HEMATOLOGY: BOARDS AND BEYOND

Question 1

Partial Thromboplastin Time (PTT)

Answer 1

Purpose: Measures the intrinsic coagulation pathway.
Procedure:
- Blood sample collected in a tube containing oxalate or citrate (to prevent coagulation).
- Calcium is added to reverse the anticoagulant effect.
- An activator like silica is added to trigger the intrinsic pathway.
- Clotting time is measured after activation.

Question 2

Intrinsic Pathway Activation

Answer 2

• Activator: Silica activates Factor XII, which then activates other coagulation factors.
  Result: This leads to thrombin activation and fibrin formation, completing the clotting process.

Question 3

Atrial Fibrillation and Stroke Risk

Answer 3

Condition: New-onset atrial fibrillation.
Risk Factors: Hypertension and diabetes (increased risk of stroke).
Management: Anticoagulation indicated for stroke prophylaxis.

Question 4

Apixaban and Anticoagulation

Answer 4

Drug: Apixaban is a factor Xa inhibitor.
Mechanism: Blocks factor Xa, preventing the conversion of prothrombin to thrombin, limiting clot formation.
Class: Novel Oral Anticoagulants (NOACs), also includes dabigatran (direct thrombin inhibitor).
Use: Alternatives to warfarin for prevention of clots in conditions like deep venous thrombosis, pulmonary embolus, and atrial fibrillation.

Question 5

Thrombin and Factor XIII Activation

Answer 5

Thrombin activates factor XIII in a proteolytic reaction using calcium as a cofactor.
Activated factor XIII cross-links fibrin, forming a stable clot.

Question 6

Factor XIII Deficiency

Answer 6

Condition: Factor XIII deficiency (genetic, rare).
Prevalence: More common in Iran due to high rates of consanguinity.

Question 7

Alpha-2 Antiplasmin Function

Answer 7

• Alpha-2 antiplasmin is a serine protease inhibitor that suppresses plasmin activity.
• Excess plasmin activity causes increased fibrinolysis, leading to breakdown of fibrinogen into fibrin degradation products.

Question 8

Clinical Presentation of Alpha-2 Antiplasmin Deficiency

Answer 8

Condition: Alpha-2 antiplasmin deficiency (rare congenital bleeding disorder).
Symptoms: Prolonged bleeding after trauma, mimicking hemophilia.

Question 9

Acquired Causes of Alpha-2 Antiplasmin Deficiency

Answer 9

Acquired causes:
- Nephrotic syndrome
- Amyloidosis
- Cirrhosis
- Disseminated intravascular coagulation (DIC).

Question 10

Patients on warfarin therapy require regular monitoring of their INR (international normalized ratio), a standardized representation of the prothrombin time (PT). Prothrombin time represents the extrinsic clotting cascade which starts with activation of factor VII and then triggers the production of Xa, thrombin, and ultimately fibrin..

Answer 10

Warfarin is a vitamin K antagonist which decreases the synthesis of clotting factors II, VII, IX, X, protein C and protein S. As a result, the PT/INR increases. Inhibition of shared intrinsic/extrinsic pathway factors (e.g., factor X) results in elevation of the PTT as well

Question 11

Mechanism of Thrombocytopenia in Chronic Liver Disease

Answer 11

• Cause 1: Decreased thrombopoietin production by the liver, which normally stimulates megakaryocyte growth and platelet production.
• Cause 2: Portal hypertension due to cirrhosis leads to hepatosplenomegaly, causing the spleen to sequester platelets, lowering the circulating platelet count.

Question 12

Coagulation Disorders in Cirrhosis

Answer 12

Cirrhosis causes decreased production of clotting factors, leading to:
- Coagulation disorders
- Thrombocytopenia
This combination results in increased bleeding risk.

Question 13

Platelet Adhesion and Disorders

Answer 13

Normal Platelet Adhesion: Requires activation by subendothelial collagen, which leads to platelet adhesion to the sub-endothelium. This process involves glycoprotein Ib.
Disorders:
- Mutations in vWF or GPIb cause abnormal platelet adhesion.
- This results in superficial bleeding, bruising, and epistaxis (nosebleeds).

Question 14

Stable Angina and Treatment in CAD

Answer 14

Condition: Stable Angina – a form of coronary artery disease (CAD) characterized by chest pain due to reduced blood flow to the heart muscle.
Chronic CAD Treatment:
Aspirin: Reduces risk of myocardial infarction by inhibiting cyclooxygenase (COX) in platelets, which decreases thromboxane A2 production (a platelet activator).
Statins (e.g., atorvastatin, rosuvastatin): Lower cholesterol levels and stabilize atherosclerotic plaques, reducing risk of plaque rupture and thrombus formation.

Question 15

Heparin-Induced Thrombocytopenia (HIT) - Type II

Answer 15

Condition: Type II Heparin-Induced Thrombocytopenia (HIT)
Occurs when antibodies form against the platelet factor 4-heparin complex, leading to platelet activation and consumption.
- Results in thrombocytopenia and risk of arterial/venous thrombosis.
Diagnostic Criteria for HIT:
>50% reduction in platelet count from baseline.
Onset >5 days after starting heparin.
Presence of arterial or venous thrombosis.
No other apparent cause for thrombocytopenia.

Question 16

Factor V Leiden Mutation and Hypercoagulability

Answer 16

Condition: Factor V Leiden Mutation
Most common genetic cause of hypercoagulability.
- Mutation makes factor V resistant to inactivation by protein C, prolonging its half-life and increasing clotting activity.
- Clinical Presentation:
Recurrent thromboses, especially in young patients without clear risk factors (e.g., estrogen use or malignancy).
- Key Evaluation:
Test for genetic hypercoagulability in young patients with unexplained thrombotic events.

Question 17

Homocystinuria

Answer 17

Cause: Deficiency of cystathionine beta-synthase enzyme, leading to accumulation of homocysteine in blood and urine.
Clinical Features:
- Marfanoid habitus: Tall, thin build with long limbs, knock knees, and chest wall abnormalities; no fibrillin gene mutations (unlike Marfan syndrome).
- Neurologic: Intellectual disability and seizures.
- Ophthalmologic: Downward lens dislocation (distinct from the upward dislocation in Marfan syndrome).
- Thrombosis and atheroma: High homocysteine levels increase risk of early atheroma formation and arterial/venous thrombosis (e.g., stroke).

Question 18

Contraception in Smokers Over 35

Answer 18

Risk: Combination oral contraceptives (estrogen-progestin) significantly increase the risk of venous thromboembolism (VTE) in women over 35 years old who smoke more than 15 cigarettes per day, due to estrogen-induced increased production of coagulation factors.
CDC Recommendation: Avoid estrogen-progestin contraceptives in this group.
Alternative Options:
- Progestin-only contraceptives (e.g., norethindrone acetate).
- Intrauterine devices (IUDs).
- Permanent sterilization (tubal ligation).

Question 19

Antithrombin Deficiency and Heparin Resistance

Answer 19

• Condition: Antithrombin deficiency leads to hypercoagulability and resistance to unfractionated heparin.
• Mechanism: Unfractionated heparin increases the activity of antithrombin III, which inhibits clotting factors. In antithrombin deficiency, heparin is ineffective because antithrombin levels are too low or the protein cannot properly bind to heparin.
• Diagnostic Sign: Lack of PTT elevation in response to heparin despite adequate dosing.
• Cause: Most commonly due to a genetic mutation that affects antithrombin’s ability to bind heparin.

Question 20

Antiphospholipid Syndrome and Lupus Anticoagulant

Answer 20

• Condition: Antiphospholipid Syndrome (APS) is associated with recurrent miscarriages and thromboembolism (DVT, arterial or venous).
• Key Marker: Lupus anticoagulant - an antibody that binds phospholipids, causing prolonged PTT and increasing thrombotic risk.
• Lab Test: Prolonged PTT that does not correct with a mixing study suggests a coagulation inhibitor like lupus anticoagulant, rather than a clotting factor deficiency.
• Diagnosis: Requires clinical evidence of thrombosis or fetal loss plus positive lab tests for antiphospholipid antibodies (e.g., lupus anticoagulant, anti-cardiolipin, or anti-β2-glycoprotein antibodies).
  Misleading Name: Despite the name, lupus anticoagulant is prothrombotic.

Question 21

Hemophilia A Genetics and Inheritance

Answer 21

• Condition: Hemophilia A is an X-linked recessive disorder caused by factor VIII deficiency. Primarily affects males.
  Inheritance Risk:
  Male with hemophilia + unaffected female:
  Daughter: Carrier, not symptomatic (inherits one abnormal X from father and one normal X from mother).
  Son: Unaffected (inherits X from mother and Y from father).
  Overall child risk: Extremely low (<1%) unless the mother is a carrier.
  Carrier Symptoms: Female carriers (one abnormal X) may have mild bleeding tendencies but do not experience the severe phenotype seen in males.
  Rare Event: If the mother is not a carrier, the chance of a child with hemophilia is essentially 0%.

Question 22

Coagulopathy and Factor VIII Inhibitors

Answer 22

Condition: Factor VIII inhibitors, a rare cause of coagulopathy, are associated with:
- Prolonged partial thromboplastin time (PTT).
- Normal prothrombin time (PT).
Mechanism: Antibodies inhibit factor VIII, impairing clotting.
Diagnosis:
- Mixing study:
Factor deficiency: PTT normalizes after mixing with normal plasma.
Inhibitor: PTT remains prolonged after mixing.
Clinical Associations:
- Often seen in patients with autoimmune diseases.
- Symptoms include excessive bleeding.
Differential Diagnosis: Factor inhibitors must be differentiated from hemophilia or vitamin K deficiency, which show correction in mixing studies.

Question 23

Desmopressin in Hemophilia A

Answer 23

Condition: Hemophilia A (factor VIII deficiency).
Mechanism of Desmopressin:
- Analog of antidiuretic hormone (ADH) without vasopressor activity.
Acts on V2 receptors in:
- Kidneys: Promotes free water reabsorption.
- Endothelial cells: Stimulates release of von Willebrand factor (vWF) and factor VIII from Weibel-Palade bodies.
- Increases factor VIII and vWF, improving bleeding in mild hemophilia A and von Willebrand disease.
Limitations:
- Only effective in quantitative factor VIII deficiencies (decreased levels).
- Ineffective for qualitative abnormalities (dysfunctional factor VIII).
Uses:
- Treating mild hemophilia A.
- Managing bleeding in von Willebrand disease.

Question 24

Warfarin and Stroke Prevention in Atrial Fibrillation

Answer 24

Indication: Atrial fibrillation with elevated embolic stroke risk.
Mechanism:
- Warfarin is a vitamin K antagonist, inhibiting synthesis of:
- Clotting factors: II, VII, IX, X.
- Anticoagulant proteins: C and S.
- Decreases factor VII (extrinsic pathway), prolonging prothrombin time (PT) and increasing INR.
Target INR:
- 2-3 to minimize stroke risk while avoiding excessive bleeding.
Alternatives: - Novel oral anticoagulants (NOACs):
- Direct thrombin inhibitors.
- Factor Xa inhibitors.

Question 25

Disseminated Intravascular Coagulation (DIC) – Pathophysiology

Answer 25

Key Mechanism:
- Over-activation of coagulation → thrombin activation → fibrinogen to fibrin conversion → widespread clot formation.
- Clotting factor consumption → simultaneous bleeding.
Triggers:
- Sepsis, trauma, malignancy.
- Sepsis mechanism: Inflammatory mediators (IL-1, TNF, endotoxin) → tissue factor release → coagulation cascade activation.

Question 26

DIC vs. Warfarin Effect

Answer 26

DIC:
- Consumption of all clotting factors, including fibrinogen → low fibrinogen is a hallmark.
Warfarin:
- Vitamin K antagonist → decreased production of factors II, VII, IX, X.
- No effect on fibrinogen.

Question 27

Hallmarks of DIC

Answer 27

Bleeding and Clotting:
- Combination of thrombosis and bleeding tendencies.
Key Lab Finding:
- Low fibrinogen indicates extensive coagulation factor consumption.