Chapter 38 - Hypercoagulable states Flashcards
Virchow’s triad
1) endothelial injury 2) stasis of blood 3) hypercoagulability
Congenital hypercoagulable defects that increase both arterial and venous thrombosis
1) Hyperhomocysteinemia 2) increased lipoprotein A
Patient risk factors for thrombosis
1) age 2) OC use 3) hormone replacement therapy 4) pregnancy 5) cancer 6) infection 7) trauma 8) surgery
Two groups of congenital hypercoagulable states associated with VTE
1) reduced natural anticoagulants: antithrombin, protein C, protein S 2) defects resulting in gain of procoagulant function: factor V leiden, prothrombin G20210 mutation, increase coag factors 8, 9, 11 and dysfibrinogenemia group 2 less thrombogenic but more common
Venous thromboembolism and inherited thrombophilias
TABLE 38.1
Prevalence of protein C or S deficiency
< 1%
Percentage of group 1 thrombophilia that will have symptomatic thrombotic event before 60 yo
30-50%
Antithrombin deficiency prevalence
0.02% of population
Three types of antithrombin deficiency
TYPE 1 = decrease antithrombin functional activity and antigen TYPE 2 = reduced activity but normal antigen levels; mutation in active inhibitory site TYPE 3 = moderate decreased activity due to impaired interaction with heparin
Deficiency of protein C prevalence
0.2% 2.5-6% in people with VTE
Action of activated protein C
Cleaves coagulant cofactor 8a and 5a
Types of protein C deficiency
TYPE 1: reduced function and antigen protein level TYPE 2: reduced function but preserved antigen level
Treatment of protein C deficiency
If VTE then consider lifelong anticoagulation especially if < 40 years
Homozygous protein C deficiency get this neonatal disorder
Purpura fulminans
Treatment of warfarin necrosis
1) FFP 2) vitamin K 3) heparin
Protein S action
vitamin K-dependent cofactor for inactivation of factor 5a and 8a by activated protein C
Types of protein S deficiency
TYPE 1: reduced function and antigen level TYPE 2: reduced function but normal antigen TYPE 3: reduced free protein S due to enhanced C4b binding but normal antigen
Protein S forms in blood
20-40% free floating = active 60-80% bound to complement binding protein C4b
Protein S level in pregnancy
Falls in 2nd and 3rd trimester
Protein S level reduction associated with
1) cancer 2) lupus 3) antiphospholipid antibody syndrome (APLAS) 4) sepsis 5) chronic inflammatory disorder 6) advanced HIV
Factor V leiden molecule pathology
1) mutation in 506 position 2) glycine for arginine 3) cleavage site to APC resistant
Factor V Leiden epidemiology
2-7% European 10% of VTE patients 30-50% of patients being worked up for thrombophilia
Other rare cleavage mutation of factor Va
Arg306Thr
Prothrombin gene mutation G20210A key points
1) increased plasma level of prothrombin 2) increased prothrombin mRNA stability 3) most common in European population 1-4%; 5-10% of VTE patients, 15% of thrombophilia patients
Ethnicity with highest factor 8 level
African american > white and asian
Measuring factor 8 activity key points
1) has to measure with ESR or CRP 2) each lab should define 90th percentile for population individually
Factor 8 level significance
increases in inflammation infection, IBD, cancer
Two metabolic pathways of homocysteine
1) vitamin B6 pathway = cystathionine beta synthase 2) folate, B12 pathway = 5,10-methylenetetrahydrofolatate reductase (MTHFR) and methionine synthase
Effect of homocysteine on thrombosis
1) toxic effect on endothelium 2) enhanced platelet acdtivation 3) oxidation of LDL-C 4) inflammatory decrease in endothelial TM 5) increase in vWF and factor 8
Lipoprotein A action
competes with tPA, plasminogen and plasmin for binding fibrin and endothelial annexin INHIBITS FIBRINOLYSIS
Sticky platelet syndrome key points
1) autosomal dominant disorder 2) early onset MI and PAD 3) hyperactivity to epinephrine and ADP 4) normal response to thrombin, collagen and arachdonic acid
Three types of platelet response in sticky platelet syndrome
TYPE 1: hyperactive to both ADP and epinephrine TYPE 2: hyperactive to epinephrine TYPE 3: hyperactive to ADP
Treatment of sticky platelet syndrome
ASA
Recurrence of VTE in unprovoked VTE
5-10% per year 50% develop by 10 years
Acquired hypercoagulable states
1) APLAS 2) cancer 3) HIT 4) chronic inflammation (IBD, Behcet’s, SLE) 5) surgery 6) pregnancy, estrogen 7) infection
APLAS key points
1) can co-exist with SLE but 50% do not 2) antibodies against lupus anticoagulant 3) antibodies bind anticardiolipin and beta 2 glycoprotein
Lupus anticoagulant and anti cardiolipin antibody effect
10x increase in VTE
APLAS on coagulation test
prolonged aPTT
Characteristic of APLAS
thrombosis at unusual sites recurrence 50% high mortality variant = CAPS
Cancer on coagulation
increase fibrinogen, factor 8 and platelet VTE 1-43% risk of VTE 7-20x increase
Nonbacterial thrombotic endocarditis
cardiac manifestation of systemic hemostatic activation in cancer patients = platelet and fibrin vegetation on cardiac valves 30-70% have lab evidence of overt DIC
Pregnancy on coagulation factor changes
1) increase fibrinogen, factor 8 2) reduce protein S
VTE risk in pregnancy
4-6x higher
Rate of left sided VTE in pregnancy
90%
Pregnant patients with these deficiency should get anticoag prophylaxis
1) antithrombin deficiency 2) protein C deficiency 3) protein S deficiency 4) antiphospholipid syndrome 5) factor V leiden
Treatment of pregnant patient with active thrombosis
LMWH full dose
HIT pathophysiology
Antibody against neoantigen on platelet factor 4 (PF4) after binding to heparin
Thrombotic rate in HIT patients
30-70%
Rate of thrombotic death in HIT
4-5%
Monitoring platelets in HIT
1) 5 days after starting heparin 2) 50% decrease triggers investigation 3) serologic screening for HIT-associated heparin/PF4 antibody
Algorithm to decide on testing or just treating new VTE patients
FIGURE 38.1
Laboratory tests to order depending on family history
FIGURE 38.2
Thrombophilic defects and tests available for testing
TABLE 38.2
