frozen to prevent the breakdown of coagulation factors. o It has large volume: 200 mL. o Activity of factor VIII present in one unit of FFP equals to its activity in 1 mL of normal fresh plasma. o It is not suitable for patients who need large volumes because it will increase the load on the heart resulting in hemodynamic problems. 18

2. Cryoprecipitate: o It is prepared from FFP as follows: § FFP is kept in refrigerator at 4˚C overnight . § The ice (frozen plasma) will thaw except small amount forming ice crystals . § ice crystals are centrifuged resulting in plasma cryosupernatant and precipitate i.e. cryoprecipitate. § cryoprecipitate contains: factor VIII, vWF, fibrinogen and factor XIII. o Its volume is only 10-12 mL and contains 80 units. o It is good for patients requiring large amount of factor VIII. 3. Factor VIII concentrate: o Pure highly concentrated factor VIII prepared from fractured blood. It is dissolved in normal saline and is given by injection. o Disadvantage: § Prepared from plasma of thousands of donors and this increases the possibility to transmit viral infection (HIV and viral hepatitis), thus, incidence of these diseases are common among hemophiliac patients. o Nowadays, it is treated by heat and radiation to kill pathogens. o DNA recombinant factor VIII using certain cell lines is also available. o Indications: § It is used in severe cases such as those undergoing surgery ( before and after surgery till the wounds are healed) § If bleeding occurs in a joint of hemophiliac patients, this factor is transfused simultaneously with aspiration of the blood as the aspiration alone leads to further bleeding and transfusing the factor alone leads to clotting and subsequent ankylosis of the joint . NB. some patient with hemophilia receiving frequent factor VIII transfusion may develop antibody against it especially if the factor is prepared from animal blood (e.g. porcine and bovine) which is more antigenic. for that patients do not respond well as factor VIII becomes neutralized by the antibodies. And to solve this problem large amount of the factor is required to overcome the antibody. Nowadays, recombinant activated factor VII is used to by-pass the step of factor VIII in coagulation pathway, but this is expensive although it is potent in bleeding control. Factor IX Disorder ( Christmas Disease) X-linked recessive. Diagnosis and extent of the deficiency are determined as in hemophilia. Treatment: o FFP. o Cyrosupernatant: which contains factor IX (see above). o Factor IX concentrate.

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von Willebrand Disease An autosomal dominant disorder manifested early in childhood. Patient presents with bleeding tendency in skin, mucous membrane and sometimes joints. Both prothrombin time and APTT are prolonged. Assay for vWF shows low level. There is prolonged bleeding time because this factor is required for the function of the platelets which is responsible for the formation of the primary hemostatic plug. Note that in hemophilia, bleeding time is NORMAL. Treatment: by FFP, cryoprecipitate, and factor VIII concentrate. Lupus Anti-coagulant auto-antibodies are produced against phospholipids which are required for intrinsic and extrinsic coagulation pathway. This result in decreased activation of factor X. Although this disease interferes with coagulation but it is found to result in thrombosis. Associated with increased incidence in women and may lead to fetal death or abortion in pregnant women.

Acquired Coagulation Disorders
Vitamin K deficiency Vitamin K is essential for the synthesis of factors II,VII and X. The first factor to be affected is FVII because it has the shortest half-life. To test the deficiency of vitamin K, Prothrombin Time test is conducted ( Test for FVII ). Deficiency of vitamin K is either : - Dietary: Vitamin K is found in leafy vegetables and animal products. - Malabsorption : Vitamin K is a fat-soluble Vitamin. Conditions where there is malabsorption of fat, such as obstructive jaundice, pancreatic or small bowel disease or steatorrhea, will essentially lead to vitamin K deficiency. Vitamin K deficiency leads to bleeding diathesis in adults and children are affected. Deficiency can cause hemorrhagic disease of newborn when the mother is deficient. The child is born with bleeding tendency. Treatment : Vitamin K supplements are used to correct the deficiency. Supplements should be given to patients with obstructive jaundice before surgery. Effect of Vitamin K is neutralized by anticoagulant drugs such as: - Coumarines ( Warfarin, Coumadin ). - Indaniduines. Hepatocellular failure Coagulation factors are synthesized in the liver. Patients with impaired liver function due to infections, fulminant hepatitis are likely to suffer from deficiency of coagulation proteins leading to bleeding diathesis


Disseminated Intravascular Coagulation (DIC) Widespread formation of thrombi in the microcirculation with consumption of platelets and coagulation proteins leading to bleeding. The underlying cause of DIC is the presence of procoagulant material in the circulation. Thrombi formation is accompanied by Fibrinlolysis which yields what is known as Fibrin Degredation Products (FDPs). These FDPs have anticoagulant effect.. Causes: • Obstetric and Gynecological causes: o Premature separation of the placenta “ Abruptioplacentae “. Some amniotic fluid reach the maternal circulation triggering DIC. o Amniotic fluid embolism. o Intrauterine fetal death. Some fetal fluids are absorbed by maternal circulation. o Septic abortion (Criminal abortion). o Ecclampsia. • Infections: o Bacterial Infections: Gram negative Septicemia ex. Meningococcal septicemia leading to hemorrhage in adrenals (WaterhouseFriderichsen Syndrome), Clostridium welchii Septicemia (Gas Gangrene). o Viral Infections: Yellow fever, Ebola Virus (Green Monkey fever), HIV. • Widespread tissue damage: o Following surgery or trauma, severe burns or even heat strokes. The damaged tissues release Tissue Factor (TF) in the circulation activating factor VII and triggering thrombi formation. • Malignancies o Such as Acute Promyelocytic Leukemia, Mucin-secreting Adenocarcinoma. • Certain sneak and invertebrate venoms. Laboratory Findings: o Peripheral blood film revealing prominent fragmentation of RBC (Schistocytes) due to fibrin deposition in small vessels. o Prolonged Prothrombin time. o Prolonged Activated Partial Thromboblastin time. o Prolonged Thrombin time. o Thrombocytopenia. To confirm diagnosis: Measure FDPs in serum and urine. Test will reveal increase beyond 10 units. Deficiency of Natural Anticoagulant o They are Protein C, Protein S and Antithrombin III. They are synthesized in the liver with requirement of vitamin K. Deficiency in one of these factors leads to thrombosis. o The deficiency is inherited as Autosomal Dominant. o Clinical picture: Thrombosis early in childhood, specially in rare, abnormal sites of thrombosis such as Carotid, Subclavian and Mesenteric Arteries.


Definition: A group of disorders having the following features: 1. Spleenomegaly with Extramedullary hemopoeisis ( Myeloid Metaplasia ). 2. Leukocytosis, occurs more in Chronic Granulocytic Leukemia. 3. Transformation into one another (each type can transform into other types). 4. Transformation into Acute Leukemia (includes all types). Types: o Polycythemia Vera. o Essential Thrombocythemia. o Essential Agogenic Myelofibrosis. o Chronic Granulocytic Leukemia. (Discussed previously) Polycythemia Vera Increase in red blood cell mass (count) and consequently Hb concentraton with increased hematopoeisis. Hb concentration: Males > 18g/dL, > 50% Hematochrit Females > 17g/dL Red cell mass : male >36 ml/Kg , female > 32ml/Kg Clinical Picture: patients present with: o General discomfort due to congestion of the circulation with increased RBCs. o Headache. o Abdominal discomfort due to enlarged spleen. o Occurrence of Thrombosis (increased blood viscosity) and/or bleeding (Thrombocytopenia due to increased RBC production) either arterial (cardiac, cerebral or peripheral) or venous (deep or superficial leg veins, cerebral, portal). o Severe itching (Pruritus) characteristically after a hot bath due to increased secretions of basophils. o Peptic Ulceration in 5-10% of patients due to occlusion of small gastric blood vessels by RBCs. Polycythemia can occur due to secondary causes such as Hypoxia (COPD. Sheesha smoking due to high CO), Congenital Heart diseases or Tumors of the Kidney. Essential Thrombocythemia Increased platelet count, million or more /µL Clinical Picture: similar to Ploycythemia Vera o Recurrent thrombosis. o Bleeding. o Peptic Ulceration. o Pruritus. o Might be associated with fibrosis of the bone marrow.

Myeloproliferative Disorders


Essential Agogenic Myelofibrosis Progressive generalized fibrosis of the bone marrow in association with the development of hematopoeisis in the spleen and liver. Clinical Picture: o Weight loss, anorexia, fever and night sweat (Hypermetabolic Symptoms). o Very huge spleen resulting in abdominal discomfort, pain and disturbance of digestion. o Anemia due to fibrosis of the bone marrow. o Decreased platelets later in the disease. Laboratory Findings: o Increased platelets and Leukocytosis with increased basophils. Later in the disease Leukopenia and Thrombocytopenia are common. o Nucleated RBCs and immature WBCs in peripheral blood picture. Known as “ Leukoerythroblastic picture“. o Normal or Increased Hb concentration. o Characteristic “ tear-drop “ red cells (Poikilocytes).


Blood Transfusion
• • Blood Components are RBC, Platelets, WBC, Plasma (contains clotting proteins) Blood components are separated from each other and stored individually. Each component is given to the patients according to their needs. Whole blood can be used in patients who are actively bleeding. But it has to be fresh (Less than one day old). It can be prepared by mixing the four blood elements together. Packed RBCs Packed RBCs are stored in CPD (Citrate-phosphate dextrose) for a maximum of 21 days. By adding Adenine to the mixture, they can be stored for 35 days. 1 unit = 200-300 mL Indications: o Bleeding patients. o Chronic Hemolysis such as Hemolytic Anemia (Thalassemia, SickleCell Anemia). o Refractory Anemia such as Aplastic Anemia. Cannot be treated by Follic acid or Iron supplements. o Leukemia patients receiving chemotherapy (suppression of bone marrow) o Surgery patients. o Obstetric women. Platelets Platelets are stored in room temperature in a “ Platelet Mixer “ for a maximum of 5 days. 1 unit = 50 mL with plasma 1 unit will increase the platelet count of the patient by 10,000/µL. Indications: o Thrombocytopenia (not the immune form) ex. Acute Leukemia, chemotherapy patients, Aplastic Anemia. Shouldn’t be given to Thrombotic Thrombocytopenic purpra (TTP). o DIC. o Patients with platelet count < 20,000/µL. o Patients with platelet count about 50,000/µL and bleeding. o Patients of platelet function defects and bleeding ex. Glanzmann's disease and Brenard-Soulier Syndrome Plasma Plasma is used as volume expander. It also contains clotting proteins. 1 unti = 200-250 mL + Clotting Proteins Indications: o Patients with deficiency in coagulation proteins. o Plasma exchange, Plasmapharesis – using plasma as therapeutic agent ex. TTP, certain neurological disorders. o Cryopercipitate in Hemophilia, Von Willebrand disease, Hypofibrinoginemia, Dysfibrinoginemia (non-functional fibrinogen).

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Complications of Blood Transfusion: 1. Hemolytic: a. Acute: Very severe reaction associated with high mortality rate. Results from Blood group non-compatibility (according to ABO system). Antibodies against the foreign RBCs are activated by their antigens resulting in the activation of complement proteins and consequent intravascular hemolysis, attraction of cytokines leading to hypotensive shock, renal failure and DIC. b. Delayed: Occurs within 4-5 days from the transfusion process. It is secondary to immune reaction by activation of memory cells and production of Antibodies. The patient has been exposed to the foreign RBCs’ antigens before and the time lag is for activation of memory cells. 2. Non-hemolytic: a. Febrile: Caused by Antibodies against the foreign WBCs of the transfused blood leading to the production of cytokines, especially Tumor Necrosis Factor (TNF) which affect the thermoregulatory center leading to fever. b. Allergic: Due to plasma contents of the transfused blood. The allergic reaction is characterized by production of IgE antibodies which lead to release of Histamine. The allergic reaction can be severe leading to Anaphylactic shock, especially in patients who are IgA deficient having antibodies against IgA. c. Transfusion-Related Acute Lung Injury (TRALI): Uncommon but severe reation. Results from precipitation of granulocytes in the capillaries of the lung leading to obstruction and acute respiratory distress.


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