2. Disorders of secondary hemostasis (coagulation cascade)

Question 1

Definition of secondary hemostasis

Answer 1

Processes that lead to stabilization of the platelet plug (white thrombus) by creating a fibrin network

Question 2

Etiology of secondary hemostasis disorders

Answer 2

1. Intrinsic pathway
   a. Factor VIII deficiency (hemophilia A)
   b. Factor IX deficiency (hemophilia B)
   c. Factor XI deficiency (hemophilia C)
2. Extrinsic pathway: factor VII deficiency (autosomal recessive bleeding disorder caused by mutation of the F7 gene)
3. Both pathways:
   a. Deficiency or inhibition of vitamin K-dependent coagulation factors II, VII, IX, and X
   Vitamin K deficiency: liver failure (e.g., cirrhosis), fat malabsorption, prolonged broad-spectrum antibiotic therapy, vitamin K antagonists (e.g., warfarin), neonatal deficiency
   b. Inhibition of coagulation factors by autoantibodies (most commonly anti-factor VIII)
   c. Disseminated intravascular coagulation (DIC)
   d. Impaired hepatic production of coagulation factors (e.g., cirrhosis)
   e. Fibrinogen deficiency
   f. Anticoagulant treatment

Question 3

What is the onset of bleeding in secondary hemostasis disorders?

Answer 3

Delayed

Question 4

Clinical manifestations in secondary hemostasis disorders

Answer 4

1. Deep tissue bleeding, e.g.:
   a. Hemarthrosis (esp. in hemophilia)
   b. Hematomas
2. Large, palpable ecchymoses

Question 5

Definition of Hemophilia

Answer 5

Hemophilias are disorders of blood clotting and consequently may lead to serious bleeding

Question 6

Epidemiology of Hemophilia

Answer 6

Average age at diagnosis:

1. Severe hemophilia: 1 month
2. Moderate hemophilia: 8 months
3. Mild hemophilia: 36 months

Question 7

Etiology of Hemophilia

Answer 7

Hemophilia is caused by an X-linked recessive defect (inherited or spontaneous mutation) or antibody production against clotting factors.

1. Hemophilia A (factor VIII deficiency): ∼ 80% of cases
2. Hemophilia B (factor IX deficiency): ∼ 20% of cases
3. Hemophilia C (factor XI deficiency): very rare; caused by an autosomal recessive defect

Question 8

Clinical presentation of Hemophilia

Answer 8

Spontaneous bleeding or delayed-onset bleeding (joints, muscular and soft tissue, mucosa) in response to different degrees of trauma

a. Repeated hemarthrosis (e.g., knee joint) → hemophilic arthropathy (i.e., destruction of the joint due to repeated hemarthrosis)
b. Recurrent bruising or hematoma formation
c. Oral mucosa bleeding, epistaxis, excessive bleeding following small procedures (e.g., dentist procedures)
d. Hemophilia C does not typically manifest with spontaneous bleeding, hemarthrosis, or deep tissue bleeding

Question 9

Lab studies for Hemophilia

Answer 9

1. Prothrombin time: normal
2. Platelet count: normal
3. Activated partial thromboplastin time (aPTT): usually prolonged

• If aPTT prolonged → mixing study
• If mixing study is positive (or if patient/family history are strongly positive) → quantitative assessment of factor activity levels

Question 10

What is the difference between anti-FVIII (coagulation factor inhibitor) and hemophilia A?

Answer 10

aPTT does not correct upon mixing plasma with patient’s plasma due to the anti-FVIII inhibitor, PTT does correct in hemophilia A

Question 11

What lab value will be changed if the extrinsic pathway of secondary hemostatic disorders is affected?

Answer 11

Increased PT

Question 12

What lab value will be changed if the intrinsic pathway of secondary hemostatic disorders is affected?

Answer 12

Increased aPTT

Question 13

Definition of Disseminated intravascular coagulation (DIC)

Answer 13

A syndrome characterized by thrombosis, hemorrhage, and organ dysfunction caused by systemic activation of the clotting cascade, which leads to platelet consumption and exhaustion of clotting factors

Question 14

Etiology of Disseminated intravascular coagulation

Answer 14

1. Infection
   - Sepsis (more commonly gram -ve organisms)
2. Trauma
   - Acute traumatic coagulopathy
   - Burns
3. Obstetric complications
   - Amniotic fluid embolism
   - Abruptio placenta
   - Retain products of conception
4. Organ failure
   - Acute pancreatitis
   - Acute respiratory distress syndrome (ARDS)
5. Malignancies
   a. Hematological
   - Acute promyelocytic leukaemia
   - Acute myelocytic leukaemia
   b. Solid tumours
   - Pancreatic
   - Ovarian
   - Gastric
   - Non-small cell lung cancer
6. Toxins
   - Snake bite
7. Immunologic
   - Acute hemolytic transfusion reaction
   - Transplant reaction
   - Extracorporeal procedures
8. Vascular malformations
   - Aortic aneurysms
   - Vasculitis
9. Dilution
   - Massive transfusion
   - Massive bleeding
10. Drug reactions

STOP Making Trouble 
S - Sepsis/snakebites 
T - Trauma 
O - Obstetric complications 
P - Pancreatitis 
M - Malignancy 
T - Transfusion

Question 15

Types of Disseminated Intravascular coagulation

Answer 15

1. Non-symptomatic
2. Bleeding type
3. Massive bleeding type
4. Organ failure type

Question 16

Pathophysiology of Disseminated intravascular coagulation (overview)

Answer 16

There are 4 concurrent events involved:

1. Initiation and propagation of coagulation (loss of localized activation of coagulation)
2. A systemic inflammatory activation → impairment of physiological anticoagulant pathways (e.g., depression of antithrombin and impairment of protein C system) and endogenous fibrinolysis (due to a consistent rise in PAI-1)
3. Activation of tissue factor pathway → factor Xa and IXa generation → increased thrombin production
4. Impaired fibrin removal due to depression of the fibrinolytic system → microthrombi production and possible obstruction of the microvasculature

Question 17

Pathophysiology of Disseminated intravascular coagulation (mechanism)

Answer 17

1. Underlying disease → ↑ tissue factor (TF) presentation (e.g., due to increased expression after trauma) → ↑ activation of thrombin → ↑ generation of fibrin → consumption of natural anticoagulants (e.g., antithrombin, thrombin-antithrombin complex (TAT), protein C)
   a. Platelet activation → hypercoagulable state
   b. ↓ Fibrinolysis → ↑ intravascular fibrin → obstruction of the microvasculature → organ dysfunction and multi-organ failure
2. ## Consumption of platelets, clotting factors, and fibrinogen → thrombocytopenia and lack of clotting factors → severe bleedingNonsymptomatic type DIC:
   Mild fibrinolysis and/or mild hypercoagulation

Bleeding type DIC:
Hyperfibrinolysis (excessive plasmin activity → increased fibrin degradation → thrombi become unstable and dissolve shortly after forming)

Massive bleeding type DIC:
Hypercoagulation and hyperfibrinolysis → consumption of platelets and all coagulation factors → bleeding diathesis

Organ failure type DIC:
↑ Cytokines → ↑ plasminogen activator inhibitor-I (PAI-I) and ↑ neutrophil extracellular traps (NETs) → hypercoagulation with hypofibrinolysis → platelet and fibrin-rich microthrombi → impaired perfusion and tissue necrosis

Question 18

Clinical presentation of Disseminated intravascular coagulation

Answer 18

1. Bleeding
   a. Hematemesis, hematochezia
   b. Hematuria
   c. Petechiae, purpura, ecchymoses
2. Massive hemorrhage: collection of blood in body cavities (hemoperitoneum, hemothorax)
3. Organ failure: primarily due to hypercoagulation
   a. Acute renal failure: oliguria
   b. Hepatic dysfunction: jaundice
   c. ARDS: dyspnea, rales
   d. Pulmonary thromboembolism: dyspnea, chest pain, hemoptysis
   e. Deep vein thrombosis: lower limb edema
   f. Waterhouse Friderichsen syndrome: adrenal infarcts → adrenal insufficiency
   g. Signs of shock

Question 19

Lab studies for Disseminated intravascular coagulation

Answer 19

1. Coagulation panel
   a. ↑ aPTT, ↑ PT
   b. ↓ Fibrinogen: indicative of associated hyperfibrinolysis
   c. Markers of fibrin breakdown: ↑ D-dimer or other FDPs
   d. ↑ Bleeding time
   e. Coagulation factors: ↓ factor V and ↓ factor VIII
2. CBC and blood smear
   a. ↓ Platelet count: due to consumption and/or bleeding
   b. ↓ Hct: occurs with bleeding
   c. Schistocytes: indicative of microangiopathic hemolytic anemia