Bleeding, Reversal, HIT and DIC

In depth

The one-page summary above is what the PDF prints. These sections go further.

Hemostasis: the cell-based model

The classic cascade describes a test tube; in vessels, coagulation runs on cell surfaces in overlapping phases (Hoffman and Monroe, 2001). This explains why a normal PT and aPTT do not exclude bleeding (low platelets or fibrinogen, hyperfibrinolysis, hypothermia) and why factor XII deficiency prolongs the aPTT without bleeding.

Platelets adhere to collagen through von Willebrand factor (GPIb), aggregate on fibrinogen bridges (GPIIb/IIIa) and expose phosphatidylserine, where the vitamin K-dependent factors assemble with calcium. Antithrombin (inactivates thrombin, Xa and IXa; heparin speeds it about 1,000-fold), TFPI, and activated protein C with protein S (destroys Va and VIIIa) confine the clot.

Plasmin, made by tPA on fibrin, splits cross-linked fibrin into fragments, including D-dimer. PT and aPTT run at 37 °C on recalcified plasma, so they miss the patient's hypothermia, acidosis and low ionized calcium.

Reading coagulation tests and TEG/ROTEM

The INR was built for warfarin. In cirrhosis, anticoagulant proteins fall with the clotting factors, so a high INR overstates bleeding risk; plasma to correct it adds volume without benefit. For an isolated long aPTT, a 1:1 mixing study that corrects suggests factor deficiency; one that stays long suggests an inhibitor (heparin, lupus anticoagulant).

False results come from heparin drawn through a line, an underfilled citrate tube or hematocrit over 55% (falsely long times), and hemolyzed or clotted samples. Acute-phase factor VIII shortens the aPTT and makes heparin look weak, which anti-Xa avoids; but heparin-calibrated anti-Xa reads falsely high for 2–3 days after apixaban or rivaroxaban. Drug-calibrated anti-Xa or dilute thrombin time measures DOAC levels; a normal thrombin time excludes meaningful dabigatran, but a normal PT does not exclude apixaban.

Viscoelastic tests (TEG, ROTEM) track a whole-blood clot as it forms, firms and lyses, reflecting platelets, fibrinogen and fibrinolysis within 10–20 min.

Anticoagulants: mechanism, monitoring and reversal

Heparin chains of 18 or more saccharides bridge antithrombin to thrombin; shorter chains inhibit only Xa, so LMWH barely moves the aPTT and protamine reverses only about 60% of it. Weight-based UFH: VTE 80 units/kg, then 18 units/kg/h (Raschke 1993); ACS 60 units/kg (max 4,000), then 12 units/kg/h (max 1,000). Give protamine no faster than 5 mg/min; reactions are likelier after NPH insulin, earlier protamine or fish allergy.

Warfarin's INR rises in 2–3 days as factor VII (t½ about 6 h) falls, but protection needs prothrombin (t½ 60–72 h) to fall: overlap heparin for 5 or more days and until the INR is 2 or more for 24 h. Protein C (t½ about 8 h) falls first, so warfarin alone or in acute HIT can cause skin necrosis or venous limb gangrene. For major bleeding, labeled 4F-PCC is 25, 35 or 50 units/kg for INR 2 to under 4, 4–6 and over 6 and acts in about 30 min; vitamin K 10 mg IV (no faster than 1 mg/min) keeps the INR down after PCC wears off. Kcentra contains heparin: avoid it in HIT.

Activated charcoal helps within about 2 h of a DOAC dose (NCS/SCCM 2016). In RE-VERSE AD (NEJM 2017, 503 patients), idarucizumab gave a median maximum dabigatran reversal of 100% within minutes, with thrombosis in 4.8% at 30 days. Andexanet improved hemostatic efficacy in intracerebral hemorrhage in ANNEXA-I (NEJM 2024: 67.0% vs 53.1%) but increased thrombotic events (10.3% vs 5.6%) and ischemic stroke (6.5% vs 1.5%), and left the US market in December 2025; the NCS/SCCM 2026 focused update suggests 4F-PCC rather than andexanet (conditional). US reversal of Xa inhibitors is therefore 4F-PCC: 50 units/kg (NCS/SCCM 2016) or a fixed 2,000 units (ACC 2020).

Argatroban (hepatic) suits kidney failure and bivalirudin (mainly enzymatic) suits liver failure. Argatroban starts at 2 mcg/kg/min, or 0.5–1.2 with liver dysfunction, heart failure, multiple organ failure or after cardiac surgery; it raises the INR, so stop it once the combined INR on warfarin exceeds 4 and recheck in 4–6 h (label). For symptomatic bleeding within 24 h of a thrombolytic, stop it, check fibrinogen and give cryoprecipitate 10 units to keep it at 150 mg/dL or more, plus tranexamic acid 1 g IV (AHA/ASA 2026).

Bleeding risk, procedures and bridging

Major bleeding (ISTH, Schulman 2005) is fatal, in a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or muscle with compartment syndrome), or drops hemoglobin 2 g/dL or more or needs 2 or more units. HAS-BLED (for AF) gives 1 point each for uncontrolled Hypertension, Abnormal kidney and liver function, Stroke, Bleeding history, Labile INR, Elderly (over 65), and Drugs and alcohol; 3 or more is high risk, a signal to fix BP, NSAIDs and alcohol, not to withhold anticoagulation. No score is validated in the ICU.

Most patients need no bridging. In BRIDGE (NEJM 2015, 1,884 patients with AF), dalteparin bridging did not prevent arterial thromboembolism (0.3% vs 0.4%) and raised major bleeding (3.2% vs 1.3%); ACCP 2022 keeps bridging mainly for mechanical valves. In PAUSE (JAMA Intern Med 2019, 3,007 patients), DOACs held on the schedule below, without bridging or levels, gave arterial thromboembolism under 1% and major bleeding up to 3%.

HIT: pathophysiology, diagnosis and treatment

PF4 from platelet α-granules binds heparin chains of about 12 or more saccharides into complexes with new epitopes. IgG against PF4–heparin cross-links platelet FcγRIIa receptors, causing platelet activation and thrombin generation. Platelets fall from consumption, and about half of patients who only stop heparin clot within 30 days. Risk is 2.6% with prophylactic UFH vs 0.2% with LMWH (Martel, Blood 2005); HIT affects well under 1% of ICU patients.

The fall is typically 50% or more, starting on day 5–10, to a median nadir of about 60,000, rarely under 20,000. It can start within 24 h if heparin was given in the past 100 days, or up to 3 weeks after heparin stops. Other clues: skin necrosis at injection sites, a reaction to an IV bolus, repeated CRRT or ECMO circuit clotting.

A low 4Ts score (0–3) has a negative predictive value of 99.8%; intermediate and high scores carry about 14% and 64% probability (Cuker, Blood 2012). The immunoassay (ELISA or rapid assays) detects anti-PF4–heparin antibodies: very sensitive, but many antibodies, especially after cardiac surgery, never activate platelets. The ELISA reports optical density (OD): the cutoff is usually 0.4, but the chance of a positive functional test reaches 50% only at 1.4 and about 89% above 2.0 (Warkentin, J Thromb Haemost 2008). The serotonin release assay (SRA), the gold standard, shows patient serum activating donor platelets at low heparin concentrations but not at high ones; results take days.

1. 4Ts 0–3: HIT excluded; keep heparin and do not test.
2. 4Ts 4–8: stop all heparin, start a non-heparin anticoagulant at treatment intensity, send the immunoassay.
3. Immunoassay negative: HIT excluded; heparin may resume.
4. Immunoassay positive: keep treating; send the SRA, especially with an intermediate score or low OD.

Argatroban or bivalirudin suits unstable ICU patients; fondaparinux or a DOAC suits stable ones. ASH 2018 suggests bilateral leg ultrasound in isolated HIT, IV vitamin K for anyone on warfarin at diagnosis, and anticoagulation at least until platelets recover to 150,000; HIT with thrombosis is usually treated 3–6 months. Antibodies fade (SRA negative at a median of 50 days, immunoassay 85 days; Warkentin, NEJM 2001), so after remote HIT with negative tests, heparin may be used during cardiac surgery only.

DIC: phenotypes, scores and management

ISTH 2025 defines DIC as acquired systemic coagulation activation with dysregulated fibrinolysis and endothelial injury, causing microthrombi, organ failure and consumptive bleeding. The update stages DIC (pre-DIC, early, overt) and separates a thrombotic phenotype with suppressed fibrinolysis (sepsis: organ failure, modest D-dimer) from a hemorrhagic one with enhanced fibrinolysis (acute promyelocytic leukemia, trauma, obstetric: oozing, very low fibrinogen, very high D-dimer).

In sepsis, the sepsis-induced coagulopathy (SIC) score flags the earlier phase: platelets 100,000–149,000 (1 point) or under 100,000 (2), INR over 1.2–1.4 (1) or over 1.4 (2), four-organ SOFA 1 (1) or 2 or more (2); 4 or more, with platelet plus INR points above 2, is SIC (ISTH 2019, kept in 2025).

Treat the cause; replace for bleeding or procedures, not numbers (ISTH 2013): platelets for bleeding under 50,000, plasma 15–30 mL/kg for long PT or aPTT, cryoprecipitate or fibrinogen concentrate for fibrinogen under 150 mg/dL. Give prophylactic heparin if not bleeding and therapeutic heparin when thrombosis dominates. Reserve tranexamic acid for hyperfibrinolytic bleeding. Antithrombin (KyberSept), activated protein C (withdrawn 2011) and thrombomodulin (SCARLET 2019: 26.8% vs 29.4% mortality, not significant) have not improved survival outside Japan.

TTP, HUS and other microangiopathies

A thrombotic microangiopathy (TMA) is hemolysis with schistocytes (high LDH, low haptoglobin, negative direct antiglobulin test), thrombocytopenia and organ injury from microvascular thrombi. In TTP, ADAMTS13 activity under 10% leaves ultralarge von Willebrand multimers uncleaved, and they trap platelets; most adult cases are immune (autoantibody to ADAMTS13). The classic pentad appears in under 10%; PT, aPTT and fibrinogen are near normal, creatinine is usually only mildly raised, and a rising troponin warns of sudden death. Untreated mortality is about 90%; with plasma exchange, 10–20%.

Draw ADAMTS13 before plasma, then start daily plasma exchange (1–1.5 plasma volumes, replaced with plasma to supply ADAMTS13) with corticosteroids; ISTH 2020 adds rituximab and caplacizumab. Exchange until platelets stay above 150,000 for 2 days. Caplacizumab blocks von Willebrand factor binding to platelet GPIb: 11 mg IV before the first exchange, then 11 mg SC daily until 30 days after the last (US label). In HERCULES (NEJM 2019), platelets normalized faster (rate ratio 1.55) and TTP death, recurrence or major thrombosis fell from 49% to 12%, with more mucocutaneous bleeding.

During exchange, watch for citrate toxicity (perioral tingling, cramps; give calcium), plasma reactions and hypotension, and give rituximab after a run (exchange removes it).

Thrombocytopenia in the ICU, including ITP

Platelets fall below 150,000 in 13–44% of ICU patients (Hui, Chest 2011), and a count that fails to recover predicts death. After surgery or massive resuscitation, counts drop for 1–4 days and recover by about day 5–7; a second fall after day 5, or no recovery, suggests HIT, sepsis, a drug or a TMA. On the smear, clumps mean EDTA pseudothrombocytopenia (recheck in a citrate tube) and schistocytes mean TMA or DIC.

Common drug culprits: vancomycin, piperacillin and other β-lactams, TMP-SMX, quinine, carbamazepine, phenytoin; GP IIb/IIIa inhibitors can drop counts within hours. ITP is a diagnosis of exclusion; ASH 2019 suggests treating newly diagnosed adults with platelets under 30,000, using prednisone (no more than 6 weeks) or dexamethasone 40 mg daily for 4 days, plus IVIG 1 g/kg when a fast rise is needed. For critical bleeding, give platelets, IVIG and high-dose steroids together.

VTE prophylaxis and treatment in critical illness

ASH 2018 suggests LMWH or UFH over no prophylaxis in critical illness, LMWH over UFH, and drug prophylaxis alone over adding compression devices, with intermittent pneumatic compression (IPC) for patients who cannot be anticoagulated. In PROTECT (NEJM 2011, 3,746 patients), dalteparin 5,000 units daily and UFH 5,000 units twice daily gave similar proximal DVT rates (5.1% vs 5.8%), but dalteparin lowered pulmonary embolism (1.3% vs 2.3%). In PREVENT (NEJM 2019, 2,003 patients), adding IPC to drug prophylaxis did not reduce proximal DVT (3.9% vs 4.2%).

• Enoxaparin 40 mg SC daily (30 mg if CrCl under 30); trauma often 30 mg twice daily; BMI 40 or more often 40 mg twice daily.
• UFH 5,000 units SC every 8–12 h in severe kidney failure or before procedures.
• Hold for active bleeding or platelets under about 50,000; after stable spontaneous ICH, start at 24–48 h (AHA/ASA 2022).

For VTE treatment, IV UFH fits patients who are unstable or have CrCl under 30 (ESC 2019 adds those who may need lysis or a procedure; AHA/ACC 2026 prefers LMWH even then); otherwise LMWH (1 mg/kg every 12 h), then a DOAC once stable (not with mechanical valves, triple-positive antiphospholipid syndrome or pregnancy). Hypotensive PE gets reperfusion: systemic lysis (alteplase 100 mg over 2 h) unless contraindicated (ESC 2019), while AHA/ACC 2026 rates lysis, catheter therapy and surgical embolectomy all reasonable (2a) with persistent hypotension. In intermediate-high risk PE, PEITHO (NEJM 2014) found tenecteplase reduced death or hemodynamic collapse (2.6% vs 5.6%) but raised hemorrhagic stroke (2.0% vs 0.2%), so lysis is kept for rescue. Use an IVC filter only when anticoagulation is impossible, and retrieve it once anticoagulation is possible.

Exam pearls

• Monitor warfarin by INR, UFH by aPTT or anti-Xa 0.3–0.7, LMWH by anti-Xa 4 h after a dose; a normal thrombin time excludes dabigatran.
• Warfarin bleed: 4F-PCC plus vitamin K 10 mg slow IV. Dabigatran: idarucizumab 5 g. Apixaban, rivaroxaban: 4F-PCC (NCS/SCCM 2026; andexanet left the US market in 2025).
• Protamine: 1 mg per 100 units of UFH from the last 2–3 h, max 50 mg, slowly; partial for LMWH; none for argatroban or bivalirudin.
• HIT: fall over 50% on day 5–10, clots not bleeding; 4Ts 0–3 rules it out; stop all heparin, start argatroban or bivalirudin; no routine platelets, no warfarin until 150,000.
• DIC: long PT, low fibrinogen, high D-dimer, falling platelets; ISTH score 5 or more; treat the cause.
• TTP: schistocytes, very low platelets, normal PT, ADAMTS13 under 10%: urgent plasma exchange, steroids, caplacizumab; avoid platelets.
• Complement-mediated HUS: eculizumab or ravulizumab plus meningococcal vaccine; STEC-HUS: supportive care.
• ICU prophylaxis: LMWH or UFH; IPC alone only when anticoagulants are unsafe.