Blood

• The causes of leukemia are largely unknown, but it thought to involve a comboination of genetic and environmental factors
• Higher chances for people who have been exposed to high levels of radiation 
• Exposure to benzene, many unknown toxins, drugs, chemicals and gases
• Viruses like the Human T-Cell leukaemia virus
• Leukemia as a second cause after aggressive chemotherapy for other cancers, such as Hodgkin's lymphoma (HL)
• Leukemia cells (hematopoietic precursor cells) have acquired mutations in their DNA that cause them to grow abnormally and lose functions of typical white blood cells.
• DNA Chromosome translocation and inversion mutations in cells

Most people diagnosed with chronic myeloid leukaemia have an abnormal chromosome called the Philadelphia chromosome.

Leukemia is suggested by the increased leukemia incidence among a number of congenital disorders [1], including Down syndrome, neurofibromatosis, and Fanconi anemia.

[1] Congenital disorder is a condition that is present from birth (Down syndrome, neurofibromatosis, and Fanconi anemia).

The leukemias are malignant neoplasms ^[1] of cells originally derived from hematopoietic precursor cells^[2]. They are characterized by diffuse replacement of the bone marrow with unregulated, proliferating, immature neoplastic cells^[3]. In most cases, the leukemic cells spill out into the blood, where they are seen in large numbers. The term leukemia (i.e., “white blood”) was first used by Virchow to describe a reversal of the usual ratio of red blood cells and white blood cells. The leukemic cells may also infiltrate the liver, spleen, lymph nodes, and other tissues throughout the body, causing enlargement of these organs.

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[1] malignant neoplasms is another term for a cancerous tumor. The term “neoplasm” refers to an abnormal growth of tissue. The term “malignant” means the tumor is cancerous and is likely to spread (metastasize) beyond its point of origin.

[2] hematopoietic precursor cells=hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis.

[3] A neoplasm is an abnormal growth of cells, also known as a tumor. Neoplastic diseases are conditions that cause tumor growth. Growth can be either benign (noncancerous) or malignant (cancerous).

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Leukemias are cancers of the white blood cells, which begins in the bone marrow.

The leukemias commonly are classified according to their predominant cell type (i.e., lymphocytic or myelocytic) and whether the condition is acute or chronic.

Leukemias are divided into four types:

• acute lymphocytic (lymphoblastic) leukemia (ALL)
• chronic lymphocytic leukemia (CLL)
• acute myelogenous (myeloblastic) leukemia (AML)
• chronic myelogenous leukemia (CML)

The lymphocytic leukemias involve immature lymphocytes and their progenitors that originate in the bone marrow but infiltrate the spleen, lymph nodes, CNS, and other tissues. The myelogenous leukemias involve the pluripotent myeloid stem cells in the bone marrow and interfere with the maturation of all blood cells, including the granulocytes, erythrocytes, and thrombocytes.

https://drive.google.com/file/d/18uijN2Ol46tx4uXd0psHP-5u-jj5VXSn/view?usp=sharing https://drive.google.com/file/d/1ubZaGeQOzrlg4InU39d-1O6alkhy5FC9/view?usp=sharing

ALL encompasses a group of neoplasms composed of precursor B (pre-B) or T (pre-T) lymphocytes referred to as lymphoblasts (see Fig. below). Approximately 90% of people with ALL have numeric and structural changes in the chromosomes of their leukemic cells. They include hyperploidy (i.e., more than 50 chromosomes), polyploidy (i.e., three or more sets of chromosomes), and chromosomal translocations and deletions. Many of these chromosomal aberrations serve to dysregulate the expression and function of transcription factors required for normal hematopoietic cell development.

The AMLs are neoplasms affecting myeloid precursor cells in the bone marrow. Most are associated with acquired *gene alterations that inhibit (prevent (an action or process)) myeloid differentiation. As a result, normal marrow elements are replaced by an accumulation of undifferentiated blast cells with a resultant suppression of the remaining progenitor cells leading to anemia (low healthy red blood cells), neutropenia (low neutrophils) and thrombocytopenia (low thrombocytes).

*Gene alteration is any change in the DNA sequence that can alter the genetic code and therefore may alter the synthesis of the protein that it encodes.

Both ALL and AML are characterized by an abrupt onset of symptoms, including:

• fatigue resulting from anemia;
• low-grade fever;
• night sweats;
• weight loss resulting from rapid proliferation_[1] and hypermetabolism^[2] of the leukemic cells;
• bleeding caused by a decreased platelet count (thrombocytopenia);
• bone pain and tenderness because of bone marrow expansion

[1] proliferation - rapid increase in the number or amount of something.

[2] hypermetabolism - metabolism at an increased or excessive rate.

Those symptoms occur in all acute leukemia but are more common in ALL:

• lymphadenopathy (the swelling of lymph nodes);
• splenomegaly (An enlarged spleen);
• hepatomegaly (An enlarged liver is one that's bigger than normal);
• CNS involvement by crossing the blood-brain barrier (more common in children that adults)

Symptoms particularly common in the monocytic form of AML:

• infiltration of malignant cells in the skin, gums, and other soft tissues
• infiltration of leukemic cell in the CNS (less common than in ALL case)

Symptoms of CNS involvement include:

• cranial nerve palsies (a lack of function of a nerve);
• headache;
• nausea (uneasiness of the stomach that often accompanies the urge to vomit, but doesn't always lead to vomiting);
• vomiting;
• papilledema (optic disc swelling that is caused by increased intracranial pressure due to any cause);
• seizures and coma.

Leukostasis is another condition that leads to formation of the high number of circulating leukemic blasts that increase blood viscosity and predisposes to the development of leukoblastic emboli with obstruction of small blood vessels in the pulmonary and cerebral circulations.

CLL, a clonal malignancy of B lymphocytes, is the most common form of leukemia in adults in the Western world. The term "chronic" in chronic lymphocytic leukemia comes from the fact that this leukemia typically progresses more slowly than other types of leukemia. The term "lymphocytic" in chronic lymphocytic leukemia comes from the cells affected by the disease 

CLL are often asymptomatic at the time of diagnosis, and lymphocytosis^[1] is noted on a complete blood count obtained for another, unrelated disorder. 

As the disease progresses, lymph nodes gradually increase in size, and new nodes are involved, sometimes in unusual areas such as:

• the scalp, orbit, pharynx, pleura, gastrointestinal tract, liver, prostate, and gonads.

People with the aggressive form of CLL experience a more rapid sequence of clinical deterioration characterized by:

• increasing lymphadenopathy (lymph nodes that are abnormal in size);
• hepatosplenomegaly (disorder where both the liver and spleen swell beyond their normal size);
• fever;
• abdominal pain;
• weight loss;
• progressive anemia;
• thrombocytopenia, with a rapid rise in lymphocyte count;
• increased susceptibility to infection reflects an inability to produce specific antibodies

[1] Lymphocytosis (lim-foe-sie-TOE-sis), or a high lymphocyte count, is an increase in white blood cells called lymphocytes. Lymphocytes help fight off diseases, so it's normal to see a temporary increase after an infection.

CML is a disorder of the pluripotent hematopoietic progenitor cell, characterized by excessive proliferation of marrow granulocytes, erythroid precursors, and megakaryocytes.

The CML cells harbor a distinctive cytogenic abnormality, the previously described Philadelphia chromosome. It is generally believed that CML develops when a single, pluripotent hematopoietic stem cell acquires a Philadelphia chromosome. Although CML originates in the pluripotent stem cells, granulocyte precursors remain the dominant leukemic cell type.

Chronic phase of disease progreses slowly, with non specific symptoms such as wekaness and weight loss. 

The most characteristic laboratory finding at the time of presentation is leukocytosis with immature granulocyte cell types in the peripheral blood. 

weakness, easy fatigability, and exertional dyspnea is present → Anemia

Abdominal fullness and discomfort is present → Splenomegaly (An enlarged spleen), which is often present at the time of diagnosis

Low grade fever, night sweats, bone pain, and weight loss → rapid proliferation and hypermetabolism of the leukemic cells.

Bleeding → dysfunctional platelets

https://drive.google.com/file/d/1GDa8j9Fg4pPII5G8MbazSn3ig-KwbxBj/view?usp=sharing

NHLs may be of B-cell, T-cell or NK-cell origin (Pic. below). It is believed to occur because of environmental, genetic and other unidentified factors. NHLs arise from lymphocytes and the site of their origination varies. Alterations in the developmental process of these cells can lead to any subtype of lymphoid neoplasms. The exact cause of alteration is unknown, but some viruses (Helicobacter pylori, human T-lymphotropic virus 1, pathogen EBV) have been linked to specific subtypes.

B-cell lymphomas is the most common NHL subtype. More common B-cell subtypes include follicular lymphoma, immunoblastic large cell lymphoma and mantle cell lymphoma.

. People with slow growing lymphomas experience:

• painless lymphadenopathy (lymph nodes that are abnormal in size)
• swollen lymph nodes
• usually asymptomatic

People with more aggressive forms experience:

• fever;
• night sweats;
• weight loss
• increase susceptibility to infections associated with hypogammaglobulinemia^[1] and a poor humoral antibody response^[2]
• Feeling full after only a small amount of food.

[1] Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood.

[2] The humoral immune response is mediated by antibody molecules that are secreted by plasma cells.

Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes

The cause of HL is largely unknown. Although exposure to carcinogens and viruses as well as genetic and immune mechanisms have been proposed as causes, none has been proved in the pathogenesis of the disease. 

A change (mutation) in the DNA of a type of white blood cell called B lymphocytes. The exact reason why this happens isn't known.

Signs and symptoms of Hodgkin's lymphoma may include:

• Painless swelling of lymph nodes in your neck, armpits or groin
• Persistent fatigue
• Fever
• Night sweats
• Losing weight without trying
• Severe itching
• Pain in your lymph nodes after drinking alcohol
• cough
• dyspnea

Other symptoms such as anemia and fatigue identify spread of the disease. In advanced HL, spleen, liver, lungs, digestive tract and occasionally the CNS may be involved. As the disease progresses, rapid proliferation of abnormal lymphocytes leads to an immunologic defect particularly in cell-mediated immune responses making the person more susceptible to infections.

Non-Hodgkin lymphoma is usually treated with chemotherapy or radiotherapy, although some people may not need treatment straight away. In a few cases, if the initial cancer is very small and can be removed during a biopsy, no further treatment may be needed.

Hodgkin lymphoma is a specialized form of lymphoma that features the presence of an abnormal
cell called a Reed–Sternberg cell.

HL differs from NHL in several respects:

1. it usually arises in a single node or chain of nodes, whereas NHL frequently originates at extranodal sites and spreads to anatomically contiguous nodes.
2. HL is characterized by the presence of large, atypical, mononuclear tumor cells, called Reed–Sternberg cells. These cells, which frequently constitute less than 1% of the total cell population, are a diagnostic hallmark of the disease.

Irradiation and chemotherapy are used in treating the disease. 

During leukopenia it is most often affects neutrophils. Neutrophils constitute the majority of blood leukocytes and play a critical role in host-dedence mechanisms against infection.They migrate to sites of infection and engulf, digest, and destroy microorganisms. 

Neutropenia is a condition where you have a low number of white blood cells called neutrophils in your blood. When you have low levels of neutrophils in your blood, your immune system is weakened, making it harder for your body to fight infection. This is called neutropenia or being neutropenic.

Neutropenia can result from decreased neutrophil production, accelerated utilization or destruction, or a shift from the blood to the tissue compartments. It can be present at birth (congenital) or arise from a number of factors that occur later in life and do not have a hereditary component (acquired).

1) Congenital neutropenia syndromes are a group of rare disorders present from birth that are characterized by low levels of neutrophils

2) Acquired neutropenia encompasses a broad spectrum of causative processes and includes primary and secondary autoimmune neutropenia, infectionrelated neutropenia, and drug-induced neutropenia . A number of bone marrow disorders, hematopoietic malignancies, and radiation therapy may induce neutropenia.

Common causes include HIV, hepatitis, tuberculosis, sepsis, and Lyme disease, among other infections. Cancer: Cancer and other blood and/or bone marrow disorders, including leukemia and lymphoma, can prevent your body from making enough healthy white blood cells, causing neutropenia.

Leukocytosis, or increased white blood cells, is a frequent sign of an inflammatory response, especially one caused by bacterial infection. The white blood cell count commonly increases from a normal value of 4000 to 10,000 cells/μL. 

Bacterial infections → increase in neutrophils (neutrophilia) 

Patasitic and allergic responses → eosinophilia ↑

Viral infections tend to produce → neutrophils ↓ (neutropenia) and lymphocytes ↑ (lymphocytosis)

Overwhelming infections and impaired ability to produce white blood cells → white blood cell ↓ (leuokopenia) 

• Neutropenia (noo-troe-PEE-nee-uh) occurs when you have too few neutrophils, a type of white blood cells
• Leukopenia - decrease in the absolute number of leukocytes (white blood cells) in the blood 
• Leukocytosis -high white blood cell count
• Polycythaemia, or erythrocytosis, means having a high concentration of red blood cells in your blood

1. Vascular constriction
2. Formation of the platelet plug
3. Blood coagulation

The coagulation process results from the activation of what have traditionally been designated the intrinsic and the extrinsic pathways, both of which form prothrombin activator.

1. The intrinsic pathway, which is a relatively slow process (can cause clotting in 1 to 6 minutes), begins in the circulation with the activation of factor XII.
2. The extrinsic pathway, which is a much faster process (can cause clotting in 15 seconds), begins with trauma to the blood vessel or surrounding tissues and the release of tissue factor or tissue thromboplastin, an adhesive lipoprotein, from the subendothelial cells.

The terminal steps in both pathways are the same-the activation of factor X and the conversion of prothrombin to thrombin. Thrombin then acts as an enzyme to convert fibrinogen to fibrin, the material that stabilizes a clot. Both pathways are needed for normal hemostasis, and many interrelations exist between them.

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Vitamin K is necessary for the synthesis of factors II, VII, IX, and X; prothrombin; and protein C. If there is a deficiency of Vitamin K or liver failure so that not enough prothrombin is created, a bleeding tendency will develop. 

Hemostasis refers to the stoppage of blood flow. It's devided in two phases: 

• Primary hemostasis - involves the formation of the platelet plug around the site of injured blood vessle 
• Secondary hemostasis - reinforces that platelet plug with the creation of protein mesh called fibrin.

Each system is activated when blood passes out of the vascular system. The intrinsic system is activated as blood comes in contact with collagen in the injured vessel wall. The extrinsic system is activated when blood is exposed to tissue extracts. However

Vessel spasm is initiated by endothelial injury and caused by local humoral mechanisms.Then endothelium cells are injured, they secrete endothelin 1. Endothelin 1 is the most powerful vasoconstrictor. It binds to receptor and activates intracellular mechanism (intracellular PIP2 calcium signaling mechanism), which causes vascular spasm.

Prostacyclin is another prostaglandin which is released from the vessel endothelium. It produced vasodilation and inhibits platelet aggregation in the surrounding uninjured endothelium.

• Vessel wall is more often sealed with a plateled plug rather than a blood clot
• Platelets (thrombocytes) arise from megakaryocytes.
• Platelet production is controlled by a protein called thrombopoietin → causes proliferation^[1] and maturation of megakaryocytes.

Liver, kidney, smooth muscle and bone marrow synthesize thrombopoietin → proliferation and maturatiom of megakaryocytes → matured megakaryocytes → thrombocytes (platelet)

[1] Proliferation -rapid increase in the number or amount of something 

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Platelet plug formation involves activation, adhesion, and aggregation of platelets. Platelets are attracted to a damaged vessel wall, become activated, and change from smooth disks to spiny spheres, exposing glycoprotein receptors on their surfaces. Platelet adhesion requires a protein molecule called von Willebrand factor, which leaks into the injured tissue from the plasma. This factor is produced by the endothelial cells of blood vessels and circulates in the blood as a carrier protein for coagulation factor VIII. Adhesion to the vessel  subendothelial layer occurs when the platelet receptor binds to vWF at the injury site, linking the platelet to exposed collagen fibers.

Calcium ions (Ca²⁺) play a major role in the tight regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII (FXIII). On top of that, platelet release ADP and TXA2 which leads to amplification of aggregation and stimulus for other platelet to combine. Combination of   ADP and TXA2 lead to the expansion of the enlarging platelet aggregate, which
becomes the primary hemostatic plug. Stabilization of the platelet plug occurs as the coagulation pathway is activated on the platelet surface, and fibrinogen is converted to fibrin. This creates a fibrin meshwork that cements the platelets and other blood components together.

A low white blood cell count (leukopenia) is a decrease in disease-fighting cells (leukocytes) in your blood. Leukopenia is almost always related to a decrease in a certain type of white blood cell (neutrophil).