Hypercoagulable states and heparin-induced thrombocytopenia

• Hypercoagulable (thrombophilic) states predispose to venous thromboembolism (VTE). They may be inherited, such as Factor V Leiden, or acquired, such as antiphospholipid syndrome, cancer, nephrotic syndrome, pregnancy, immobilisation or surgery.
• Most inherited thrombophilias raise relative risk several-fold but absolute annual risk remains low. Anticoagulation decisions rest mainly on whether the clot was provoked and on bleeding risk, not on the thrombophilia result. ^[1]
• Thrombophilia testing should be selective. It changes management in antiphospholipid syndrome and in a few specific situations, but rarely in Factor V Leiden or the prothrombin variant. ^[1]
• Heparin-induced thrombocytopenia (HIT) is a different problem: an immune-mediated, strongly pro-thrombotic reaction to heparin that typically appears 5 to 10 days after starting heparin. Stop all heparin and start a non-heparin anticoagulant immediately. ^[2]
• In HIT, do not start warfarin until the platelet count has recovered (usually at least 150 x 10^9/L) and overlap it with a non-heparin anticoagulant for at least 5 days; starting warfarin alone can cause venous limb gangrene or warfarin skin necrosis. ^[2]

By the end of this page you should be able to:

1. List the inherited and acquired hypercoagulable states and compare their relative risks of VTE.
2. Decide whether thrombophilia testing is indicated in a given patient, and time it correctly.
3. Plan anticoagulation for VTE in the presence of thrombophilia, including drug choice and duration.
4. Recognise and manage warfarin skin necrosis.
5. Recognise HIT, estimate pre-test probability with the 4T score, arrange the right laboratory tests, and treat it safely.
6. Adapt evaluation and treatment when tests or drugs are unavailable.

Hypercoagulability means the balance of haemostasis tilts towards clot. The acquired "cup" (oestrogens, pregnancy, cancer, nephrotic syndrome, surgery, immobilisation) often weighs more than the gene. Treatment decisions therefore rest on clinical context, not on a laboratory result alone. ^[6]

Thrombophilia is the synonym used in the literature. Clotting has three lines of defence: the vessel wall, platelets, and the coagulation proteins. Hypercoagulable states disturb the last of these, either by adding a procoagulant (Factor V Leiden, prothrombin G20210A) or by losing an anticoagulant (antithrombin, protein C, protein S). ^[1]

VTE (deep vein thrombosis and pulmonary embolism together) rises steeply with age. Inherited thrombophilias are common but their absolute thrombotic rates are low. Heterozygous Factor V Leiden is carried by 3 to 8 percent of people of European descent, yet its absolute annual VTE rate in asymptomatic carriers is about 0.28 percent. ^[1]

Geography matters: Factor V Leiden and the prothrombin G20210A variant are most common in European-descent populations and are much less common in many Asian and African populations. ^[1]

These are single-gene disorders of the coagulation cascade or its control proteins.

Notes:

• Relative risks come from family cohorts of relatives of thrombotic probands and may overstate population-level rates. ^[1]
• Natural anticoagulant deficiency (antithrombin, protein C, protein S) carries the highest individual relative risk but is rare. ^[1]
• MTHFR C677T polymorphism is common (10 to 15 percent homozygous) but is not an independent VTE risk factor when folate and vitamin B12 are adequate, and testing for it is not recommended. ^{[1] [5]}

These are not detected by a thrombophilia panel; they must be recognised clinically. ^[1][6]

• Antiphospholipid syndrome (APS). An autoimmune thrombophilia with lupus anticoagulant, anticardiolipin and/or anti-beta-2-glycoprotein I antibodies. Clinically diagnosed APS affects about 0.05 percent of the general population but 1 to 5 percent of people presenting with VTE. Triple-positive disease (all three antibodies) carries a very high recurrence risk. APS changes the choice and duration of anticoagulation, so testing matters here. ^[1]
• Cancer, a high-risk state in its own right: tumour and treatment both promote thrombosis; cancer-associated thrombosis is a distinct pro-thrombotic state. ^[6]
• Myeloproliferative neoplasms (for example JAK2, CALR or MPL mutations). ^[1]
• Paroxysmal nocturnal haemoglobinuria (PNH). ^[1]
• Nephrotic syndrome (urinary loss of antithrombin and other proteins, together with increased hepatic synthesis of procoagulants). ^[6]
• Pregnancy and the puerperium, plus exogenous oestrogens (combined oral contraceptive, hormone replacement): increase thrombotic risk several-fold, particularly on top of an inherited thrombophilia. ^[1][6]
• Major surgery and immobilisation (transient, usually high short-term risk). ^[1][6]
• HIV infection, inflammatory bowel disease, nephrotic syndrome, and other chronic inflammatory states also predispose. ^[6]

Homocysteine above about 13 to 15 micromol/L is common. Homocystinuria (levels 100 to 400 micromol/L) is a rare autosomal recessive cause with childhood lens dislocation, mental retardation, marfanoid habitus and VTE. Moderate hyperhomocysteinaemia is a weak risk factor for incident and recurrent VTE; in one study, recurrence risk was 1.8-fold higher when homocysteine was above the 90th centile (20.1 micromol/L). B12 or folate deficiency (pernicious anaemia, thyroid disease) is an under-recognised reversible contributor. ^[6]

Coagulation is normally limited by two natural brakes: antithrombin (which neutralises thrombin and Factor Xa) and the protein C / protein S system (which inactivates Factors Va and VIIIa, with Factor V Leiden blocking this by making Factor V resistant to activated protein C). Deficiency or resistance removes the brake; the prothrombin variant raises substrate. ^[1]

APS antibodies activate endothelium, platelets, complement and tissue factor-bearing monocytes: a "two-hit" model in which the antibody is a persistent pro-thrombotic first hit, and infection, surgery or pregnancy provides the second hit that produces a clinical thrombosis. Cancer creates a pro-coagulant environment through tissue factor expression and inflammation; nephrotic syndrome loses antithrombin in the urine while the liver overproduces procoagulants. ^[1][6]

HIT is an immune reaction to heparin in which IgG antibodies bind multimolecular complexes of platelet factor 4 (PF4) and heparin on the platelet surface, activating platelets through Fc gamma RIIa and generating a burst of thrombin. Platelets fall, but this is not consumptive bleeding: it is platelet activation, so thrombosis, not haemorrhage, is the feared complication. ^[4]

PF4 is a positively charged chemokine released from platelet alpha granules. Heparin's strong negative charge brings PF4 molecules together; neutralisation of charge exposes new epitopes, forming the antigen. This charge stoichiometry also explains why unfractionated heparin (UFH) carries about a 10-fold higher risk of HIT than low-molecular-weight heparin (LMWH) or fondaparinux. ^[2]

HIT occurs in 1 to 3 percent of patients receiving UFH and less frequently with LMWH. Women have about twice the risk of men, and post-cardiac/orthopaedic surgery patients on UFH 1 to 5 percent versus medical or obstetric patients 0.1 to 1 percent. ^{[2] [7]}

HIT is classified into subtypes: classic HIT (heparin-dependent antibodies), autoimmune HIT (both heparin-dependent and heparin-independent antibodies; includes delayed-onset, persistent, heparin-flush and fondaparinux-associated HIT), and spontaneous HIT-like syndromes that occur without proximate heparin exposure. ^[4]

HIT is a clinicopathological syndrome: the diagnosis needs both a compatible clinical picture and platelet-activating anti-PF4 antibodies. ^[2]

Most thrombophilias declare themselves with an ordinary (or slightly unusual) venous clot: a painful swollen calf (DVT) or sudden breathlessness and pleuritic chest pain (PE). Arterial events are uncommon except in APS or hyperhomocysteinaemia. A first VTE at a young age (about 40 or under), an unusual site (cerebral, portal, mesenteric or renal vein), unprovoked recurrence, or a strong family history should raise suspicion of an inherited thrombophilia. ^[6]

The typical and most common manifestation is thrombocytopenia: thrombocytopenia is defined as a platelet count under 150 x 10^9/L, or (more broadly) a 30 to 50 percent fall even if the nadir remains above 150 x 10^9/L. ^[2]

Characteristic onset is 5 to 10 days after starting heparin (day 1 is day 0). This is "typical-onset HIT". Other time patterns are recognised:

• Rapid-onset HIT: an abrupt platelet fall within 24 hours in a patient who still has circulating HIT antibodies from a recent exposure, usually within the last month and occasionally up to 100 days earlier. ^[2]
• Delayed-onset HIT: thrombocytopenia beginning at least 5 days after heparin has been stopped (a mean of 9.2 days in one series), driven by heparin-independent antibodies. Platelets take longer to recover and thrombosis risk is high. Cases have also been reported up to 3 weeks later. ^[2][4]
• In up to 25 percent of HIT patients, thrombosis precedes the fall in platelet count. ^[2]

Thrombosis is the dominant complication: 17 to 55 percent of untreated patients with isolated (thrombocytopenic) HIT go on to develop DVT, PE or arterial thrombosis (limb artery, stroke, myocardial infarction, each 3 to 10 percent). About 5 to 10 percent of patients with HIT die, usually from thrombosis. ^[2]

Less common manifestations: venous limb gangrene (5 to 10 percent of HIT patients with DVT treated with a vitamin K antagonist), necrotising skin lesions at heparin injection sites, adrenal haemorrhagic necrosis from adrenal vein thrombosis, and acute systemic reactions within 30 minutes of an intravenous heparin bolus. Despite low platelets, bleeding signs are rare. ^[2]

Post-cardiac surgery, the platelet count falls about 38 percent after bypass and then recovers. Two patterns point to HIT: a fall beginning more than 4 days after surgery, and thrombocytopenia persisting more than 4 days after surgery. ^[2]

For a patient who becomes thrombocytopenic after heparin, the key question is whether this is HIT or something else. HIT should be considered with a compatible low platelet count in a heparin-exposed patient, but sepsis, drug-induced thrombocytopenia, marrow failure, TTP and pseudothrombocytopenia are common. The 4T score exists precisely to estimate this probability.

For a patient presenting with VTE, the differential is the breadth of provoking states rather than an alternative cause: ask about surgery, immobilisation, pregnancy, hormones, cancer, nephrotic syndrome, infection and family history before labelling a clot "idiopathic".

Testing should be done only when the result will change management. ^[6] Agreement across guidelines is that routine testing after a provoked clot is discouraged. ^[1]

A practical, management-oriented approach:

• Do not test in a clearly provoked VTE (major provoking factor such as surgery, trauma or prolonged immobilisation), because anticoagulation duration is driven by the provocation, not by the genotype. ^[1]
• Antiphospholipid syndrome is the exception: test for lupus anticoagulant, anticardiolipin and anti-beta-2-glycoprotein I antibodies in unprovoked or minor-provoked VTE, because APS changes drug choice (vitamin K antagonist rather than a direct oral anticoagulant in many cases) and duration. ^[1]
• Hereditary thrombophilia (Factor V Leiden, prothrombin variant, antithrombin, protein C, protein S) may be tested when the patient has a weakly or unprovoked VTE, is under 40, has a first-degree relative with VTE, or has thrombosis in an unusual site, family planning, or wants an informed decision about stopping anticoagulation. ^[1][6]
• Do not test for MTHFR in the evaluation of VTE. ^[1]
• Testing for cancer, myeloproliferative neoplasm and PNH is part of the work-up of an unexplained clot, especially with constitutional symptoms or an abnormal full blood count. ^[1]

Natural anticoagulant proteins behave like acute-phase reactants and are consumed during an acute clot. Testing too early produces false labels of "deficiency". ^[1][6]

• Acute phase: test late, ideally at least 6 weeks after the clot (or after delivery). ^[6]
• Factor V Leiden and prothrombin G20210A (DNA tests): unaffected by anticoagulation and can be done at any time, although results rarely change immediate care. ^[1]
• Protein C, protein S and antithrombin assays: defer until the acute episode has passed; if on warfarin, wait 2 weeks after stopping, and 2 to 3 days after stopping a direct oral anticoagulant. ^[1]
• Lupus anticoagulant: confounded by heparin and direct oral anticoagulants; test off these drugs where possible, and confirm at least 12 weeks later (transient infection-induced antibodies are common in the acute phase). ^[1]
• Heparin, LMWH and direct oral anticoagulants interfere with clot-based assays; consult the coagulation laboratory when unsure. ^[1]

• 4T score (below) is the bedside pre-test probability tool.
• Anti-PF4/heparin immunoassay (ELISA): highly sensitive (about 100 percent sensitivity for pathogenic antibody, optical density (OD) threshold 0.4), but moderate specificity; positive results in low-pre-test patients usually do not mean HIT. Quantitative reporting of OD matters: an OD above 1.0 with an intermediate or high 4T score gives an accuracy close to the functional assay. ^{[2] [7]}
• Functional assay (serotonin release assay (SRA) or heparin-induced platelet activation (HIPA)): the reference standard, available only in specialist centres, confirms whether the antibody actually activates platelets. ^[2]
• The anti-PF4 antibody persists for weeks after platelet recovery (subacute HIT), so a positive ELISA alone is not proof of active HIT. ^[2]

HIT probability by 4T score: 0 to 3 points = low (under 1 percent), 4 to 5 = intermediate (about 10 percent), 6 to 8 = high (about 50 percent). ^[3]

Laboratory thresholds: ELISA considered positive at OD 0.400 or above; further stratified low positive 0.400–1.000, moderate 1.000–2.000, strong above 2.000. ^[7]

The principles:

• Use a standard heparin-based regimen for the acute clot (unfractionated heparin, LMWH, fondaparinux or a direct oral anticoagulant). ^[6]
• Duration: 6 weeks to 3 months for a clot provoked by a transient risk factor; longer for persistent risk factors. ^[6]
• Vitamin K antagonist (VKA), for example warfarin, is dosed to an INR of 2.0 to 3.0. ^[6] For APS, a VKA is generally preferred over a direct oral anticoagulant, especially in triple-positive or high-risk APS. ^[1][2]
• Direct oral anticoagulants (rivaroxaban, apixaban, dabigatran, edoxaban) are standard for most other patients. ^[6]

Duration of anticoagulation depends on provoked versus unprovoked, recurrence risk and bleeding risk (HAS-BLED-style thinking), not usually on the thrombophilia:

• A single clot clearly provoked by a transient factor: treat the acute episode (about 3 months) and stop, unless the thrombophilia is antithrombin, protein C or protein S deficiency, APS, compound heterozygosity, or there is other high-risk disease, where secondary (indefinite) prophylaxis is more often recommended. ^[6]
• Unprovoked VTE or recurrent VTE: prolonged (indefinite) anticoagulation is generally preferred, particularly with APS. ^[1][6]
• Isolated heterozygous Factor V Leiden or prothrombin G20210A alone does not usually justify secondary prophylaxis after a first provoked clot. ^[6]

Warfarin-induced (coumarin) skin necrosis is rare (0.01 to 0.1 percent of warfarin users) but serious. It results from the early, disproportionate fall of protein C relative to the longer-lived procoagulant factors when warfarin is started without adequate overlap, creating a transient hypercoagulable window. ^[5]

Clinical features: typically middle-aged patients, predominantly women. Lesions appear 3 to 10 days (up to 2 weeks) after starting warfarin, most often on the thighs, buttocks, breasts or trunk. Onset is sudden painful erythema, then petechiae, haemorrhagic bullae and, within 24 hours, full-thickness necrosis. Up to 40 percent of cases require surgical debridement and 15 percent are fatal. ^[5]

Risk factors: inherited or acquired protein C or S (and antithrombin) deficiency, APS, factor V Leiden, obesity, starting high-dose warfarin without heparin bridging, liver disease, and restarting warfarin after interruption. ^[5]

Treatment and prevention:

• Stop or reverse warfarin promptly and give vitamin K. ^[2]
• Give therapeutic heparin (or LMWH/fondaparinux) to restore anticoagulation. ^[2]
• In HIT specifically, vitamin K should be given if a VKA was already started when HIT was diagnosed. ^[2]
• Start warfarin late and low: only when the platelet count has recovered, at a maximum starting dose of 5 mg (warfarin) with overlap for at least 5 days and until the INR is in target, then re-check the INR once the non-heparin drug has worn off. ^[2]
• Prevention: always bridge with heparin/LMWH, avoid high loading doses (maximum 5 mg), and recognise the at-risk (thrombophilic) patient in advance. ^[5]

The first step is to suspect it. Stop all heparin immediately (including flushes and heparin-coated catheters) and start a non-heparin anticoagulant (argatroban, lepirudin, danaparoid, fondaparinux, bivalirudin, or a direct oral anticoagulant in selected cases), even before laboratory confirmation, because thrombosis occurs in about 5 percent of patients per day untreated. ^[2]

Practical points:

• Choice of non-heparin anticoagulant depends on context. The Chest guideline suggests argatroban, lepirudin or danaparoid with normal renal function; argatroban with renal insufficiency; bivalirudin for urgent cardiac surgery or percutaneous coronary intervention; danaparoid in pregnancy. ^[2]
• Platelet transfusion is not routine. Give platelets only if there is bleeding or a high-bleeding-risk invasive procedure. ^[2]
• Monitoring after HIT: platelets should be monitored for at least as long as the exposure lasts in high-risk patients (risk over 1 percent), every 2 to 3 days from day 4 to day 14 of heparin, or until heparin is stopped. ^[2]
• Low or low-intermediate 4T scores have a high negative predictive value (over 96 percent), so a low score plus a negative or weak immunoassay effectively excludes HIT. ^[1][3][7]
• Drug availability matters: many smaller centres have only fondaparinux and argatroban. East African practice often relies on fondaparinux or LMWH avoidance plus, where available, danaparoid or direct oral anticoagulants.

• Recurrent VTE, particularly with persistent risk factors (cancer, APS, antithrombin/protein C/S deficiency).
• Post-thrombotic syndrome after DVT.
• Chronic thromboembolic pulmonary hypertension after PE.
• Pregnancy loss in APS and antithrombin deficiency.

• Arterial and venous thrombosis (above), with up to 5 to 10 percent mortality.
• Venous limb gangrene (5 to 10 percent with HIT on a vitamin K antagonist).
• Delayed and persistent (refractory) HIT requiring prolonged non-heparin anticoagulation.
• Heparin-flush HIT from minimal heparin exposure.
• Adrenal haemorrhagic necrosis.

• Bleeding (the main risk).
• Skin necrosis (above).
• Teratogenicity in pregnancy: warfarin embryopathy; use heparin in pregnancy.

Most inherited thrombophilias confer low absolute risk: the majority of carriers live without thrombosis. The untreated risk of recurrence after a first VTE is higher with antithrombin, protein C or protein S deficiency, APS, combined defects and cancer, and lower with isolated Factor V Leiden or prothrombin variant. ^[6]

HIT carries a serious short-term thrombosis risk but improves once non-heparin anticoagulation is established and heparin is withdrawn. The antibody usually clears over weeks; heparin can be reconsidered later (short-term, usually after antibody clearance) in selected patients needing cardiac surgery. ^[2]

Warfarin skin necrosis, if recognised early and anticoagulated appropriately, usually heals; delayed recognition requires surgery and may be fatal. ^[5]

• Avoid unnecessary prolonged immobilisation; use mechanical and pharmacological prophylaxis in hospital, surgery and cancer. ^[6]
• Do not screen the general population for thrombophilia: many positives never clot, and the harms (anxiety, over-treatment, insurance or social consequences) outweigh benefit. ^[6]
• Targeted screening may be justified in high-risk settings (before pregnancy in a woman with a known familial thrombophilia, before hormone therapy, before high-risk surgery). ^[6]
• For heparin exposure, choose LMWH or fondaparinux over UFH whenever possible (lower HIT risk), monitor platelets in high-risk patients, and avoid "heparin flush" exposure where a non-heparin catheter-lock (for example saline or regional citrate) suffices. ^[2][4]
• Women with thrombophilia and recurrent pregnancy loss benefit from evaluation; APS in pregnancy is managed with low-dose aspirin plus heparin. ^[6]

Pregnancy. All oestrogen-containing contraception and hormone replacement increase VTE risk; combined hormonal contraception is best avoided in thrombophilia. In pregnancy and the puerperium, LMWH is the anticoagulant of choice; warfarin is teratogenic and is withheld until postpartum. APS in pregnancy uses low-dose aspirin plus LMWH. Danaparoid is preferred for HIT in pregnancy. ^[2][6]

Children. Thrombosis is rare and usually requires an underlying trigger; inherited thrombophilia is seldom the sole cause in infancy. PNH and myeloproliferative disease should be excluded.

Older adults. Risk of VTE rises steeply with age; acquired factors (cancer, immobilisation, surgery, oestrogen) dominate. Bleeding risk from anticoagulation also rises with age, re-tuning every decision about duration. ^[6]

Immunocompromised and critically ill patients. HIT and thrombosis in intensive care often coexist with sepsis, multi-organ failure and thrombocytopenia from marrow failure; the 4T score is less reliable in complex ICU patients, so haematology input and functional assays carry more weight. ^[3]

• Heparin-free where sensible: LMWH or fondaparinux cost more than UFH but cause far less HIT. Where only UFH exists, monitor platelets from day 4 to 14 in any patient at over 1 percent HIT risk, and switch to LMWH or fondaparinux promptly if suspicion arises. ^[2]
• Platelet counting is cheap. A fall beginning after day 4 post-surgery (or thrombocytopenia lasting more than 4 days after cardiac surgery) should prompt HIT testing, even if ELISA or SRA are unavailable; treat clinically with fondaparinux or direct oral anticoagulants where possible and refer. ^[2][4]
• Fondaparinux is widely available as a synthetic, non-heparin option for suspected HIT or DVT; danaparoid and argatroban are often scarce. Referral to a centre with haematology and (ideally) SRA capability expedites confirmation. ^[4]
• Warfarin skin necrosis: easily mistaken for cellulitis or necrotising fasciitis in resource-limited settings. Check the timing (3 to 10 days after starting or reintroducing warfarin). Treat by stopping warfarin, reversing with vitamin K, and restarting anticoagulation with heparin/LMWH. ^[5]
• Acquired thrombophilia: weigh cost before ordering a thrombophilia panel; testing is justified mainly for APS (which alters management) and for young patients with unprovoked or unusual-site thrombosis. ^[1]
• Homocysteinaemia is often reversible with B12, folate and thyroid treatment; check and correct these before labelling it lifelong thrombophilia. ^[6]

• Hypercoagulable states raise venous thrombosis risk; they are common but most carriers never clot. ^[6]
• Antithrombin, protein C and protein S deficiency are rare but high-risk (roughly 10-fold relative risk). Factor V Leiden and prothrombin G20210A are common but low-to-moderate risk. ^[1]
• Factor V Leiden varies by ethnicity (3 to 8 percent European descent versus under 2 percent many other groups). ^[1]
• MTHFR C677T should not be tested in VTE evaluation. ^[1]
• APS is the acquired thrombophilia that genuinely changes management (VKA over direct oral anticoagulant; longer duration; pregnancy prophylaxis). ^[1]
• Many other acquired causes (cancer, nephrotic syndrome, pregnancy and oestrogen, surgery, immobilisation, myeloproliferative neoplasm, PNH) are not picked up by thrombophilia panels and must be recognised clinically. ^[1][6]
• Hyperhomocysteinaemia is a weak risk factor; severe homocystinuria is rare; vitamin B12 and folate (and thyroid) deficiency are reversible causes. ^[6]
• Testing should be selective: routine testing after provoked VTE is not recommended; test APS when stopping anticoagulation, and hereditary thrombophilia in young, unprovoked or unusual-site clots. ^[1][6]
• Anticoagulant duration follows provocation and recurrence/bleeding risk; isolated heterozygous Factor V Leiden or prothrombin variant alone rarely justifies indefinite anticoagulation. ^[6]
• HIT is an immune, pro-thrombotic reaction 5 to 10 days after heparin. Stop all heparin, start a non-heparin anticoagulant, and confirm with ELISA then functional assay. ^[2]
• The 4T score (0 to 3 low, 4 to 5 intermediate, 6 to 8 high) has a very high negative predictive value; low score plus weak assay excludes HIT. ^[3][7]
• In HIT, do not start warfarin until platelets recover (about 150 x 10^9/L); overlap for at least 5 days; give vitamin K if warfarin was already started. ^[2]
• Warfarin skin necrosis is a rare but serious early complication (3 to 10 days) driven by protein C depletion; treat by stopping warfarin, reversing with vitamin K and anticoagulating with heparin/LMWH; prevent by bridging and low initial doses. ^[5]

Hypercoagulable states connect naturally with the other haematology topics on MedGrasp: deep vein thrombosis and pulmonary embolism, anticoagulant drugs (heparin, warfarin, direct oral anticoagulants), antiphospholipid syndrome, nephrotic syndrome, cancer-associated thrombosis, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, and pregnancy and thrombosis. Links to these will be added once those topics are verified.

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