The HITS Keep Coming Marc J. Kahn, MD, MBA, FACP Peterman-Prosser Professor Tulane University School...
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Transcript of The HITS Keep Coming Marc J. Kahn, MD, MBA, FACP Peterman-Prosser Professor Tulane University School...
The HITS Keep Coming
Marc J. Kahn, MD, MBA, FACPPeterman-Prosser Professor
Tulane University School of MedicineNew Orleans, LA
Clinical Case
You are asked to see a 43 year old women following bilateral elbow fractures with new onset thrombocytopenia. The patient suffered a fall in a dog park and sustained bilateral radial and ulnar fractures requiring open reduction. She has a history of antiphospholipid antibody syndrome and is maintained on warfarin. Her platelet count fell from 290K to 50 K over five days. She is asymptomatic.
Definitions
• Lupus anticoagulant: prolongation of a clotting time (aPTT, DRVVT)
• Antiphospholipid Antibody: antibodies to cardiolipin, phospholipid, or b2GP1
• APLA Syndrome: thrombosis with APLA
Lupus Anticoag Anti cardiolipin AB
Anti b2GP1
Anti phospholipid AB
Antiphospholipid Antibody Syndrome
• High rate of arterial and venous thrombosis– 32% DVT– 9% PE– 13% CVA– 8% fetal loss
• 5-15% warfarin failure in preventing recurrence
Ann Rheum Dis. 2011
Management of APLAS
• INR 2.0 to 3.0• INR 3.0 to 4.0 is NOT better*• Indefinite anticoagulation
*J Thromb Haemost. 2005;3:848-53.
Thrombocytopenia and APLAb
• Estimated that up to 25% patients with thrombocytopenia may have APLAb
• Nearly 25% patients with APLAb have thrombocytopenia
Our Patient’s Platelets
2-Nov
3-Nov
4-Nov
5-Nov
6-Nov
7-Nov
8-Nov
9-Nov
10-Nov
11-Nov
12-Nov
13-Nov
14-Nov
15-Nov
16-Nov
17-Nov
18-Nov
19-Nov
20-Nov
21-Nov
0
50
100
150
200
250
300
DDx of Thrombocytopenia
• Drug induced• Heparin Induced• Sepsis/DIC• TTP• Catastrophic APLA syndrome• Not routine APLA due to sudden drop
Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.
John Lazarchick, ASH Image Bank 2011; 2011-1376
Peripheral smear
Ruled out diagnosis
• TTP• DIC/Sepsis• Catastrophic APLAS
Heparin Induced Thrombocytopenia
• Occurs 5 or more days after heparin therapy• Can occur faster in patients with prior
exposure (Warkentin NEJM 2001;344:1286)• estimated to occur in up to 3% patients
treated with unfractionated heparin• 24-fold increased relative risk of thrombosis
Representative Case of Typical-Onset Heparin-Induced Thrombocytopenia, Followed by a Rapid-Onset Episode.
Warkentin TE, Kelton JG. N Engl J Med 2001;344:1286-1292.
HITT pathophysiology
P
PF4 + heparin
IgG
Platelet activation, aggregation and clearance
Aster RH. N Engl J Med 1995;332:1374-1376.
Platelet factor 4 (PF4)
• Expressed in megakaryocytes• stored in platelet a-granules• highest heparin affinity of any platelet basic
protein derived compound• physiologic function remains unknown
– ? Role in thrombosis– ? Role in platelet recovery after radiation
• chemokine class of molecule
4 T’s
• Thrombocytopenia (>50% fall)• Timing (5 to 10 days after heparin)• Thrombosis (new)• Thrombocytopenia from other causes• Very HIGH negative predictive value
J Thromb Haemost 2006;4:759
HIT workup
• ELISA for heparin/platelet factor 4 antibodies– Sensitivity = >90%– Specificity = 24-90%
• Functional serotonin release assay– Sensitivity > 90%– Specificity>90%
14C-serotonin release assay
+ 14C-serotonin + pt. serum + heparin
DPM
[heparin]0.1 0.2
Management of HIT
• Need for anticoagulation• AVOID WARFARIN as initial therapy• Argatroban• Lepirudin• Bivalirudin (off-label)• Fondaparinux (off-label)
Warfarin and HITT
• Associated with venous limb gangrene– Warkentin, et al. Ann Int Med 1997;127:804.
Factor Half-life (hrs)
II 72
VII 8
IX 24
X 39
Protein C 14
Protein S 42
Argatroban
• Small molecule direct thrombin inhibitor• Licensed by FDA for HIT in 2000• IV infusion• Follow aPTT• Also increases PT• Metabolized by the liver
Lepirudin (Refludan®)
• Direct thrombin inhibitor• Recombinant hirudin from medicinal leech• IV infusion• Follow aPTT• Cleared by the kidney
Bivalirudin (Angiomax®)
• Direct thrombin inhibitor• Synthetic congener of naturally occurring
leech anticoagulant• IV infusion• Cleared by kidney• Follow aPTT• Not FDA approved for treatment of HIT
Fondaparinux (Arixtra®)
• Synthetic pentasaccharide Xa inhibitor• subQ daily injection• Renal excretion• If monitoring necessary, anti Xa assay• Not FDA approved for treatment of HIT
Low molecular weight heparin
antithrombin Factor Xa
Thrombin
Unfractionated heparin Low mol wt heparin
Low molecular weight heparins
• Less likely to cause HIT than UFH• But, in one study, 62% of HIT cases caused by
dalteparin (Semin Thromb Hemost. 2011;37:653)
• Best avoided in setting of HIT
Thrombosis in hospitalized patients
• HIT• APLA Syndrome• Trauma• Brain injury• Pelvic surgery• Orthopedic surgery• Pregnancy• Cancer
VT Prevention in Medical Patients
• Importance of risk stratification• No difference in outcomes between LMWH
and UFH• Mechanical prophylaxis provided no benefit
with harm in stroke patients
Ann Int Med. 2011;155:602.
Platelet transfusion
• Bleeding very uncommon in HIT• Transfused platelets can cause aggregation
and thrombosis• Platelet transfusions are to be avoided in HIT
unless significant bleeding
Back to the Patient
Heparin-PF4 ELISA NEGATIVESerotonin Release Assay POSITIVEClinically consistent with HITTreated with Fondaparinux
When to start warfarin?
Platelet counts
11-Nov
12-Nov
13-Nov
14-Nov
15-Nov
16-Nov
17-Nov
18-Nov
19-Nov
20-Nov
21-Nov
22-Nov
23-Nov
24-Nov
25-Nov
26-Nov
27-Nov
28-Nov
0
20
40
60
80
100
120
140
160
180
200
Patient
• Warfarin started when platelet count normalized
• Fondaprinux stopped when INR >3.0• Patient D/C from hospital without thrombosis
or bleeding• Returned to work on warfarin
How often do we need to monitor INR?
Warfarin monitoring every 12 weeks is not inferior to monitoring every 4 weeks in patients on stable warfarin doses.
Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med. 2011;155(10):653-9,
12 week monitoring
• Patients stable for 6 months• Otherwise uncomplicated patients
Pearls
• Antiphospholipid antibodies increase risk for arterial and venous thrombosis
• Typical patient with APLAS requires INR 2.0 to 3.0
• Clinical suspicion important in diagnosis HIT• AVOID WARFARIN with acute HIT• HIT requires anticoagulation
Questions