Blood

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). 

A person may develop leukopenia due to the following conditions: autoimmune conditions, such as rheumatoid arthritis, lupus, and Sjögren's disease. cancers, such as Hodgkin lymphoma, leukemia, and myelofibrosis. infection, such as influenza, HIV, and hepatitis.

Polycythemia, or erythrocytosis, means having a high concentration of red blood cells in your blood.

Primary polycythemia is caused by neoplastic disease of the pluripotent cells of the bone marrow, that start to over-produce red blood cells accompanied by elevated white cell and platelet count. 

Secondary polycythemia is caused as a compensatory response to hypoxia with increase in the level of erythropoietin. Hypoxia may be result of leaving at high altitude, chronic heart and lung disease, and smoking. 

Primary polycythemia

Increase in the red blood cell count (due to neoplastic disease of stem cells) → hemoglobin level ↑ | blood volume ↑ | viscosity ↑ | hematocrit ↑ → large ↓ in cardiac output and blood flow (pripary due to viscosity ↑) → such symptoms: 

• hypertension;
• headache;
• dizziness;
• inability to concentrate;
• difficulty with hearing and vision ← due to ↓ cerebral blood flow

Venous stasis^[1] → visual changes of body tissue color:

• plethoric appearance of dusky redness, even cyanosis (lips, fingernails, mucous membrane);

↑ concentration of blood cells → itching, pain in the fingers or toes

hypermetabolism → night sweats, weight loss. 

[1] Venous stasis - condition in which veins have problems moving blood back to the heart

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Secondary polycythemia

Hypoxia (altitude, smoking, lung disease) → release of erythropoietin^[2] by kidney → increase formation of red blood cells in BM → symptoms:

• Fatigue;
• Headache;
• Dizziness;
• Blurred vision;
• Weakness;
• Reduced mental acuity

[2] Erythropoietin - a hormone secreted by the kidneys that increases the rate of production of red blood cells in response to falling levels of oxygen in the tissues

Thrombocytosis is a disorder in which body produces too many platelets (count above 1.000.000/μL)

The most common underlying causes of secondary thrombocytosis include:

• tisue damage due to surgery;
• infection;
• cancer;
• chronic inflammatory conditions: rheumatoid arthritis (inflammation or swelling of one or more joints) and Crohn disease. 

Primary thrombocytosis is caused by abnormalities in thrombopoietin receptor and platelet binding, causing hihger-than-expected levels of free thrombopoietin. 

Hormone thrombopoietin

The common clinical manifestations of essential thrombocytosis are:

• thrombosis (pulmonary embolism, poertal and hepatic vein);
• hemorrhage.
• burning of the fingers due to occlusion of the arterioles by platelet aggregates

Thrombocytopenia is a condition that occurs when the platelet count in blood is too low (<150.000/μL)

• Decreased platelet production because of loss of bone marrow function (aplastic anemia);
• Replacement of the bone marrow by malignant cells (leukemia);
• Radiation therapy and drugs (Examples include heparin, quinine, sulfa-containing antibiotics and anticonvulsants.);
• Infection with human immunodeficiency virus (HIV);
• cytomegalovirus;
• antiplatelet antibodies (self-destruction)
• Pregnancy. Thrombocytopenia caused by pregnancy is usually mild and improves soon after childbirth.

https://www.mayoclinic.org/diseases-conditions/thrombocytopenia/symptoms-causes/syc-20378293#:~:text=Thrombocytopenia%20signs%20and%20symptoms%20may,Prolonged%20bleeding%20from%20cuts

Thrombocytopenia signs and symptoms may include:

• Easy or excessive bruising (purpura)
• Superficial bleeding into the skin that appears as a rash of pinpoint-sized reddish-purple spots (petechiae), usually on the lower legs
• Prolonged bleeding from cuts
• Bleeding from your gums or nose
• Blood in urine or stools
• Unusually heavy menstrual flows
• Fatigue
• Enlarged spleen

https://www.mayoclinic.org/diseases-conditions/thrombocytopenia/symptoms-causes/syc-20378293#:~:text=Thrombocytopenia%20signs%20and%20symptoms%20may,Prolonged%20bleeding%20from%20cuts

There are four primary causes of anemia:

1. excessive loss of red blood cells from bleeding;
2. destruction (hemolysis) of red blood cells;
3. defective red blood cell production;
4. inadequate red blood cell production because of bone marrow failure.

Manifestations (symptoms) → pathophysiology (the functional changes that accompany a particular syndrome/ disease)

Increased (↑); (↓) decreased/reduced; (→) due to/because of

Tissue hypoxia due to → The oxygen-carrying capacity of hemoglobin is reduced (↓)  

Tissue hypoxia can give rise to ←  fatigue, weakness, dyspnea^[1], and sometimes angina

Headache, faintness, and dim vision →  due to Hypoxia of brain tissue 

Pallor of the skin^[2], mucous membranes^[3], conjunctiva, and nail beds → Redistribution of the blood from cutaneous tissues or a lack of hemoglobin  

Tachycardia^[4] and palpitations^[5] may occur as → body tries to compensate with an increase in cardiac output.

Flow-type systolic heart murmur → changes in blood viscosity

Diffuse bone pain and sternal tenderness → due to accelerated erythropoiesis^[6] 

In hemolytic anemias: jaundice → caused by ↑ blood levels of bilirubin

Aplastic a.: petechiae and purpura → reduced platelet function.

[1] Dyspnea - Shortness of breath

[2] Pallor of the skin - unusual lightness of skin color compared with your normal complexion.

[3] Mucous membrane (mucosa) - is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs.

[4] Tachycardia - is the medical term for a heart rate over 100 beats a minute. 

[5] Heart palpitations are feelings of having a fast-beating, fluttering or pounding heart.

[6] Erythropoiesis is the process which produces red blood cells (erythrocytes)

Hemolytic anemia is characterized by the following:

• The premature destruction of red cells
• The  retention  in  the  body  of  iron  and  the  other  products  of  hemoglobin destruction
• An increase in erythropoiesis

Almost all types of hemolytic anemia are distinguished by normocytic^[1] and normochromic^[2] red cells. Because of the red blood cell’s shortened life span, the bone marrow is usually hyperactive, resulting in an increased number of reticulocytes^[3] in the circulating blood. As with other types of anemias, the person experiences easy fatigability, dyspnea, and other signs and symptoms of impaired oxygen transport. In hemolytic anemia, red cell breakdown can occur within or outside the vascular compartment.

[1] Normocytic cells - means you have normal-sized red blood cells, but you have a low number of them.

[2] Normochromic anemia - form of anemia in which the concentration of hemoglobin in the red blood cells is within the standard range, but there is an insufficient number of red blood cells.

[3] Reticulocytes are slightly immature red blood cells.

• A diet lacking in certain vitamins and minerals. A diet consistently low in iron, vitamin B-12
• Intestinal disorders. Having an intestinal disorder that affects the absorption of nutrients in your small intestine
• Pregnancy. Being pregnant and not taking a multivitamin with folic acid and iron
• Chronic conditions. If you have cancer, kidney failure
• Family history
• Menstruation

Different types of anemia have different causes. They include:

• Vitamin deficiency anemia. Besides iron, your body needs folate and vitamin B-12 to produce enough healthy red blood cells. A diet lacking in these and other key nutrients can cause decreased red blood cell production.
• Anemia of inflammation. Certain diseases — such as cancer, HIV/AIDS, rheumatoid arthritis, kidney disease
• Aplastic anemia. This rare, life-threatening anemia occurs when your body doesn't produce enough red blood cells
• Anemias associated with bone marrow disease. A variety of diseases, such as leukemia and myelofibrosis, can cause anemia by affecting blood production in your bone marrow.
• Hemolytic anemias. This group of anemias develops when red blood cells are destroyed faster than bone marrow can replace them. Certain blood diseases increase red blood cell destruction.
• Sickle cell anemia. This inherited and sometimes serious condition is a hemolytic anemia. It's caused by a defective form of hemoglobin that forces red blood cells to assume an abnormal crescent (sickle) shape.

• 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.