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1982 Part XII Hemostasis and Thrombosis

3
Immunizing heparin exposure
HIT-Ab (OD) 2

1
0
0 2 4 6 8 10 12 14 16
Days
300
Macrovascular to microvascular thrombosis
Postoperative
thrombocytopenia,
day 1-4 (hemo-
dilution, platelet
consumption)
Platelet count (x10 9 L –1 ) “Delayed-onset” or Thrombotic potential Progressive platelet activation
200
Consumptive coagulopathy
intensifies during 2nd week
INR ↑, aPTT ↑, ↓ fibrinogen
“autoimmune” HIT
UFH
Protein C pathway activation
100
(intra- or
perioperative) and PF4 release (vicious cycle)
± UFH or LMWH
prophylaxis ± Heparin “flushes”

0
0 2 4 6 8 10 12 14 16
Days
Indirect (AT-mediated) 1. Long half-life achieves stable levels of anticoagulation.
factor Xa inhibitors 2. No interference with activation of the protein C pathway.
(danaparoid, fondaparinux) 3. Specific assays accurately measure drug levels (anti-Xa activity).
4. Inhibition of HIT-Ab-induced platelet activation (danaparoid only).
Direct thrombin 1. PTT monitoring can be unreliable, e.g., DIC, liver disease, warfarin.
inhibitors (DTIs) 2. Short half-lives — risk for “rebound” hypercoagulability.
(hirudin, argatroban, 3. Interfere with thrombin-induced activation of protein C pathway.
bivalirudin) 4. Reversible DTIs (argatroban, bivalirudin) could block thrombin
inhibition by AT.
Vitamin K antagonists 1. Vitamin K antagonists do not inhibit thrombin or its generation.
(warfarin, acenocoumarol, 2. Predispose to protein C depletion (vitamin K–dependent factor).
phenprocoumon) 3. Raise the PTT, thus risking DTI underdosing or interruption.
4. Long half-lives, thus any adverse effects could persist for days.
Fig. 133.4 CONCEPTUAL FRAMEWORK OF HEPARIN-INDUCED THROMBOCYTOPENIA:
FOCUS ON HEPARIN-INDEPENDENT PLATELET ACTIVATION AND DELAYED-ONSET
(“AUTOIMMUNE”) HEPARIN-INDUCED THROMBOCYTOPENIA. The upper panel shows the time-
line of heparin-induced thrombocytopenia (HIT) antibody (HIT-Ab) formation, as judged by optical density
units in an antiplatelet factor 4/polyanion enzyme immunoassay. The middle panel illustrates a platelet count
decline in the absence of heparin (or with small amounts of heparin, e.g., heparin flushes) indicating delayed-
onset HIT, with intensification of HIT-associated hypercoagulability from day 7–14, especially after stopping
heparin. Patients with this clinical profile often have HIT-associated consumptive coagulopathy (overt dis-
seminated intravascular coagulopathy [DIC]), and are at risk for confounding of activated partial thrombo-
plastin time (aPTT)-monitored direct thrombin inhibitor treatment. The lower panel compares different classes
of anticoagulant for expected effects on HIT-associated hypercoagulability, including the risk for aPTT con-
founding in the setting of HIT-associated DIC. AT, Antithrombin; DTI, direct thrombin inhibitor; INR,
international normalized ratio; LMWH, low-molecular-weight heparin; PF4, platelet factor 4; PTT, partial
thromboplastin time; UHF, unfractionated heparin. (From Warkentin TE: Agents for the treatment of heparin-
induced thrombocytopenia. Hematol Oncol Clin North Am 24:755, 2010.)