Lecture 2- Hematology

what happens to cells in a hypoxic environment

• cells cannot sustainably make ATP

  • backup=anaerobic glycolysis

    • inefficient- requires to much glucose to be available

    • produces LACTIC ACID- buildup destroys cell proteins

• not enough ATP→ decline in Na/K pump

  • no longer able to maintain fluid balance (cell swelling) and resting potential (cell dysfunction)

hypoxia

tissue do not receive enough oxygen for metabolic need

• sx depend on CHRONICITY AND SEVERITY

  • acute or severe of often medical emergency and can present with profound sx

  • mild or chronic can prod vague sx

    • ex. COPD

    • fatigue

    • exertional dyspnea

    • dizziness

    • headache

• leads to hypoperfusion of the brain

anemia

• reduction in red cell mass of decrease in quality or quantity of hemoglobin

2 primary mechanisms- anemia

1) diminished/defective RBC production (erythropoiesis)

2) increased RBC destruction (hemolysis) or loss

clinical manifestations of anemia

• pallor of skin, mucous membranes, lips, nail beds, and conjunctivae

  • reduced heme concentration

• cyanosis

• jaundice

  • if hemolysis present (RBCs release bilirubin)

• abdominal pain, nausea

  • decreased perfusion to GI tract

  • worse after meal

• claudication

  • exertion causes pain/cramping of muscles (MC calves) due to reduced blood flow

• weakness, fatigue, dizziness, fainting, lethargy

  • decreased CNS perfusion

• exertional dyspnea

  • increased O2 demand with exertion

compensation

1) increase CO by elevating HR→ tachycardia, palpitations

• may eventually lead to heart failure

2) increase availability of O2 by increasing rate and depth of breathing→ tachypnea, dyspnea

classification of anemia

1) by underlying mech

2) by changes in the erythrocyte size or hemoglobin content

anemia classification: changes in size

• “-cytic”

• normocytic

• microcytic (small)

• macrocytic (larger)

anemia classification: changes in hemoglobin concentration

• “-chromic”

• normochromic

• hypochromic

• hyperchromic

anemias of diminished erythropoiesis

• microcytic anermias

  • iron deficiency

  • anemia of chronic disease

• macrocytic anemia

  • B12 and folate deficiency

  • aplastic anemia

iron deficiency anemia

• insufficient iron→ small, hemoglobin deficient RBCs

  • HYPOCHROMIC MICROCYTIC

  • may still have normal # of RBCs, but still low carrying capacity of O2

• results in tissue hypoxia

  • fatigue

  • exertional dyspnea

  • pallor

why do ppl become iron deficient

• iron demand > iron intake and absorption

• increase iron demand:

  • bleeding (menses, GI bleeding)

  • pregnancy

• decrease intake or absoprtion

  • diets insufficient in iron

  • chronic intestinal inflammation

    • duodenum

  • decreased gastric acidity (proton pump inhibitors)

    • stomach acid needed to reduce iron to more easily absorbed (FE2- ferrous) state

anemia of chronic disease

• presents similar to Fe deficiency, but no reported bleeding

• occurs in many chronic inflammatory disease states

  • cancer

  • autoimmune

  • chronic infection

• WILL NOT IMPROVE WITH IRON THERAPY

  • there is enough iron, it is just sequestered

major effects of chronic inflammation

1) inflammatory cytokines DECREASES EPO production and bone marrow response to EPO

• fewer RBCs produced

2) increased hepcidin production

• decrease iron absoprtion

• decreases recycling of iron (prevents stored iron from being released)

hepcidin

• produced by liver

• respond to changes in serum iron

• when iron levels are HIGH, hepcidin turns “on”

  • blocks absorption of iron in duodenum

  • blocks release of iron from splenic macrophages and liver

• when iron levels are LOW

  • hepcidin turn off and allows release/absorption of iron

why does hepcidin production increase due to chronic inflammation

• many pathogens feed on iron, therefore, reducing iron availability helps to inhibit bacterial growth by limiting fuel source

• can be cancer, inflammation, etc

anemia of chronic disease- decrease RBC production

• inflammatory cytokines reduce response of myeloid stem cells to EPO

• inflammatory cytokines decrease EPO production by the kidneys

anemia of chronic disease- decreases iron availability

• inflammatory cytokines increase release of hepcidin→

  • macrophage iron sequestration

  • impaired dietary iron absorption

  • decrease iron release from liver

vitamin B12 and folate deficiencies

• crucial for erythroblast maturation- SYNTHESIS OF DNA

• cells can enlarge but do not divide→ macrocytic and hyperchromic

  • carry less oxygen and die prematurely

how do ppl become B12 and folate deficient

1) insufficient intake

• B12- strict vegetarian diet

• folate- less common in dev countries

  • alcoholics, elderly, food insecurity

  • increased demand (pregnancy)

2) impaired absorption

• pernicious anemia

• malabosorption (ex. crohns and celiac)

• bariatric surgery

pernicious anemia

• B12 absorption

  • parietal cells of the stomach secrete intrinsic factor (binds to B12 as travels through GI)

  • intrinsic factor necessary for B12 absorption in terminal ileum

• autoimmune disease

  • antibodies destroy parietal cells→ no intrinsic factor→ B12 deficiency

• any amnt of supplementation wont help bc cant absorb

B12 and folate deficiency symptoms

• fatigue

• headache

• dyspnea

B12 deficiency symptoms

• paresthasias

• gait disturbances

• cognitive disturbances

• COFACTOR NEDED FOR MYELIN SYNTHESIS

primary mechanisms for hemolytic anemia

1) issues with RBC structure

• more RBCs get trapped and removed in the spleen

2) RBC is targeted

• immune mediated hemolysis

• infections

clinical relevance: hereditary spherocytosis

• genetic mutation that changes structural protein that makes RBC membrane → no longer bioconcave→ spherical cells get trapped in sinusoidal cap of spleen→ spleen

hemolysis: issues with RBC targeting

• leads to accelerated RBC destruction

• erythrocytes are targeted within the vascualture

• immune system

  • drug induced hemolytic anemia

• infections

  • ex. malaria

clinical manifestations: hemolytic anemia

• fatigue

• headaches

• dyspnea

• jaundice due to bilirubin accumulation

• abdominal pain

  • splenomegaly due to splenic sequestration

disorders of hemostasis

• bleeding disorders

  • platelet disorders

  • coagulation disorders

• thromboembolic disease

  • clot too much

thrombocytopenia

can be due to:

• insufficient production

  • liver disease (liver makes TPO→ make platelets, therefore if diseased, decreased proc)

  • drugs

• increased consumption of platelets

  • autoimmune

platelet dysfunction

• bleeding due to dysfunction in platelet plug formation

• can be:

  • congenital (Vonwillebrand disease)

  • acquired (medication)

von wilebrand disease

• congenital defect in the vWG gene, resulting in dysfunction or no presence of vWF

• platelets fail to adhere and aggregate to the site of bleeding, therefore no formation of plug

antiplatelet drugs

disruption of platelet adherence and aggregation

• aspirin- blocks production of TXA2 (stickiness)

• clopidogrel- block production of ADP (aggregation)

coagulation disorder

deficiencies in clotting factors resulting in impaired fibrin mesh

• congenital: hemophilia

• aqcuired:

  • liver disease

  • vitamin K deficiency

  • anticoagulants

hemophilia

• congenital gene defects result in impaired production of clotting factors VII and IX

vitamin K deficiency

• vit K= responsible for activating CF

• unavailable to power the enzymatic rxns that lead to fibrin production

causes of vit K deficiencies

• deficit in diet

• prolonged antibiotic use (disruption of intestinal microbiome)

• fat malabsorption

• liver disease

liver disease

• diminished production of clotting factors and platelets → impaired fibrin formation and thrombocytopenia

anticoagulants

• warfarin

  • inhibits activity of vitamin K

• direct oral anticoagulation (DOACs)

  • inhibit clotting factor activity

• heparin

  • inactivates clotting factors

types of clots

• thrombus

• embolus

thrombus

• stationary clot attached to vessel wall

• may grow large and cause obstruction

• ex. DVT

embolus

• detached thrombus that travels through blood vessel

• may occlude smaller vessel downstream causing acute ischemia

• ex. embolic stroke or PE

what helps prevent clots from forming when they shoudlnt?

• blood flow

• protein C- inhibits activation of CF

• thrombomodulin- activates protein C

virchow triad of hypercoagulability

increased risk of clotting

• vascular endothelial injury: lose heparin and thrombomodulin

• hypercoagulable blood: oral contraceptive and infections

• abnormal blood flow (stasis): sedintary

why does vascular endothelial injury promote clotting

• exposure of collagen

• reduction/removal of N2O, heparin, and thrombomodulin

common causes of clotting due to endothelial injury

• vascular catheter

• surgery

• smoking

• systemic inflammation

• trauma

why does abnormal blood flow promote clotting

• stagnant platelets “stick”

common causes for clotting due to abnormal blood flow

• immobility

  • post op state

  • paralysis

  • extended travel

• atrial fibrillation

  • blood pools in atria→ most common in L atria appendage→ increase risk of stroke

why does hypercoagulation of blood promote clotting

• blood is naturally more prone to clots

common causes of clotting due to hypercoagulable blood

• deficiencies in anti-clotting proteins

• mutations in CF that increase their activity

• estrogens (OCPs, pregnancy)

• cancer

• liver and renal dz