Lecture 13: Thrombotic Disorders Flashcards
What are the three possible causes of Thrombosis?
The causes of underlying venous and arterial thrombosis can be broken down according to three possible causes, including 1) s_tasis of blood flow_, 2) hypercoagulability of the components of blood, and 3) changes to the blood vessel wall.
The first two mainly apply to venous thrombosis.
Virchow’s triad
What are some causes of vascular injury?
- Trauma
- Surgical manipulation
- Prior thrombosis
- Atherosclerosis
What are some causes of Stasis?
- Immobility
- Post-op state, debility, coma
- “Economy class syndrome”
- Pressure
- Catheter, tumour obstruction
- Increased viscosity
- Polycythaemia
- Dehydration
- EPO
What are the causes of Blood hypercoagulability?
- Increased procoagulants
- Decrease in inhibitors
- Impaired fibrinolysis (rare)
What is Deep Vein Thrombosis?
Deep vein thrombosis (DVT) occurs when a blood clot (thrombus) forms in one or more of the deep veins in your body, usually in your legs. Deep vein thrombosis can cause leg pain or swelling, but also can occur with no symptoms.
What is a thrombosis?
Pathological clotting occurring within blood vessels is referred to as thrombosis.
What is a Pulmonary Embolism?
Clot starts off in the deep veins, and some or all travel into the vena cava- heart-lungs and stuck there.
Pulmonary Embolism (PE)
1/2000 people annually, ~5 to 10% fatal
Massive PE is associated with sudden death (15% of these), mortality >50%. It can lead to hypotension, and severe right heart strain (acute dilatation) due to back pressure from pulmonary arteries.
What are the symptoms/signs of DVT?
Nonspecific/common
Symptoms and signs:
- Unilateral leg swelling
- Unilateral leg pain
- Discolouration and oedema
What are the symptoms/signs of PE?
Nonspecific/common
Symptom triad:
- Pleuritic pain (chest pain)
- Shortness of breath
- Haemoptysis
Signs:
- Tachycardia
- Tachypnoea
- Hypoxia
Because the symptoms of DVT and PE are so non-specific, what can you do to assist with Clinical Diagnosis?
(to Reduce the need for imaging).
Studies have shown that using a clinical score (algorithms) which includes some r_isk factors, symptoms and sign_s is helpful to classify the patient as high or low risk.
-
High risk patients should be tested further with radiology to exclude or confirm the thrombus.
- For DVT, this is most often ultrasound;
- For PE, most often computed tomography pulmonary angiography (CTPA) or V/Q scan.
- _In low risk patients, D-dimer tes_t is used.
- If D-dimer test is normal, then thrombus is unlikely.
- If D-dimer is elevated, further testing is needed with imaging.
What does the D-dimer test actually measure?
D-Dimer Testing
D dimer is breakdown products of fibrin
- Positive in 83-98% of DVT and PE (depending on method)
- Also positive in patients without VTE (inflammation, surgery)
- High NPV but low PPV.
- Should be interpreted with a clinical score
62 year old male presents with a 5 day history of right leg pain and swelling
Symptoms include pain, tenderness, swelling
History continued:
- No personal or family history of VTE
- On symptoms enquiry, recent 4kg weight loss
- On examination, limb findings (right calf and thigh 5 and 3cm larger than the left, with pitting oedema to the knee)
Ultrasound diagnostic test for DVT:
- Ultrasound shows extensive clot in the superficial femoral vein to the popliteal vein
- 1/3 symptomatic DVT are proximal. Untreated up to half will embolise
Diagnose
Our patient:
- Other investigations showed an iron deficiency anaemia
- Colonoscopy shows tumour
-
Deep vein thrombosis in a patient with undiagnosed cancer
- Cancer can often trigger thrombosis
Consider the possible Cause as well as diagnosis and treatment
What are the…
1) Symptoms
2) Signs
3) D-dimer results
4) What other investigations might you do?
Of someone with PE
Diagnosis of PE with classic symptom triad of pleuritic pain, shortness of breath, haemoptysis
Signs include tachycardia, tachypnoea, hypoxia
This patient has normal basic blood tests except for a D-dimer which is positive.
Investigations include CT pulmonary angiography and V/Q scan.
What is Thrombophilia?
What are some causes of thrombophilia?
Thrombophilia is tendency to develop thrombosis. It manifested as venous thromboembolism (VTE).
- It can be acquired or inherited or both (term usually applied to hereditary).
- Multi-hit theory
Causes associated with familial thrombophilia include:
- Abnormal inhibitor function includes resistance to activated protein C (secondary to point mutation of factor V gene (factor V Leiden))
- Deficiency of inhibitors includes antithrombin (rare, high risk for future thrombosis), protein C, protein S deficiency
- Increased factor levels includes prothrombin gene mutation 20210A, elevated factor VIII
- Dysfibrinogenemia (very rare)
With exception of antithrombin deficiency, diagnosis of a genetic marker does not substantially change management of VTE.
What increases the risk of venous thromboembolism? (VTE)
Venous thromboembolism (VTE) is a condition in which a blood clot forms most often in the deep veinsof the leg, groin or arm (known as deep veinthrombosis, DVT) and travels in the circulation, lodging in the lungs (known as pulmonary embolism, PE).
~30-40% are spontenous
- About 50% of these will have hereditary factor which increases risk: thombophilia
~2/3 VTE cases will have an underlying risk factor (provoked events).
Important contributor causes to consider are:
- Active cancer,
- Recent surgery or trauma, hospitalization,
- Obesity, pregnancy, h_ormone replacement_ or combined oral contraceptive pill,
- Immobility (longhaul air travel >4hr increase relative risk by ~2 folds, but with low absolute risk (1/4,656)),
- Malignancy (up to 20%, e.g. myeloproliferative disease, antiphospholipid syndrome**)
Many minor factors may be involved, or the patient may have an underlying genetic risk factor (hereditary thrombophilia), which may further increase the risk.
Describe Factor V Leiden
Factor V Leiden (rs6025) is a variant (mutated form) of human factor V which causes an increase in blood clotting (hypercoagulability)
In normal coagulation, factor Va enhances factor X activation, while f_actor Va is inactivated by protein C._
- This is achieved by cleaving factor V molecule at residue arginine 506. In this way, protein C slows coagulation (Xa production) and acts as a natural anticoagulant.
Factor V Leiden is a variant form of factor V due to mutation arginine (R) to glutamine (Q) at residue 506.
- This form of factor V is _resistant to cleavage by activated protein C (_activated protein C resistance).
- In patients with this mutation, protein C is unable to act as an anticoagulant. Therefore, factor Xa activation continues (Va levels ~20% higher).
- Patients with the factor V Leiden mutation have an increased risk of venous thrombosis.
- Heterozygotes carry a 3-7 folds increased risk of thrombosis
- Homozygotes carry a 50-100 folds increased risk of thrombosis
Activated protein C resistance (APCr) is measured by a coagulation based assay and factor V Leiden by direct DNA analysis.
How do you treat PE and DVT?
Treatment Plan: Anticoagulation
Treatment plan is for anticoagulation!! Therefore:
- Low molecular weight heparin used initially
- Immediate effect
- Requires antithrombin: inactivation of Xa and IIa (thrombin)
- Heparin prolonges the APTT/1+1: Antithrombin deficiency does not!
- Warfarin at same time (minimum 5 days of overlap with LMWH)
- Alternatively, a novel oral agent
These drugs i_nhibit coagulatio_n, allows own fibrinolytic mechanisms to operate unhindered by further clotting
Mortality from PE (excluding patients with systemic malignancy) is ~5% and is higher if untreated.
Untreated DVTs frequently extend and may embolise. Post thrombotic syndrome (a chronically painful swollen leg due to occlusion of the veins) can be disabling. Therefore, immediate treatment is needed with anticoagulation.
Describe Wafarin
Warfarin
Warfarin is an oral anticoagulant, which in_hibits recycling of vitamin K_ and therefore reduces production of active vitamin K dependent clotting factors (II, VII, IX, X).
It takes time for reduced available vitamin K to reduce production of active clotting factors (half-life of prothrombin is 2 days). Therefore, usually 5 to 7 days to a therapeutic level.
Monitored using prothrombin ratio adjusted for international standardisation, which is international normalised ratio (INR) (therapeutic range of 2-3)
- While warfarin is effective, it requires regular monitoring with INR testing. It has many _drug interaction_s (antibiotics, anticonvulsants, amiodarone, diltiazem, citalopram, etc.).
- As the INR rises >4, risk of bleeding increases further.
Drug interactions and reversal strategies for warfarin are discussed further in the coagulation laboratory and should be understood.
Describe the two different types of Direct acting Oral Anticoagulants (DOACs)
New Direct Acting Oral Anticoagulants (DOACs)
Dabigatran directly inhibits Thrombin
Direct acting oral anticoagulants (DOACs) are oral direct inhibitors of activated clotting factor. It has half-life 9 to 14 hours. Dabigatran can be partially dialyzed.
-
Dabigatran (thrombin or IIa) and rivaroxaban (Xa) are both the same as warfarin for the treatment of VTE
- Dabigatran taken twice daily, and rivaroxban taken once daily.
- Probably superior to warfarin for anticoagulation in atrial fibrillation (dabigatran available in NZ), due to better stroke prevention with similar rates of bleeding
- Advantages include no monitoring needed, fixed dose; l_ess intracranial haemorrhage_ (compared to warfarin)
- Disadvantages include r_enal excretion (especially dabigatran)_ retained with renal impairment
Need to know
