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Topic Overview

Plasma Proteins :

Serum Electrophoretic Pattern — Normal & Abnormal

(All points grounded in the retrieved text)

Normal Pattern

Serum proteins separate into 5 major fractions on agar electrophoresis:
Albumin → α1 → α2 → β → γ
(Albumin has the maximum mobility, γ-globulins have minimum mobility)
Gamma globulins contain immunoglobulins (antibodies).
α1 mainly contains α1-antitrypsin.
α2 mainly contains α2-macroglobulin.
β contains LDL.

Abnormal Electrophoretic Patterns

Chronic infections: smooth, wide-based γ-globulin increase.
Multiple myeloma: sharp M-spike due to monoclonal immunoglobulins.
Plasma (instead of serum): Fibrinogen forms a prominent band in γ region (may mimic M-band).
Primary immune deficiency: reduced γ-globulin fraction.
Nephrotic syndrome: massive loss of small proteins → prominent α2 band (macroglobulin retained).
Cirrhosis: low albumin, wide β band; β–γ bridging.
CLL: reduced γ-globulins.
α1-antitrypsin deficiency: thin or missing α1 band.

Albumin

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Major plasma protein; synthesized in liver.
Single polypeptide chain; molecular weight ~69,000 Da.
Present in CSF and interstitial fluid because it can leave circulation.
Half-life: ~20 days; liver synthesizes ~12 g/day (25% of hepatic protein synthesis).
Important functions:
- Maintains oncotic pressure
- Transports numerous substances (fatty acids, bilirubin, drugs, Ca²⁺, hormones).

Transport Proteins (Carrier Proteins)

(Based on Table 28.1)

Major Transport Proteins & Their Functions

Albumin: transports fatty acids, bilirubin, calcium, drugs like aspirin, sulphonamides.
Prealbumin (Transthyretin): transports steroid hormones, thyroxine, retinol.
Short half-life (1 day).
Retinol Binding Protein (RBP): transports vitamin A; indicator of protein turnover.
Thyroxine Binding Globulin (TBG): transports T3, T4.
Transcortin (CBG): transports cortisol and corticosterone; increased in pregnancy.
Haptoglobin: binds free hemoglobin; low in hemolysis; acute phase protein.
Transferrin: transports iron; prevents iron loss.
Hemopexin: binds free heme; prevents iron loss.
HDL / LDL: lipoprotein carriers for cholesterol & lipids.

Polymorphism

(Grounded in PDF)

A protein shows different phenotypes in a population; only one form seen in each person.
Seen in:
- Haptoglobin (Hp1-1, Hp2-1, Hp2-2)
- Transferrin
- Ceruloplasmin
- α1-Antitrypsin
- Immunoglobulins
Useful for genetic and anthropological studies.

Acute Phase Proteins

Levels increase 50–1000 fold during inflammation, infection, trauma, neoplasia.
Synthesized mainly by the liver under cytokine stimulation (IL-6, IL-1, TNF-α).
Rise early in inflammation and fall early during recovery.

Major Acute Phase Proteins

C-Reactive Protein (CRP)
Ceruloplasmin
Haptoglobin
Fibrinogen
α1-Antitrypsin
Complement proteins

C-Reactive Protein (CRP)

Named for its reaction with C-polysaccharide of pneumococci.
A β-globulin, molecular weight 115–140 kDa.
Synthesized in the liver.
Activates complement and enhances phagocytosis.
Rises rapidly and falls rapidly (faster response than ESR).
High-sensitivity CRP correlates with coronary artery disease risk.

Ceruloplasmin

A blue-colored α2-globulin containing 6–8 copper atoms per molecule.
Molecular weight ~160 kDa.
Synthesized mainly in the liver; copper incorporated during intracellular processing.
Plasma half-life: 4–5 days.

Functions

Acts as ferroxidase (oxidizes Fe²⁺ → Fe³⁺ for transferrin binding).
Major antioxidant in plasma.
Carries 90% of plasma copper (rest loosely bound to albumin).

Decreased Levels

Wilson’s disease
Malnutrition
Nephrotic syndrome
Cirrhosis

Increased Levels

Active hepatitis
Biliary cirrhosis
Pregnancy
Estrogen therapy
Obstructive biliary disease
Inflammatory states and malignancy

Alpha-1-Antitrypsin (A1AT)

Major component of the α1-globulin fraction.
A protease inhibitor, especially against neutrophil elastase.

Electrophoresis Finding

In A1AT deficiency → thin or absent α1 band.

Clinical Importance

Deficiency causes:
- Early-onset emphysema/COPD (due to unchecked elastase activity).
- Cholestatic liver disease/cirrhosis (due to A1AT accumulation in hepatocytes).
It is also an acute phase protein, so levels may rise in inflammation.

Alpha-2-Macroglobulin (A2M)

A major protein component of the α2-globulin fraction.
Very large molecular weight (~725 kDa), hence cannot pass the glomerular filter easily.

Functions

Acts as a pan-protease inhibitor: inhibits trypsin, chymotrypsin, plasmin, kallikrein.
Binds and inactivates proteases by trapping them inside its structure.
Transports cytokines and growth factors.
Helps in immune modulation and inflammation control.

In Electrophoresis

Produces a prominent α2 band because of large size.
In nephrotic syndrome, smaller proteins are lost in urine, but A2M is retained →
α2 band becomes markedly increased.

Clinical Significance

Increased in:
- Nephrotic syndrome (classic)
- Diabetes mellitus
- Hyperestrogenic states (pregnancy, estrogen therapy)
Decreased in:
- Acute pancreatitis
- Severe liver disease

Negative Acute Phase Proteins

(Proteins whose levels decrease during inflammation)

During inflammation, the liver shifts toward synthesis of positive acute phase proteins, causing a drop in the synthesis of certain normal plasma proteins. These are called negative acute phase proteins.

Major Negative Acute Phase Proteins

Albumin
- Falls because liver prioritizes acute phase proteins.
- Also decreases due to increased capillary leakage.
Prealbumin (Transthyretin)
- Sensitive indicator of nutritional status.
- Drops rapidly in inflammation.
Transferrin
- Decreases because iron sequestration reduces iron transport.
- Helps reduce availability of iron to pathogens.
Retinol Binding Protein (RBP)
- Decreases in inflammation and malnutrition.
Apolipoproteins (A-I, A-II)
- Mild decrease.

Clinical Utility

Helps differentiate acute inflammation from chronic states.
Low albumin + high CRP indicates acute phase response.
Prealbumin & transferrin reductions help monitor malnutrition vs inflammation.

Clotting Factors (Coagulation Factors)

There are 13 factors, mostly made in the liver. Many require vitamin K for synthesis (II, VII, IX, X).

List of Clotting Factors

Factor I – Fibrinogen
Factor II – Prothrombin
Factor III – Tissue factor (Thromboplastin)
Factor IV – Calcium (Ca²⁺)
Factor V – Proaccelerin
Factor VII – Proconvertin
Factor VIII – Antihemophilic factor A
Factor IX – Christmas factor / AHF B
Factor X – Stuart–Prower factor
Factor XI – Plasma thromboplastin antecedent
Factor XII – Hageman factor
Factor XIII – Fibrin-stabilizing factor

Coagulation Pathways

Intrinsic pathway: XII → XI → IX → VIII
Extrinsic pathway: Tissue factor (III) + VII
Both converge on common pathway: X → V → Prothrombin → Thrombin → Fibrinogen → Fibrin → XIII (crosslinking)

Vitamin K–dependent factors

II, VII, IX, X + Protein C & Protein S

Anticoagulants

Substances that prevent clot formation in vitro or in vivo.

Natural Anticoagulants

Heparin
- Enhances antithrombin III → inactivates IIa (thrombin), Xa, IXa.
Antithrombin III
- Inhibits thrombin and factors IXa, Xa, XIa, XIIa.
Protein C
- Vitamin K–dependent; activated by thrombin–thrombomodulin complex.
Protein S
- Cofactor for Protein C.
TFPI (Tissue factor pathway inhibitor)
- Inhibits tissue factor–VIIa complex.

Clinical Anticoagulants

Heparin
- Immediate effect.
- Monitored by aPTT.
Warfarin
- Inhibits vitamin K recycling.
- Affects II, VII, IX, X.
- Monitored by PT/INR.
Direct Oral Anticoagulants (DOACs)
- Dabigatran (IIa inhibitor), Rivaroxaban/Apixaban (Xa inhibitors).

In Vitro Anticoagulants

EDTA – binds calcium
Citrate – binds calcium (used in coagulation studies)
Oxalate – precipitates calcium
Heparin – used for arterial blood gas samples

Fibrinolysis

Process that breaks down fibrin clots.

Key Components

Plasminogen – inactive precursor
Plasmin – active fibrinolytic enzyme
Converts fibrin into Fibrin Degradation Products (FDPs), including D-dimer.

Activation of Plasminogen

tPA (tissue plasminogen activator) – endothelial origin
Urokinase
Factor XIIa

Inhibitors of Fibrinolysis

α2-antiplasmin – inhibits plasmin
PAI-1 – inhibits tPA and urokinase

Clinical Use

Elevated D-dimer → DIC, thrombosis, pulmonary embolism.
Thrombolytic drugs:
- Streptokinase
- Alteplase (tPA)
- Tenecteplase (TNK)

Hemophilia

Hemophilia A

Deficiency of Factor VIII.
Most common inherited coagulation disorder.
X-linked recessive.
Prolonged aPTT, normal PT & platelet count.
Clinical:
- Hemarthrosis
- Deep muscle bleeds
- Prolonged bleeding after injury

Hemophilia B

Deficiency of Factor IX (Christmas disease).
X-linked recessive.
Similar presentation to hemophilia A.

Hemophilia C

Factor XI deficiency, autosomal recessive.
Mild bleeding tendency.

Diagnosis

Prolonged aPTT
Mixing test corrects aPTT
Specific factor assays confirm diagnosis

Treatment

Factor VIII/IX concentrates
Desmopressin (DDAVP) for mild Hemophilia A (releases stored Factor VIII & vWF)
Avoid intramuscular injections & NSAIDs

Important Points to Remember — Plasma Proteins

Plasma proteins are synthesized mainly in the liver, except immunoglobulins, which are formed by plasma cells.
Serum electrophoresis shows 5 major bands:
Albumin → α1 → α2 → β → γ
Albumin has the highest mobility and contributes most to oncotic pressure.
Gamma globulin fraction contains immunoglobulins (IgG, IgA, IgM, IgD, IgE).
Nephrotic syndrome shows ↓ albumin, ↓ α1, ↓ γ, and marked ↑ α2 (due to α2-macroglobulin retention).
Cirrhosis shows β–γ bridging due to increased IgA.
Multiple myeloma shows a sharp M-band in γ region.
Albumin transports fatty acids, bilirubin, Ca²⁺, drugs; low albumin occurs in liver disease, nephrotic syndrome, malnutrition.
Prealbumin (transthyretin) is a sensitive marker of protein-energy malnutrition.
Transferrin is a negative acute phase protein; ↑ in iron deficiency anemia.
Haptoglobin decreases in hemolysis due to binding hemoglobin.
Ceruloplasmin contains 6–8 copper atoms; low in Wilson’s disease.
C-Reactive Protein (CRP) rises rapidly in inflammation; high-sensitivity CRP predicts coronary artery disease risk.
Alpha-1-antitrypsin (A1AT) is a protease inhibitor; deficiency causes early-onset emphysema.
Alpha-2-macroglobulin is massively increased in nephrotic syndrome (cannot be filtered due to large size).
Negative acute phase proteins: albumin, prealbumin, transferrin, RBP.
Clotting factors: II, VII, IX, X are vitamin K–dependent.
Factor VIII deficiency→ Hemophilia A, X-linked recessive.
Fibrinolysis is mediated by plasmin, activated by tPA, urokinase, streptokinase.
D-dimer increases when fibrin is degraded → used to detect thrombosis & DIC.

FAQs — Plasma Proteins (Viva-oriented)

1. What are the major fractions seen on serum electrophoresis?

Albumin, α1, α2, β, γ.

2. Which fraction is largest in normal serum?

Albumin (50–60% of total proteins).

3. What causes α1 band to disappear?

Alpha-1-antitrypsin deficiency.

4. What causes a marked increase in α2 band?

Nephrotic syndrome (retention of α2-macroglobulin).

5. What is β–γ bridging and where is it seen?

Fusion of β and γ region; seen in cirrhosis.

6. Which condition shows an M-spike on electrophoresis?

Multiple myeloma.

7. Name the major transport proteins in plasma.

Albumin, prealbumin, RBP, TBG, CBG, transferrin, hemopexin.

8. What is the function of haptoglobin?

Binds free hemoglobin; ↓ in hemolysis.

9. What is the main function of ceruloplasmin?

Copper transport and ferroxidase activity (Fe²⁺ → Fe³⁺).

10. Where is CRP synthesized and when does it rise?

Synthesized in the liver; rises in acute inflammation.

11. What are negative acute phase proteins?

Proteins that decrease during inflammation—albumin, prealbumin, transferrin, RBP.

12. What is the clinical significance of alpha-1-antitrypsin deficiency?

Causes early-onset emphysema due to unopposed elastase activity.

13. Why is alpha-2-macroglobulin high in nephrotic syndrome?

Large size prevents filtration → accumulates in plasma.

14. Which clotting factors are vitamin K–dependent?

II, VII, IX, X, Protein C, Protein S.

15. What activates plasminogen?

tPA, urokinase, streptokinase.

16. What is elevated in active fibrinolysis?

D-dimer.

17. What is the defect in Hemophilia A?

Factor VIII deficiency, X-linked recessive.

18. What happens to prothrombin time in liver disease?

PT becomes prolonged (liver synthesizes most clotting factors).

19. What is the carrier protein for retinol?

Retinol Binding Protein (RBP).

20. Which protein has the role of anti-oxidant and copper carrier?

Ceruloplasmin.

MCQs — Plasma Proteins

1. The major protein fraction seen on serum electrophoresis is:

A. α1-globulin
B. α2-globulin
C. Albumin
D. γ-globulin
Answer: C

2. A sharp M-band in the γ region suggests:

A. Cirrhosis
B. Nephrotic syndrome
C. Multiple myeloma
D. Hemolytic anemia
Answer: C

3. β–γ bridging in electrophoresis is characteristic of:

A. Acute inflammation
B. Cirrhosis
C. Nephrotic syndrome
D. Primary immune deficiency
Answer: B

4. The α1 region mainly contains:

A. Haptoglobin
B. Ceruloplasmin
C. Alpha-1-antitrypsin
D. Fibrinogen
Answer: C

5. In nephrotic syndrome, the fraction that becomes markedly elevated is:

A. Albumin
B. α1
C. α2
D. γ
Answer: C

6. Which plasma protein transports the highest proportion of copper?

A. Albumin
B. Transferrin
C. Ceruloplasmin
D. Hemopexin
Answer: C

7. Low ceruloplasmin levels are seen in:

A. Wilson’s disease
B. Hemochromatosis
C. Pregnancy
D. Estrogen therapy
Answer: A

8. Which protein rises rapidly and falls rapidly during inflammation?

A. Albumin
B. CRP
C. TBG
D. Transferrin
Answer: B

9. Negative acute phase proteins include:

A. CRP
B. Haptoglobin
C. Albumin
D. Fibrinogen
Answer: C

10. Alpha-2-macroglobulin is typically increased in:

A. Liver cirrhosis
B. Hemolytic anemia
C. Nephrotic syndrome
D. Multiple myeloma
Answer: C

11. Retinol Binding Protein is a transporter of:

A. Vitamin D
B. Vitamin A
C. Thyroxine
D. Cortisol
Answer: B

12. A thin or absent α1 band on electrophoresis indicates:

A. Hypoalbuminemia
B. A1AT deficiency
C. Wilson’s disease
D. IgA deficiency
Answer: B

13. Which is a vitamin K–dependent protein?

A. Fibrinogen
B. Ceruloplasmin
C. Factor VII
D. Factor VIII
Answer: C

14. CRP belongs to which fraction in electrophoresis?

A. Albumin
B. α1
C. β
D. γ
Answer: C

15. The main ferroxidase in plasma is:

A. Transferrin
B. Ceruloplasmin
C. Hemopexin
D. Ferritin
Answer: B

16. Haptoglobin decreases in:

A. Obesity
B. Hemolysis
C. Nephrotic syndrome
D. Hypothyroidism
Answer: B

17. Which of the following increases in pregnancy and estrogen therapy?

A. α1-antitrypsin
B. Transferrin
C. Ceruloplasmin
D. Albumin
Answer: C

18. Factor VIII deficiency leads to:

A. Hemophilia B
B. Hemophilia A
C. Hemophilia C
D. Von Willebrand disease
Answer: B

19. Plasmin breaks down fibrin to produce:

A. Ferritin
B. D-dimer
C. Reticulin
D. Heme
Answer: B

20. Which transport protein binds cortisol?

A. CBG (Transcortin)
B. TBG
C. Albumin
D. Hemopexin
Answer: A

Clinical Case–Based Questions — Plasma Proteins

Case 1 — M-band in γ region

A 58-year-old man presents with bone pain and recurrent infections. Serum electrophoresis shows a sharp M-spike in the γ region.
Q: What is the most likely diagnosis?

Answer: Multiple myeloma
Explanation: Monoclonal Ig production creates a narrow M-band.

Case 2 — β–γ Bridging

A 45-year-old male with long-standing alcoholism shows merging of β and γ bands on electrophoresis.
Q: What condition does this pattern suggest?

Answer: Liver cirrhosis
Explanation: Increased IgA causes β–γ bridging.

Case 3 — Nephrotic pattern

A child presents with pitting edema. Serum electrophoresis shows high α2 band and very low albumin.
Q: What disorder is most likely?

Answer: Nephrotic syndrome
Explanation: Loss of smaller proteins in urine; large α2-macroglobulin is retained → α2 spike.

Case 4 — Thin α1 band

A 20-year-old nonsmoker develops early-onset emphysema. Serum electrophoresis shows absent α1 band.
Q: Which protein is deficient?

Answer: Alpha-1-antitrypsin
Explanation: A1AT deficiency → absent α1 region.

Case 5 — Low ceruloplasmin

A 14-year-old boy presents with tremors and Kayser–Fleischer rings. Lab reports show very low ceruloplasmin.
Q: What is the most likely diagnosis?

Answer: Wilson’s disease
Explanation: Defective copper incorporation → low ceruloplasmin.

Case 6 — Elevated CRP

A 30-year-old woman develops fever and joint swelling. CRP is markedly elevated but ESR is normal.
Q: What does this imply?

Answer: Very early acute inflammation
Explanation: CRP rises before ESR.

Case 7 — High haptoglobin

A patient recovering from intravascular hemolysis shows increasing haptoglobin levels.
Q: What does low haptoglobin indicate during active hemolysis?

Answer: Binding and clearance of free hemoglobin
Explanation: Haptoglobin decreases because it binds Hb-released in hemolysis.

Case 8 — High transferrin

A 28-year-old woman with fatigue shows high transferrin and low ferritin.
Q: What condition is most likely?

Answer: Iron deficiency anemia
Explanation: Transferrin increases to capture more iron.

Case 9 — Copper overload signs absent

A pregnant woman shows high ceruloplasmin, but no neurologic signs.
Q: What explains this elevated ceruloplasmin?

Answer: Physiological rise during pregnancy
Explanation: Estrogen increases ceruloplasmin synthesis.

Case 10 — Elevated α2-globulin without edema

A diabetic patient’s electrophoresis shows mildly elevated α2-macroglobulin but normal albumin.
Q: Why may α2-macroglobulin be elevated in diabetes?

Answer: Compensatory increase due to glycation & inflammation
Explanation: Chronic hyperglycemia increases A2M synthesis.

Case 11 — Severe malnutrition

A child with severe protein-energy malnutrition has very low prealbumin and RBP.
Q: Why are these low?

Answer: Short half-life & rapid fall during malnutrition
Explanation: Prealbumin (2 days) and RBP (12 hours) drop quickly.

Case 12 — Prolonged PT/INR

A patient with jaundice has prolonged PT/INR but normal platelet count.
Q: What major plasma proteins are affected in liver failure?

Answer: Clotting factors (II, VII, IX, X)
Explanation: Liver synthesizes vitamin K–dependent factors → PT prolongs.

Case 13 — D-dimer elevation

A 45-year-old man presents with sudden dyspnea; D-dimer is high.
Q: What does this indicate?

Answer: Active fibrinolysis due to thrombosis/PE
Explanation: Plasmin degrades fibrin → D-dimer formation.

Case 14 — Hemarthrosis in a child

An 8-year-old boy has recurrent joint bleeding. aPTT is prolonged; PT normal.
Q: What is the likely diagnosis?

Answer: Hemophilia A or B
Explanation: Intrinsic pathway factors (VIII or IX) are deficient.

Case 15 — Low albumin, but normal globulins

A 50-year-old patient with chronic liver disease shows very low albumin but normal γ-globulins.
Q: Why are gammaglobulins preserved?

Answer: Produced by plasma cells, not the liver
Explanation: Liver failure reduces albumin but immunoglobulins remain.

Viva Voce — Plasma Proteins (Short Q&A)

1. What is the major plasma protein?

Albumin.

2. Where are most plasma proteins synthesized?

Liver.

3. Which plasma proteins are NOT synthesized in the liver?

Immunoglobulins (made by plasma cells).

4. What is the normal albumin level?

3.5–5.0 g/dL.

5. What is the main function of albumin?

Maintains oncotic pressure and transports many molecules.

6. Which band moves fastest on electrophoresis?

Albumin band.

7. What does β–γ bridging indicate?

Liver cirrhosis.

8. What does an M-band represent?

Monoclonal immunoglobulin (multiple myeloma).

9. Which band contains α1-antitrypsin?

α1-globulin band.

10. Which fraction is markedly increased in nephrotic syndrome?

α2-globulin (due to α2-macroglobulin).

11. What is the function of haptoglobin?

Binds free hemoglobin.

12. Why is haptoglobin low in hemolysis?

It is consumed while binding Hb.

13. What is the function of transferrin?

Iron transport.

14. Which transporter carries vitamin A?

Retinol Binding Protein (RBP).

15. What is the major copper-carrying protein?

Ceruloplasmin.

16. What enzyme activity does ceruloplasmin have?

Ferroxidase activity (Fe²⁺ → Fe³⁺).

17. Low ceruloplasmin is seen in which disease?

Wilson’s disease.

18. Which protein rises rapidly in acute inflammation?

C-Reactive Protein (CRP).

19. Name two negative acute phase proteins.

Albumin, Transferrin.

20. Name two vitamin K–dependent factors.

II and VII (also IX, X).

21. Which factor deficiency causes Hemophilia A?

Factor VIII.

22. Which factor deficiency causes Hemophilia B?

Factor IX.

23. What is the role of plasmin?

Breaks down fibrin → fibrinolysis.

24. What test detects fibrin degradation?

D-dimer test.

25. What activates plasminogen physiologically?

tPA (tissue plasminogen activator).

26. What is the main inhibitor of plasmin?

α2-antiplasmin.

27. What happens to PT in liver failure?

PT is prolonged.

28. Which plasma protein has the shortest half-life?

RBP (12 hours).
Prealbumin is next (~2 days).

29. What causes absent α1 band on electrophoresis?

Alpha-1-antitrypsin deficiency.

30. Why is α2-macroglobulin high in nephrotic syndrome?

Large size → cannot be filtered → accumulates.

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