In contrast to other drug-induced thrombocytopenia, significant spontaneous bleeding is rare with HIT even when thrombocytopenia is severe. This makes the diagnosis of HIT very perplexing. Clinical picture alone will not provide enough clues for the diagnosis. A careful history about the use and allergic reactions to medications, diseases that necessitate heparin use, and date and duration of heparin use should be obtained from the patient. Ancillary procedures should supplement history and physical examination in making a diagnosis.

HIT can be classified into three subtypes:

1. The typical HIT presents on days 5 to 14 of heparin therapy in previously heparin-unexposed patients.
2. Rapid-onset HIT, which is defined as a platelet count drop within hours of heparin administration, occurs on patients with pre-existing anti-PP4/heparin antibodies [5]. The presence of pre-existing antibodies suggests that the patient has one of the following: recent heparin therapy (generally within the last month), previous heparin treatment or major surgery
3. HIT that occurs 1 to 2 weeks after heparin administration is referred to as delayed-onset HIT. This is often associated with disseminated intravascular coagulation (DIC) [20].

• Falling

  Evaluation: 4Ts Feature Score 2 points 1 point 0 points Thrombocytopenia >50% fall and platelet nadir 20-100 × 109/L 30%-50% fall or platelet nadir 10-19× 109/L >30% fall or platelet nadir < 10× 109/L Timing of platelet count fall Clear onset on day 5 [slideshare.net]

  Timing 2 points if the fall is between days 5–10 after commencement of treatment 1 point if the fall is after day 10. [en.wikipedia.org]

  Thrombocytopenia +0 Platelet count fall < 30% or platelet nadir < 10 Platelet count fall 30-50% or platelet nadir 10-19 Platelet count fall > 50% and platelet nadir > 20 Timing of Platelet Count Fall +0 Platelet count fall exposure 30-100 days ago Onset [predictivemedicine.northwell.edu]

  Platelets fall more than 50% from baseline (or, almost always, more than 30%). This typically occurs 5 to 12 days after beginning heparin exposure. [cancertherapyadvisor.com]

• Pathologist

  College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy. The clinical use and laboratory monitoring of low-molecular weight heparin, danaparoid, hirudin and related compounds, and argatroban. [link.springer.com]

  The UT San Antonio team presented data at the Texas Society of Pathologists 2015 annual meeting that summarized their experience. [captodayonline.com]

  The American College of Chest Physicians, in collaboration with the College of American Pathologists, have published a guideline15 in relation to monitoring of platelet count in patients at high risk for HIT. [ncbi.nlm.nih.gov]

• Thrombosis

  DTI, direct thrombin inhibitor; HITT, HIT with thrombosis; SRA, serotonin release assay. [bloodjournal.org]

  Thrombosis 2 points in new proven thrombosis, skin necrosis (see below), or systemic reaction 1 point if progressive or recurrent thrombosis, silent thrombosis or red skin lesions No points if there are no symptoms. [en.wikipedia.org]

  (risk of thrombosis, 30%-75%) 1-7 are increased significantly. [revespcardiol.org]

  […] or other sequelae New thrombosis (confirmed); skin necrosis; acute systemic reaction after IV UHF bolus Progressive or recurrent thrombosis; erythematous skin lesions; thrombosis suspected but not proven None Other causes of thrombocytopenia None apparent [slideshare.net]

  Less often, arterial thrombosis (eg, myocardial infarction) may occur. For that reason, the disorder is sometimes termed heparin-induced thrombocytopenia and thrombosis (HITT). [emedicine.medscape.com]

• Skin Lesion

  lesions; suspected thrombosis not proven Progressive or recurrent thrombosis; non-necrotizing skin lesions; suspected thrombosis not proven afafafaf New thrombosis (confirmed); skin necrosis; acute systemic reaction after UFH bolus afafafaf Other causes [predictivemedicine.northwell.edu]

  Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common-isolated thrombocytopenia, venous thromboembolism, acute limb ischemia-to less common but specific presentations-necrotizing skin lesions at heparin injection sites [ncbi.nlm.nih.gov]

  Adamek] Abstract Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common—isolated thrombocytopenia, venous thromboembolism, acute limb ischemia—to less common but specific presentations—necrotizing skin lesions at heparin [doi.org]

  The patient diagnosed with HIT must be positive for HIT antibodies and meet at least one additional criterion: • A platelet count decrease of 30% to 50% below baseline, regardless of the actual value • A venous or arterial thrombosis • A skin lesion at [mdedge.com]

• Erythema

  Minimal erythema in the feet was noted. Both feet were cold to the touch with no crepitation or fluctuance. [consultant360.com]

• Epistaxis

  A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. [ncbi.nlm.nih.gov]

• Confusion

  A 78-year-old man with a history of severe aortic stenosis presented with confusion, irregular behaviour and dyspnoea 8 days following transcatheter aortic valve replacement. [ncbi.nlm.nih.gov]

  This scheme may be ill-advised as it encourages conflation and confusion between two profoundly different clinical syndromes, one of which can be lethal. [pulmccm.org]

Complete Blood Count

HIT commonly presents as a decrease in platelet count.
The thrombocytopenia is defined as:

• Platelet count drop of not less than 100,000/L 
• Platelet count drop of >50% from the baseline platelet count.

Enzyme-linked assay

The diagnosis of HIT can only be established by using enzyme-linked assays to detect antibodies against heparin-PF4 complexes or heparin-dependent platelet activation.

The current gold standard among the different enzyme-linked assays is the serotonin release assay (SRA). Other tests such as the polyspecific antigen assays (IgG/A/M) and the IgG-specific enzyme-immunoassay (EIA) are at par with SRA in terms of sensitivity (99%) in detecting HIT antibodies [21]. What distinguishes SRA from other tests is its 95-99% diagnostic specificity compared to polyspecific IgG/A/M (50-75%) and IgG-EIA (55-90%) [22].

The SRA works by utilizing washed platelets loaded with serotonin to detect the presence of HIT antibodies in a patient’s serum. Heparin addition to the platelets should trigger platelet activation and subsequent serotonin release when HIT antibodies are present.

• Decreased Platelet Count

  This complex formation will result in platelet activation which causes formation of blood cloths leading to decrease platelet counts and eventually thrombocytopenia. [medical-institution.com]

The management of HIT can be broken down into 4 steps:

Stop all heparin administration

The offending agent should be removed immediately to stop further release of HIT antibodies.

Switch to an alternative anticoagulant

The following are some choices of anticoagulant to be used:

• Direct thrombin inhibitors (DTIs)

DTIs bind directly to thrombin and do not require binding to plasma cofactors such as antithrombin. This characteristic makes it appealing to use in HIT. Lepirudin and Agatroban are DTIs that are clinically proven to safely treat HIT.

• Lepirudin

The recommended dose is 75mcg/kg/hr and the dosage should be titrated based on aPTT monitoring. The recommended aPTT level is 45-70 seconds. It is important to note that lepirudin is cleared by the kindneys. It should not be used by patients with renal insufficiency.

• Agatroban

The recommended dose is 1 mcg/kg/hr that is titrated based on aPTT monitoring. The level of aPTT should be maintained at 45-70 seconds. It is important to remember that agatroban is metabolized in the liver. Patients with hepatic problems should not use this drug.

• Fondaparinux

Fondaparinux is a synthetic analogue of the unique pentassachardie sequence in heparin. However, fondaparinaux binds only to antithrombin and not thrombin. It also does not bind to plasma proteins; therefore, it does not activate platelets and cause release of and bind to PF4. The recommended dosage for fondaparinux in treatment of HIT is 2.5mg OD given subcutaneously.

Do not give platelet transfusions

Thrombocytopenia is a result of the circulating HIT antibodies causing intravascular coagulation. Therefore, the underlying cause (heparin) should be removed rather than give an unnecessary transfusion. Platelet transfusion will only be rendered useless since the platelets will become activated and participate in coagulation as it reaches the circulation.

Do not give warfarin until the platelet count reaches the lower normal limit of 150 x 109/L

HIT causes thrombin generation that consumes protein C. Warfarin is a vitamin K antagonist that depletes the protein C (a vitamin K-dependent anticoagulant) further. The end result is skin necrosis if the protein C in the body becomes insufficient.

Warfarin should only be given once platelet count is normal. It should be overlapped for 5 days with the alternative anticoagulants to maintain the half-lives of all the clotting factors.

The major complications of HIT such as DVT and PE occur in 6-10 out of 100 cases [19]. Early recognition and diagnosis is the key to avoiding unwanted complications.

The thrombocytopenia usually becomes corrected after 7 days in majority of patients. The circulating HIT antibodies will be cleared by the body after approximately 6-8 weeks unless there is re-exposure to heparin therapy.

The main etiology of HIT is a history of treatment with heparin, particularly unfractionated heparin (UFH).

•  UFH easily binds to platelets. Binding between the two causes a release of PF4, which together with heparin is the main presenting antigen of HIT. 
• UFH possesses a strong affinity to PF4. Their binding produces conformational changes within the PF4 [1]. These changes invoke an immunologic response led by IgG antibodies.

The risk of HIT is dependent on the type of heparin used for treatment.

• Use of low-molecular weight heparin (LMWH) is preferred over unfractionated heparin (UFH) because of the lower risk for HIT [6]. 
• LMWH’s affinity to bind with plasma proteins, platelets, and PF4 is significantly lower than UFH’s. Therefore, the chances of triggering an IgG response from platelet activation and PF4-heparin complex decreases as well.
• The use of LMWH significantly decreases the risk of HIT by 5 to 10 times [1] [7] [8]. 
•  The only reason behind the recent increase in incidence of LMWH-induced HIT is that the use of LMWH is increasing in popularity too.One confounder to the risk of developing HIT with LMWH is prior exposure to UFH therapy. Previously exposed patients have a higher risk with LMWH treatment [9].

HIT is reported to occur in 0.2% to 5% of heparin-treated adults.

• This is a rough approximate because the challenge of clinical recognition of HIT is a very daunting task [1]. 

The typical detection of HIT occurs in between days 5 to 14 of heparin therapy.

• The range is variable due to the varying amounts of heparin available in the circulation of each individual. People who are known to receive UFH treatment can have an earlier course of HIT.

It is very rare to see thrombocytopenia below the value of 100,000/L in patients with HIT. Baseline levels should be obtained prior to heparin treatment. A drop of 50% from the baseline should provide a high index of suspicion among patients with heparin use [1].

HIT is frequently seen in surgical patients with comparison to medical patients.

• Major surgery induces inflammation and the activation of platelets. Activated platelets then promote the release of PF4. Consequently, PF4 will bind with endogenous non-heparin factors (e.g. an inflammatory process) to form PF4-non-heparin complexes. The body responds to these complexes by eliciting a B-cell mediated antibody response [10]. Memory cells are formed with the inflammatory process. These cells can become active again when heparin is introduced. The PF4-heparin complexes may trigger the same memory cells to mount an immunologic response. 

The type of surgery also plays a factor in HIT.

• A cardiopulmonary bypass increases the risk of HIT by 2 to 3 % compared to other major surgical procedures. The underlying cause is an increase in IgG antibody formation rate against the PF4-heparin complexes after operation. The rate increases significantly increases between the post-operative days 5 to 14 [11]. 

The incidence of HIT is very low (less than 1%) in both critically ill patients [12] and those undergoing chronic hemodialysis [14]. HIT occurs in less than 0.1% of pregnant women [13].

Females are more likely to be affected with HIT than males [1].

• The odds ratio of female sex to suffer from HIT is 2.37 [8].

A late complication of HIT is thrombosis. Thrombosis that is venous in origin is more common than arterial [1] with a ratio of 2:1 [14].

•  Lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common venous thrombotic manifestations. 
• Arterial thrombosis can manifest as ischemic stroke or acute myocardial infarction (MI).

Heparin’s high-molecular weight is largely in part to its content of at least 18 saccharide units. These saccharide units enable heparin to bind to antiithrombin. However, the saccharide units are not exclusive to antithrombin alone. They also bind to platelets, which release PF4 upon activation, and plasma proteins such as PF4, which carries a great affinity for heparin. A heparin-PF4 complex, which is fortified by forming linear mulitimolecular clusters [15], can carry presenting antigens. An immune-mediated IgG antibody response ensues to neutralize the antigens by binding to the F domain of PF4. The antibody-antibody interaction promotes platelet aggregation and coagulation [16] by activating platelets which release thrombin-generating microparticles. Therefore, HIT’s thrombocytopenic manifestation is a result of intravascular platelet activation [17] caused by the immunologic response to the PF4-heparin antigen. The PF4-heparin complex antibodies also activate monocytes [18] and neutrophils. This leads to a prothrombotic platelet—monocyte—neutrophil linkage that further augments the formation of thrombosis in HIT.

HIT is an immunologic response to the administration of heparin. Careful switch to LMWH or other alternative anticoagulants must be discussed with the patient, especially high-risk patients, to ensure safety. These drugs may be more expensive than heparin but the cost-effectiveness of their administration in terms of safety is invaluable.

Heparin is a frequently used anticoagulant that works by activating antithrombin. A unique pentassacharide sequence found in heparin wraps around antithrombin to activate it. The activated antithrombin directly inhibits factor Xa and binds to thrombin. The newly formed antithrombin-thrombin complex renders thrombin inactive.

Unfortunately, heparin does not exclusively bind to thrombin and factor Xa. It also attaches to the endothelium which affects the half-life of the drug. It also binds to other plasma proteins such acute phase reactants and platelet factor 4 (PF4) [1]. PF4 is released by activated platelets in the presence of thrombus and is highly attracted to heparin. 

Binding of heparin to PF4 produces a PF4-heparin complex that is perceived as antigen. This triggers a cascade of IgG antibodies that are directed against the complex’s antigen. The interaction of the antigen with the antibody promotes activation of platelets and subsequent generation of platelet microparticles. These microparticles exhibit a prothrombotic effect by binding clotting factors and generating thrombin formation. The antibody-mediated process is known as Heparin-Induced Thrombocytopenia (HIT). Despite the thrombocytopenia, the major clinical complication of HIT is venous and/or arterial thrombosis [2] caused by the release of platelet microparticles.

It is important to note that HIT is a clinicopathologic syndrome [3]. Clinical presentation alone will not provide sufficient evidence to diagnose HIT. The suspected HIT patient must be check for the presence of circulating IgG antibodies against the PF4-heparin antigen. The main limiting factor with ancillary diagnosis is that the antibodies present in HIT do not present in a typical primary (initially IgM followed by IgG) or secondary response fashion (persistence of IgG) [4]. Therefore, timing is key to solve the HIT mystery. The IgG antibodies typically rise between days 4-10 after the first heparin dose [5]. Therefore, prompt diagnostic procedures during these days should be done as soon as HIT is suspected to ensure accurate diagnosis and early intervention with alternative anticoagulants. A timely diagnosis will prevent life-threatening complications from arising.

Heparin-induced thrombocytopenia (HIT) is a sudden drop in platelet count after the use of heparin for treatment. This is mainly due to an immunologic or allergic response to some contents produced as heparin enters the blood. It occurs from 0.2-5% of patients receiving heparin and is very variable since each individual has a different response to heparin treatment.

Risk Factors

Females

• Females are more likely to suffer from HIT.

Previous Surgery

• Previous surgery prompts a person to make antibodies (defense cells). These cells may trigger HIT once heparin comes into contact with the defense cells. 

Previous Heparin Treatment

• Previous or recent treatment with heparin may trigger a delayed immune system response to heparin and cause HIT.

Symptoms

HIT rarely produces symptoms and signs of bleeding. The only objective data that can raise suspicion of HT is a low platelet count that is either:

• Below 100,000/L
• Greater than 50% lower from the baseline value

It is best to consult your physician for monitoring if you are undergoing heparin treatment. This holds true especially for first timers to ensure safety since HIT can be very tricky to diagnose. A timely diagnosis is key to preventing unwanted complications of heparin such as deep vein thrombosis (DVT), pulmonary embolism(PE), myocardial infarction (MI), or stroke.

Treatment

Treatment of HIT should be done under the supervision of a physician. Blood monitoring is done throughout the treatment to make sure that bleeding or complications do not take place.

Prognosis

The allergic response to heparin usually clears out totally after 6-8 weeks. The platelet count should return to normal after a week of stopping heparin treatment.

1. Longo D, Kasper D, Jameson J, et al. Harrison’s Principles of Internal Medicine 18th ed. New York: McGraw-Hill; 2011.
2. Greinacher A. Heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7 (Suppl. 1): 9–12.
3. Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79: 1–7. 
4. Greinacher A, Kohlmann T, Strobel U, Sheppard JA, Warkentin TE. The temporal profile of the anti-PF4/heparin immune response. Blood 2009; 113(20):4970-6
5. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344: 1286–92.
6. Warkentin TE, Levine M, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N. Engl. J. Med 1995. 332: 1330-1335.
7. Martel N, Lee J, Wells PS. Risk for heparin induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106(8): 2710-2715.
8. Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparininduced thrombocytopenia. Blood. 2006; 108(9):2937-2941.
9. Prandoni, P., Siragusa, S., Girolami, B., Fabris, F. & Belzoni Investigators Group. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. Stood 2005; 106: 3049-3054.
10. Allman D, Pillai S. Peripheral B cell subsets. Curr Opin Immunol 2008; 20: 149–57.
11. Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk of heparin-induced thrombocytopenia. Blood 2000; 96(5):1703-1708.
12. Crowther MA, Cook DJ, Albert M, et al. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care. 2010; 25(2):287-293. 
13. 13.) Sanson BJ, Lensing AW, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost. 1999; 81(5):668-672
14. Greinacher A, Farner B, Kroll H, et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients. Thromb Haemost. 2005; 94(1):132-135.
15. RauovaL, Z, Kowalska MA, ArepallyGM, Cines DB, Poncz M. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis:diagnostic and therapeutic implications. Blood 2006; 107: 2346–53.
16. KeltonJG, SheridanD, SantosA, et al. Heparin-induced thrombocytopenia:laboratory studies. Blood 1988; 72: 925–30.
17. Chong BH, Murray B, Berndt MC, et al. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83: 1535–41.
18. Arepally G, Ponzc M, Cines DB. Immune vascular injury in heparininduced thrombocytopenia. In: Heparin-induced thrombocytopeni, 4th edn. Informa Healthcare, 2007: 209–25.
19. Arnout J, de Gaetano G, Hoylaerts M, et al, eds. Thrombosis: Fundamental and Clinical Aspects. Leuven, Belgium: Leuven University Press; 2003.
20. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia.Ann Intern Med. 2002; 136(3):210-215.
21. Greinacher A, Juhl D, Strobel U, et al. Heparin-induced thrombocytopenia:a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost 2007; 5: 1666–73.
22. Warkentin TE, Sheppard JA, Moore JC, et al. Laboratory testing for the antibodies that cause heparininduced thrombocytopenia:how much class do we need? J Lab Clin Med 2005; 146: 341–6.