Circulatory System – High-Yield Core

Main functions

• Deliver O2 and nutrients absorbed from GIT to tissues
• Remove CO2 via lungs + metabolic wastes via kidneys
• Maintain temperature regulation
• Distribute hormones/regulatory substances

Basic organization

• Blood pumped by heart → closed vascular system
• Left ventricle → arteries → arterioles → capillaries
• Capillaries exchange with interstitial fluid
• Capillaries → venules → veins → right atrium
• Some interstitial fluid enters lymphatics, returning via:
• Thoracic duct
• Right lymphatic duct

→ into venous circulation

Blood movement mechanisms

• Primary: heart pumping
• Additional systemic forward drivers:
• Elastic recoil of arterial walls during diastole
• Skeletal muscle compression of veins during activity
• Negative intrathoracic pressure during inspiration

Resistance regulation

• Blood viscosity contributes minimally
• Major determinant: vessel diameter
• Mainly arterioles

Blood flow control

• Each tissue regulates its own flow via:
• Local chemical signals
• Neural influences
• Humoral factors
• Allows redistribution of flow without affecting total systemic flow

Systemic vs pulmonary

• All blood passes through lungs
• Systemic circulation arranged as parallel circuits

→ enables different organs to receive different flows as needed

Scope of chapter

• Focus on:
• Blood + lymph
• Cells they contain
• Pressure + flow principles of systemic circulation
• Additional topics covered elsewhere:
• Homeostatic flow regulation → Ch 32
• Pulmonary circulation → Ch 34
• Renal circulation → Ch 37
• Immune functions of blood → Ch 3

BLOOD AS A CIRCULATORY FLUID – Exam-Ready Core

• Blood = plasma + cellular elements
• Plasma = protein-rich fluid
• Formed elements = RBCs, WBCs, platelets
• Normal circulating blood volume = ≈ 8% body weight
• = ~5600 mL in 70-kg adult
• Plasma = 55% of blood volume

Bodyfluid compartments

BONE MARROW – High Yield

• Site of formation of:

RBCs + many WBCs + platelets

• Fetal hematopoiesis also in liver + spleen
• Extramedullary hematopoiesis in adults if marrow destroyed/fibrosed
• In children: all bone cavities active
• By age 20: long bone cavities inactive except upper humerus + femur
• Red marrow = active hematopoiesis
• Yellow marrow = inactive, fatty infiltration
• Bone marrow = one of the largest organs (≈ liver size/weight)
• One of the most metabolically active tissues

CELL PERCENTAGES + LIFE SPAN LOGIC (Very High-Yield)

• Marrow composition:
• 75% = myeloid WBC precursors
• 25% = RBC precursors
• Reason:
• WBC lifespan short
• RBC lifespan long

→ so marrow must continuously produce more WBCs

HEMATOPOIETIC STEM CELLS (HSCs)

• HSCs = bone marrow stem cells capable of forming all blood cells
• Differentiate → committed progenitor cells
• Separate pools for:
• megakaryocytes
• lymphocytes
• erythrocytes
• eosinophils
• basophils
• neutrophils + monocytes from common precursor
• HSCs also give rise to:
• osteoclasts
• Kupffer cells
• mast cells
• dendritic cells
• Langerhans cells
• HSCs few in number but can completely repopulate marrow after destruction

TOTIPOTENT STEM CELLS + ETHICS (Trimmed but complete)

• HSCs originate from uncommitted totipotent stem cells
• Totipotent cells can form any body cell
• Adults have small number; easier to isolate from embryonic blastocysts
• Major interest for regenerative medicine
• Ongoing ethical debate

WHITE BLOOD CELLS — Core Facts

• Normal count: 4000–11,000 WBC/µL
• Granulocytes (PMNs) = most numerous WBCs
• Young PMNs: horseshoe nucleus
• Older PMNs: multilobed nucleus
• Neutrophils: granules stain neutral
• Eosinophils: granules stain with acidic dyes
• Basophils: granules stain with basic dyes (implied, high-yield)
• Agranulocytes:
• Lymphocytes → large round nucleus + thin rim of cytoplasm
• Monocytes → abundant agranular cytoplasm + kidney-shaped nucleus
• WBC function:
• Work together for immune defense against bacteria, viruses, parasites, tumors

PLATELETS — Exam Essentials

• Small cytoplasmic fragments, no nucleus
• Size: 2–4 µm
• Count: ≈300,000/µL
• Function: aggregate at vascular injury to form platelet plugs
• Half-life: ~4 days
• Source: megakaryocytes in marrow pinch off platelet fragments
• Distribution:
• 60–75% circulating
• Remainder mostly in spleen
• Splenectomy → thrombocytosis (↑ platelet count)

Red Blood Cells, Hemoglobin, Spleen – High-Yield Compression (~80%)

Red Blood Cells (Erythrocytes)

• Carry hemoglobin to transport oxygen.
• Shape = biconcave disks → ↑ surface area + flexibility.
• Produced in bone marrow; lose nuclei before circulation.
• Lifespan ≈ 120 days in humans.
• Counts:
• Men ≈ 5.4 million/µL
• Women ≈ 4.8 million/µL
• Volume fraction of RBCs = hematocrit.
• Size ≈ 7.5 µm diameter, 2 µm thick.
• Each contains ≈ 29 pg hemoglobin.
• Total in adult male ≈ 3 × 10^13 RBCs and ≈ 900 g hemoglobin.
• RBC production (erythropoiesis) regulated by:
• Erythropoietin
• Interleukins IL-1, IL-3, IL-6
• GM-CSF

Role of the Spleen

• Major blood filter.
• Removes aged or abnormal RBCs.
• Detects rigidity → less flexible RBCs can't pass slits in sinusoidal lining.
• Stores platelets.
• Major immune function.

Hemoglobin – Structure & Types

• O2-carrying pigment.
• MW ≈ 64,450.
• 4 subunits: each = heme + globin polypeptide.
• Normal adult Hb: Hemoglobin A = α₂β₂.
• Minor adult Hb:
• HbA₂ = α₂δ₂ (≈2.5%).
• Glycated Hb derivatives exist:
• HbA1c (glucose bound to β chain terminal valine)
• Used clinically to monitor long-term diabetes control.

Reactions / Chemical Behavior of Hemoglobin

Oxygen binding

• Fe²⁺ in heme binds O₂ → forms oxyhemoglobin.
• Affinity affected by:
• pH
• Temperature
• 2,3-BPG concentration in RBCs

Competitive binding

• CO competes strongly w/ O₂:
• Forms carboxyhemoglobin.
• Hemoglobin affinity for CO >> O₂, displacing O₂ → decreased delivery.

Methemoglobin reduction

• Fe³⁺ form = methemoglobin (cannot bind O₂).
• A reduction system converts metHb → Hb.
• Congenital absence → hereditary methemoglobinemia.

Hemoglobin in the fetus + synthesis + catabolism

Fetal Hemoglobin (HbF)

• Normal fetal blood contains HbF.
• Structure: α₂γ₂ (γ replaces β chains of adult HbA).
• γ chain differs from β by 37 amino acids.
• Normally replaced by HbA soon after birth.
• In some individuals, HbF persists lifelong.
• HbF binds 2,3-BPG less strongly → higher O₂ affinity.
• Therefore ↑ O₂ content at same PO₂ vs adult Hb.
• Function: facilitates O₂ transfer from mother → fetus, especially late gestation when fetal O₂ demand ↑.
• Early embryonic hemoglobins:
• Gower I: ζ₂ε₂
• Gower II: α₂ε₂
• Hemoglobin switching is regulated by oxygen availability:
• Hypoxia → favors HbF production via
• ↑ erythropoietin
• direct effects on globin gene expression

Hemoglobin Synthesis

• Normal blood Hb content: 16 g/dL (male), 14 g/dL (female).
• Total Hb in a 70-kg man: ~900 g.
• About 0.3 g Hb destroyed + 0.3 g synthesized per hour.
• Heme synthesized from glycine + succinyl-CoA.

Hemoglobin Catabolism

• Aged RBCs removed by tissue macrophages.
• Hb → globin + heme.
• Heme → biliverdin via heme oxygenase.
• Produces CO (gas signaling molecule like NO).
• Biliverdin → bilirubin, excreted in bile.
• Iron is recycled for new Hb synthesis.
• White light converts bilirubin → lumirubin, shorter half-life.
• Basis of phototherapy for neonatal jaundice (hemolysis).
• Iron essential for Hb synthesis; blood loss → iron deficiency anemia unless replaced.

Red Cell Fragility – High-Yield Clinical Core

Concept

• RBCs shrink in hypertonic solutions.
• In hypotonic solutions they swell → become spherical → eventually rupture (hemolysis).
• Free hemoglobin released → plasma becomes red.

Normal osmotic fragility values

• Isotonic plasma = 0.9% NaCl
• Hemolysis begins: ~0.5% saline
• 50% hemolysis: 0.40–0.42%
• Complete hemolysis: ~0.35%

Hereditary spherocytosis

• RBCs are spherocytic at baseline → hemolyze more easily in hypotonic solution.
• Also trapped + destroyed in spleen → common cause of hereditary hemolytic anemia.
• Cause: mutations in RBC membrane skeleton proteins, including:
• spectrin
• band 3
• ankyrin
• These proteins normally maintain membrane shape + flexibility → defects increase osmotic fragility.

Other causes of hemolysis

• Drugs: penicillin, sulfa drugs
• Infections
• ↑ risk when G6PD deficient.
• G6PD deficiency ↓ NADPH (from hexose monophosphate pathway).
• NADPH required to maintain RBC membrane stability.
• Severe deficiency: impaired neutrophil bacterial killing → ↑ infection risk.

Therapeutic points

• Severe hereditary spherocytosis: splenectomy (but ↑ sepsis risk).
• Mild cases: folate supplementation ± transfusions.
• Other hemolytic anemias: treat underlying cause.
• Autoimmune forms may respond to corticosteroids.

Blood Types & ABO – High-Yield Summary

Blood group antigens = agglutinogens

• Located on RBC membranes.
• Many exist; most important = A & B antigens.

ABO System – Genetics + Antigens

• A & B antigens inherited as Mendelian dominants.
• 4 major types:
• A → A antigen
• B → B antigen
• AB → both A & B
• O → neither

Antigen biochemistry

• A and B = complex oligosaccharides differing in terminal sugar.
• H gene → codes for fucose transferase → makes H antigen (base structure).
• Enzymes add sugars to H antigen:
• Type A → enzyme adds N-acetyl-galactosamine
• Type B → enzyme adds galactose
• AB → both enzymes
• O → no enzyme → H persists

Agglutinins (naturally occurring antibodies)

• Exposure to bacterial/food antigens → newborn develops antibodies against missing antigen.
• Patterns:
• A → anti-B
• B → anti-A
• O → anti-A + anti-B
• AB → none
• Mixing mismatched blood → antibodies bind incompatible RBCs → agglutination.

Blood typing

• Mix patient RBCs with known antisera and observe agglutination.

Transfusion Reactions

• Occur when recipient antibodies attack donor RBC antigens.
• Donor plasma rarely causes agglutination (diluted in recipient).

Mechanism

• RBCs agglutinate → hemolysis → free Hb ↑ → complications:
• Mild bilirubin rise
• Severe jaundice
• Renal tubular damage → anuria → death

Compatibility Concepts

• Universal recipient = AB (no agglutinins in plasma)
• Universal donor = O (no antigens on RBCs)

⚠ Still must cross-match because:

• Other blood group systems exist
• Sensitization/transfusion reaction possible

Cross matching

• Mix donor RBCs + recipient plasma and check for agglutination.
• Also advisable to check donor plasma vs recipient cells.

Autologous transfusion

• Withdraw patient’s own blood before elective surgery
• With iron, 1000–1500 mL withdrawn over ~3 weeks
• Benefits:
• Avoid disease transmission
• No risk of incompatibility reaction

Clinical Box – Abnormal Hemoglobin Production

Two major inherited disorders

1. Hemoglobinopathies
• Abnormal globin chains produced.
2. Thalassemias
• Chains structurally normal
• But reduced/absent synthesis due to regulatory gene defects.

1000 abnormal hemoglobins identified in humans.

Hemoglobin S – key example

• α chains = normal
• β chains = valine replaces glutamic acid at one position.
• Causes sickle cell anemia.

Inheritance pattern

• Heterozygous (AS) → ~50% abnormal Hb + 50% normal.
• Homozygous (SS) → all Hb abnormal.
• Possible to inherit two different abnormal hemoglobins from parents.

Population genetics

• Harmful mutations usually disappear.
• Mutations with survival advantage persist/spread.
• Many abnormal hemoglobins harmless; others → abnormal O₂ binding or anemia.

Sickle mechanism

• Low O₂ → HbS polymerizes → RBCs sickle → hemolysis + vaso-occlusion.

Selective advantage

• HbS gene common because heterozygosity protects against malaria.
• Origin: Africa.
• Prevalence:
• ~40% heterozygous in some African regions
• ~10% in African Americans

Therapy Highlights

• Hemoglobin F inhibits HbS polymerization.
• Hydroxyurea ↑ HbF production → major benefit in sickle disease.
• Hematopoietic stem cell transplant: benefit in severe cases.
• Prophylactic antibiotics helpful.

Thalassemia treatment

• Severe anemia → repeated transfusions
• Risks: iron overload → need iron chelation drugs
• Stem cell transplant also being explored.

ABO & Rh – High-Yield 80% Notes (gives 100% result)

ABO inheritance

• A and B are dominant alleles; O is recessive
• Genes follow Mendelian inheritance
• Possible alleles: A, B, O
• Genotypes and phenotypes:
• AA or AO → type A
• BB or BO → type B
• AB → type AB (codominance)
• OO → type O

Type B parent examples

• Parent with type B may be:
• BB (homozygous)
• BO (heterozygous)
• If both parents are type B, possible child genotypes:
• BB
• BO
• OO (only if both parents are BO)

Paternity inference

• Blood typing can:
• exclude a man from being father
• cannot confirm fatherhood
• More precise when other antigen systems also tested
• DNA fingerprinting → exclusion rate ≈ 100%

Other blood group antigens (non-ABO)

• Major systems besides ABO:
• Rh, MNS, Lutheran, Kell, Kidd, many others
• Antigen polymorphism extremely high
• Total possible phenotypes → hundreds of billions+
• Evolutionary significance unknown

Rh system

• Next most clinically important after ABO
• Based on antigens: C, D, E
• D antigen most immunogenic = key determinant
• Rh-positive → has antigen D
• Rh-negative → lacks antigen D and can make anti-D antibodies
• Anti-D development requires exposure to D-positive RBCs:
• prior transfusion
• fetomaternal hemorrhage (pregnancy)
• Once sensitised → risk of hemolytic transfusion reaction if given Rh+ blood
• Population:
• Whites → 85% Rh+, 15% Rh–
• Asians → >99% Rh+

HEMOLYTIC DISEASE OF THE NEWBORN (Rh) – High-Yield 80% Notes

Why it happens

• Mother = Rh-negative
• Fetus = Rh-positive
• Fetal RBCs enter maternal blood ⟶ sensitization
• Mother makes anti-D IgG antibodies
• In next pregnancy, anti-D crosses placenta ⟶ hemolysis in fetus/newborn

How sensitization occurs

• Usually at delivery
• Can occur during pregnancy via fetomaternal hemorrhage
• Also via Rh-positive transfusions in Rh-negative individuals (≈50% get sensitized)

Effect on fetus/newborn

Hemolysis →

• Fetal anemia
• Severe jaundice (↑ unconjugated bilirubin)
• Hydrops fetalis (generalized edema)
• Kernicterus → bilirubin deposition in basal ganglia
• BBB more permeable in infants
• Bilirubin conjugation immature

Severe cases → in-utero death possible.

First pregnancy usually safe because

• Sensitization develops postpartum, so fetus not yet exposed

Risk in subsequent pregnancies

• ≈17% of Rh-positive fetuses from sensitized Rh-negative mothers develop disease

Prevention

• Give Rh immune globulin (anti-D Ig) postpartum to Rh-negative mother who delivered Rh-positive infant
• Passive anti-D prevents maternal active antibody formation
• Reduces disease incidence >90%
• Can also give during pregnancy if fetal Rh status known
• Fetal Rh typing possible from amnio or CVS

Plasma – High-Yield Exam Summary (80% length, full results)

What is plasma?

• Liquid portion of blood containing ions + inorganic + organic molecules in transit.
• Normal volume ≈ 5% of body weight

= ~3.5 L in a 70-kg adult.

• Clots on standing unless anticoagulant present.

Plasma vs Serum

• If blood clots and clot removed → fluid = serum.
• Serum composition ≈ plasma minus:
• fibrinogen
• clotting factors II, V, VIII
• Serum has higher serotonin (released from platelets during clotting).

Plasma proteins

Main groups:

1. Albumin
2. Globulins
3. Fibrinogen

Physiologic roles

• Capillaries impermeable to plasma proteins → proteins exert oncotic pressure (~25 mmHg) pulling water into blood.
• Contribute ~15% of blood buffering via weakly ionizable COOH/NH2 groups.
• At physiologic pH (7.40) → mostly negatively charged.
• Some have specific functions: antibodies, coagulation proteins.
• Others act as nonspecific carriers for solutes, drugs, hormones.

Clotting factors – name list

(Must-memorize for OSCE/MCQs)

• I – fibrinogen
• II – prothrombin
• III – thromboplastin
• IV – calcium
• V – proaccelerin (labile factor)
• VII – proconvertin (stable factor)
• VIII – antihemophilic factor A
• IX – Christmas factor (antihemophilic B)
• X – Stuart-Prower factor
• XI – PTA (antihemophilic C)
• XII – Hageman factor
• XIII – fibrin-stabilizing factor
• HMW-K – Fitzgerald factor
• Pre-K – Fletcher factor
• Ka – kallikrein
• PL – platelet phospholipid

Core exam takeaways

• Serum = plasma – clotting proteins.
• Albumin = main contributor to oncotic pressure.
• Clotting factor numbers + names are standard exam recall.
• Plasma proteins help maintain:
• oncotic pressure
• acid–base buffering
• transport of substances

Origin of Plasma Proteins – High-Yield Summary (80% length, full result)

Where plasma proteins come from

• Antibodies → synthesized by lymphocytes / plasma cells.
• Most other plasma proteins → synthesized in the liver.

Albumin – synthesis and turnover

• Normal albumin levels: 3.5–5.0 g/dL.
• Total exchangeable pool: 4–5 g/kg body weight.
• 38–45% intravascular, rest mostly in skin/extravascular
• 6–10% degraded daily.
• Liver synthesizes 200–400 mg/kg/day to replace losses.
• Albumin can cross capillary walls via vesicular transport.
• Synthesis decreases in fasting, increases in nephrosis (compensates for urinary albumin loss).

Hypoproteinemia – key causes and consequences

Plasma protein levels stay normal early in starvation but fall in:

• prolonged starvation
• malabsorption syndromes
• liver disease → ↓ hepatic synthesis
• nephrosis → ↑ urinary protein loss

Effects:

• ↓ plasma oncotic pressure → edema develops.
• Rare congenital deficiencies (example: afibrinogenemia) → defective clotting.

Major liver-synthesized plasma proteins & essential functions (selected high-yield)

Core take-home exam concepts

• Liver = main source of plasma proteins.
• Albumin turnover + regulation tightly controlled.
• Hypoproteinemia → decreased oncotic pressure → edema.
• Nephrosis causes increased hepatic albumin synthesis but still protein loss.
• Congenital absence of clotting proteins → bleeding disorders.

HEMOSTASIS – High-Yield Compression

Definition & Goal

Hemostasis = processes that:

• stop bleeding after vessel injury
• keep blood fluid inside vessels (balance between pro-coag & anti-coag)

Sequence After Vascular Injury

When small vessel damaged → 2 major stages:

1. Immediate vasoconstriction

• reduces blood loss
• may temporarily obliterate lumen
• mediated by substances released from adhered platelets:
• serotonin
• other vasoconstrictors

2. Temporary platelet plug

• platelets bind exposed collagen
• platelet activation + aggregation → loose plug

3. Definitive fibrin clot

• platelet plug reinforced by fibrin meshwork

Clotting Mechanism (Coagulation Cascade)

Key final reaction

Soluble fibrinogen → fibrin

• catalyzed by thrombin
• fibrin monomers polymerize
• cross-linked by:
• activated factor XIII
• requires Ca2+

THROMBIN formation

Prothrombin → thrombin by activated factor X (Xa)

Thrombin actions beyond fibrinogen cleavage:

• activates platelets
• activates endothelial cells + leukocytes
• uses PARs (protease-activated receptors), GPCRs

Activation of Factor X (2 pathways)

Intrinsic Pathway (contact activation)

Triggered by exposure to collagen or glass

Sequence:

• XII → XIIa (activated by HMW kininogen + kallikrein)
• XIIa → XIa
• XIa → IXa
• IXa + VIIIa (released from vWF) + PL + Ca2+ → activates X

Extrinsic Pathway (tissue factor)

Triggered by tissue thromboplastin (TPL / Tissue Factor)

Sequence:

• TPL + VIIa → activates IX + X

Regulation:

• inhibited by tissue factor pathway inhibitor (TFPI) which complexes with:
• TPL
• VIIa
• Xa

Common Pathway Key Points

Activated X + V + PL + Ca2+ →

• converts prothrombin → thrombin

→ thrombin converts fibrinogen → fibrin → cross-linked clot

Essential ideas for exam success

• platelet plug = primary hemostasis
• fibrin clot = secondary hemostasis
• Ca2+ + PL essential for many steps
• VIII requires vWF
• XIII cross-links fibrin
• intrinsic = contact activation
• extrinsic = tissue factor
• both converge at factor X

ANTICLOTTING MECHANISMS – High-Yield 80% Note (full exam effect)

The body prevents unwanted intravascular clotting through anticoagulant + fibrinolytic systems.

1. Platelet regulation balance

• Thromboxane A2 (TXA2) → platelet aggregation (pro-clot)
• Prostacyclin (PGI2) from intact endothelium → inhibits aggregation
• Balance = clot at injury site while lumen stays patent.

2. Antithrombin III (ATIII)

• Circulating serine protease inhibitor
• Inhibits active Factors IXa, Xa, XIa, XIIa
• Heparin accelerates ATIII activity
• Basis of clinical heparin therapy.

3. Thrombomodulin–Protein C system

• Endothelial cells express thrombomodulin
• Thrombin normally activates clotting factors, but when bound:
• Thrombin becomes anticoagulant
• Activates Protein C
• Activated Protein C (APC) + Protein S cofactor
• Inactivate Factors Va, VIIIa
• Inactivate inhibitor of t-PA

→ ↑ plasmin formation.

4. Plasminogen–Plasmin fibrinolytic system

• Plasmin = fibrinolysin
• Breaks down fibrin + fibrinogen → FDPs
• FDPs inhibit thrombin = anti-clot reinforcement.
• Plasmin formed from plasminogen
• Activated by t-PA, u-PA, thrombin
• Bond cleaved to activate plasmin: Arg560–Val561

5. Endothelium surface protection

• Cells express plasminogen receptors
• Bound plasminogen → easier activation
• Maintains clot-resistant vessel walls.

6. Knockout evidence (mice) – high-yield concept

• t-PA OR u-PA knockout: slowed fibrinolysis + mild fibrin deposition
• Both knocked out: extensive spontaneous fibrin deposition

→ proves physiological role of plasminogen activators.

7. Clinical fibrinolytic agents

• Recombinant t-PA → used in MI + stroke
• Streptokinase (bacterial enzyme) → fibrinolytic for early MI

Super-High Yield Takeaways (1-minute recall)

• ATIII inhibits IXa, Xa, XIa, XIIa → accelerated by heparin.
• Thrombin switches to anticoagulant when bound to thrombomodulin.
• APC + Protein S shut down Va + VIIIa + remove t-PA inhibition.
• Plasmin breaks fibrin + generates FDPs which inhibit thrombin.
• Endothelium = anticoagulant surface via PGI2 + thrombomodulin + t-PA.
• Recombinant t-PA/streptokinase dissolve clots clinically.

CLINICAL BOX – Abnormalities of Hemostasis

1. Bleeding disorders – due to clotting factor problems

• Selective deficiencies of coagulation factors → hemorrhagic disease.
• Hemophilia A = Factor VIII deficiency (most common inherited).
• von Willebrand disease
• ↓ platelet adhesion (vWF normally binds platelets to collagen).
• ↓ plasma factor VIII (vWF stabilises VIII).
• Cause: congenital or acquired defects.
• vWF normally cleaved/inactivated by ADAM-13 metalloprotease, especially in ↑ shear areas.
• Vitamin K deficiency
• ↓ absorption of fat-soluble vitamins (e.g., biliary obstruction, malabsorption).
• ↓ vit-K–dependent clotting factors → bleeding tendency.

2. Thrombosis = intravascular clotting

• Different from physiologic extravascular clot to stop bleeding.
• Risk ↑ when:
• Sluggish blood flow (stasis → accumulation of activated clotting factors).
• Vessel wall damage
• Atherosclerotic plaques.
• Damaged endocardium.
• Can occlude arterial supply to organs.
• Embolization:
• Fragments break off → travel to other organs.
• Classic: pulmonary embolism from leg veins.

3. Inherited hypercoagulable states

• Protein C deficiency
• Uncontrolled coagulation.
• Severe congenital form → fatal in infancy if untreated.
• Activated protein C resistance
• Commonest hereditary thrombophilia.
• Factor V gene point mutation (Factor V Leiden) → APC cannot inactivate factor V.
• Protein S mutation – rare cause of thrombosis.
• Antithrombin III deficiency – also increases thrombotic risk.

4. Disseminated Intravascular Coagulation (DIC)

• Triggered by:
• septicemia
• extensive tissue injury
• other systemic inflammatory states
• Mechanism:
• Widespread fibrin deposition → thrombosis of small/medium vessels.
• Massive consumption of platelets and clotting factors → bleeding + thrombosis simultaneously.
• Cause appears to be ↑ thrombin formation due to ↑ tissue factor (TPL) activity and inadequate inhibitors.

5. Therapeutic highlights

• Hemophilia A:
• replacement of factor VIII (plasma-derived or recombinant).
• von Willebrand disease:
• desmopressin (DDAVP) → stimulates release of factor VIII + vWF
• used prophylactically for dental work/surgery.
• Thrombotic conditions:
• anticoagulants e.g., heparin.

Exam triggers summarised in one breath

Hemophilia A = ↓VIII

vWF disease = ↓vWF + ↓VIII + adhesion defect

Vit K deficiency → ↓ clotting factors

Factor V Leiden = APC resistance → thrombosis

Protein C/S or antithrombin III deficiency → thrombosis

DIC = fibrin deposition + consumption coagulopathy → bleed + clot

Anticoagulants – high-yield exam summary

Heparin

• Natural anticoagulant in the body.
• Works by enhancing antithrombin III, a serine protease inhibitor.
• Antithrombin III inactivates IXa, Xa, XIa, XIIa.
• Unfractionated heparin = shorter half-life, variable response.
• Low-molecular–weight heparins (LMWH):
• longer half-life
• more predictable anticoagulant effect → easier dosing + monitoring

Reversal

• Protamine sulfate (basic protein) binds heparin irreversibly → neutralizes effect.

Calcium removal (in vitro only)

• Ca²⁺ required for multiple coagulation reactions.
• Very low Ca²⁺ in vivo = incompatible with life.
• Clotting can be prevented in vitro by:
• oxalates → form insoluble calcium salts
• chelators (e.g., EDTA) → bind Ca²⁺

Vitamin K antagonists

• Coumarin derivatives: dicumarol, warfarin.
• Mechanism:
• inhibit vitamin K activity in γ-carboxylation
• block conversion of glutamic acid → γ-carboxyglutamic acid residues

Vitamin K–dependent clotting proteins (very high yield)

• II (prothrombin)
• VII
• IX
• X
• Protein C
• Protein S

These factors require vitamin K–dependent γ-carboxylation before secretion into blood.

Exam-critical takeaways (fast recall)

• Heparin = activates antithrombin → works immediately, reversible by protamine.
• LMWH = predictable kinetics + longer half-life.
• Warfarin = blocks vitamin K–dependent carboxylation → slow onset.
• Ca²⁺ removal prevents clotting only outside the body.
• Vitamin K–dependent factors = II, VII, IX, X + C, S.

Clotting factor deficiencies – KEY HIGH-YIELD SUMMARY

These factor deficiencies → bleeding tendency, many congenital.

Factor → Disease → Characteristic cause

• I – Afibrinogenemia
• Absent fibrinogen
• Causes: placental separation consumption; rare congenital
• II – Hypoprothrombinemia
• ↓ prothrombin
• Cause: ↓ hepatic synthesis due to vitamin K deficiency (eg. liver disease, malabsorption)
• V – Parahemophilia
• Congenital
• VII – Hypoconvertinemia
• Congenital
• VIII – Hemophilia A
• X-linked recessive (factor VIII gene defect)
• Most common hemophilia
• IX – Hemophilia B (Christmas disease)
• Congenital
• X-linked recessive
• X – Stuart-Prower deficiency
• Congenital
• XI – PTA deficiency
• Congenital
• XII – Hageman trait
• Congenital
• Usually no bleeding, paradoxical ↑ thrombosis risk (very exam-worthy clinical twist)

Clinical pearl for exams

→ Factors II, VII, IX, X are vitamin-K dependent + synthesized in liver.

LYMPH – High-Yield Summary (80% words, 100% results)

• Definition
• Lymph = tissue fluid that enters lymphatic vessels.
• Drainage pathway
• Ultimately enters venous blood via:
• Thoracic duct
• Right lymphatic duct
• Clotting ability
• Contains clotting factors → can clot on standing in vitro.
• Protein content
• Contains proteins that crossed capillary walls.
• Lower protein than plasma (~7 g/dL plasma).
• Protein content varies by site drained (e.g., liver highest).
• Fat transport
• Water-insoluble fats absorbed from intestine enter lymphatics.
• Thoracic duct lymph becomes milky after a meal due to chylomicrons.
• Lymphocytes
• Enter blood mainly through lymphatic system.
• Thoracic duct lymph has appreciable lymphocyte numbers.

Exam-critical takeaways

• Lymph = tissue fluid → lymphatics → venous return.
• Contains clotting factors + proteins < plasma.
• GI lymph after meals = chyle → milky fat-rich lymph.
• Thoracic duct = major return pathway for lymph + lymphocytes.

If you want, I can extract MCQs from this content or produce a mind map.

Protein content of lymph – KEY PATTERN to memorize

Protein content ↑ as lymph drains organs with high vascular permeability.

Organ → Protein content (g/dL)

• 0 → choroid plexus, ciliary body
• ≈2 → skeletal muscle, skin
• ≈4 → lung, GI tract
• ≈4.4 → heart
• ≈6.2 (highest physiologic) → liver

Why liver highest?

→ sinusoidal capillaries highly permeable → large proteins enter lymph.

Why choroid plexus/ciliary body minimal protein?

→ blood–aqueous / blood–CSF barriers exclude protein.

Fast exam triggers

• VIII & IX = hemophilias A/B (X-linked).
• Vitamin K deficiency affects II, VII, IX, X → prolonged PT early.
• Hageman XII deficiency → no bleeding but ↑ clotting risk.
• Lymph protein highest in liver, lowest in brain/eye barriers.

Structural Features of the Circulation – High-Yield Summary

1. Endothelium

• Single cell layer lining blood vessels; interface between blood + vessel wall.
• Large endocrine/paracrine organ.
• Responds to:
• Shear flow
• Stretch
• Circulating substances
• Inflammatory mediators
• Secretes:
• Vasoactive substances
• Growth factors/regulators
• Helps maintain vascular tone, thrombosis balance, permeability.

2. Vascular Smooth Muscle (VSM)

• In media of vessel wall.
• Key role: regulate blood pressure + vascular tone.
• Membrane ion channels: K+, Ca2+, Cl−.
• Contraction: myosin light chain (MLC) phosphorylation pathway.
• Can undergo prolonged contraction = maintains tone.
• Latch-bridge mechanism contributes to sustained contraction.

Ca2+ dynamics in VSM

• Voltage-gated Ca2+ influx → global Ca2+ ↑ → contraction.
• Ca2+ entry triggers ryanodine-mediated SR Ca2+ release → Ca2+ sparks.
• Local Ca2+ sparks activate BK (big potassium) Ca2+-activated K+ channels → ↑ K+ efflux → membrane hyperpolarizes → closes voltage Ca2+ channels → relaxation.
• β1 subunit of BK channel crucial for Ca2+ spark sensitivity.

Knockout → ↑ vascular tone + hypertension.

3. Arteries & Arterioles

• Vessel wall layers:
• Intima = endothelium + connective tissue.
• Media = smooth muscle.
• Adventitia = connective tissue.
• Large elastic arteries (aorta):
• Elastic laminas allow stretch in systole & recoil in diastole.
• Arterioles:
• Less elastic tissue, more smooth muscle.
• Innervation:
• Sympathetic (noradrenergic) → constrict.
• Some cholinergic → dilate.
• Major determinant of total peripheral resistance (TPR).

→ Small radius change → large resistance change.

4. Capillaries

• Arterioles → metarterioles → capillaries.
• Precapillary sphincters present upstream.
• Main function: exchange of gases, nutrients, waste.
• Endothelial gaps/pores vary:
• Liver sinusoids gaps 600–3000 nm → proteins pass → hepatic role.
• Permeability varies by organ (hydraulic conductivity).

5. Pericytes (capillary + postcapillary venules)

• Contractile cells around endothelium.
• Release vasoactive substances.
• Produce basement membrane + ECM constituents.
• Regulate junctional flow, especially in inflammation.
• Related to mesangial cells of kidney glomerulus.

One-glance exam triggers 💯

• Endothelium = active organ, not passive lining.
• Arterioles = resistance vessels → TPR control.
• BK channels activated by Ca2+ sparks → relaxation.
• Large elastic arteries → elastic recoil → diastolic flow.
• Pericytes regulate endothelial permeability + inflammation.
• β1-subunit knockout → ↑ vascular tone + hypertension.

High-Yield Structural Features – Lymphatics, Veins & Angiogenesis

LYMPHATICS – Core facts

• Function: return excess filtered plasma + proteins from interstitium → venous circulation.
• Drainage path: lymph vessels coalesce → enter right/left subclavian veins at junctions with internal jugular veins.
• Contain valves; pass through lymph nodes.
• Ultrastructure differences from blood capillaries:
• No endothelial fenestrations
• Little/no basal lamina
• Open intercellular junctions (loose, non-tight) → allow fluid/protein entry.
• Clinical relevance: lymphatics prevent edema; lymph obstruction → lymphedema.

ARTERIOVENOUS ANASTOMOSES (A-V shunts)

• Location: fingers, palms, ear lobes.
• Structure: short, thick-walled muscular channels directly connecting arterioles → venules.
• Innervated intensely by sympathetic vasoconstrictors.
• Function: bypass capillaries; important for thermoregulation in skin.

VENULES & VEINS

• Venules: walls only slightly thicker than capillaries.
• Veins:
• Thin-walled, easily distended (high capacitance vessels).
• Little smooth muscle, but can constrict via:
• Sympathetic noradrenergic nerves
• Circulating vasoconstrictors e.g., endothelins.
• Venous tone changes crucial for circulatory regulation + venous return.

Venous valves

• Intima folds forming valves → prevent backflow.
• Present in limb veins.
• Absent in:
• very small veins
• great veins
• veins of brain + viscera.

ANGIOGENESIS

• Definition: new vessel formation required for growth + repair.
• Physiologic roles:
• fetal development + childhood growth
• wound healing
• corpus luteum formation post-ovulation
• re-growth of endometrium post-menses
• Pathologic role:
• tumor growth depends on angiogenesis.

Vasculogenesis vs angiogenesis

• Vasculogenesis:
• embryonic formation of primitive leaky capillaries from angioblasts.
• Angiogenesis:
• branching of new vessels from preexisting vessels.

Regulation

• Key factor: VEGF (vascular endothelial growth factor).
• multiple isoforms; receptors are tyrosine kinases.
• work with co-receptors neuropilins.
• Major role in vasculogenesis; other factors regulate budding/maturation.
• Lymphangiogenesis also regulated by certain VEGF isoforms → formation of lymphatic vessels.

Clinical significance

• Tumors cannot grow without angiogenesis.
• VEGF antagonists / anti-angiogenic drugs now widely used in oncology.

Rapid exam triggers 💯

• Lymphatics → open endothelial junctions + almost no basal lamina.
• Drain into subclavian → internal jugular junctions.
• A-V shunts in digits/ears → thermoregulation, sympathetically controlled.
• Veins = high capacitance; venoconstriction controlled by sympathetic nerves.
• Valves absent in brain/viscera/great veins.
• VEGF = key driver; required for tumors → target for cancer therapy.
• Vasculogenesis from angioblasts; angiogenesis from preexisting vessels.

Circulatory Physiology — Biophysical Core

FLOW, PRESSURE, RESISTANCE

• Blood moves from high → low pressure (except brief inertia-driven movement).
• Exact analogy to electrical Ohm relationship:

Flow = Pressure difference / Resistance

• Effective perfusion pressure = arterial mean − venous mean.
• Resistance units: normally dyne·s/cm5, sometimes simplified to "R units":

Example: mean aortic pressure = 90 mmHg, cardiac output = 90 mL/s → R = 1 unit.

MEASURING BLOOD FLOW

Main clinical techniques:

• Doppler (velocity measurement via frequency shift).
• Indicator dilution/Fick applications:
• Kety N2O for cerebral flow.
• PAH clearance for renal flow.
• Venous occlusion plethysmography
• occlude venous return → rising limb volume proportional to arterial inflow.

APPLYING PHYSICAL PRINCIPLES

• Blood is not an ideal fluid and vessels are not rigid tubes.
• But physical laws still help explain trends and limits.

LAMINAR VS TURBULENT FLOW

• Laminar: velocity profile highest in center, zero at vessel wall.
• Turbulence risk increases with velocity and pipe diameter; decreases with viscosity.
• Reynolds number (Re):

Re = (density × diameter × velocity) / viscosity

• Re < 2000: laminar
• Re > 3000: turbulent
• Turbulence occurs distal to stenosis → bruits/Korotkoff sounds.
• Branching points → disturbed flow → ↑ risk of atherosclerotic plaque formation.

SHEAR STRESS

• Endothelial wall stress = viscosity × (velocity gradient).
• Altered shear triggers endothelial gene expression:
• growth factors, integrins, signaling proteins.
• Primary cilia + ion channels + cytoskeleton act as mechanosensors.

VELOCITY VS FLOW

Flow = area × velocity

Velocity = flow ÷ cross-sectional area

Velocity trends:

• Fastest: aorta
• Slowest: capillaries (very large total area)
• Speeds up again toward vena cava

Clinical measure: arm-to-tongue circulation time ≈ 15 seconds.

POISEUILLE-HAGEN RELATIONSHIPS

Flow proportional to:

• pressure difference
• radius⁴

Flow inversely proportional to:

• viscosity
• tube length

Resistance = (8 × viscosity × length) ÷ radius⁴

Small radius changes → huge resistance changes:

• +19% radius doubles flow
• radius doubled → resistance falls to ~6% original

Arteriolar constriction/dilation is the dominant regulator of total peripheral resistance and organ perfusion.

VISCOSITY

Determinants:

• hematocrit
• plasma composition
• RBC deformability

Important effects:

• Fahraeus-Lindqvist phenomenon in small vessels (<100 µm):
• RBCs migrate centrally → plasma near wall → effective viscosity ↓
• hematocrit changes minimally alter resistance unless extreme

Clinical:

• Polycythemia → ↑ viscosity → heart workload ↑
• Severe anemia → viscosity ↓ → resistance ↓ → somewhat compensates for reduced O2 carrying capacity
• Paraproteinemias & rigid RBCs → viscosity increases markedly.

CRITICAL CLOSING PRESSURE

• Vessel collapses when internal pressure falls below surrounding tissue pressure.
• Explains why flow stops before pressure reaches zero.
• Occurs in resting tissue where precapillary sphincters/metarterioles are constricted.

LAW OF LAPLACE

Wall tension = pressure × radius ÷ wall thickness

Key implications:

• Small radius → low wall tension → capillaries safe despite thin walls.
• Dilated cardiac chambers need more tension to generate pressure → heart failure worsens.
• Alveoli need surfactant to prevent collapse as radius shrinks (expiration).
• Applies also to bladder and other hollow organs.

RESISTANCE VS CAPACITANCE VESSELS

• Veins: major blood reservoir → capacitance vessels
• partially collapsed → large volume increase causes little pressure rise
• Small arteries + arterioles: major resistance vessels.

Resting blood volume distribution:

• ~50% systemic veins
• 18% pulmonary circulation
• 12% heart chambers
• Arterioles: 1%
• Capillaries: 5%
• Arteries: 8%
• Aorta: 2%

Transfusion distribution:

• <1% enters arterial high-pressure system
• majority enters veins + pulmonary + non-LV heart chambers (low-pressure system)

High-Yield Arterial & Arteriolar Circulation — 80% Version

1. Velocity & Flow

• Aortic mean velocity ≈ 40 cm/s
• Systolic velocity peak ≈ 120 cm/s
• Brief reverse flow just before aortic valve closure
• Elastic recoil during diastole → continuous forward flow
• Flow delivered non-pulsatile → ↑ inflammatory markers, ↑ resistance, ↓ perfusion (pump experiments)

2. Arterial Pressure

• Typical brachial pressure: 120/70 mmHg
• Pulse pressure = systolic – diastolic
• Mean arterial pressure ≈ DP + 1/3(PP)
• Pressure drop minimal in large arteries
• Major pressure decline in small arteries + arterioles → major peripheral resistance sites
• Mean pressure at end of arterioles ≈ 30–38 mmHg
• Pulse pressure declines to ~5 mmHg by end-arterioles

3. Gravity Effects

• Pressure change = 0.77 mmHg per cm vertical distance
• Example if MAP at heart = 100 mmHg:
• Head at 50 cm above: ≈ 62 mmHg
• Foot at 105 cm below: ≈ 180 mmHg
• Effect applies to venous pressure similarly

4. Pressure measurement principles

• Direct cannula reading: measures end pressure
• Side-arm pressure lower due to kinetic→potential conversion
• Bernoulli law: total energy constant = pressure + kinetic
• Narrowing increases velocity, reduces lateral pressure → stenosis self-maintains

5. Auscultatory method

• Cuff inflated above systolic → artery occluded → silent
• Lower cuff pressure → Korotkoff sounds begin = systolic pressure
• Further lowering → sounds muffled → then disappear
• disappearance = diastolic in most resting adults
• muffling = diastolic in children, post-exercise, hyperthyroidism, AR
• Sounds due to turbulent flow exceeding critical velocity

6. Normal BP control + variation

• BP = cardiac output × peripheral resistance
• Emotions ↑ both → transient BP rise
• 20% hypertensives show white coat elevation
• BP falls up to 20 mmHg during sleep; blunted in HTN
• With age:
• systolic rises lifelong
• diastolic rises then falls when arterial stiffness increases
• pulse pressure therefore ↑ with age

7. Sex differences

• BP lower in young women vs men until ~55–65 years
• Lower pre-menopause blood pressure may contribute to lower CV risk

CAPILLARY CIRCULATION — High-Yield 80% Summary

Why capillaries matter

• Only ≈5% of blood volume is in capillaries at any time.
• But they are the only exchange site for:
• O₂ + nutrients → tissues
• CO₂ + wastes → blood
• Exchange determines tissue survival.

Pressures + Flow

• Typical capillary pressures:
• Arteriolar end ≈ 32 mmHg
• Venular end ≈ 15 mmHg
• Pulse pressure ↓ to ~5 mmHg at arteriolar end, 0 at venous end.
• Blood velocity is very slow (~0.07 cm/s) → ↑ exchange time.
• Transit time through a capillary: 1–2 seconds.

Exchange across the capillary wall

Mechanisms:

1. Diffusion (dominates)
• O₂, glucose diffuse from blood → interstitial fluid
• CO₂ diffuses from tissues → blood
2. Filtration + reabsorption
3. Vesicular transport (minor)

Starling forces rule filtration

Fluid movement formula:

Fluid movement = k [ (Pc – Pi) – (πc – πi) ]

Where:

• Pc = capillary hydrostatic pressure (pushes out)
• Pi = interstitial hydrostatic pressure
• usually –2 mmHg subcutaneously
• positive in liver, kidney
• ≈ +6 mmHg in brain
• πc = plasma colloid osmotic pressure (pulls fluid in)
• πi ≈ negligible normally
• k = capillary filtration coefficient (permeability × surface area)

General rule:

• Arteriolar end: filtration (Pc high → fluid out)
• Venular end: reabsorption (πc dominates → fluid in)

Organ variations:

• Kidney glomerulus → filtration entire length
• Intestine → reabsorption entire length

Total body fluid handling:

• ~24 L/day filtered
• ~85% reabsorbed
• remaining returns via lymphatics

Flow-limited vs diffusion-limited

• If a solute equilibrates near arteriolar end → flow-limited
• If it does NOT equilibrate → diffusion-limited

Active vs inactive capillaries

At rest:

• Many capillaries collapsed
• Low intracapillary pressure

In active tissues:

• Metarterioles + precapillary sphincters dilate
• Vasodilator metabolites cause relaxation → more blood enters

Substances increasing permeability:

• Substance P
• Bradykinin
• Histamine

Mechanical stimulus → precapillary sphincter contraction → vessels empty (white reaction)

Hypertension — 80% core that gives 100% results

Definition + Primary Mechanism

• Sustained ↑ systemic arterial pressure.
• Most commonly from ↑ peripheral resistance.

Pathologic Consequences

• ↑ afterload → LV hypertrophy
• due to activation of early response genes → fetal growth genes
• hypertrophy worsens outcomes
• More muscle → ↑ myocardial O₂ demand
• ↓ coronary flow becomes more dangerous
• smaller vessel narrowing can trigger ischemia
• ↑ risk of:
• atherosclerosis
• MI, even without hypertrophy
• heart failure (compensatory mechanisms fail)
• stroke (thrombosis + hemorrhage)
• chronic kidney disease
• Active BP control prevents HF, CKD, strokes even in mild hypertension.

Types & Causes

Essential Hypertension

• Cause unknown; majority.
• Likely polygenic + environment.
• Treatable, not curable.

Secondary Hypertension

Caused by identifiable physiological derangements:

Renal mechanisms

• ↓ renal blood flow → ↑ renin → ↑ angiotensin → vasoconstriction

Coarctation of aorta

• ↑ peripheral resistance + ↑ renin

Catecholamine excess

• pheochromocytoma secretes NE/E → vasoconstriction, episodic hypertension

Hormonal causes

• Estrogen ↑ angiotensinogen → pill hypertension
• ↑ aldosterone/mineralocorticoids → Na⁺ retention → hypertension
• ↓ renin (negative feedback)

Low-renin hypertension

• 10–15% essential hypertension cases

Monogenic genetic causes (rare but high-yield)

• Glucocorticoid-remediable aldosteronism (GRA)
• ACTH-sensitive aldosterone synthase hybrid gene
• Treat by ↓ ACTH with glucocorticoids
• 11β-hydroxylase deficiency
• ↑ deoxycorticosterone → mineralocorticoid excess → hypertension
• ↓ 11β-hydroxysteroid dehydrogenase
• cortisol & progesterone stimulate mineralocorticoid receptors → Na⁺ retention
• ENaC mutations (Liddle syndrome)
• ↓ ENaC degradation → ↑ Na⁺ reabsorption → volume expansion → hypertension

Therapeutic Principles & Major Drug Classes

Lower BP via ↓ resistance and/or ↓ volume:

• α-blockers
• peripheral or CNS sympatholysis
• β-blockers
• ↓ renin + ↓ cardiac output
• ACE inhibitors
• ↓ angiotensin II formation → vasodilation + ↓ aldosterone
• Calcium channel blockers
• relax vascular smooth muscle → ↓ resistance

VENOUS CIRCULATION – High-Yield Summary (80% words → 100% results)

How venous return works

• Blood flows toward heart mainly by cardiac pump.
• Aided by:
• ↓ intrathoracic pressure during inspiration (thoracic pump)
• skeletal muscle contraction compressing veins (muscle pump)
• venous valves preventing backflow

Venous pressures + gravity

• Venules: 12–18 mmHg
• Great veins outside thorax: ≈5.5 mmHg
• Central venous pressure (CVP at RA): ≈4.6 mmHg, fluctuates with breathing + heart.
• Gravity changes pressure: +0.77 mmHg/cm below RA; −0.77 mmHg/cm above RA.
• Gravity affects veins > arteries.

Venous flow + velocity

• As veins merge → cross-sectional area ↓ → velocity ↑
• In great veins: ≈10 cm/s (≈¼ aortic velocity)

Thoracic Pump

• Inspiration: intrapleural pressure falls from –2.5 to –6 mmHg
• CVP drops from ~6 mmHg → ~2 mmHg
• Diaphragm descent ↑ intra-abdominal pressure = pushes blood upward.

Heartbeat effects

• Atrial pressure waves: a, c, v in venous pulse.
• During systole AV valves pulled down → atrium expands → sucks blood in.
• Two venous flow peaks when rate slow:
• systole (AV valve pull down)
• early diastole (rapid ventricular filling)

Muscle Pump

• Standing: ankle venous pressure 85–90 mmHg
• Rhythmic muscle contractions ↓ it to <30 mmHg
• Prevents pooling + supports venous return.
• Varicose veins: incompetent valves → stasis + ankle edema.

Venous pressure in head

• Upright: pressure above heart ↓ due to gravity.
• Neck veins collapse where pressure ~0.
• Dural sinuses rigid → pressure subatmospheric, may reach –10 mmHg.
• Surgical risk: opened sinus can suck air → air embolism.

Air embolism

• Air compressible → blocks blood flow
• Large volume stops circulation = sudden death
• Small bubbles lodge in vessels → ↑ resistance + ischemia
• Brain emboli → severe neuro injury
• Treatment: hyperbaric oxygen ↓ bubble size
• Lethal amount varies: ~5–100 mL

Measuring venous pressure

• Direct: catheter into great veins → CVP.
• Peripheral venous pressure ≈ CVP + distance from heart.
• Arm/antecubital mean:
• Central veins: 4.6 mmHg
• Antecubital vein: 7.1 mmHg
• Saline manometer: convert blood mm to mmHg by ÷13.6
• Jugular venous distension height estimates CVP.

Factors altering CVP

↓ CVP

• negative-pressure breathing
• shock

↑ CVP

• positive-pressure breathing
• straining
• ↑ blood volume
• heart failure
• SVC obstruction (antecubital pressure may reach 20+ mmHg)

LYMPHATIC CIRCULATION & INTERSTITIAL FLUID VOLUME – High-Yield 80% Summary

Lymphatic circulation

• Capillary filtration > reabsorption, excess enters lymphatics → prevents ↑interstitial pressure + maintains fluid turnover.
• Normal lymph flow: 2–4 L/day.
• Initial lymphatics
• No valves, no smooth muscle.
• In muscle, intestine.
• Fluid enters via loose endothelial junctions.
• Fluid propelled by muscle + arteriole/venule pulsations.
• Collecting lymphatics
• Valves + smooth muscle.
• Contract peristaltically → main pumping mechanism.
• Venous suction, skeletal muscle, inspiration help flow.

Other lymphatic functions

• Return escaped proteins:
• Liver/intestine leak most.
• Amount returned/day = 25–50% of total plasma protein pool.
• Transport absorbed long-chain fatty acids + cholesterol from intestine.

Interstitial fluid volume regulation

Depends on:

• capillary pressure
• interstitial pressure
• oncotic pressure gradient
• filtration coefficient
• number of perfused capillaries
• lymph flow
• total ECF volume
• precapillary vs postcapillary resistance
• precapillary constriction ↓filtration
• postcapillary constriction ↑filtration

Edema = abnormal ↑ interstitial fluid volume.

Mechanisms ↑ interstitial fluid volume / edema formation

(see Table 31-12)

1. ↑ Filtration pressure

• ↑ venous pressure: heart failure, venous obstruction, incompetent valves, ↑ECF volume, gravity dependent limbs
• Venular constriction

2. ↓ Oncotic pressure gradient

• ↓ plasma proteins (cirrhosis ↓ synthesis; nephrosis loss in urine)
• Osmotically active metabolites accumulate in active tissues.

3. ↑ Capillary permeability

• Histamine
• Kinins
• Substance P

4. Inadequate lymph flow

• Lymphatic obstruction → lymphedema (high protein fluid)
• Chronic → fibrosis.
• Causes:
• radical mastectomy (axillary node removal)
• filariasis (worms obstruct lymphatics → elephantiasis)

Functional examples

• Active muscle:
• capillary pressure ↑ beyond oncotic level along whole capillary
• metabolite accumulation ↓ oncotic gradient

→ ↑ filtration → muscle swelling ≈25% despite ↑ lymph flow

• Dependent edema:
• standing still / long travel
• muscle pump absent → venous pressure transmitted to capillaries

→ dependent edema, esp. ankles

• Salt/water retention:
• ↑ECF → ↑ interstitial volume → edema risk
• occurs in: HF (↑ venous P), cirrhosis (↓ protein synthesis → ↓ oncotic P), nephrosis (protein loss)