# Presentation: 933203

## Heparin-Induced Thrombocytopenia

**Lawrence Rice, MD**
**Chief, Division of Hematology**
**Clinical Chief, Hem/Onc Service**
**The Methodist Hospital**
**Weill Cornell Medical College**
**Houston, Texas**

## DVT in a Breast Cancer Patient

- 69-year-old woman, first Dx Breast Ca in 2002, 		on and off chemotherapy last 2 years for 	recurrent pleural metastases
- First left leg DVT in March ‘06
- July ’06  Admitted for progressive leg pain and swelling, worse DVT, despite outpatient warfarinRx IV heparin, IVC filter (platelets 350K)
- Two weeks later:	Discharged on warfarin (platelets 81K; had been ~80K last several days)

- HIT With Cancer

## Some Lessons from this Case

- HIT is a common problem
- HIT engenders an extreme risk for serious thrombotic complications
- Unopposed warfarin increases this risk
- IVC filters should be avoided
- Alternative anticoagulants should be started expeditiously
- Therefore, clinicians must be highly informed and remain vigilant for HIT

## There are more than 100 HIT stories in the Medical Center every year...

## Frequency of HITPerspectives

- More than 1 trillion units heparin used yearly in US; 1/3 of hospitalized exposed (12 million)
- Unfractionated heparin – 3 - 5% incidence;		Heart surgery 2.5% incidence
- LMWHeparin, Catheter-flushes -- ~0.5%
- Warkentin, NEJM ’95, 11/332 SQ heparin v. 0/333 LMWH developed HIT
- Laster, 1988, 10/2,000 (0.5%) HIT exposed only to coated vascular catheter
- Frequency of thromboemboli – 30-75%

**Notes:**
Heparin-Induced Thrombocytopenia (HIT): An Overview
Key Point: Broad overview of what the presentation will discuss in detail.
The anticoagulant heparin is used in more than 12 million patients per year1 for treating and preventing thromboembolic disorders in medical and surgical patients.2 Its importance as an anticoagulant has been well established by its effectiveness, rapid onset of action, ease of laboratory monitoring, and cost.
Heparin can cause 2 forms of thrombocytopenia. This slide kit is primarily concerned with immune-mediated thrombocytopenia, or HIT, which occurs in up to 1% to 3% of patients receiving unfractionated heparin and in up to 2% of patients undergoing orthopedic surgery receiving low molecular weight heparin (LMWH).2 HIT is a serious condition with about 50% of patients at risk of life- or limb-threatening thromboses if they remain untreated.3 All forms of heparin should be discontinued in the presence of HIT.4,5 An alternate anticoagulant should be strongly considered to treat HIT as well as the underlying condition. The Food and Drug Administration (FDA) has approved 2 anticoagulants for use in patients with HIT, lepirudin and argatroban.

1. Fahey VA. Heparin-induced thrombocytopenia. J Vasc Nurs. 1995;13(4):112-116. 2. Warkentin 
TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-
molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335. 
3. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 
1996;101(5):502-507. 4. Warkentin TE, Barkin RL. Newer strategies for the treatment of heparin-
induced thrombocytopenia. Pharmacotherapy. 1999;19(2):181-195. 5. Chong BH. Heparin-induced 
thrombocytopenia. Br J Haematol. 1995;89(3):431-439.

## Some Paradoxes of HIT

- Heparin, the most powerful anticoagulant of the twentieth Century, saving uncountable lives and limbs, *also produces the most extreme hypercoagulable disorder, costing thousands yearly their lives and limbs.*
- HIT, an immune reaction to an anticoagulant that lowers platelet count, rarely causes bleeding,
-     *it causes thromboses,(and platelet transfusions are contraindicated).*
- Health professionals should be knowledgeable about a reaction that is common, often catastrophic, preventable, treatable, iatrogenic, and a major source of litigation,*yet textbooks and medical curriculae pay little attention,*
*	**and prevailing lack of awareness is shocking.*

## Heparin-Induced Thrombocytopenia (HIT): Pathophysiology1

- *Places patient at greater risk from primary thrombotic problem.
- 1. Adapted from Aster RH. *N Engl J Med*. 1995;332(20):1374-1376.

**Notes:**
Heparin-Induced Thrombocytopenia (HIT): Pathophysiology
Key Point: HIT is an immune disease resulting in an extremely pro thrombotic state.
Platelet activation results in release of platelet factor 4 (PF4) and microparticles.
Administered heparin interacts with PF4 to form PF4-heparin complexes. PF4 released from activated platelets is also present on the surface of endothelial cells and macrophages. 
Immunoglobulin G (IgG) antibodies react with the PF4-heparin complexes to form immune complexes (PF4-heparin-IgG).
These immune complexes bind to Fc receptors on circulating platelets.1
Binding of immune complexes to platelet Fc receptors results in platelet activation and further release of PF4. Activated platelets trigger a number of events, including activation of even more platelets and activation of the coagulation pathways through platelet-derived microparticles.1-3 
PF4 in excess of the amount that can be neutralized by available heparin binds to glycosaminoglycans on endothelial cell surfaces and monocytes/macrophages. These form additional targets for antibody binding and promote thrombin generation as a result of immune activation. 
Platelet activation of the coagulation pathways, plus tissue factor expression on activated endothelial cells and monocytes lead to enhanced thrombin generation.2
Because thrombin also upregulates its own generation through feedback mechanisms and cellular activation, the result is an ongoing prothrombotic state that increases the risk of thrombosis.3,4
Because thrombin plays a key role in HIT, it is an important target for therapeutic intervention with such agents as direct thrombin inhibitors.4

1. Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med. 1995;332(20):1374-1376. 
2. Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 2nd ed. New York, NY: Marcel 
Dekker, Inc; 2001. 3. Warkentin TE, Hayward CP, Boshkov LK, et al. Sera from patients with heparin induced 
thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the 
thrombotic complications of heparin-induced thrombocytopenia. Blood. 1994;84:3691-3699. 4. Fenton JW,
Ofosu FA, Brezniak DV, Hassouna HI. Thrombin and antithrombotics. Semin Thromb Hemost. 1998;24:
87-91.

## Heparin-Induced Thrombocytopenia (HIT):Clinical Consequences if Untreated

- 	**Sequelae****	****Incidence**
- 	New thromboses	~50%
- 	(arterial or venous)
- 	Amputation	~21%
- 	Death	~30%

- 1. Warkentin TE, Kelton JG. *Am J Med.* 2. King DJ, Kelton JG. *Ann Intern Med.*

**Notes:**
Heparin-Induced Thrombocytopenia (HIT): Clinical Consequences if 
Untreated
Key Point: HIT puts patients at a high risk for dramatic clinical sequelae 
		including new thrombosis, amputation, and death.
Although HIT itself has a relatively low reported incidence, the frequency of serious life- and limb-threatening complications is high. It is estimated that new thromboses occur in as many as 50% of patients with HIT.1 Associated morbidity and mortality rates are also high. The natural history is such that up to 21% of patients with thrombosis2 will undergo limb amputation, and up to 30% will die from all causes.2,3
Venous thromboembolic events, including deep vein thrombosis and pulmonary embolism, tend to occur more frequently in HIT patients than do arterial thrombotic events, but the incidence varies by patient population and practice patterns.1,4

1. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J 
Med. 1996;101(5):502-507. 2. King DJ, Kelton JG. Heparin-associated thrombocytopenia. 
Ann Intern Med. 1984;100(4):535-540. 3. Refludan® [package insert]. Wayne, NJ: Berlex 
Laboratories; 2001. 4. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced
thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. 
N Engl J Med. 1995;332(20):1330-1335.

## Risk of Thrombosis with HITAfter Heparin is Stopped(if an effective alternative is not begun)

- Warkentin and Kelton. *Am J Med* 1996;101.

**Days after isolated HIT recognized **

- 100
- 90
- 80
- 70
- 60
- 50
- 40
- 30
- 20
- 10
- 0

**52.8%**

- 0

- 2

- 4

- 6

- 10

- 12

- 14

- 16

- 8

- 18

- 22

- 26

- 28

- 30

- 24

- 20

- Risk of Thrombosis with HITAfter Heparin is Stopped(if an effective alternative is not begun)

**Cumulative frequency of thrombosis (%)**

**Notes:**
This graph illustrates the cumulative frequency of thrombotic events in patients with HIT who present with isolated thrombocytopenia.5
The majority of thrombotic events occurred within the first week of  diagnosis; there was a subsequent 30-day cumulative risk of thrombosis of more than 50%.5
This study included 62 patients whose diagnosis was based on isolated thrombocytopenia.5
Upon recognition of HIT, 36 of the 62 patients were treated by discontinuation of heparin alone, and 21 of the 62 patients were treated with warfarin following cessation of heparin.
There was no significant difference in the thrombotic event rate between the two treatment groups.

## HIT is a Clinico-Pathologic Syndrome

- Fall in platelet counts (generally >50%)
- Appropriate time after heparin initiation  	 (5-12 days)
- Extreme risk for venous or arterial 	thromboembolic complications
- Eventually:
- Serologic confirmation of platelet-activating 	heparin-PF4 antibodies

## Clinical Suspicion for HITThe 4 T’s (Warkentin, 2003)

- Thrombocytopenia
- Timing
- Thrombosis
- oTher causes for low platelets
-   award 0–2 points for how typical for HIT
-   high prob 6–8 pts; intermed 4-5; low 0-3
- The 5th T: The Test

## HIT Temporal Variants

*Courtesy of Dr Ahjad AlMahameed Cleveland Clinic, OH.*

## Distribution of Platelet Count

- Warkentin. *Semin Hematol* 1998;35(4):9-16.

**Notes:**
This graph shows the platelet count nadir of 142 patients with serologically confirmed HIT: 127 HIT patients had platelet count nadirs less than 150 x 109/L, and 15 HIT patients had platelet count nadirs above 150 x 109/L.8
There is a log-normal distribution of the platelet count nadirs; the median platelet count is approximately 60 x 109/L.8
Unlike other drug-induced immune thrombocytopenia syndromes, HIT is only occasionally complicated by very severe thrombocytopenia; approximately 5% of patients with HIT have a platelet count below 15 x 109/L.8
The majority of patients with HIT develop thrombosis, regardless of whether there is a case of severe, moderate, or mild thrombocytopenia.8

## Laboratory Tests for Heparin-PF4 Antibodies

- Commercially available ELISAs			Highly sensitive (95-99%); High “false 		positive” rates; titer important
- Serotonin-release assays				Technically demanding; variation lab-		to-lab; limited availability
- Platelet aggregation assays				Poor reproducibility
- Multiple others							Flow cytometry or fluorescence-based		Rapid bedside immunoassays
- Newer tests in development

## ACCP Antithrombotic GuidelinesChest supplement, Sept. 2004,Chapter on HIT: Monitoring, Dx and Rx

- Examples of Evidence-Based Recommendations:
- “postoperative prophylaxis with UFheparin (HIT risk > 1%), at least every other day platelet count monitoring between post-op days 4-14 or until UFH is stopped (2C)”
- “postoperative prophylaxis with LMWheparin (HIT risk 0.1-1%), platelet count monitoring every 2 to 3 days between days 4-14 (2C)”

## Treatment of Other Drug-Induced Thrombocytopenias

- Stop the drug
- Consider platelet transfusions
- Consider other measures to reduce bleeding risk
- Once platelets rise, the reaction is over
- Stop all heparin exposures
- Initiate an alternative anticoagulant on suspicion
- Do NOT transfuse platelets; initiate warfarin early
- Risk of thrombosis extends weeks after platelet recovery

**Treatment of Heparin-Induced Thrombocytopenia**

- Rice L. *Arch Intern Med. *2004;164:1961-1964.

## Alternative Anticoagulants 

| Drug | Indications |
| --- | --- |
| Argatroban | FDA-approved for HIT           (also for PCI)  |
| Lepirudin | FDA-approved for HIT |
| Bivalirudin | PCI (including HIT patients) |
| Fondaparinux               (pentasac.) | Prophylaxis and Rx of   VTE |
| Danaparoid | Approved for HIT in Canada, Europe, Aust. |
|  |  |

## The Key to Avoiding Catastrophes from HIT is Awareness, Vigilance, High Degree of Suspicion

**When a patient...**
- experiences a drop in platelet counts
- develops thrombosis

**Consider HIT during/soon after heparin exposure***

**** Heparin exposure may be through virtually any preparation (including LMWH), any dose, or any route of heparin (including flushes and coated lines)***

**Notes:**
Heparin has become one of the most commonly used products in the hospital setting; its use is increasing with the number of procedures performed in cardiovascular medicine and orthopedics.
Patients receiving heparin in the hospital setting should be frequently monitored for platelet count to identify HIT as early as possible.
When HIT is thought to occur, administration of heparin should be stopped immediately, and if indicated, initiate an alternative anticoagulant that does not cross-react with heparin-dependent antibodies. Antibody testing may be useful in confirming the diagnosis of HIT.
Although various factors have been associated with a high risk for the development of HIT, HIT has occurred with all types of heparin, all routes of heparin administration, and all heparin dose levels.1,2

## HIT Summary

- A distinct clinico-pathologic syndrome
- Common—among most common causes 	of thrombocytopenia in hospital
- Serious, always potentially catastrophic
- Unique pathophysiology and testing
- Unique complication profile: 	Thromboemboli
- Unique management: 			alternative anticoagulants

## Proposed ICD-9 CM

- New Code
- 289.84 Heparin-induced thrombocytopenia (HIT)
- A new 5 digit subclassification code as follows:
- 287 Purpura and other hemorrhagic conditions
- 287.4 Secondary thrombocytopenia
- Post-transfusion purpura
- Thrombocytopenia (due to):
- Dilutional
- Drugs
- Extracorporeal circulation of blood
- Platelet alloimmunization
- Use addition E code to identify cause
- Add	**Excludes:**  *Heparin-induced thrombocytopenia (289.84)*

## Proposed ICD-9 CM

- A new 5 digit subclassification code as follows:
- 289 Other diseases of blood and blood-forming organs
- 289.8  other specified diseases of blood and blood-forming organs
- 289.81  Primary hypercoagulable state
- 289.82  Secondary hypercoagulable state
- Add	**Excludes:**  *Heparin-induced thrombocytopenia (289.84)*
*289.83 Myleofibrosis*
*New Code*
*289.84 Heparin-induced thrombocytopenia (HIT)*