2015 L8 Case 7 Fem!Harry

Deep Vein Thrombosis (DVT)

A medical condition characterized by the formation of blood clots within deep veins, typically in the legs.

Risk factors for DVT

Stasis of blood flow, vessel wall injury, and a hypercoagulable state - promotes clot formation within a deep vein. If not detected and treated, DVT can extend proximally within veins or embolise to lungs.

Symptoms of DVT

Localized leg pain, swelling, warmth, and redness; may also be asymptomatic.

Pulmonary Embolism (PE)

Occurs when a blood clot travels to the lungs and blocks one or more pulmonary arteries.

Symptoms of PE

Chest pain, shortness of breath, rapid heart rate, coughing up blood, and anxiety.

PE risk factors

• Previous history of DVT or PE

• Prolonged mobility e.g. flight, bed rest

• Major surgical procedures, especially orthopedic

• Pregnancy

• Cancer

• Oral contraceptives or HRT

• Obesity

• Smoking

Well’s score

A clinical tool used to assess the probability of a DVT or PE.

Ultrasonography for DVT

A non-invasive imaging technology used to identify DVT clots using high-frequency sound waves to penetrate tissues (1-18MHz) - good for soft tissues

Piezoelectric effect

Application of mechanical stress generates electrical current, used in imaging techniques. Electrical impulses are used to trigger mechanical vibrations in a crystal

• Sound waves bounce from surface in body and return to transmitter

• Piezoelectrical effect once more generates an electrical pulse

• Image formed by delay in echo returning and intensity of echo

Thrombotic Conditions

• Thrombus (clot) that occurs under inappropriate conditions

• Results from homeostatic imbalance

• Thrombophilia

Thrombophilia

A tendency towards forming thrombi, can be inherited or acquired.

Factor V Leiden

A mutation in the FV gene

• essential co-factor for FXa

• homeostasis: activated C protein (aPC) degrades FV

• mutation in SNP called rs6025 - causes arginine to glutamine mutation at 506 position

• FVL mutation confers resistance to aPC

Protein C

A vitamin K-dependent zymogen that inactivates FVa and FVIIIa, requiring cofactors FV and Protein S to function.

• activated by binding to thrombin

• cleaves FVa in 3 distinct locations Arg306, Arg506, Arg679

Protein S

A vitamin K dependant factor

• binds strongly to negatively charged surfaces of platelets

• once bound to platelets, forms a Ca2+ complex with aPC

FVL Epidemiology

• Most common inherited thrombotic disorder

• Around 5% caucasians have FVL mutation

• Autosomal dominant (a single copy of a mutated gene from one parent can cause the trait or disorder to be expressed in the offspring) inheritance but demonstrates incomplete penetrance (where not all individuals with a genetic mutation exhibit symptoms or the trait associated with that mutation)

FVL Diagnosis

• Genetic

• aPC resistance test

• Molecular methods are more routine and utilise allele-specific PCR to identify pathogenic polymorphism

  • utilises polymorphism specific, fluorescently labelled probe

FVL Risk Factors

• Oral contraceptives

• Smoking - inhaled products usually toxic to endothelial cells, causes pro-coagulants to release

• Long-distance aeroplane rides - cause venous stasis, skeletal muscle not contracting and pushing blood to heart and blood pools. Platelets bind to each other when not doing anything

Oestrogen and DVT

• Increases coagulant response, Factor 8, 12, 13, 7, 10 and pro-thrombin

• F13 responsible for crosslinking fibrin strands, making fibrin clot strong

• Esp in pregnancy as its maintained, keeps vascular endometrium is thick and placenta nourished

• Also decreases coagulant inhibitors e.g. Protein S and Antithrombin, fibrinolytic proteins e.g. plasminogen activator = no plasmids and no clot breakdown

• Also increases vWF

Fibrin degradation products

• Fibrin degraded sequentially by plasmin

• Insoluble mass becomes soluble

• D-Dimers

D-dimer

A fibrin degradation product used as a diagnostic marker for DVT and PE; higher levels indicate a greater likelihood of a thrombotic event.

Antithrombin Deficiency

• Common coagulopathy

• 2 types

  • Type 1: Rate of synthesis error (most common)

  • Type 2: Functional error

Antithrombin (III)

A small glycoprotein synthesized by the liver that inhibits serine protease coagulation factors e.g. FIXa, FXa, TF:FVlla, thrombin. Forms stable 1:1 complex with target enzymes

Binds to heparin sulphate on cell surfaces which it requires as a co-factor

Type 1 AD

• Common causes: single nucleotide polymorphisms and very short indels in SerpinC1 gene (AT3)

• Short deletions can range from 1-30 nucleotides

• Consequences: inappropriate stop codons, mRNA splice sites, 92 genetic mutations

Anti-phospholipid Syndrome (APS)

A condition where antibodies are produced against phospholipids, often associated with recurrent miscarriages and clotting issues.

Lupus Anticoagulant

Antibodies found in patients with APS that can prolong clotting time; confirmed by phospholipid addition.

• Venom from Russel viper activates FX

• If LA present, clotting time is prolonged

• Excess of phospholipids added

• If corrects time, LA confirmed

Type 2 AD

Relate to loss of function within protein e.g.

• heparin binding defects

• reactive site defects

• mutations with pleotropic when one gene influences two or more seemingly unrelated phenotypic traits.

Anti-Phospholipid Syndrome (APS)

• Caused by spontaneous production of antibodies against phospholipids e.g. lupus anti-coagulant

• Often seen in systemic auto-immune disorders, not always the case

• Causes of reoccuring miscarriages

APS Pathophysiology

• Igs produces can be heterogenous and target many elements of haemostatic mechanism

  • Prothrombin

  • Protein S

  • Protein C

  • Annexin

Heparin

A widely used anticoagulant that can be unfractionated or low molecular weight, increasing the activity of antithrombin.

• endogenously produced in the body

• glycosaminolaters

• Heterogenous in size and activity

• Prescribed as both an unfractioned and fractioned formula

• Low weight heparin has diff activity to unfractioned

• HMW increases activity of AT by a lot

• LMW inhibits FXa

i

Heparin-induced Thrombocytopenia

• May be associated with unfractioned heparin and increased risk of thrombosis

• HIT is an immune mediated process; heparin binds to F4 and acts as a hapten stimulating an antibody response

• PF4 major regulator or endogenous heparin activity as its released from α granules

• IgG-PF4-Heparin complex activates platelets, causing thrombosis

Vaccine Induced Thrombocytopenia

• Associated with AstraZeneca COVID vaccine

• Believed to be due to similar mechanism as HIT

Warfarin

A common medication for thrombo-embolic disease that inhibits vitamin K-dependent clotting factors. Also used as rat poison.

Direct FXa inhibitors

Novel anticoagulant drugs like Apixaban, Edoxaban, and Rivaroxaban that do not require regular INR tests.

• Apixaban used as alternative to warfarin and doesnt require regular INR

• Apixaban is a direct reversible inhibitor of FXa but doesnt inhibit platelet aggregation

INR (International Normalized Ratio)

A measurement used to monitor the effect of warfarin on blood clotting.

• Higher INR = slow blood clotting etc.

• frequency of INR varies but more frequent when starting warfarin and less once desired INR range is stable

Anticoagulants

• Heparin

• Warfarin

• Streptokinase

  • thrombolytic produced by beta-haemolytic Streptococci

  • Activates plasmin from plasminogen

  • Induces systemic hypercoaguable state