Stopping What You Started: Hemostatic Therapy for Thrombolytic-Associated Hemorrhagic Conversion

While anticoagulation reversal for anticoagulant-associated bleeding gets a lot of press (see recent publication of ANNEXA-I and the seemingly endless discourse that followed)1, the approach to handling bleeding secondary to thrombolysis is arguably more controversial and certainly less clear cut. Entire guidelines and bodies of evidence have explored ideal reversal strategies for warfarin, factor Xa inhibitors, other anticoagulants, and antiplatelets, but discussion surrounding what to do when a patient experiences major bleeding after thrombolysis is generally relegated to a small section of review articles and guidelines with a simple explanation for the brevity – there just isn’t a lot of evidence guiding what to do.

A patient who developed significantly worsening level of arousal and worse left-sided facial droop ~2 hours after receiving tenecteplase. She received cryoprecipitate and tranexamic acid and eventually required a decompressive hemicraniectomy. She required inpatient rehabilitation and recovered to an mRS of 3.

In 2017, AHA/ASA tried to address this by publishing a dedicated statement on the treatment and outcomes of patients who experience hemorrhagic transformation after thrombolysis for acute ischemic stroke.2 The paper outlines the pathophysiology, risk factors, potential prognosis, and management of hemorrhagic conversion, with a large portion of the paper dedicated to examining specific medical therapies for symptomatic and asymptomatic ICH. Like many guidelines, however, nearly every therapy comes with a familiar qualifier – “the use of x therapy in most patients with sICH is controversial but may be considered…”

So, what are the considerations? Little has been published on thrombolytic “reversal” since, and with the rise of tenecteplase (and reteplase?3 Here we go again…) which may have specific considerations as well, it’s worth a deep dive into what the evidence is regarding reversal and designing a pragmatic operational workflow for approaching hemostatic therapy for thrombolytic-associated bleeding.

One piece of nomenclature - for convenience, I will refer to certain therapies as thrombolytic "reversal." This is, realistically, slang: it's not possible to "reverse" a thrombolytic which is entirely pharmacokinetically cleared by the time the sICH is discovered, but hemostatic therapy can help blunt the hyperfibrinolysis triggered by thrombolysis. 

Key Points

  • Hemorrhagic conversion/sICH occurs in approximately 3-5% of patients treated with thrombolysis and most frequently occurs within 36 hours of thrombolytic administration, with a median onset time of 8 hours
  • Thrombolysis remains pharmacologically active for about 24 hours which extends beyond when the drug is actually detectable in the serum. Thus, sICH that occurs within 24 hours of administration is worth reversing
  • The risks of  hemostatic therapy likely outweigh the benefits in patients with asymptomatic hemorrhagic conversion. Asymptomatic hemorrhagic conversion is variably associated with worse outcomes compared to no hemorrhagic conversion at all, but risks of blood products and aggressive BP control likely outweigh the benefit of hemostasis when bleeds are small, unlikely to cause mass effect, and are not causing symptoms
  • Specific therapies, including dosing and timing of administration, are poorly researched. Cyroprecipitate (10 units) or fibrinogen concentrate (40-70 units/kg) and antifibrinolytics (tranexamic acid [1 g] and aminocaproic acid [4 g]) have the largest body of evidence and make the most pharmacodynamic sense to use as hemostatic therapy

Why Does Thrombolysis Make You Bleed?

This may seem like a silly question, but understanding the pharmacology of thrombolysis is crucial to understanding what to do when things go wrong. Alteplase and tenecteplase both act by stimulating the conversion of plasminogen to plasmin. Plasmin binds to fibrin, catalyzing fibrin degradation and clot dissolution. Like anticoagulants, thrombolytics don’t directly cause bleeding, but they entirely inhibit the coagulation system from stopping bleeding that has occurred. In stroke, given the friability of the cerebral circulation, a ruptured vessel from reperfusion injury, high blood pressure, or some other reason will essentially continue until sufficient mass effect tamponades the bleeding or therapy is administered to stop the thrombolytic activity.

Importantly, while thrombolytic agents themselves have particularly short plasma half-lives (alteplase is completely undetectable within an hour of administration), catalyzed thrombolytic activity persists for up to and potentially exceeding 24 hours.4–6 Therefore, if symptomatic bleeding occurs after a thrombolytic is administered, administration of hemostatic therapy is likely reasonable even up to 24 hours after thrombolysis was given.

Monitoring and Timing of Hemorrhagic Conversion

All stroke centers have protocols in place to monitor patients for the development of complications after thrombolysis, of which bleeding and hemorrhagic transformation is the most feared complication. Most commonly, this monitoring period concludes at 24 hours with a routine monitoring head CT to assess for the presence of any degree of hemorrhagic conversion. While this practice is a relic of the NINDS trial protocol and the utility has been questioned,7,8 it remains standard practice at most institutions. Asymptomatic hemorrhagic conversion is detected in nearly 20% of patients who receive thrombolysis this way, and the exact timing of onset is thus unknown. Symptomatic hemorrhagic conversion, however, is readily detected by change in neurologic status which should prompt immediate imaging to confirm the diagnosis. While the exact definition of “symptomatic” ICH varies, median time from thrombolysis to the development of sICH has been reported to be about 7-8 hours.9,10

Common sICH Definitions



Any hemorrhage seen on CT associated with any clinical suspicion for hemorrhage or decline in neurologic status


Any hemorrhage seen on CT associated with clear clinical deterioration or increase in NIHSS of at least 4 points


Local or remote PH-2 conversion associated with an NIHSS that is at least 4 points higher than baseline, the lowest value between baseline and the occurrence of hemorrhage, or death

The supermajority of sICH occurs within 24 hours of thrombolysis, with one analysis of 940 patients who received alteplase in Finland revealing 86% of NINDS-criteria, 88.9% of ECASS-II criteria, and 85.7% of SITS-MOST criteria sICH occurred within 24 hours of administration. This correlates with the expected pharmacodynamic effect of thrombolysis. While the parent medication (either alteplase or tenecteplase) is completely cleared by the liver within 3-6 hours of administration, plasmin activity remains elevated for approximately 24 hours after administration.4,6 

Evidence Evaluating Thrombolytic Reversal

None of the major clinical trials of alteplase or tenecteplase for ischemic stroke included a standardized method of treating or handling hemorrhagic conversion after thrombolysis, and thus the evidence evaluating the impact of reversal is limited to retrospective cohort studies and case reports. Unfortunately, this means all data reporting outcomes of reversal are significantly affected by confounding by indication – sicker patients are more likely to receive treatment, and so comparisons between treated and untreated patients are uneven comparisons. Regardless, at least three cohort studies have specifically evaluated a) what therapies patients receive, b) the characteristics of treated vs non-treated patients, and c) some aspect of the patients’ clinical outcomes. I have summarized the highlights of the three studies below:


Goldstein et al 201011

Alderazi et al 201410

Yaghi et al 20159

Received alteplase, n




Experienced sICH, n (%)

20 (5.7%)

48 (5.2%)

[3 were enrolled in clinical trials – final n of 45]

128 (3.2%)

Definition Used


Unclear, 32 (3.5%) met NINDS criteria


Any Reversal Given, n (%)

11 (55%)

19 (42.2%)

49 (38.2%)

Treatment Received, n (%) – proportion of reversed





5 (45.5%)

7 (36.8%)

40 (81.6%)


1 (9.1%)


2 (4.1%)


7 (63.6%)

18 (94.7%)

26 (53.1%)


3 (27.2%)

4 (21.0%)

37 (75.5%)

Vitamin K

4 (36.4%)


7 (14.3%)




6 (12.2%)

Initial ICH volume, mL

Mean (SD)

65.3 (56.2)

Mean (SD), reversal vs none

48.1 (41.4) vs 35.3 (61.8)

Median (range)

25 (1-245)

Expansion >33%, n (%) – of patients with follow up imaging

4/10 (40%)

11/32 (34.3%)

22/82 (26.8%)

Mortality, n (%)

15 (75%)

19 (42.2%)

67 (52.3%)

Likely the first thing to jump out is how in all three, only somewhere between a third and a half of patients received any reversal at all. This is likely a function of the severity of the patients. While this is not distinctly explored in most studies, Alderazi reported a significantly higher post-thrombolysis NIHSS (27 vs 17), lower GCS at time of ICH (7 vs 9), and higher ICH volume (48.1 vs 35.3 mL) in patients who received any treatment which likely contributed to decision making regarding treatment.10 These differences dampen the confidence in assessments of clinical outcomes. Goldstein only reported discharge disposition; of the 5 surviving patients, 1 went home (did not receive reversal) and 4 went to rehab (of which 3 received reversal).11 Alderazi reported a significant univariate association between receiving reversal and an mRS of 5-6 at 90 days (OR 9.53, 95% CI 1.09-83.44), but this was no longer significant after adjustment for baseline severity (OR 5.98, 95% CI 0.61-58.41).10 Interestingly, Yaghi reported a numeric reduction in mortality associated with reversal (29.9% vs 47.5%, p = 0.06).9 While hypothesis generating only, this difference from previous studies may reflect the multicenter nature of the study which partially removes single-center treatment biases. In other words, some centers may treat more liberally than others which may reduce the impact of confounding by indication (although this was not specifically explored).

Beyond mortality and functional outcomes, rates of hematoma expansion have also been explored between those who received reversal vs no reversal. In Goldstein, three of the four patients who experienced >33% hematoma expansion received any reversal product, compared to three of the six who did not.11 Similar rates were reported in Alderazi and Yaghi – 33.3% of those who received any reversal experienced vs 35% of patients who did not in Alderazi experienced >33% hematoma expansion, and 50.0% of those who received anything vs 59.1% who did not experienced expansion in Yaghi. Interestingly, Yaghi revealed patients who received platelet transfusion were significantly more likely to experience hematoma expansion (50.0% vs 21.7%, p = 0.01), but this could be type 1 error. Ultimately, the effect of reversal of reversal on hematoma expansion would need a randomized trial to account for confounding (which would arguably be unethical to conduct), but it can at least be concluded that hemostatic therapy (with the possible exception of platelet transfusion) does not worsen hematoma size.

So, it seems reasonable (and logical) that hemostatic therapy/reversal is reasonable in a patient with sICH within 24 hours. What specific agents do you use? Rationale for each therapy type is well-described in the 2017 AHA/ASA statement,2 but I will provide a brief synopsis here and provide my opinion for why some of the therapies make more sense than the others.


Considering thrombolytics catalyze the metabolism of fibrin in clots and can deplete fibrinogen stores thus impairing the stability of formed clots, it seems logical to replace fibrinogen when a patient bleeds after receiving a thrombolytic. Cryoprecipitate is a combination of insoluble coagulation products extracted from centrifuged thawed plasma and is made up not just of fibrinogen, but also factor VIII, von Willebrand factor, factor XIII, fibronectin, and platelet microparticles.12 One “unit” is the 15-20 mL of insoluble content extracted from centrifuged and thawed FFP; blood banks typically release 5 or more units in a single “pool” (one bag of ~100 mL of cryo). While exact content varies from unit to unit, the Association for Advancement of Blood and Biotherapies (AABB) sets unit standards at a minimum of 150 mg of fibrinogen, 80 IU of factor VIII, 50-75 units of factor XIII, and 100-150 IU of vWF in each unit of cryoprecipitate.13

Association of lowest fibrinogen with
the extent of bleeding (16)

Cryoprecipitate has been suggested as a treatment for thrombolysis-associated hypofibrinogenemia and bleeding since thrombolysis was first established as a therapy for acute coronary syndromes.14–16 This was established as a therapy of course not through any randomized or prospective means, but simply through the observation that patients bled more when their fibrinogen tanked, and thus fixing that problem must be the thing to do. With streptokinase, Timmis and colleagues described a total body fibrinogen regeneration rate of approximately 94 mg/kg/day, meaning that it could take 20-30 hours for a patient to attain a fibrinogen concentration of 150-200 mg/dL after streptokinase depleted their stores.17

Ultimately, the data supporting cryoprecipitate for hemorrhagic conversion after thrombolysis is similarly limited. Despite thrombolysis being standard of care for ischemic stroke for nearly 3 decades, the first mention of managing hemorrhagic transformation in a treatment guideline was in 2013 – “Although no study has been conducted to determine the best  way  to  manage  post–intravenous  rtPA  hemorrhage,  many  rtPA-associated  hemorrhage  protocols  call  for  the  use  of  cryoprecipitate  to  restore  decreased  fibrinogen  levels.”18 The three cohort studies described above9–11 support this supposition, and to date the two studies have specifically evaluated cryoprecipitate for thrombolysis-associated hemorrhagic conversion. One described a case series of 19 patients where the mean time from alteplase initiation to cryoprecipitate initiation was 7.1 hours, patients received a median of 1 pool of cryo, and hemostasis was achieved in only 4 of 15 patients with repeat head CTs available.19 Interestingly, 2 of 11 patients who received cryo alone vs 2 of 4 patients who received cryo and aminocaproic acid achieved hemostasis, but the law of small numbers likely applies here.20 The second describes a case series of 12 patients; 66.7% of patients had bleeds discovered within 4 hours of administration, 4 had an antifibrinolytic co-administered, and only 4 of 12 achieved hemostasis (1 of 4 who received an antifibrinolytic).21

Conceptually, however, giving cryo makes sense. It also seems to make sense in vitro – in a TEG study where investigators spiked blood samples from 10 volunteers with tPA, cryo, factor XIII isolate, and fibrinogen concentrate, all 3 reasonably restored clot stability after tPA induced a hyperfibrinolytic state. Notably, potentially confirming the finding from Verkerk’s cohort, the combination of cryo and aminocaproic acid completely neutralized hyperfibrinolysis, returning Ly30 and Ly60 (the percent clot remaining at 30 and 60 minutes after the study began) from 100% and 91%, respectively.22

Effect of specific therapies on TEG-based measures of fibrinolysis (22)

So, in the absence of good data, cryo does appear to be a reasonable first line therapy for bleeding associated with thrombolytics. Cryo does come with the many downsides transfusions are known for – while a type and screen is not strictly required for cryoprecipitate, some institutions may require it still and delivery of blood products from the blood bank can take a significant amount of time depending on the resources available for product acquisition. Cryo also needs to thaw, which can take 10-20 minutes which may further delay therapy. Fibrinogen concentrate products (RiaSTAP, Fibryga) may partially rectify this – both are stable at room temperature, only need reconstitution prior to administration, and avoid the risk of transfusion reactions with cryo. The use of RiaSTAP for alteplase-associated hemorrhagic conversion has been described in one cohort of 24 patients.23 At the authors’ institution, an empiric dose of 2 RiaSTAP vials (approximately 2000 mg) is administered to patients with hemorrhagic conversion regardless of baseline fibrinogen concentration. Patients frequently received other adjunct therapies, including 6 patients who also received cryo. Fibrinogen concentrations increased from a median of 256 mg/dL to 316 mg/dL after therapy, and 19 of 22 patients with available repeat imaging did not experience further hematoma expansion.

Regardless of the product chosen, replacement of fibrinogen should one of the first interventions when thrombolytic-associated sICH is identified. Fibrinogen concentrations should be re-checked 1-2 hours after therapy completion, and if persistently <150-200 mg/dL, therapy should be repeated. Importantly, due to its clot-bound fibrin specificity, tenecteplase is unlikely to significantly affect serum fibrinogen concentrations, so while fibrinogen concentrations should still be checked post-therapy, it may not be a reliable target in TNK-treated patients.5

Effect of ALT and TNK on different coagulation parameters. Note than TNK barely affects fibrinogen concentrations. (5)

Antifibrinolytic Therapy

Antifibrinolytic therapy with tranexamic acid (TXA) or ε-aminocaproic acid (EACA) seems like a logical choice to inhibit the effects of thrombolytics/fibrinolytics, and I found it odd how infrequently these therapies are reported in the early studies evaluating lytic-associated bleeding. They work by mimicking the lysine moiety plasminogen binds to that initiates fibrinolysis. By binding to plasminogen with higher affinity than fibrin, it competitively inhibits fibrinolysis and thus may partially prevent worsening bleeding after thrombolysis. Despite this rational mechanism, it was initially used with caution because “serious thrombotic complications have been reported with antifibrinolytic agents,”14 a supposition seemingly driven by a case report from 1962 where a woman experienced profound thrombotic complications after aminocaproic acid was administered for bleeding. Reading the case report from today’s lens, the patient had DIC, so the thrombotic complications are not particularly surprising, and the risk of thrombosis with antifibrinolytics does not translate to patients without DIC. A meta-analysis of 216 studies including over 125,000 patients revealed an essentially nil risk of thrombosis vs control – in fact, thrombosis risk was actually lower in some disease states.24 Point being – risk of thrombosis is not a reason to avoid antifibrinolytics.

Likely due to historical concerns for thrombosis, data evaluating antifibrinolytics for thrombolytic bleeding are limited to case reports and case series. 


No. of Patients

Lytic Received

Received Cryo?

Antifibrinolytic Dose


French et al24




TXA 1 g over 10 min followed by 10 mg/kg over 1 hour


Yaghi et al9




EACA (dose not reported)


Hailu et al25




TXA 1 g over 15 mins


Rosafio et al26




TXA 1 g


Verkerk et al19




EACA 4 g bolus followed by 1 g/hr (in 3/6)


Bailey et al21




TXA 1 g over 10 minutes followed by 1 g over 8 hours (1)

TXA 15 mg/kg over 20 min (1)

EACA 5 g over 1 hour followed by 1 g/hr for 8 hours (1)

TXA 1 g over 10 min (1)


 So, a sum total of 13 patients have been described in the literature. While not exactly the most robust body of evidence, the relative lack of toxicity (no thrombosis was reported in any of the above publications) and theoretical synergy with cryoprecipitate makes it a part of standard therapy for thrombolytic-associated hemorrhagic conversion in my practice. Additionally, TXA premix bags can be stocked in the ED or NeuroICU and are much easier to acquire and administer than blood or factor products. I prefer TXA over EACA because of its longer duration of activity (and the fact EACA needs to be compounded in central pharmacy), but it is important to note that the risk of seizure is slightly higher with TXA than EACA (granted, this has been mostly observed in the cardiac surgery population who receive much higher doses of both agents).28

Fresh Frozen Plasma, Platelet Transfusion, Prothrombin Complex Concentrates/Factor VIIa

Data are even more limited for products beyond cryo and antifibrinolytics, and with good reason. While there is at least one case report describing recombinant factor VIIa for thrombolytic-associated hemorrhagic conversion,29 use of these products should be limited to patients who have a concurrent coagulopathy that is worth managing (say, patient on warfarin and INR is 1.6 or the patient is on DAPT). 

Proposed Workflow and Treatment of sICH After Thrombolysis

Rapid identification and diagnosis of sICH is crucial for appropriate management. Any new or worsening focal neurologic deficit, worsening in level of arousal, sudden-onset headache (especially if associated with a sudden increase in blood pressure), new nausea or vomiting, or new concerning neurologic symptoms not immediately attributable to an alternative cause should prompt emergent head CT to rule out hemorrhagic transformation. Dual-energy CT can be used to limit the confounding effect of contrast staining in patients who recently underwent CT angiography or thrombectomy.

If sICH is detected, the following algorithm can be considered:

1.    Order type and screen if one is not available

2.    Initiate intensive blood pressure control, with a goal SBP of <140

a.    IV push or continuous infusion CCBs should be used first line

b.    IV push:

                                          i.    Labetalol IV 10 mg x1, recycle BP in 2-3 minutes, and can re-dose 10-40 mg every 5-10 minutes until a cumulative dose of 300 mg is reached

                                         ii.    Hydralazine IV 10 mg x1 (less preferred because of variable response and ICP concerns), recycle BP in 2-3 minutes, and can re-dose 10 mg every 10 minutes until a cumulative dose of 240 mg is reached

c.     IV infusion:

                                          i.    Nicardipine IV 5 mg/hr, recycle BP in 5 minutes, and up-titrate by 2.5 mg/hr every 5 minutes until target BP reached, max 15 mg/hr (do not exceed this titration speed because of risk of over-shooting BP target)

                                         ii.    Clevidipine IV 2 mg/hr, recycle BP in 1-2 minutes, and double infusion dose every 60-90 seconds until target BP reached, max 32 mg/hr

                                        iii.    Do not use nitroprusside or nitroglycerin for acute BP control in neurologic emergencies because of risk of increased ICP

d.    Invasive blood pressure monitoring is ideal for agent titration, but arterial line placement should be considered high risk until 24 hours post-thrombolysis. Consider placing after completion of hemostatic agents.

3.    Measure STAT coags: PT/INR, PTT, platelet count, fibrinogen

a.    If TEG or ROTEM is available, consider collecting a baseline TEG/ROTEM

4.    Order and administer 10 units of cryoprecipitate or 40-70 mg/kg of fibrinogen concentrate (reasonable to empirically dose with 2 vials, or roughly 2000 mg)

a.    Blood banks release cryoprecipitate in “pools” which typically contain 5-10 units of cryoprecipitate each. If unable to determine how many units are in a pool, reasonable to order 2 pools

5.    Order and administer tranexamic acid 1 g over 10 minutes or aminocaproic acid 4 g over 30 minutes

a.    An optional infusion could be considered after initial bolus:

                                          i.    Tranexamic acid 125 mg/hr for 8 hours

                                         ii.    Aminocaproic acid 1 g/hr for 8 hours

6.    Other hemostatic products have a limited role and should only be considered in specific circumstances

a.    FFP 12 mL/kg: Limited to no role (only use if no other agents available). Consider PCC if patient was on warfarin prior to thrombolysis and pre-treatment INR was >1.4.

b.    Platelet transfusion 8-10 units: Limited role. Worsens outcomes in spontaneous ICH29 and may increase rates of hematoma expansion in thrombolysis-associated sICH.9 Consider if patient was on antiplatelet therapy prior to thrombolysis and the patient is going for a neurosurgical procedure (EVD, craniectomy, clot evacuation)

c.     4FPCC 15-50 Factor XI units/kg : Only consider if patient was on warfarin prior to thrombolysis and pre-treatment INR was >1.4. PCC is unlikely to sustainably improve INR elevations associated with liver disease.

d.    FVIIa 20-160 mcg/kg: Limited role. If patient was on warfarin prior to thrombolysis and pre-treatment INR was >1.4, consider PCC.

e.    Vitamin K 10 mg: Only consider if patient was on warfarin prior to thrombolysis and pre-treatment INR was >1.4. Vitamin K is unlikely to improve INR elevations associated with liver disease.

f.      Andexanet alfa: Only consider if patient was administered a thrombolytic within 18 hours of last dose of a factor Xa inhibitor. Dose high vs low dose based on manufacturer package dosing instructions.

g.    Idarucizumab 5 g: Only consider if patients was administered a thrombolytic within 18-24 hours of last dose of dabigatran or patient was on dabigatran and baseline coag studies (PTT or dTT) suggest residual anticoagulant effect.

h.    Desmopressin 0.3 mcg/kg: Unclear role. Could consider if a patient was on ticagrelor prior to thrombolysis and is undergoing a neurosurgical procedure (EVD, craniectomy, clot evacuation) because platelet transfusion does not reduce ticagrelor antiplatelet activity. 

7.    Re-draw fibrinogen 1-2 hours after cryoprecipitate/fibrinogen concentrate is complete

a.    Goal fibrinogen is >150-200 mg/dL; consider re-dosing if persistently low

                                          i.    Note: tenecteplase does not significantly affect fibrinogen concentration

b.    If baseline TEG/ROTEM collected, repeat to assess for normalization of LY30/ML/marker of thrombolysis; consider repeating or extending antifibrinolytic if still elevated

8.    Assess for signs of hydrocephalus or significant mass effect/increased intracranial pressure and consider whether bolus hyperosmolar products are appropriate

9.    Obtain a stability head CT at 6-8 hours to ensure hematoma stability

10.  If hematoma has expanded, consider repeating or extending antifibrinolytic

Do not initiate antiplatelets or chemical VTE prophylaxis for at least 48 hours, depending on size and severity of sICH and specific patient characteristics


In short, thrombolytic "reversal" is little-studied and our current approach is largely informed by case reports and series and broad-strokes cohort studies. Cryoprecipitate and antifibrinolytics remain the mainstay of hemostatic therapy to blunt the hyperfibrinolysis that underpins thrombolysis-associated bleeding, but prospective studies are badly needed to study how to best approach hemorrhagic conversion after thrombolysis.

Andrew Webb, PharmD, BCCCP

Clinical Pharmacist, Neurocritical Care

Massachusetts General Hospital



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