74(5) Coagulation Disorders Flashcards
What are the inherited hypercoagulable states?
- Factor V Leiden Mutation
- Prothrombin G202120A Mutation
- Antithrombin III Deficiency
- Protein C and S Deficiencies
- Hyperhomocysteinemia
- Sickle Cell Disease
What is the most common primary HS?
Factor V Leiden (affects 5-15% of pop)
Mechanism behind FVLM?
Mutated FVa is resistant to degradation by activated protein C (APC), thus the coag cascade remains activated for longer than normal.
Manifestations of FVLM?
- VTE (3-6 fold inc risk if hetero, 30-140 fold inc risk if homo)
- Cerebral, mesenteric, portal vein and postsurgical thrombosis.
- Pregnancy loss.
Second most common inherited HS?
Prothrombin G202120A Mutation (affects 1-3% of pop)
Mechanism behind Prothrombin G202120A mut?
AD mut of prothrombin gene leading to elevated circulating plasma levels of prothrombin.
Antithrombin III Function?
Serine protease inhibitor (syn in liver). A natural antigoag that inactivates thrombin (IIa) and FXa (and to lesser extent FIXa, FXIa, FXIIa).
Two forms of Antithrombin III Deficiency?
Type 1: quantitative def (low levels of anticoag)
Type 2: qualitative (normal levels of improper function)
Acquired causes of Antithrombin III Def?
- Increased consumption due to:
- Inc coag (DIC, sev injury/trauma, cardiopulm bypass, MAHA)
- endothelial damage (hemolytic-uremic syn)
- venoocclusive dis (in BMT recip)
- Decreased synthesis:
- Chronic liver dis
- Protein loss:
- Nephrotic syn
- Ascites
- Protein-losing enteropathy
- Meds
- Heparin (-induced thrombocytopenia; pro coag effect)
- L-asparaginase (impaired prot syn)
Function of Protein C and S?
Activated protein C (APC) combines with protein S on the plt surface to inactivate FVa and FVIIIa.
Acquired Protein C or S Deficiency?
- Liver disease (dec synthesis)
- Vit K def
- Warfarin use
- Pregnancy
- Sex hormone therapy
- Chronic inf (eg. HIV)
What is Homocysteine?
A sulfhydryl-containing aa formed during methionine metab. High levels lead to inc risk of venous and arterial thrombosis - mech not clear, possibly related to endothelial dysfunction.
Mechanisms behind inherited Hyperhomocysteinemia?
Mut in homocysteine pathway enzymes. Commonly a C to T missense mut (sub Val for Ala) in Methyltetrahydrofolate reductase (MTFR) gene, resulting in hypofunctioning, thermolabile variant and elevated homocysteine levels.
Manifestations of hyperhomocysteinemia?
- Increased risk of cardiovascular events
2. 2-4 fold increased risk of VTE (20-fold if coexpressed with FVLM)
Acquired causes of hyperhomocysteinemia?
- Renal or thyroid disease
- Smoking
- Aging
- Vit B12, B6, or folate deficiency
What mut is Sickle Cell Disease caused by?
AR hemolytic anemia caused by single nucleotide mut substituting Val for Glutamic acid at 6th position of the B-hgb gene, causing polymerization of Hgb when deoxygenated and leading to Hgb S.