Pathological Inhibitors of Coagulation

Question 1

Two categories of pathological inhibitors

Answer 1

• specific = Ab against a specific coag factor (anti-factor VIII); interferes with coagulation
• non-specific = Ab that has no action against one specific coagulation factor; multiple targets; interferes with testing

Question 2

two mechanisms of specific factor inhibitors

Answer 2

• directly inhibit clotting factor activity
• bind to the non-active site of coagulation factor to form immune complex
  > cleared from circulation
• occur after transfusion, clotting factor replacement therapy, or spontaneously*
• inhibitors of factor VIII are most frequent*

Question 3

inhibitors can be : (2)

Answer 3

• immediate or delayed reacting

- time and temperature dependent

Question 4

confirmation of specific inhibitor

Answer 4

• perform specific factor assays for all suspected factors
  > depending on PT/aPTT results
• inhibitors levels can be quantified using the Bethesda inhibitor assay
  > test based on specific factor assay to measure factor activity level

Question 5

what are pathological inhibitors?

Answer 5

• acquired inhibitors of coagulation
• form spontaneously pr develop secondary to an underlying disorder- Abs
• in vivo and in vitro effects (may not be the same!; can cause probs w routine coag testing

Question 6

alloimmune anti-FVIII

Answer 6

• can develop in some patients with hemA who are on factor replacement therapy
• hemA patients make no to very little FVIII (therapeutic factor seen as foreign)
• Ab to FVIII develops; inhibits FVIII

Question 7

autoimmune anti-factor VIII

Answer 7

-spontaneously develop after pregnancy, or in older patients w underlying disease
- can also occur in patients w autoimmune or inflammatory disease
> rheumatoid arthritis, SLE, inflammatory bowel disease
- “acquired hemophilia” = autoAb acts as an inhibitor to FVIII; no genetic defect but leads to symptoms of hemophilia like bleeding in soft tissues, Gi, etc.

Question 8

characteristics of Anti-FVIII

Answer 8

• FVIII circulates bound to vWF so Ab directed to FVIII portion
• delayed-reacting
• temperature-dependent
• usually IgG antibodies

Question 9

treatment of anti-FVIII

Answer 9

• low titre Ab (<5): treat with high dose of FVIII
• high titre (>5):
  > Ab inhibits any recombinant FVIII
  > may benefit from immunosuppressive medication
• prothrombin complex concentrates (PCCC) to bypass VIII-dependent step in intrinsic pathway (FVIII inhibitor bypassing activity (FEIBA))
  > HemLibra = Ab that mimics FVIII

Question 10

antiphospholipid Abs

Answer 10

• non-specific inhibitor
• can develop in response to infections, drugs, autoimmune disease, or spontaneously
• bind to protein-phospholipid complexes
  > in vitro = acts like an anticoagulant
  > in vivo = increased clotting tendency
  
  • caused of acquired thrombophilia
  • associated with strokes, arterial disease , etc.

Question 11

lupus anticoagulant

Answer 11

• non-specific inhibitor
• immediate reacting
• non-temperature dependent
• affects phospholipid- dependent coag tests
  > X formation of tenase and prothrombinase complexes
• prolonged aPTT only = lower phospholipid concentration (compared to PT reagent)

Question 12

confirmatory tests for lupus antcoagulant

Answer 12

use systems that bypass or neutralize inhibitor

Question 13

dilute Russell’s Viper Venom Time (DRVVT)

Answer 13

• confirmatory test for lupus anticoagulant (LA)
• Russell’s viper venom will clot plasma by direct activation of FX in the presence of a phospholipid
  > patient should have normal levels of X, V, prothrombin, and fibrinogen
• concentration of phospholipid is low so test will be able to detect LA