Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition that occurs following exposure to heparin and affects approximately 1–5 % of patients on heparin. Venous and/or arterial thrombosis is the major clinical finding in HIT. Mortality rates up to 20 % were seen in patients with HIT, but have improved with early recognition and intervention.

Two forms of HIT are recognized. Type I HIT (nonimmune heparin-associated thrombocytopenia) is characterized by a mild, transient fall in platelet count (rarely <100,000/μL) that typically develops within the first 2 days of heparin exposure and resolves with continued heparin use. Type I HIT is not associated with thrombosis and is of no clinical significance. Type II HIT is immune-mediated and associated with thrombosis. Type II HIT will be discussed from hereon.

HIT is caused by IgG autoantibodies directed against complexes of platelet factor 4 (PF4) and heparin. Platelet Fc receptors bind the antibody-heparin-PF4 complex, resulting in activation of platelets and subsequent procoagulant response with thrombin generation. HIT antibodies also bind to endothelial cells, leading to endothelial cell activation with increased tissue factor and thrombin generation [14]. Thrombocytopenia occurs when the IgG-coated platelets are removed by the macrophages of the reticuloendothelial system and during platelet consumption for thrombi formation.

The majority of HIT patients (85–90 %) present with thrombocytopenia, less than 150,000/μL, 5–14 days after exposure to heparin, regardless of the dose or route of administration. HIT occurs predominantly with exposure to unfractionated heparin, and is more common in women and surgical patients [15, 16]. The platelet count falls greater than 50 % from baseline with a mean nadir of 60,000/μL. However, 5 % of patients may not develop thrombocytopenia but demonstrate a 30–50 % drop in platelet count. Platelet counts rarely fall below 20,000/μL and bleeding is hardly seen. Rapid onset HIT (within the first 24 h of exposure) occurs in patients previously exposed to heparin within the previous 100 days secondary to the presence of HIT antibodies already in the patient’s plasma. Delayed onset HIT has been described and is seen up to 3 weeks after heparin exposure, caused by high titers of platelet-activating heparin-induced IgG resulting in heparin-independent platelet activation, in addition to heparin-dependent activation [17].

Thrombosis is seen in up to 50 % of patients with HIT. Thrombocytopenia often precedes thrombosis. Venous thromboembolism occurs more frequently than arterial thrombi. Pulmonary embolism was the most common life-threatening thrombotic event, occurring in 25 % of all patients [18]. Complications of HIT include ischemic limb gangrene resulting in amputation, skin necrosis, myocardial infarction, stroke, organ infarction, or post-intravenous heparin anaphylaxis. The increased thrombotic risk persists for days to weeks after discontinuation of heparin [19].

The initial suspicion of HIT is clinical. A clinical scoring system, such as the 4T’s score, is used to guide the determination of HIT and need for further investigation. The 4T’s score has been validated and assesses the degree of Thrombocytopenia, Timing relative to heparin exposure, presence of Thrombosis, and other causes for thrombocytopenia. One study reported a negative predictive value of a low 4T’s score of 0.998 and positive predictive value of an intermediate and high score of 0.14 and 0.64, respectively [20, 21]. Essentially, a low 4T’s score rules out HIT and intermediate or high scores require further testing for HIT.

HIT antibodies can be demonstrated by immunoassays (enzyme-linked immunosorbent assays [ELISA]) that detect anti-PF4/heparin antibodies or functional assays (serotonin-release assay [SRA]) that detect heparin-dependent platelet activation by patient serum. It is important to note that all cases of HIT are caused by platelet-activating antibodies, but not all PF4/heparin complex antibodies result in HIT (some antibodies are clinically insignificant). There is data showing clinical correlation between immunoassays and SRAs. A weakly positive ELISA (OD 0.40 to <1.00) was associated with a less than 5 % low probability of a strongly positive SRA and increased to approximately 90 % with an OD greater than 2.00 [22]. The SRA is more specific and is considered the “gold standard” for diagnosing HIT, but it is less widely available, more complex and may take up to several days. The SRA is especially useful in cases of indeterminate immunoassays (OD 0.4 to 2.0).

Patients with HIT (presumptive due to intermediate or high 4T score, or confirmed by SRA) should have all heparin products stopped, including heparin flushes. A non-heparin anticoagulant should then be substituted due to the increased thrombotic risk, unless there is bleeding or a high risk of bleeding. Treatment should not be delayed while awaiting confirmative laboratory testing. Early intervention may prevent thrombotic events and subsequent morbidity and mortality [23]. Alternative anticoagulants used to treat HIT include direct thrombin inhibitors (argatroban, bivalirudin), fondaparinux (anti-factor Xa inhibitor), and danaparoid. The choice of anticoagulant agent depends on the patient’s renal and hepatic function. Vitamin K antagonists (VKA) such as warfarin should not be given in acute HIT and should only be started when the platelet count has recovered to at least 150,000/μL due to the increased risk of venous limb gangrene and skin necrosis [24]. The non-heparin anticoagulant should be continued for a minimum overlap of at least 5 days with VKAs and the target international normalized ratio (INR) has been reached. If the patient had been on VKA therapy at the time HIT was diagnosed, Vitamin K should be given. Target-specific oral anticoagulants, such as rivaroxaban and dabigatran, should be effective treatment for HIT based on principle, however, clinical data is limited and their off-label use is considered on a case by case basis [25]. Anticoagulation with a non-heparin anticoagulant should be continued for at least 2–3 months in patients with HIT, and for at least 3–6 months in patients with associated thrombosis. If the diagnosis of HIT is excluded, heparin may be resumed. Patients with confirmed HIT should avoid heparin, including low molecular weight heparin (LMWH) due to strong cross-reactivity of the HIT antibody, for life.

Antiphospholipid syndrome (APS) is an acquired thrombophilic state characterized by venous and arterial thrombosis, as well as recurrent miscarriages and pregnancy complications, in the presence of antiphospholipid antibodies [26]. Antiphospholipid antibodies (APL) are autoantibodies directed against phospholipids and phospholipid-binding proteins. APL may occur in the absence of disease (primary APS), or are often seen in association with other diseases, especially systemic lupus erythematosus. They occur in other rheumatologic conditions, or may be associated with infections—bacterial or viral, medications such as hydralazine and phenytoin, and malignancy. APL may be seen in healthy individuals, up to 5 %, but these are usually transient and of no clinical significance. Thrombosis appears to occur through various mechanisms including activation of platelets and endothelial cells, increased tissue factor and thrombin generation, and interference with antithrombotic pathways [27].

APS is diagnosed based on the revised Sapporo classification, which requires at least one clinical and one laboratory criteria [28]. Clinical criteria include either the confirmed presence of venous, arterial, or small vessel thrombosis in any tissue or organ, or pregnancy complications such as three or more unexplained early pregnancy losses, one or more unexplained fetal death of at least 10 weeks gestation, or one or more preterm delivery prior to 34 weeks of gestation due to eclampsia, preeclampsia, or placental insufficiency. The persistence of the following APL on two or more occasions at least 12 weeks apart must be demonstrated on laboratory testing: lupus anticoagulant (LA), anticardiolipin antibodies (ACL) immunoglobulin G (IgG) and immunoglobulin M (IgM) in moderate or high titers, or anti-β₂-glycoprotein-I antibodies (anti-β₂GPI) in moderate or high titers. Lupus anticoagulants are detected by various functional coagulation assays that result in prolonged clotting times. ACL and β₂GPI antibodies are detected by ELISA. Triple positivity is associated with a higher risk of thrombosis. Testing for additional antibodies, such as antiphosphatidylserine antibodies, is not recommended as their association with thrombosis is not well established.

Venous thromboembolism is the most common clinical manifestation of APS. Other clinical findings that do not meet criteria include thrombocytopenia, livedo reticularis, valvular disease, neurological manifestations such as memory impairment and white matter lesions on MRI, and rare episodes of bleeding due to prothrombin antibodies. Catastrophic APS may be seen in a small proportion of patients who develop widespread thrombosis with multiorgan failure.

Patients with APS and venous thromboembolism are treated using standard anticoagulation with unfractionated heparin or LMWH, followed by warfarin targeting an INR of 2–3 [29]. LA may interfere with PTT and PT/INR anticoagulation assays and in such cases other studies are employed, such as anti-factor-Xa, chromogenic factor X, or factor II activity, to determine the level of anticoagulation. The recommendation is to continue anticoagulation indefinitely in patients with confirmed APS due to the high risk of recurrence [30]. Target specific oral anticoagulants are not recommended for treating VTE in APS until more evidence becomes available for their use in such patients. The treatment of arterial thrombosis is controversial and options include antiplatelet therapy, anticoagulant therapy, or both. Treatment for catastrophic APS includes anticoagulation and glucocorticoids, and possibly IVIG, plasma exchange, and other immunosuppressants such as cyclophosphamide [31]. Pregnant women with APS should be treated with LMWH and/or low-dose aspirin based on their history and clinical presentation.

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell clonal disorders characterized by the overproduction of one or more of hematopoietic cells. MPNs have the potential to evolve into myelofibrosis or acute myeloid leukemia. The four most common MPNs are polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia (CML). Other MPNs include chronic neutrophilic leukemia, chronic eosinophilic leukemia, and mastocytosis. CML is associated with a balanced translocation between 9 and 22 [t(9;22)9q34;11)] called the Philadelphia chromosome. PV, ET, and MF are Philadelphia chromosome negative and in many cases are characterized by JAK2 mutations. These mutations cause constitutive activation of the JAK2 tyrosine kinase (gain of function) resulting in increased cell proliferation and survival. Almost all patients with PV have a JAK2 V617F or exon 12 mutation, whereas ET and PMF display 50–60 % JAK2 V617F mutations [32]. Additional mutations, such as CALR and MPL, are detected in patients with JAK-2 negative MPNs.

MPNs are rare and seen in approximately 0.5–3 per 100,000 persons depending on the subtype [33]. MPNs, especially PV and ET , are associated with an increased risk of thrombosis, both venous and arterial. Thrombosis in unusual locations, such as the splanchnic circulation and cerebral veins, should raise the suspicion for an underlying MPN. MPNs accounted for 40 % of Budd Chiari syndrome and 31 % of portal vein thrombosis [34]. The pathogenesis of thrombosis is complex and involves various processes, such as increased inflammatory cytokines, leukocyte-derived proteases, and endothelial adhesion molecules, leading to a procoagulant environment. Patients may present with fatigue, fever, night sweats, pruritus, early satiety due to splenomegaly, erythromelalgia, headaches, vision changes, and bleeding due to acquired von Willebrand disease.

Treatment depends on the underlying disease and aims to prevent or minimize complications, especially thrombotic risk in ET and PV [35]. Low dose aspirin, with or without hydroxyurea (an antimetabolite), is recommended in patients at high thrombotic risk, those with prior thrombosis and age greater than 60 years [36]. Phlebotomy and/ or hydroxyurea are used to control hematocrit in PV. Platelet lowering agents, such as hydroxyurea or anagrelide, are used in ET patients at increased thrombotic risk. Low risk or asymptomatic patients with MPN may be observed. Supportive measures such as red blood cell or platelet transfusions are used for significant cytopenias. Hematopoietic cell transplantation is the only curative treatment for PMF but is associated with significant transplant-related mortality and so is reserved for specific patients. Ruxolitinib is a JAK1/JAK2 inhibitor approved for treatment of certain MPNs, for whom hydroxyurea has failed or those with high risk MF.