PATHO– Hematologic Disorders: RBC Disorders 🧬 – IRAT 8 (Part 2-Secondary Homeostasis )

🩸 Secondary Hemostasis Flashcards:

What is the main function of secondary hemostasis?

To stabilize the weak platelet plug through the coagulation cascade.

What does the coagulation cascade generate to stabilize the platelet plug?

Thrombin, which converts fibrinogen → fibrin to form a stable platelet–fibrin thrombus.

Where are coagulation factors produced and in what form?

In the liver, in an inactive state.

What three things are required to activate the coagulation cascade?

1. Exposure to activating substance

2. Phospholipid surface of platelets

3. Calcium

What activates the extrinsic pathway of secondary hemostasis?

Tissue thromboplastin, which activates factor VII.

What activates the intrinsic pathway of secondary hemostasis?

Subendothelial collagen, which activates factor XII.

What are the 6 main disorders of secondary hemostasis?

1. Hemophilia A

2. Hemophilia B

3. Coagulation factor inhibitor

4. Von Willebrand disease

5. Vitamin K deficiency

6. Disseminated intravascular coagulation (DIC)

What are the typical clinical features of secondary hemostasis disorders?

1. Deep tissue bleeding (muscles, joints → hemarthrosis).

2. Rebleeding after surgery.

3. Bleeding due to coagulation factor abnormalities.

🔴Lab: 
What does Prothrombin Time (PT) measure?

The extrinsic pathway → factor VII and common pathway (factors II, V, X, fibrinogen).

🔴Lab: What does Partial Thromboplastin Time (PTT) measure?

The intrinsic pathway → factors XII, XI, IX, VIII and common pathway.

What type of bleeding pattern is characteristic of secondary hemostasis disorders?

Deep tissue and delayed bleeding, not mucocutaneous.

What is Hemophilia A?

A genetic disorder causing Factor VIII (8) deficiency → a secondary hemostasis disorder affecting the coagulation cascade.

What is the inheritance pattern of Hemophilia A?

X-linked recessive, seen primarily in males 👦 — but can also arise de novo

🩸 Which clotting factor is deficient in Hemophilia A?

Factor VIII (deficiency → impaired intrinsic pathway).

Which coagulation pathway is affected in Hemophilia A, and how is it tested?

The intrinsic pathway, assessed by ↑ PTT ⏱;

PT (N)

How does Factor VIII deficiency cause bleeding?

It causes impaired secondary hemostasis, preventing stabilization of the initial weak platelet plug 🩹 → defective fibrin clot formation.

What are the hallmark clinical features of Hemophilia A?

• Deep tissue bleeding into muscles & joints (hemarthrosis) 🦵

• Rebleeding after surgery or trauma 🩺

• Severity depends on the degree of Factor VIII deficiency

What are the key lab findings in Hemophilia A?

• PTT → Increased (intrinsic pathway affected)

• PT → Normal (extrinsic pathway intact)

• Factor VIII → Decreased

• Platelet Count → Normal

• Bleeding Time → Normal

What is Hemophilia B?

A genetic disorder of secondary hemostasis → caused by a deficiency of coagulation Factor IX (Christmas disease).

What is the inheritance pattern of Hemophilia B?

X-linked recessive → usually affects males 👦, females are typically carriers 👩‍🦰.

What is the pathophysiology of Hemophilia B?

A:

• Factor IX deficiency → impaired intrinsic pathway.

• ↓ activation of Factor X → ↓ thrombin → ↓ fibrin formation.

• Results in unstable clots and deep bleeding.

🧪What are the key lab results in Hemophilia B?

• PTT → Increased (intrinsic pathway)

• PT → Normal (extrinsic pathway)

• Factor IX → Decreased

• Platelet count → Normal

• Bleeding time → Normal

What are the main clinical features of Hemophilia B?

• Deep tissue bleeding → muscles, joints (hemarthrosis 🦵)

• Rebleeding after surgery/trauma

• Prolonged bleeding after minor injuries

• Severity → depends on Factor IX activity

  • Mild 5–40 %, Moderate 1–5 %, Severe < 1 %

🧫How is Hemophilia B diagnosed?

• ↑ PTT, normal PT, low Factor IX.

• Mixing study → PTT corrects (normal plasma adds missing factor).

💊How is Hemophilia B managed?

• Factor IX concentrate replacement (prophylactic or on-demand).

• Desmopressin (DDAVP) → not effective (works only for Hemophilia A).

• Avoid aspirin / NSAIDs 🚫.

• Gene therapy 🧬 under investigation.

Clinical Case 1: A 9-year-old boy has recurrent painful knee swelling after minor falls. Labs: ↑ PTT, normal PT, low Factor IX.

→ Diagnosis: Hemophilia B
→ Mechanism: Intrinsic pathway defect (Factor IX deficiency) → impaired coagulation cascade → hemarthrosis and deep bleeding.

Clinical Case 2: A 25-year-old man bleeds excessively after a tooth extraction. PT normal, PTT prolonged. His father and uncle have similar history.

A:
→ Diagnosis: Hemophilia B
→ Deficient factor: Factor IX
→ Inheritance: X-linked recessive

Compare the 2 treatment options for Hemophilia A and B.

Treatment

Hemophilila A: Factor VIII ± DDAVP

Hemophilia B: Factor IX (replacement only)

Von Willebrand Disease (vWD)- What is Von Willebrand Disease (vWD)?

A genetic deficiency or defect of von Willebrand Factor (vWF) — the most common inherited coagulation disorder.

Why is vWD considered a disorder of both primary and secondary hemostasis?

• Primary: vWF mediates platelet adhesion to subendothelial collagen.

• Secondary: vWF stabilizes Factor VIII, so its deficiency can also prolong PTT.

What is the role of vWF in primary hemostasis?

• Binds to exposed collagen at injury sites.

• Links platelets via the GPIb receptor → platelet adhesion.

• Low vWF → impaired platelet adhesion → mucosal bleeding.

What is the role of vWF in secondary hemostasis?

A:

• Stabilizes Factor VIII and prevents its rapid degradation.

• ↓ vWF → ↓ Factor VIII half-life → ↑ PTT (intrinsic pathway).

What are the typical clinical features of vWD?

• Mild mucosal bleeding: epistaxis (nosebleeds), menorrhagia (heavy periods), gum bleeding.

• Skin bleeding: easy bruising, petechiae (less common).

• Occasional deep bleeding: hemarthrosis (less frequent than in hemophilia).

What are the key lab findings in vWD?

A:

• ↑ Bleeding time (defective platelet adhesion)

• ↑ PTT (↓ Factor VIII stability)

• Normal PT

• Normal platelet count

What tests help diagnose vWD?

• vWF antigen level (quantitative)

• Ristocetin cofactor activity (tests platelet aggregation via vWF–GPIb)

• Factor VIII assay

How is vWD treated?

• Desmopressin (DDAVP): increases release of vWF and Factor VIII from endothelial cells.

• vWF concentrates for severe cases.

• Avoid aspirin/NSAIDs (increase bleeding risk).

Clinical Case 1: A 17-year-old girl reports frequent nosebleeds and heavy menstrual periods. Labs show ↑ PTT, ↑ bleeding time, normal PT and platelet count.

A:
→ Diagnosis: Von Willebrand Disease
→ Mechanism: ↓ vWF → defective platelet adhesion + ↓ Factor VIII stability.

Clinical Case 2: A 25-year-old man has prolonged bleeding after dental extraction. PTT is slightly prolonged, PT normal. Ristocetin test shows decreased platelet aggregation.

A:
→ Diagnosis: Von Willebrand Disease
→ Confirmatory test: Ristocetin cofactor assay.
→ Treatment: Desmopressin (DDAVP).

📊 Flashcard 11 – Quick Comparison

Feature	vWD	Hemophilia A	Hemophilia B
Deficient Factor	vWF (affects VIII)	VIII	IX
Hemostasis Type	Primary & Secondary	Secondary	Secondary
PTT	↑	↑	↑
PT	Normal	Normal	Normal
Bleeding Time	↑	Normal	Normal
Bleeding Pattern	Mucosal + mild deep	Deep/joint	Deep/joint
Treatment	DDAVP, vWF conc.	Factor VIII, DDAVP	Factor IX

A 12-year-old boy presents to the emergency department with severe, spontaneous bleeding into his knee

joint (hemarthrosis). He has a known history of a genetic bleeding disorder.

Lab results show:

• Bleeding Time: Normal

• PT: Normal

• PTT: Increased

Which of the following is the most likely diagnosis?

a) Immune Thrombocytopenia (ITP)

b) Von Willebrand Disease

c) Hemophilia A

d) Glanzmann Thrombasthenia

✅ Answer: c) Hemophilia A

Vitamin K Deficiency 🧬💊

What is Vitamin K deficiency?

A condition causing significant bleeding due to a lack of vitamin K–dependent coagulation factors, impairing the liver’s ability to produce functional clotting proteins.

What is the main function of vitamin K in coagulation?

Vitamin K is required for gamma-carboxylation of glutamate residues on clotting factors → allows calcium binding and activation of:
Factors II, VII, IX, X and Proteins C & S.

How does the liver activate vitamin K?

• The liver converts oxidized vitamin K → reduced vitamin K using the enzyme epoxide reductase.
  Activated vitamin K then gamma-carboxylates coagulation factors, making them functional.

What happens when vitamin K is deficient?

• Liver still produces coagulation factors, but they remain inactive (uncarboxylated).

• This causes ↓ activation of Factors II, VII, IX, X and Proteins C & S → impaired clot formation → bleeding.

Which coagulation pathways are affected by vitamin K deficiency?

Both the extrinsic (Factor VII) and intrinsic (Factor IX) pathways, as well as the common pathway, are affected.

What are the key lab findings in Vitamin K deficiency?

• PT → Increased (extrinsic/common pathway)

• PTT → Increased (intrinsic/common pathway)

• Bleeding Time → Normal

• Platelet Count → Normal

What type of bleeding occurs in vitamin K deficiency?

Deep tissue bleeding (e.g., muscle or joint hemorrhage, post-surgical bleeding) — a secondary hemostasis pattern.

What kind of bleeding occurs in Vitamin K deficiency?

Deep tissue bleeding (muscles, joints, surgical sites) — characteristic of secondary hemostasis disorders.

Which populations are at greatest risk for Vitamin K deficiency?

• Newborns 👶: lack GI flora that synthesize vitamin K.

• Patients on long-term antibiotics 💊: antibiotics kill gut bacteria → ↓ vitamin K production.

• Patients with malabsorption 🌿: decreased fat-soluble vitamin absorption (A, D, E, K).

Pathophysiology Summary:
What happens when the liver can’t activate vitamin K?

↓ Vitamin K → ↓ gamma-carboxylation → inactive Factors II, VII, IX, X → ↓ thrombin → ↓ fibrin → unstable clot and bleeding.

Why do antibiotics or malabsorption cause vitamin K deficiency?

• Antibiotics kill intestinal bacteria → ↓ endogenous vitamin K.

• Malabsorption of fats → ↓ absorption of fat-soluble vitamins, including vitamin K.

What type of bleeding occurs in vitamin K deficiency?

• Significant bleeding due to loss of multiple clotting factors.

• Deep tissue bleeding (muscles, joints, surgical sites) typical of secondary hemostasis disorders.

Which coagulation factors are affected in vitamin K deficiency?

Factors II, VII, IX, X and Proteins C & S (vitamin K–dependent factors).

What are the lab findings in vitamin K deficiency?

• PT → Increased (extrinsic/common pathway)

• PTT → Increased (intrinsic/common pathway)

• Bleeding time → Normal

• Platelet count → Normal

Why are both PT and PTT increased in vitamin K deficiency?

Because both the intrinsic and extrinsic pathways are affected through loss of vitamin K–dependent clotting factors.

Quick Summary Table: 

Feature	Vitamin K Deficiency
Affected Factors	II, VII, IX, X, Proteins C & S
PT	↑ (extrinsic/common)
PTT	↑ (intrinsic/common)
Bleeding Time	Normal
Platelets	Normal
Bleeding Pattern	Deep tissue bleeding
At-Risk Groups	Newborns, antibiotic use, malabsorption

Clinical Case:
A 65-year-old man on prolonged antibiotic therapy develops easy bruising and prolonged bleeding after venipuncture. Labs show ↑ PT and ↑ PTT with normal platelets.

→ Diagnosis: Vitamin K Deficiency
→ Mechanism: Antibiotics destroyed gut flora → ↓ vitamin K → ↓ activation of Factors II, VII, IX, X.

Newborn Case: A 3-day-old newborn develops bleeding from the umbilical stump. PT and PTT are both elevated.

→ Diagnosis: Hemorrhagic disease of the newborn (Vitamin K deficiency).
→ Prevention: Administer vitamin K injection at birth.

A patient presents with prolonged bleeding after surgery. The patient is malnourished and has been on long-term broad-spectrum antibiotics. Which of the following is the expected finding on coagulation tests?

✅ Answer: D. Both PT and PTT are increased

Heparin-Induced Thrombocytopenia (HIT) 🩸
What is Heparin-Induced Thrombocytopenia (HIT)?

A condition where platelet activation and destruction occur secondary to heparin therapy, leading to thrombocytopenia and thrombosis.

Pathophysiology Step 1:
What is the initial immune reaction in HIT?

• Heparin binds to Platelet Factor 4 (PF4) → forms a PF4–heparin complex.

• The immune system makes IgG antibodies against this complex → forms immune complexes.

Pathophysiology Step 2:
What happens when the immune complex forms in HIT?

The IgG–PF4–heparin complex binds to Fc receptors on platelets, causing:

• Platelet activation and aggregation → thrombosis

• Platelet destruction by splenic macrophages → thrombocytopenia

What are the two major clinical outcomes of HIT?

• Thrombocytopenia → due to platelet destruction

• Thrombosis → due to platelet activation and release of procoagulant microparticles

Mechanism Summary

Summarize the mechanism of HIT.

Heparin → binds PF4 → immune complex (PF4–heparin–IgG) → activates platelets via Fc receptor → causes both bleeding (↓ platelets) and clotting (↑ activation).

Lab Findings: 

What are the lab findings in HIT?

• Platelet count → Decreased (thrombocytopenia)

• PT/PTT → Normal or mildly prolonged
  (depends on clotting factor consumption or secondary effects)

What are the key clinical features of HIT?

• Bleeding (due to thrombocytopenia)

• Thrombosis (paradoxical — due to platelet activation)

• May lead to DVT, PE, or limb ischemia.

When does HIT typically occur after starting heparin therapy?

Usually 5–10 days after heparin exposure (time needed to form antibodies).

Diagnosis: How is HIT diagnosed?

• Clinical suspicion (↓ platelets after heparin)

• Confirm with anti-PF4 antibody assay or serotonin release assay.

How is HIT treated?

1. Stop all heparin immediately.

2. Start a non-heparin anticoagulant (e.g., argatroban, fondaparinux).

1. Do NOT give warfarin until platelets recover (risk of skin necrosis).

Clinical Case
A 58-year-old patient on heparin for DVT develops a drop in platelet count from 250,000 → 90,000 after 7 days. Despite thrombocytopenia, he develops a new DVT.

→ Diagnosis: Heparin-Induced Thrombocytopenia
→ Mechanism: IgG antibodies against PF4–heparin complex activate platelets → thrombosis + thrombocytopenia.

What is Disseminated Intravascular Coagulation (DIC)?

A pathologic, widespread activation of the coagulation cascade, leading to microthrombi formation and consumption of platelets and clotting factors → causes bleeding and thrombosis simultaneously.
It is secondary to another disease process.

What happens in the pathophysiology of DIC?

• Widespread activation of coagulation → microthrombi form in small vessels.

• Causes ischemia and infarction in tissues.

• Consumption of platelets & coagulation factors → leads to paradoxical bleeding (consumptive coagulopathy).

Dual Process: What are the two major complications of DIC?

• Thrombosis → ischemia, organ failure.

• Bleeding → mucosal bleeding, IV site oozing, petechiae.

Common Causes (Etiology)

Q: What are the major causes of DIC?

1. Obstetric complications – tissue thromboplastin from amniotic fluid.

2. Sepsis – endotoxins & cytokines (TNF, IL-1) induce tissue factor.

3. Adenocarcinoma – mucin activates coagulation.

4. Acute promyelocytic leukemia (APL) – primary granules activate clotting.

5. Rattlesnake venom – directly activates coagulation.

Mnemonic for DIC Causes

Q: What is the mnemonic for DIC causes?

“STOP Making Trouble”

• S – Sepsis / Snake bites 🐍

• T – Trauma

• O – Obstetric complications

• P – Pancreatitis

• M – Malignancy (especially APL, adenocarcinoma)

• T – Transfusion

🧪What are the laboratory findings in DIC?

1. Platelet count → Decreased (thrombocytopenia)

2. PT/PTT → Increased (consumption of clotting factors)

3. Fibrinogen → Decreased (used up)

4. Fibrin split products (D-dimer) → Increased (fibrinolysis marker)

5. Microangiopathic hemolytic anemia → schistocytes on smear (RBCs sheared by microthrombi).

What is the best screening test for DIC?

D-dimer test → Elevated
→ Indicates fibrin breakdown and ongoing clot formation & dissolution.

Treatment Overview: How is DIC managed?

• Treat underlying cause (e.g., infection, malignancy).

• Supportive care:

  • Transfuse platelets and fresh frozen plasma (FFP) if bleeding.

  • Cryoprecipitate if fibrinogen is very low.

  • Heparin may be used in cases with predominant thrombosis.

A 35-year-old woman develops profuse bleeding during childbirth. Labs show ↓ platelets, ↑ PT/PTT, ↓ fibrinogen, ↑ D-dimer, and schistocytes on smear.

→ Diagnosis: Disseminated Intravascular Coagulation (DIC)
→ Likely cause: obstetric complication (amniotic fluid embolism).

🧩 Quick Recall Tips

• 🩸 DIC: ↑ PT/PTT, ↑ D-dimer, ↓ fibrinogen

• 🧠 TTP: neuro + normal PT/PTT

• 🧺 HUS: renal + normal PT/PTT

X

Thrombosis & Virchow’s Triad 🩸🧬
What is thrombosis?

The pathologic formation of a blood clot (thrombus) within the intact vascular system, leading to obstruction of blood flow and potential tissue ischemia or infarction.

What are the main causes/risk factors for thrombosis?

1. Protein C and S deficiency

2. Factor V Leiden mutation

3. Antithrombin III deficiency

4. Estrogen effects (oral contraceptives, pregnancy)

What are the three major risk factors for thrombosis (Virchow’s Triad)?

1. Disruption of blood flow

2. Endothelial cell damage

3. Hypercoagulable state

How does disruption of blood flow cause thrombosis?

1. Stasis or turbulence → prevents normal laminar flow → platelets & clotting factors contact endothelium → ↑ thrombosis risk.

2. Normally: blood flow keeps platelets dispersed and inactive.

3. Examples: immobilization, cardiac wall dysfunction, aneurysm.

Why does endothelial cell damage increase risk of thrombosis?

It removes protective mechanisms that normally prevent clot formation:

• Blocks exposure of subendothelial collagen and tissue factor.

• Produces PGI₂ and NO → vasodilation + inhibits platelet aggregation.

• Secretes heparin-like molecules → activate antithrombin III (inhibits thrombin).

• Releases tissue plasminogen activator (tPA) → converts plasminogen → plasmin → degrades fibrin & clotting factors.

What are the four major antithrombotic functions of healthy endothelial cells?

1. Blocks exposure to collagen & tissue factor.

2. PGI₂ + NO release → inhibit platelet aggregation.

3. Heparin-like molecules → activate antithrombin III.

4. tPA release → activates fibrinolysis (plasmin formation).

Hypercoagulable States:
What is a hypercoagulable state, and what are examples?

A condition with excessive procoagulant activity or deficiency of anticoagulants → ↑ thrombosis risk.
Examples:

• Protein C/S deficiency (↓ inhibition of Factors V & VIII).

• Factor V Leiden mutation (resistant to Protein C).

• Antithrombin III deficiency (↓ inhibition of thrombin).

• Estrogen exposure (↑ hepatic coagulation factor synthesis).

What are common clinical settings that promote thrombosis via Virchow’s Triad?

• Post-surgery or immobilization → blood stasis.

• Atrial fibrillation → turbulent blood flow.

• Smoking or hypertension → endothelial injury.

• Inherited disorders or OCP use → hypercoagulability.

Common Sites of Thrombosis

Q: Where do thrombi commonly form?

• Deep veins (DVTs) of legs (especially post-surgery or immobilization).

• Heart chambers (from wall damage or atrial fibrillation).

• Arteries (atherosclerosis-related).

What are major complications of thrombosis?

• Infarction (ischemic tissue necrosis).

• Embolization → pulmonary embolism (PE) or stroke.

• Chronic venous insufficiency (due to repeated DVTs).

Why does endothelial cell damage increase the risk of thrombosis?

Because it disrupts the protective barrier of the endothelium, exposing subendothelial collagen and tissue factor, which activate platelets and the coagulation cascade.

What are the main causes of endothelial damage?

1. Atherosclerosis

2. Vasculitis

3. Elevated homocysteine levels

Homocysteine & Thrombosis

Q: How do vitamin B₁₂ and folate deficiency contribute to thrombosis?

They cause mildly elevated homocysteine levels, which damage endothelium and increase the risk of thrombosis.

What is a hypercoagulable state?

A condition caused by excess procoagulant proteins or defective anticoagulant proteins, leading to increased clot formation.

What is the classic presentation of a hypercoagulable state?

• Recurrent DVTs or

• DVT at a young age (<50 years old) without clear provocation.

What are the three components of Virchow’s Triad in thrombosis?

• Disruption of blood flow

• Endothelial cell damage

• Hypercoagulable state

Protein C and S Deficiency 🧬
What is Protein C and S deficiency?

An autosomal dominant disorder causing low levels of Protein C and/or Protein S, leading to a hypercoagulable state(↑ risk of thrombosis).

What is the normal function of Protein C and Protein S?

They are anticoagulant proteins that inactivate Factors V and VIII, providing negative feedback on the coagulation cascade.

Are Proteins C and S vitamin K dependent?

✅ Yes — both are vitamin K–dependent proteins, synthesized in the liver.

What happens when there is Protein C or S deficiency?

• ↓ Protein C/S → ↓ inactivation of Factors V and VIII

• ↓ negative feedback → procoagulant state

• ↑ risk of venous thrombosis