HC39: Thrombosis

Cause

Thrombosis is caused by a decrease in anticoagulant factors. Deep vein thrombosis (DVT) has the following symptoms:

• Red skin
• Warm
• Painful calf
• Swelling
• Shining skin
• Pain while walking

In 40% of cases with suspected DVT, the clinical diagnosis is correct. Ultrasounds of the vessels in the leg are primarily used to diagnose DVT. In normal situations, the vein compresses and becomes hard to see. In case of thrombosis, the vein doesn’t become compressed as much. DVT differs from arterial thrombosis because it occurs at sites of stasis.

Post thrombotic syndrome

Post thrombotic syndrome (PTS) is a persistent swollen and painful leg as a result of DVT. Symptoms are:

• Swollen leg
• Heavy feeling leg
• Pain
• Varicose veins
• Discoloration of the skin
• Ulceration

In post thrombotic syndrome, accumulation of thrombotic platelets causes a leaky valve. Current treatment to prevent the development of post-thrombotic syndrome consists of compression stockings → the venous pressure is increased.

Pulmonary embolism

A pulmonary embolism (PE) is an embolization of a venous thrombus into the pulmonary artery. Symptoms are:

• Breathlessness
• Pleural pain
• Hemoptysis
• Fever
• Shock

A very deadly form of pulmonary embolism is a saddle embolism → almost always results in death.

Imaging:

Diagnosis of pulmonary embolism requires objective imaging:

• CT-scans
  • Are primarily used
  • White contrast fluid is injected → gray areas show blood clots
• Chest X-rays
  • In acute phases of pulmonary embolisms
  • Rules out other diseases mimicking pulmonary embolism
  • After a few days, pulmonary infiltrates may become visible → infarcts
• Ventilation-perfusion scan: shows radioactivity in the lungs → if there is radioactivity, no blood is present
  • Perfusion: intravenous injection of radioactive technetium macro-aggregated albumin
    • Tc99m-MAA
  • Ventilation: inhalation of gaseous radionuclides in aerosol
    • Xenon-133
• Pulmonary angiography
  • Was used in the past
  • Contrast fluid is injected into the pulmonary artery with a catheter

Diagnostic strategies:

Diagnostic strategies for pulmonary embolism may consist of an algorithm, such as the clinical decision rule:

• Symptoms of DVT → 3
• Heart rate >100/min → 1,5
• Immobilization >3 days or operation in the past 4 weeks → 1,5
• DVT or PE in medical history → 1,5
• Hemoptysis → 1
• Malignancy → 1
• PE is more likely than any alternative diagnosis → 3

In case there are less than 4 points, a D-dimer test is done:

• D-dimers <500 ng/ml → no PE
• D-dimers >500 ng/ml → possibly PE

In case there are more than 4 points or D-dimers are >500 ng/ml, a CT or perfusion scan is made:

• Normal → no treatment
• PE → treatment
• Other diagnosis → treatment

Currently, a more simple way is used → the YEARS algorithm. If 3 YEARS items are present, a D-dimer test needs to be ordered:

• Clinical signs of DVT
• Haemoptysis
• If pulmonary embolism is the most likely diagnosis

This prevents a lot of unnecessary CT-scans.

Treatment

The primary aim of treatment of venous thrombosis is to prevent occurrence of pulmonary embolism. Current regular treatment of DVT and PE consists of:

• Subcutaneous LMWH followed by vitamin K antagonists
• Direct oral anticoagulants with or without initial LMWH
  • Are starting to take over the role of vitamin K antagonists

The duration of treatment for DVT and PE doesn’t differ and depends on the risk of recurrence after a first episode. In cancer patients with venous thrombosis, the first 6 months of treatment consists only of LMWH. This isn’t the case when a patient doesn’t have cancer.

Unfractioned heparin:

Unfractioned heparin leads to a 1000-fold increase of natural inhibitory effects of antithrombin. Heparin is injected into the veins. It is a sugar molecule which binds to anti-thrombin, the natural inhibitor of the coagulation cascade. If anti-thrombin is bound to heparin, it becomes much more active in inhibiting factor Xa → the next step in the coagulation system cannot take place.

The dosage is based on body weight and adjusted by APTT monitoring. Heparin immediately works when injected. LMWH works the same, but only inhibits factor Xa and not thrombin. Dosage of LMWH is based on body weight and adjusted for renal function.

An example of antagonizing heparin and LMWH is protamin:

• Neutralizes the effect of heparin completely
• Neutralizes the effect of LMWH partially
  • Approximately 50%
• Doesn’t neutralize the effect on pentasaccharide

Vitamin K antagonists:

Vitamin K antagonists (VKA) have a completely different mechanism than heparins. Instead of blocking clotting factors, they reduce the production of clotting factors. This leads to reduced levels of clotting factors → inhibition of the coagulation system. Clotting factors normally are produced in the liver:

• FII
• FVII
• FIX
• FX

When these factors leave the liver, they are not yet ready to function → a small molecular group needs to be added to function. Vitamin K is a katalyser for this reaction → for each clotting factor which is produced, 1 molecule of vitamin K is used. Vitamin K is reused to remain sufficient. Vitamin K antagonists block this recirculation of vitamin K → clotting factor production stops in the liver.

Examples of vitamin K antagonists are:

• Acenocoumarol
• Fenprocoumon

Vitamin K antagonists have a variable dosage based on INR monitoring. The first effect of VKAs occurs after about 6 hours. After 12-24 hours, the clear effect is present. More vitamin K does not act faster, but eventually leads to more and prolonged neutralizing of the VKA effect. Intravenous vitamin K does not act substantially faster. The effect of vitamin K antagonists can be antagonized with:

• Vitamin K
• Infusion of prothrombin concentrate
  • Contains plasma derived purified vitamin K dependent clotting factors II, VII, IX and X
• Plasma infusion

Direct oral anticoagulants:

Direct oral anticoagulants (DOAC) are also known as new oral anticoagulants (NOAC). Similar to heparin, they inhibit the action of thrombin factors. They bind directly to factors IIa or Xa without the need of anti-thrombin (which is the case in LMWHs). There are 2 types of DOACs:

• Thrombin inhibitors
  • Dabigatran
    • Contains “tr” → thrombin inhibitor
    • Idarucizumab
• Factor Xa-inhibitors
  • Rivaroxaban
    • Contains “xa” → factor Xa inhibitor
  • Apixaban
    • Contains “xa” → factor Xa inhibitor
  • Edoxaban
    • Contains “xa” → factor Xa inhibitor

There are no licensed Xa-inhibitors available yet. Xa-inhibitors are mainly used for supportive care such as transfusion of red blood cells or plasma. Potentially, prothrombin concentrates can be used as antagonists.