19. Haemostasis and Thrombosis

Question 1

What is haemostasis

Answer 1

arrest of blood loss from damaged vessels

Question 2

What is thrombosis

Answer 2

pathological formation of haemostatic plug within the vasculature in the absence of bleeding

Question 3

What are the predisposing factors of Virchow

Answer 3

1. injury to the vessel wall
2. altered blood flow
3. abnormal coagulability of the blood

Question 4

Describe the cogulation cascade

Answer 4

Vascular injury activates the intrinsic and extrinsic pathway:
-F12 is activated.
-Activated F12 catalyses the activation of F11.
-Activated F11 catalyses the activation of F9.
-Activated F7,8,9 and Ca2+ catalyse the activation of F10.
-Activated F5,10 cataylse the conversion of prothrombin II to activated thrombin II.
Activated thrombin II catalyse conversion of fibrinogen to fibrin.
-F13 catalyses fibrin to fibrin clot.

Question 5

Mechanism of venous thrombosis

Answer 5

1. activation of endothelial cells
2. binding of leukocytes to P and E-selectins, platelets to vWF (Von Willebrand factor), and TF+MV (tissue factor containing microvesicles) to P-selectin.
3. induction of TF expression on leukocytes - coagulation cascade
4. formation of fibrin rich thrombus

Question 6

Less common sites for Venous Thrombosis (VTE)

Answer 6

upper limbs, mesenteric veins, hepatic veins, cerebral veins, portal vein

Question 7

Symptoms of deep vein thrombosis

Answer 7

Pain, swelling, erythema

• below knee, lower rate of progression
• above knee, higher risk of developing PE

Question 8

Symptoms of pulmonary embolism

Answer 8

SOB, chest pain, tachycardia, tachypnoea, hemoptysis, dyspnoea, low O2 stats, normal chest x-ray (use CT pulmonary angiogram)

Question 9

What is pulmonary embolism

Answer 9

acute onset of pleuretic chest pain

Question 10

Diagnosis of DVT

Answer 10

Imaging - ultrasound of veins of lower limb

MRI venogram or CT angiogram - more sensitive

Question 11

Treatment of DVT

Answer 11

Anticoagulation for at least 3 months
- for unprovoked DVT, it is hard to take patient of anticoagulant because nothing can be asked about the patient’s history that woulf cause it - unpredictable

Question 12

Risk factors of PE

Answer 12

1. signs of DVT (swelling etc)
2. heart rate > 100
3. immobilization > 2 days or recent injury < 4 weeks
4. haemoptysis
5. cancer
6. previous DVT

Question 13

Treatment of VTE in

a) pregnancy
b) cancer

Answer 13

a) low molecular weight heparin
- does not cross placenta
b) DOACS (direct oral anticoagulants) / LMWH
- better than warfarin - less bleeding and recurrent thrombosis
- DOACS higher rates of bleeding compared to LMWH

Question 14

What is antiphospholipid antibody syndrome

Answer 14

• also known as Hughes syndrome
• autoimmune, hypercoagulable state caused by antiphospholipid antibodies
• provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as:
  a) miscarriage - 3 consecutive first trimester
  b) stillbirth - foetal loss in 2nd or 3rd trimester
  c) preterm delivery - due to severe preeclampsia.

Question 15

Important note about the lab test for antiphospholipid antibody syndrome

Answer 15

a positive lab test on 2 separate occasions at least 12 weeks apart
active = show presence of antibodies to phospholipid binding proteins
-lupus anticoagulant
-anticardiolipin antibodies
-anti-beta-2 glycoprotein 1 antibodies

Question 16

Clue of lupus anticoagulant

Answer 16

prolonged aPTT (activated partial thromboplastin time)

Question 17

Treatment of antiphopholipid antibody syndrome

Answer 17

Aspirin and/or warfarin

-warfarin better than DOACS in APS

Question 18

VTE treatment

Answer 18

Initially:
a) anticoagulation - don’t wait for scan results
2 options:
1. LMWH and warfarin
- LMWH given for min. 5 days until INR>2 for over 24 hours
- target INR = 2.5
2. DOAC
- regime depends on agent
- e.g. Rivaroxaban and Apixaban - no LMWH lead in
- e.g. Edoxaban or dabigatran - need 1 week of LMWH before commencing

Question 19

What is post-thrombotic syndrome

Answer 19

swollen, painful leg post DVT

Question 20

What is disseminated intravascular coagulation

Answer 20

condition in which blood clots form throughout the body, blocking small blood vessels

Question 21

Presentation of DIC

Answer 21

• acute haemorrhagic disorder
• indolent, subacute thrombotic disorder
• bleeding from nose, mucous membrane, …

Question 22

Lab presentation of DIC

Answer 22

• prolonged PT
• prolonged aPTT
• low fibrinogen
• high D-Dimer
• low platelet count

Question 23

Pathophysiology of DIC (wiki explained)

Answer 23

-the body is maintained in a balance of coagulation and fibrinolysis. The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin to stable fibrin clot. The fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in fibrin degradation products (FDPs) or fibrin split products (FSPs). In a state of homeostasis, the presence of plasmin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for the breakdown of clots, or fibrinolysis.

In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding. One critical mediator of DIC is the release of a transmembrane glycoprotein called tissue factor (TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumor necrosis factor, and endotoxin. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon exposure to blood and platelets, TF binds with activated factor VIIa (normally present in trace amounts in the blood), forming the extrinsic tenase complex. This complex further activates factor IX and X to IXa and Xa, respectively, leading to the common coagulation pathway and the subsequent formation of thrombin and fibrin.

Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.

Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a positive feedback loop develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs and this has been attributed to the entrapment and consumption of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC.

Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in an excess of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage. The excess plasmin also activates the complement and kinin systems. Activation of these systems leads to many of the clinical symptoms that patients experiencing DIC exhibit, such as shock, hypotension, and increased vascular permeability. The acute form of DIC is considered an extreme expression of the intravascular coagulation process with a complete breakdown of the normal homeostatic boundaries.

Activation of the intrinsic and extrinsic coagulation pathways causes excess thrombus formation in the blood vessels. Consumption of coagulation factors due to extensive coagulation in turn causes bleeding.

Question 24

Shortened explanation of pathophysology of DIC

Answer 24

Underlying disorder causes systemic activation of coagulation.
This in turns causes widespread, intravascular fibrin deposition, which leads to thrombosis.
On the other hand, it also causes consumption of platelets and clotting factors, which in then results in bleeding.

Question 25

Function of anticoagulants

Answer 25

Prevention of stroke and systemic thromboembolism

Question 26

Side effects of oral anticoagulants

Answer 26

Atrial fibrillation

Question 27

Side effects of Anti-Xa agents

Answer 27

• since its route of excretion is renal, it may cause renal impairment
• concentration affected by CYP(cytochrome P450) inhibitors/inducers
• prolongs PT

Question 28

Example of direct thrombin inhibitors

Answer 28

Dabigatran

• renal excretion
• prolonges thrombin time
• prolongs aPTT but not PT

Question 29

What is warfarin and what does it do

Answer 29

Vit K antagonist

• prevent gamma-carboxylation of glutamic acid residues of F2,7,9,10
• inhibits Vit K epoxide reductase - required to form active Vit K
• inhibit production of anticoagulant protiens - protein C,S

Question 30

DIC treatment

Answer 30

• fibrinogen replacement

- fresh frozen plasma - target normal PT and aPTT

Question 31

Note for PT and aPTT

Answer 31

PT
-Factors 1,2,5,7,10
aPTT
-Factors 2,5,8,9,10,11,12
(note factors 3,4,6 don't exist)