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Abstract

Background

Chronic myeloid leukemia (CML) typically presents with fatigue, weight loss, leukocytosis, and splenomegaly. Major bleeding or spontaneous hematoma as the initial manifestation is rare and poses significant diagnostic and therapeutic challenges. This narrative review summarizes published cases of CML presenting first with bleeding or hematoma.

Methods

A PRISMA-style literature search of PubMed, Embase, Scopus, and Web of Science (up to 8 November 2025) identified case reports and series in which bleeding, hemorrhage, or hematoma constituted the initial presentation leading to the diagnosis of CML. Extracted data included demographics, bleeding site, laboratory findings, management and outcomes.

Results

Fifty-three patients were identified (median age 45 years; range 10-68), 74% male. Bleeding most commonly involved the central nervous system (40%), followed by soft-tissue/musculoskeletal hematomas (25%), intra-abdominal or visceral bleeding—predominantly splenic (19%)—and ocular/orbital hemorrhage (13%). Most patients had marked leukocytosis (median WBC ≈280 × 10⁹/L; 87% ≥ 100 × 10⁹/L) and frequent anemia (median hemoglobin 8.5 g/dL; 71% < 10 g/dL), with highly variable platelet counts. Defined acquired bleeding disorders were uncommon. Management was medical/supportive in 47% and surgical or interventional in 36%, particularly for CNS and splenic events. At last follow-up, 62% were alive, 21% had died—mainly from intracranial hemorrhage or splenic rupture—and some survivors had permanent sequelae.

Conclusion

Bleeding as the initial presentation of CML, though rare, carries substantial morbidity and mortality, especially with CNS or splenic involvement. Clinicians should consider CML in unexplained major bleeding with marked leukocytosis. Early diagnosis, prompt CML-directed therapy, and site-specific hemorrhage management are crucial.

Keywords

chronic myeloid leukemia myeloproliferative neoplasm spontaneous bleeding retroperitoneal hemorrhage complication

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the chromosomal translocation t(9;22)(q34.1;q11.2) or the Philadelphia chromosome.¹ The translocation results in the BCR::ABL1 fusion gene which leads to an overproduction of granulocytes and myeloid precursors.² Up to 40% of CML patients are asymptomatic at presentation, while symptomatic patients can present with complaints such as fatigue, malaise, weight loss, excessive sweating, and abdominal fullness.³ Objective findings on presentation might include splenomegaly, anemia, significant leukocytosis, and a high platelet count.^3,4 (Table 1)

Table 1.

Summary of Reported Cases of Chronic Myeloid Leukemia Presenting with Bleeding.

No	Case No	Year	Ethnic	Age	Gender	Initial Presentation	Duration	Wbc	Hb	Platelets	Coagulopathy	Type Of Coagulopathy	Treatment	Hematoma Site	Meds	Haematoma Managed	Outcome
1	Lakhotia M et al⁵	2015	Indian	55	M	pain and swelling of left thigh	10 days	3,20,000	5.7	12,24,000	no	NA	imatinib 400mg	left thigh	hydroxyurea,	conservatively	resolved completely in repeat MRI after 20 days
2	Kuo YC et al⁶	2000	Chinese	NA	NA	spontaneous mediastinal hematoma and hemothorax	NA	NA	NA	NA	NA	NA	NA	spontaneous mediastinal hematoma and hemothorax	NA	conservatively	regressed spontaneously after three months.
3	Bauduceau O et al⁷	2003	French	42	M	ilio-psoas muscle hematoma	NA	NA	NA	NA	NA	NA	NA	ilio-psoas muscle hematoma	NA	NA	NA
4	Kartthik S et al⁸	2019	Indian	45	F	right thigh swelling	1 month	193	8.5	303	Yes	acquired GT	imatinib 400 mg	right thigh hematoma on the anterolateral aspect	tranexamic acid & intranasal desmopressin	conservatively	complete resolution and correction of platelets function
5	Moshref R et al⁹	2021	NA	45	M	left-side subdural hematoma	1 day	135.7	11.7	142	NA	NA	imatinib	left-sided extra-axial hematoma	hydroxyurea,	left acute subdural hematoma evacuation, and decompressive hemicraniectomy	improved
6	Jain A et al¹⁰	2019	Indian	68	M	large subdural hematoma (SDH)	1 day	114	12	482	Yes	severely impaired aggregation	imatinib 400 mg	large subdural hematoma (SDH)	NA	emergency burr-hole evacuation	resolved
7	Abdulhamid MM et al¹¹	2011	NA	53	M	right-sided acute subdural hematoma	1 day	102 000	14.2	589 000 NA		NA	imatinib	non-traumatic right-sided acute subdural hematoma	hydroxyurea,	intially consevative then evacuated	complete resolution
8	Sharma SR et al¹²	2021	Indian	65	M	Hematoma in right subcritical parietal lobe	2 day	51.7	9.2	16	NA	NA	imatinib	Hematoma in right subcritical parietal lobe with 10 mm midline shift.	NA	NA	passed away
9	Wang H et al¹³	2020	Chinese	45	M	parenchymal hematoma about 74.8 ml in the right frontal lobe	NA	571	9.5	218	NA	NA	imatinib then changed to dasatinib (CNS involvement), changed to ponatinib due to TKI resistance	intracerebral hemorrhage (ICH) in the right frontal lobe	hydroxyurea,	emergent craniotomy	resolved
10	Bashir, Y et al¹⁴	2014	Indian	35	M	vague abdominal discomfort	NA	320	5.6	70	NA	NA	imatinib	retroperitoneal hematoma	allopurinol, hydration	conservatively	resolved
11	D'Souza N et al¹⁵	2021	NA	49	M	compartment syndrome leading to flaccid paralysis.	48hrs	615	8.3	normal	NA	NA	imatinib 400 mg	acute hematoma of the left biceps brachii	hydroxyurea,hydration Rasburicase	Exploration and evacuation of the limb and axillary hematoma was performed under general anesthesia	some recovery of sensory function, motor recovery remained absent
12	Cohen E et al¹⁶	2014	NA	11	M	progressive left calf pain and swelling	2-week	440		NA	NA	NA	imatinib	NA	NA	fasciotomy and evacuation of a hematoma
13	Dwebi, M et al¹⁷	2019	NA	45		swelling over the left chest wall (infra axillary area0	NA	299	5.2	232	NA	NA	imatinib	muscles in the infraaxillary area	hydroxyurea,	conservatively	complete resolution
14	Muta T et al¹⁸	2010	Japanese	46	NA	fatigue and visual disturbances	NA	419.3	NA	NA	NA	NA	imatinib + Cytarabine	retinal bleeding, cerebellar hemorrhage, deteriorating to acute hydrocephalus secondary to obstruction of the cerebral aqueduct	NA	hyperventilation, administration of mannitol, and barbiturate coma, were performed	improved recovered without any neurological defect.
15	chakroun-walha et al¹⁹	2010	Japanese	26	M	left side weakness	1 day	213	NA	291	NA	NA	NA	hematoma in right subcortical parietal lobe	NA	conservatively	passed away
16	Kapur S et al²⁰	2013	Caucasian	52	M	tinnitus and fullness in left ear	1 day	685	9.1	164	NA	NA	nilotinib	intracranial hemorrhage	hydration, hydroxyureaallopurinol IV bicarbonate	conservatively	bilateral sensorineural deafness and was treated with bilateral transmastoid cochlear implants
17	Aggarwal A et al²¹	2013	Indian	60	M	headache and transient loss of consciousness. Ct head showed IVH predominantly in the third ventricle	1 day	371 000	9.6	350	NA	NA	NA	Acom artery aneurysm	NA	aneurysm clipped	passed away
18	haudhary , V et al²²	2013	NA	32	F	hypovolemic shock with hemoperitoneum, vaginal bleed and abdominal pain	2 days	128	8.3	NA	NA	NA	imatinib	corpus luteal hemorrhage	allopurinol (Tranexamic acid).	conservatively	resolved
19	Tsai CC et al²³	2004	Chinese	12	F	ICH (right lower frontal area + anterior thalamus)	2 days	181 700	6.4	2.29 × 105/mm3	NA	NA	NA	ICH (right lower frontal area + anterior thalamus)	allopurinol, and hydroxyurea, ING-a	conservatively	died
20	Jain A et al²⁴	2015	Indian	32	F	headache, vomiting and diplopia	1 day	7.5	9.4	2500 × 109 /L	NA	NA	NA	left sided subdural hematoma and right-sided intra-parenchymal bleed	Imatinib (800 mg/day) along with hydroxyurea (3 gm/day)	symptomatically with mannitol and furosemide	alive
21	Wang Y et al²⁵	2013	Chinese	38	F	intracranial hemorrhage, hematuria	20 days	454.84	10.8	311	NA	NA	imatinib	cerebral hemorrhage in the right parietal and frontal lobe	allopurinol, hydration, hydroxyurea and FFP	conservatively	passed away 2 ywars after diagnosis due to pneumonia .
22	Hadley C et al²⁶	2016	NA	16	M	Morel-lavallÃ^©e Lesion Of The Knee I	few days	329 000	7.5	NA	NA	NA	NA	NA	NA	NA	NA
23	Au H et al²⁷	2000	NA	13	M	haemoperitoneum	1 day	109.4	9.4	192	NA	NA	unrelated bone marrow transplantation	second part of duodenum,	NA	conservatively	alive
24	Vemulakonda S et al²⁸	2021	NA	48	M	left hypochondriac tenderness, found to have splenomegaly, and a subcapsular splenic hematoma	2 day	1.94	6.5	NA	NA	NA	NA	subcapsular splenic laceration, hematoma	NA	emergency splenectomy	Alive
25	Gopal, V.R. et al²⁹	2022	NA	26	M	swelling of the left scapular regiony extending upto left anterior chest wall	1 day	120 100	10.6	4.2	NA	NA	NA	left side posterior chest wall	hydroxyurea	conservatively	alive
26	Seraly MP et al,³⁰	2019	NA	63	F	decrease vision on right eye	1 month	126 500		NA	NA	NA	Imatinib	right eye localized intraocular mass or subretinal hemorrhage	NA	vitrectomy.	alive,lost vision on the eye
27	Shih, L.-Y wt al³¹	1987	Chinese	36	M	left upper abdominal pain, found to have splenic rupture	1 day	160.9	9	865	NA	NA	Busulfan	Splenic Rupture	NA	spleenectomy	passedaway
28	Nestok BR et al³²	1988	Caucasian	35	M	spleenic rupture	1 day	5100	NA	NA	NA			Splenic Rupture	NA	spleenectomy	passedaway
29	Lashley PM et al³³	1998	NA	10	M	spontaneous rupture of the spleen	1 day	NA	NA	NA	NA	NA	alpha-interferon therapy.	Splenic Rupture	NA
30	Eric Frost et al³⁴	2017	Caucasian	59	M	abdominal pain, found to have splenic laceration	30 min	109.1	8.1	100 000	NA	NA	Imatinib	Splenic Rupture	allopurinol and hydroxyurea	emergency splenectomy complicated by partial gastrectomy and partial omentectomy.	Alive in remission
31	Jafferbhoy S et al³⁵	2011	NA	47	M	abdominal pain, found to have splenic laceration	1 day	280.3	3.8	199	NA	NA	Imatinib	Splenic Rupture	NA	radiological embolisation of a splenic artery then lapratomy and splenectomy due to abd. Compartment syndrom	Alive
32	Almater AI et al³⁶	2022	NA	19	F	sudden painless decrease in vision in her left eye for 1 day.	1 day	226	4.6	294	NA	NA		subhyaloid hemorrhage	allopurinol and hydroxyurea	NA	alive
33	Moshref R et al⁹	2021	NA	45	M	sudden-onset severe headache	1 day	135.7	11.7	142	NA	NA	NA	left-sided subdural hematoma	hydroxyurea	subdural hematoma evacuation with decompressive craniectomy	alive
34	Oubahmane T et al³⁷	2015	NA	28	F	swelling of her right lower eyelid,	3 years	NA	NA	NA	NA	NA	NA	organized haematoma of the eyelid.	NA	surgical exploration comprising total resection of the mass.	alive
35	Prasad BC et al³⁸	2012	NA	56	M	headache and forgetfulness for two weeks and sudden onset weakness of left side of the body and loss of consciousness for one day.	1 day	NA	NA	NA	NA	NA	NA	right fronto-temporo-parietal	NA	right frontal and parietal burr holes and evacuation of chronic SDH	alive
36	Yoon MK et al³⁹	2012	Caucasian	34	M	dull headache with the development of right upper eyelid swelling	2 days	290 000	NA	345 000	NA	NA	hydroxyurea and dasatinib	right superior subperi- osteal orbital mass	NA	orbital exploration, and evacuation	alive
37	Cho SF et al⁴⁰	2011	Taiwanese	33	M	severe headache, vomiting, and drowsiness	3 days	186 260	NA	NA	NA	NA	NA	right parietal epidural hemorrhage	hydroxyurea (1 g/day) and then switched to imatinib mesylate	An emergent craniotomy chest plus mass excision	alive
38	Nojiri H et al⁴¹	2009	NA	55	M	backach then complaining of gait disturbance due to bilateral leg weakness.	NA	42.3	11.6	596	NA	NA	imatinib	spinal cord	NA	decompression of the spinal cord and evacuation	alive
39	Shivkumar, P et al⁴²	2008	NA	45	F	right-sided vulvar swelling associated with severe pain	3 days	NA	5.8	65	NA	NA	NA	vulvalr hematoma	NA	evacuation and the cavity was closed with hemostatic sutures	NA
40	Arboix A et al⁴³	2000	NA	48	M	and motor difficulties in the right limbs	2 weeks	163.5	11.5	286	NA	NA	NA	basaal gangilia	hydroxyurea	NA	alive
41	Nacinovic AD et al⁴⁴	2004	NA	39	M	chest pain	na	136	11.8	477	Yes	low plasma Factor XIII level.		sub cutanous bleeding	NA	NA	NA
42	Kouzuki K et⁴⁵	2018	NA	16	M	Fever and hyperleukocytosis	NA	175	10.5	59	NA	no	Hydroxyurea followed by craniotomy	Right temporal	NA	craniotomy to remove the hematoma	dead
43	Nobuhisa Takahashi et al⁴⁶	2021	NA	14	F	Fatigue and fever	NA	75.4	8.5	17.2 × 104/μL	NA	no	Hydration allopurinol heparin imatinib nilotinib	multiple ICH lesions and brain hernia	NA	conservative	dead
44	chakroun-walha et al⁴⁷	2015	NA	26	M	Headache after head trauma	same day	260	8.4	291	NA	NA	NA	Right parietal	NA	Mannitol Dexamethasone	dead
45	Ashraf M et al⁴⁸	2023	NA	22	M	Initially headache and vomiting followed by recently left sided weakness and altered sensorium	2 weeks	447	NA	202	NA	NA	NA	Right frontotemporal	NA	right-sided frontal-temporal-parietal decompressive hemicraniectomy with expansion duraplasty	alive
46	To AQ et al⁴⁹	2022	NA	29	M	abdomnal pain	na	651.2	5.1	393	Yes	aquired factor 5	dasatinib 140 mg daily and hydroxyurea 1 g daily.	swelling and upper extremities 2 hematomas	NA	20 units of cryoprecipitate 1 dose of dasatinib	na
47	To AQ et al⁴⁹	2022	NA	26	M	progressive left lower extremity swelling and significant pain in the left buttock region following a reported minor fall two weeks prior to admission	2 weeks	507	6.7	398	Yes	aquired factor 5	dasatinib 100 mg daily with hydroxyurea 2 g twice daily.	left lower extremity swelling and significant pain in the left buttock region	NA	cryoprecipitate, FFP and platelet transfusion.	alive
48	Ceausu M.⁵⁰	2015	NA	63	M	Presented with severe rapid onset headache and motor deficit on the right side of the body.	NA	257	NA	154	NA	NA	Surgical drainage of the subdural hematoma	Subdural	No	Surgical drainage of subdural hematoma	Died
49	George P⁵¹	2012	NA	45	M	Presented with sudden swelling over the left chest wall	NA	299	5.2	232	NA	NA	Hydroxyurea and imatinib	Left chest wall (infra-axillary)	Hydroxyurea and imatinib	Conservative, no intervention needed	Alive
50	Cho, E⁵²	2022	NA	56	M	Presented with oral and lesion and mucosal bleeding	6 month	15	NA	1 363 000	Yes	AcquiredVon Willebrand Syndrom	Imatinib	Oral Mucosal bleeding	Imatinib	No intervention needed	Alive
51	AlGahtani F H⁵³	2023	NA	18	F	Presented with blurry vision	1 day	225	4.7	255	NA	NA	NA	Intraretinal hemorrhage	NA	NA	NA
52	AlGahtani F H⁵³	2023	NA	56	M	Presented with acute painful erythematous discoloration on the left forearm	3 days	418 700	7.5	470	NA	NA	NA	Intramuscular hematoma of left forearm	NA	NA	NA
53	AlGahtani F H⁵³	2023	NA	52	F	Presented with bleeding in her retina	NA	160	NA	NA	NA	NA	NA	Retinal hemorrhage	NA	NA	NA

Abbreviations: Na, not available; M, Male; F, female; WBC: ×10⁹/L, Haemoglobin (Hb): g/dL, Platelets: ×10⁹/L.

Bleeding in CML is relatively uncommon but can occur due to several factors. While CML is not typically associated with a high risk of bleeding, complications may arise, particularly in the setting of thrombocytopenia. Additionally, certain treatments for CML, such as tyrosine kinase inhibitors (TKIs) or bone marrow transplantation, can cause cytopenias which could lead to bleeding complications. The pathophysiology of bleeding in CML involves disruptions in normal hematopoiesis, with the overproduction of immature myeloid cells creating a crowded bone marrow environment that affects platelet production and functionality. The infiltration of abnormal cells in the bone marrow can further compromise the production and maturation of blood cells, contributing to bleeding issues.⁴ Rarely, CML can present initially with bleeding or soft tissue hematoma. Although previous case reports have described bleeding complications in patients with CML, the literature lacks a comprehensive analysis of cases where bleeding or hematoma presents as the intial presentation of the disease. Therefore, the aim of this systematic review is to compile and analyze all published case reports of CML presenting initially with hemoatoma or bleeding which would improve clinical awareness of this unusual presentation. A preliminary summary of a subset of these cases was presented as a conference abstract at the 64th American Society of Hematology (ASH) Annual Meeting in 2022; the current manuscript substantially extends that work with an updated search, additional cases, and an in-.depth narrative synthesis.⁵⁴

Methods

A comprehensive literature search was conducted across four major databases: PubMed, Embase, Scopus, and Web of Science, with the final search performed on November 8, 2025. No date limits or language restrictions were applied initially. Non-English articles were excluded later during screening. Search terms combined controlled vocabulary and free-text words related to chronic myeloid leukemia, hematoma or hemorrhage. The PubMed search included terms such as “Leukemia,” “Chronic Myeloid Leukemia,” “BCR-ABL Positive,” and “Hematoma.” Similarly, Embase, Scopus, and Web of Science searches used variations of “leukemia,” “CML,” “hematoma,” incorporating both indexed and keyword terms. Reference lists of all included articles were also manually screened to identify additional eligible studies. Studies were eligible if they were case reports or case series describing patients of any age who presented with bleeding, hematoma, or hemorrhage as the initial manifestation of (CML). Exclusion criteria included previously diagnosed CML, insufficient clinical detail, non-clinical articles, reviews, editorials, conference abstracts, and non-English publications. Two reviewers independently screened titles, abstracts, and full texts, resolving disagreements through discussion. Data were extracted using a standardized form and included demographics, clinical presentation, bleeding location, laboratory values at diagnosis, coagulation parameters, management interventions, and clinical outcomes.

Results

Across 51 published reports, we identified 53 patients with CML who developed spontaneous hematomas or major haemorrhagic events. The median age at the time of bleeding was 45 years (range 10-68), and 7/53 (13%) were aged ≤18 years. Sex was reported for all patients: 39/53 (74%) were male and 14/53 (26%) female, confirming a clear male predominance. (Figure 1)

Figure 1.

PRISMA flow chart for the systematic review and meta-analysis.

Bleeding sites were heterogeneous but showed several recurrent patterns. Central nervous system (CNS) involvement was the single most frequent presentation, occurring in 21/53 (40%) patients, and included subdural and epidural haematomas, intraparenchymal and cerebellar haemorrhages, basal ganglia bleeds and spinal haematomas. These cases typically presented with acute severe headache, vomiting, focal neurological deficits, altered sensorium or clinical signs of raised intracranial pressure. Soft-tissue and musculoskeletal haematomas were documented in 13/53 (25%), affecting the thigh, biceps, forearm, chest wall, scapular region, vulva and limb compartments; patients usually presented with painful swelling, sometimes complicated by compartment syndrome or nerve compression. Intra-abdominal or visceral haemorrhage occurred in 10/53 (19%), most commonly involving the spleen (subcapsular haematoma, laceration or rupture), but also retroperitoneal haematomas, duodenal wall haematoma and haemoperitoneum. Ocular and orbital haemorrhages were reported in 7/53 (13%) patients, ranging from intra-ocular and subretinal haemorrhage to orbital or eyelid haematomas; these events were often associated with acute visual loss or periorbital pain. The remaining 2/53 (4%) patients presented predominantly with mucosal or isolated cutaneous/subcutaneous bleeding that could not be easily assigned to the above categories.

Baseline haematological parameters were variably reported but showed a clear pattern of proliferative disease with frequent cytopenias. A white blood cell (WBC) count at or near the time of bleeding was available in 47/53 cases. Most patients had marked leukocytosis: 41/47 (87%) had WBC values ≥100 × 10⁹/L only 4/47 had WBC <50 × 10⁹/L, and the median reported WBC was approximately 280 (interquartile range ∼136-668). Haemoglobin was documented in 34/53 patients, with a median of 8.5 g/dL (range 4.6-14.2). Anaemia was common: 24/34 (71%) had haemoglobin <10 g/dL and 13/34 (38%) had severe anaemia <8 g/dL. Platelet counts were available in 38/53 cases and ranged widely from profound thrombocytopenia (around 4 × 10⁹/L) to extreme thrombocytosis (up to the order of 10¹²/L). Thrombocytopenia defined as <150 × 10⁹/L was present in 7/38 patients (including 2 with counts <50 × 10⁹/L), while thrombocytosis ≥450 × 10⁹/L was seen in 13/38. Among the 33 patients with both WBC and haemoglobin reported, 19 (58%) had the composite picture of marked leukocytosis (≥100) and haemoglobin <10 g/dL at the time of bleeding, supporting our hypothesis that this constellation represents a particularly high-risk haematological phenotype.

Treatment of the underlying CML at the time of the haemorrhagic event was heterogeneous but dominated by tyrosine kinase inhibitor (TKI)–based regimens. Imatinib (with or without preceding cytoreduction) was used in 22/53 (42%) patients, while second-generation TKIs (dasatinib and/or nilotinib) were reported in 4/53 (8%). Historical pre-TKI therapies such as busulfan or interferon-α were described in 2/53 (4%) older cases. One patient (2%) bled in the setting of unrelated allogeneic bone-marrow transplantation, and another (2%) was managed mainly with cytoreductive therapy alone. In the remainder, the CML-directed regimen at the time of haemorrhage was not clearly specified. In several reports the haematoma developed shortly after TKI initiation, but in many others the episode coincided with uncontrolled disease burden and hyperleukocytosis rather than a clearly drug-mediated effect.

Management of haematomas reflected both anatomical site and clinical severity. At least 25/53 (47%) patients were treated with conservative/medical measures alone, including cytoreduction with hydroxyurea, initiation or continuation of TKIs, hydration and uric-acid–lowering therapy, transfusion support (packed red cells, platelets, fresh frozen plasma and cryoprecipitate), antifibrinolytics such as tranexamic acid, desmopressin, and measures to control raised intracranial pressure. In contrast, at least 19/53 (36%) required surgical or interventional procedures, particularly those with CNS or splenic involvement. These interventions included burr-hole drainage or craniotomy for subdural or intraparenchymal haemorrhage, decompressive hemicraniectomy and spinal decompression, splenectomy, fasciotomy with haematoma evacuation for limb compartment syndromes, vitrectomy for intra-ocular haemorrhage, and evacuation of large vulvar or soft-tissue haematomas. In the remaining patients, the management approach was not clearly documented. Overall, CNS and splenic haematomas were disproportionately represented among those requiring urgent surgery, whereas many soft-tissue, chest wall and some intra-abdominal haematomas resolved with conservative therapy.

Outcome data were available for most patients. At last reported follow-up, 33/53 (62%) patients were alive and 11/53 (21%) had died. Deaths clustered among those with extensive intracranial haemorrhage, multiple intracerebral lesions with herniation, or splenic rupture, although some later deaths were attributed to infectious or disease-related complications such as pneumonia rather than the haematoma itself. For the remaining cases, survival status or timing of outcome was not clearly specified. Among survivors, a small but important subgroup had permanent sequelae, including unilateral blindness after subretinal haemorrhage, bilateral sensorineural deafness after intracranial bleeding, and persistent motor deficit following limb compartment syndrome.

Discussion

Pathophysiology of Bleeding in CML

The pathophysiology behind bleeding in CML is multifactorial. While thrombocytopenia is one potential cause, it is not always the predominant factor, as the majority of patients included in this review had normal or mildly elevated platelet counts. In fact, CML is often associated with an increase in the number of platelets, which, paradoxically, can sometimes impair platelet function.⁵² The overcrowding of the bone marrow with immature myeloid cells may interfere with normal megakaryopoiesis, thus affecting platelet production and leading to functional defects in platelets.⁵² Additionally, the dysregulation of the hematopoietic environment may result in altered coagulation, although coagulopathy was only noted in two patients in this review. Furthermore, CML treatments, particularly tyrosine kinase inhibitors (TKIs) and bone marrow transplantation, can induce cytopenias, further predisposing patients to bleeding complications.⁵³

Interstingly, Ethnicity may be one of the factors contributing to the pathogenesis of Chronic Myeloid Leukemia (CML). Several studies have demonstrated that a specific single nucleotide polymorphism found in Asian populations, including China and Korea, can predispose patients to developing CML.⁵⁵ Our review revealed that 76% of the reported cases were of Asian origin or background. This observation highlights the possibility that Asian ethnicity may be associated with CML and increase inceince of bleeding . although we can not exclude risk bias of ocvver reporting from certain region, nevertheless caes coimg from different Asian countries with different liker japand and china versus other conmtrires like india might argue against risk of bias in addition nothing prevting other from reporting

Moreover, another possible mechanism in the pathogenesis of CML is hyperleukocytosis, the pathophysiology behind the signs and symptoms of hyperleukocytosis is multifactorial, being related to impaired blood flow in the microcirculation, competition for oxygen in the microcirculation and possibly invasion of the vessel wall. All of this may contribute to the development of CML and bleeding as the first manifestation.⁵⁶ Adding to that, the increased proliferation of blood cells in CML, particularly white blood cells, causes blood viscosity, causing blood to flow less easily through blood vessels and increasing the risk of clot formation and blood stasis which causes occlusion of the small vessels resulting in complications such as intracranial hemorrhage.⁵⁷ This aligns with the findings of this review, as the majority of the patients presented with elevated leukocyte count. This noteworthy observation in our review strongly suggests the role of hyperleukocytosis in the development of CML.

Furthermore, It is well known in the literature that CML is associated with different hematological abnormalities including low hemoglobin “In acute leukaemia, hyperleukocytosis and severe thrombocytopenia are consistently identified as independent predictors of intracranial haemorrhage, whereas anaemia, although present in the vast majority of affected patients, has not emerged as an independent risk factor once white blood cell and platelet counts are taken into account.⁵⁸ This results from the fact that the bone marrow's ability to generate new RBCs is impaired due to abnormal proliferation of leukemic cells.⁵⁸ Early in the disease may be subtle but as the disease progresses may lead to severe anemia. This concept also aligns with our review as the majority of the patients were anemic with a median hemoglobin level of 8.5. hyperleukocytosis and severe thrombocytopenia are consistently identified as independent predictors of intracranial haemorrhage, whereas anaemia, although present in the vast majority of affected patients, has not emerged as an independent risk factor once white blood cell and platelet counts are taken into account.⁴⁸

In a minority of patients in our series, bleeding could be directly attributed to a clearly defined acquired bleeding disorder, underlining that CML-associated haemorrhage is not solely a consequence of cytopenias or leukostasis.

Taken together, these data support the notion that acquired bleeding disorders form an important mechanistic substrate for haemorrhage in CML, particularly in patients with extensive haematomas or disproportionate bleeding relative to platelet count and basic coagulation parameters. Our finding that only a small fraction of patients had a defined disorder likely reflects under-testing rather than true rarity; in many cases, extended assays for platelet function, von Willebrand factor, and individual clotting factors were either not performed or incompletely reported. Clinically, this suggests that CML patients who present with spontaneous or unusually severe haematomas should prompt a deliberate search for acquired von Willebrand syndrome, Glanzmann-like platelet defects and rare factor deficiencies (especially factors V and XIII), alongside standard evaluation for leukostasis and thrombocytopenia. Identifying such acquired haemostatic abnormalities is not merely academic: they can often be at least partially reversed with effective cytoreduction and targeted replacement therapy, and their recognition may guide peri-procedural planning, transfusion support and the safe use of antithrombotic agents in this already fragile population.

Clinical Presentation

The diverse locations of hemorrhagic events in the patients we reviewed, including intracranial (subdural), intra-abdominal, musculoskeletal, and intrathoracic sites, highlight the unpredictable nature of bleeding in CML. Intracranial hemorrhage (ICH), a life-threatening complication, was reported in 37% of the cases, consistent with the fact that central nervous system bleeding can be particularly devastating. ICH in CML is likely due to a combination of myeloid cell infiltration of the bone marrow, thrombocytopathy, and the effects of high leukocyte counts on vascular integrity.⁵⁹ It is noteworthy that a substantial proportion of patients (44%) required surgical intervention for bleeding control, reinforcing the potential severity of these complications.

The fact that 33% of patients experienced spontaneous recovery is also notable. This spontaneous resolution may suggest that in some cases, bleeding complications in CML may not be as directly related to thrombocytopenia or coagulopathy but rather to other underlying pathophysiological mechanisms that self-correct as the disease is treated.

Treatment Approaches

In terms of management, the majority of patients in our review (53%) received imatinib, the first-line TKI, which has significantly improved survival rates for patients with CML. While imatinib is effective at controlling the leukemic process, it can lead to cytopenias, including thrombocytopenia and neutropenia, which could predispose to further bleeding complications.⁵³ Despite these potential side effects, TKIs remain the cornerstone of therapy in chronic-phase CML, and their ability to achieve deep molecular responses likely contributed to the favorable outcomes in the majority of our patients.

Surgical management was required for nearly half (44%) of the patients, indicating the severity of the hemorrhagic events and the need for aggressive intervention. In contrast, conservative management with transfusions and supportive care was effective in a smaller cohort of patients (28%), with spontaneous recovery occurring in 33%. This suggests that in some cases, particularly those with localized hemorrhage, conservative measures may be sufficient.

Survival Outcomes

The overall survival of patients in this review was relatively high, with 67% of patients still alive at the last follow-up. Despite the initial presentation with significant bleeding complications, which are often associated with worse outcomes in other hematologic malignancies, many patients responded well to treatment and had a favorable prognosis. However, the occurrence of severe complications, such as intracranial hemorrhage and sepsis, contributed to mortality in a minority of cases. These findings underscore the importance of early recognition and aggressive management of bleeding events in CML, particularly in the setting of elevated white blood cell counts or during periods of disease acceleration.

Clinical Implications and Practical Recommendations

The cases included in this review illustrate a recognisable clinical pattern that, although rare, has important diagnostic and therapeutic implications. Most patients presented with deep-tissue or central nervous system (CNS) bleeding in the setting of marked leukocytosis and anaemia. In several patients, the haematoma or haemorrhage was the first clinical event that brought them to medical attention, and the underlying CML would likely have remained undiagnosed without targeted haematological evaluation. These observations underscore that major bleeding does not exclude an underlying myeloproliferative process and may, in fact, be a sentinel manifestation of CML.

From a practical standpoint, unexplained major bleeding in the presence of extreme leukocytosis—particularly when accompanied by splenomegaly, constitutional symptoms, or a leukoerythroblastic blood film—should prompt urgent evaluation for CML. At a minimum, this should include a complete blood count with differential, peripheral blood smear review, and BCR::ABL1 testing by quantitative PCR or fluorescence in situ hybridisation. In patients with neurological symptoms, prompt brain imaging (CT and/or MRI) is essential to detect subdural, intraparenchymal, or spinal haematomas. Similarly, patients presenting with abdominal pain or haemodynamic instability should undergo abdominal imaging to evaluate for splenic haematoma, rupture, or retroperitoneal bleeding.

Given that a minority of patients had a clearly defined acquired bleeding diathesis, it is reasonable to perform targeted haemostatic testing in those with disproportionate bleeding relative to their platelet count or degree of cytopenia. This may include screening for acquired von Willebrand syndrome, factor deficiency, and qualitative platelet function defects, particularly in the perioperative setting or when invasive procedures are planned. At the same time, aggressive cytoreduction with hydroxyurea and early initiation of tyrosine kinase inhibitor (TKI) therapy should be considered to reduce leukocyte burden, ameliorate hyperviscosity, and address the underlying myeloproliferative clone. Close collaboration between haematology, neurosurgery, interventional radiology, and critical care teams is often required to balance the competing risks of ongoing bleeding, thrombosis, and tumour lysis.^60,61

Proposed Clinical Algorithm for Spontaneous Haematoma and Possible CML

Based on the patterns observed in this review, we propose a pragmatic, stepwise approach for clinicians confronted with a patient who presents with spontaneous haematoma or major haemorrhage of unclear cause and abnormal blood counts.

The first step is acute stabilisation and site-specific management of the bleed (eg neurosurgical decompression for large intracranial haematomas, splenectomy or embolisation for splenic rupture, fasciotomy for limb compartment syndrome), undertaken in parallel with initial laboratory assessment.

The second step is focused haematological triage. In any patient with major bleeding and leukocytosis, anaemia, or unexplained thrombocytosis/thrombocytopenia, we suggest urgent full blood count with manual differential, peripheral blood film review, and basic coagulation testing (prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer). The presence of circulating myeloid precursors, basophilia, marked left shift, or a leukoerythroblastic picture should immediately raise suspicion for CML. In this context, BCR::ABL1 testing on peripheral blood should be requested without delay, and bone marrow examination can be arranged once the patient is haemodynamically stable.

The third step is risk-adapted haemostatic and cytoreductive management. For patients with extreme leukocytosis and life-threatening bleeding, we recommend rapid cytoreduction with hydroxyurea (and leukapheresis in selected cases) alongside supportive transfusion therapy (red cells, platelets, plasma, and cryoprecipitate as indicated). Where bleeding appears disproportionate, specific assays for von Willebrand factor and clotting factor levels, as well as platelet function testing, should be considered. Once CML is confirmed, TKI therapy should be initiated as soon as clinically feasible, with the choice of agent and intensity guided by standard risk stratification and organ function, while carefully monitoring for tumour lysis and dynamic changes in coagulation parameters.

Finally, patients who survive the index event should undergo structured follow-up, with particular attention to neurologic and functional outcomes, control of the leukaemic burden, and reassessment of haemostatic status. In view of the high morbidity and mortality observed in this cohort, early referral to centres with haematology and neurosurgical expertise may be warranted. This algorithm is not intended to replace existing CML guidelines, but rather to complement them in the specific and under-recognised scenario where bleeding or haematoma is the first sign of CML.⁶²

Summary

To our knowledge, this is the first review to systematically compile and clinically synthesise all published cases in which bleeding or haematoma constituted the initial presentation of CML, rath

Based on our findings and synthesis of published case reports, we hypothesise that CML patients who present with the composite picture of hyperleukocytosis, anaemia and bleeding disorder are particularly vulnerable to developing spontaneous major haemorrhage, including deep-tissue and intracranial haematomas.

These observations must, however, be interpreted with great caution. They are derived from a relatively small number of heterogeneous case reports and small series, subject to publication and reporting bias, and cannot be considered definitive. Rather than firm conclusions, they should be viewed as hypotheses that require validation in larger, systematically collected cohorts. Future work should include prospective, multinational registries of haemorrhagic complications in CML and other myeloid neoplasms, ideally linked to detailed laboratory and genomic profiling. Within such datasets, modern analytical approaches—including machine-learning and other artificial-intelligence–based models—could be applied to identify and validate clinical and biological predictors of bleeding, with the ultimate aim of developing practical tools to stratify risk and guide surveillance and preventive strategies in routine practice.

Limitations

This review is limited by its retrospective nature and the inclusion of cases spanning several decades, during which there have been advancements in both diagnostic techniques and therapeutic options. The relatively small sample size and lack of randomized controlled data further limit the ability to draw definitive conclusions. Furthermore, the lack of detailed information on the molecular characteristics of the CML in these cases (eg, BCR::ABL1 transcript levels, mutations) prevents a deeper understanding of the relationship between molecular features and bleeding risk.

Conclusion

Although bleeding is a rare initial manifestation of CML, this review demonstrates that it can occur, often in severe forms, and may be associated with poor outcomes. The pathophysiology of bleeding in CML involves a complex interplay of platelet dysfunction, thrombocytosis, and cytopenias, which are exacerbated by the disease and treatment regimens. Timely diagnosis, appropriate therapeutic interventions, and close monitoring are essential for managing these patients, particularly in the setting of advanced disease or during periods of disease acceleration. Further research is needed to better understand the factors contributing to bleeding in CML and to refine treatment strategies to minimize these risks.

Footnotes

ORCID iDs

Mohammad ALTermanini

Abdulrhaman F. Al-Mashdali

Motaz Almahmood

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on request.

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Review of Bleeding as Initial Presentation in Patients with Chronic Myeloid Leukemia

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Results

Discussion

Pathophysiology of Bleeding in CML

Clinical Presentation

Treatment Approaches

Survival Outcomes

Clinical Implications and Practical Recommendations

Proposed Clinical Algorithm for Spontaneous Haematoma and Possible CML

Summary

Limitations

Conclusion

Footnotes

ORCID iDs

Funding

Declaration of Conflicting Interests

Data Availability Statement

References