Platelet count and risk of major bleeding in venous thromboembolism

Figures & data

Figure 1. Flowchart illustrating the composition of the study population. VTE, venous thromboembolism

Table I. Baseline characteristics according to quartiles of platelet count measured at venous thromboembolism diagnosis

	Quartiles of platelet count (10^9/L)
	≤192 (n = 192)	193–239 (n = 192)	240–299 (n = 174)	≥300 (n = 186)
Age (years), mean±SD	71 ± 12	70 ± 13	70 ± 13	66 ± 14
Sex, males	61 (117)	51 (98)	42 (73)	40 (75)
BMI^a (kg/m^2), mean±SD	27.2 ± 4.4	27.6 ± 4.3	27.7 ± 4.9	27.2 ± 5.0
Hypertension^b	18 (34)	18 (35)	22 (38)	12 (23)
eGFR (ml/min/1.73^2), mean±SD	67.1 ± 24.4	70.7 ± 22.8	73.6 ± 23.1	78.6±24.5
Previous stroke	8 (15)	6 (11)	8 (14)	9 (16)
History of bleeding^c	4 (8)	6 (11)	4 (7)	9 (17)
Anemia^d	36 (69)	26 (49)	29 (51)	47 (87)
Active cancer^e	26 (49)	19 (36)	21 (37)	31 (57)
VTE characteristics
DVT	55 (106)	58 (111)	62 (108)	56 (105)
PE ± DVT	45 (86)	42 (81)	38 (66)	44 (81)
Unprovoked	47 (91)	44 (85)	47 (82)	33 (61)
Provoked	53 (101)	56 (107)	53 (92)	67 (125)
Trauma	9 (18)	8 (16)	9 (15)	9 (17)
Surgery	10 (20)	12 (23)	16 (28)	21 (39)
Acute medical conditions^f	11 (21)	12 (23)	9 (16)	19 (35)
Immobilization^g	24 (47)	24 (46)	18 (31)	20 (38)
Initial thrombolytic therapy	7 (13)	4 (8)	4 (7)	4 (7)
Planned treatment type
Heparin^h	21 (40)	18 (34)	16 (28)	23 (43)
Heparin^h and VKA	63 (120)	71 (136)	68 (118)	61 (114)
DOAC	6 (11)	3 (6)	7 (13)	6 (12)
Planned duration of anticoagulation
≤3 months	19 (36)	23 (45)	26 (46)	30 (55)
>3 including 6 months	39 (75)	42 (80)	37 (64)	28 (52)
>6 including 12 months	29 (56)	26 (49)	24 (42)	27 (51)
>12 months	13 (25)	9 (18)	13 (22)	15 (28)

Categorical variables are shown as percentages with numbers in brackets, % (n).

SD, standard deviation; BMI, body mass index; VKA, vitamin K antagonist; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; PE, pulmonary embolism; eGFR, estimated glomerular filtration rate.

^aBMI was calculated as weight in kilograms divided by the square of height in meters (kg/m²) in the Tromsø study.

^bSystolic blood pressure >160 mmHg.

^cA history of bleeding was present if a previous bleeding event was specifically noted in the medical records of VTE cases.

^dhemoglobin <11.5 g/dL for women and <13.0 g/dL for men.

^eActive cancer at the time of VTE diagnosis.

^fAcute myocardial infarction, ischemic stroke or major infectious disease within 12 weeks prior to VTE.

^gConfined to bed >3 days, wheel-chair, or long-distance travel exceeding 4 hours within the last 14 days prior to VTE event.

^hLow molecular weight heparin or unfractionated heparin.

Table II. The 1-year risk of major bleeding according to quartiles of platelet count measured at venous thromboembolism diagnosis

Quartiles of platelet count (10^9/L)	Major bleeding	IR (95% CI)	HR (95% CI)^a	HR (95% CI)^b	HR (95% CI)^c	SHR (95% CI)^c
All VTE patients
≤192	6	3.8 (1.7–8.6)	1 (reference)	1 (reference)	1 (reference)	1 (reference)
193–239	15	9.2 (5.6–15.3)	2.7 (1.0–6.9)	2.7 (1.0–7.0)	2.4 (0.9–6.3)	2.5 (1.0–6.5)
240–299	16	11.0 (6.7–17.9)	3.1 (1.2–8.0)	3.2 (1.2–8.2)	2.8 (1.1–7.4)	3.1 (1.2–8.0)
≥300	18	12.8 (8.1–20.3)	4.3 (1.7–10.9)	4.4 (1.7–11.2)	3.4 (1.3–8.8)	3.2 (1.2–8.6)
p for trend			.002	.002	.01	.02
VTE patients without cancer
≤192	5	4.1 (1.7–9.8)	1 (reference)	1 (reference)	1 (reference)	1 (reference)
193–239	9	6.3 (3.3–12.2)	1.9 (0.6–5.6)	2.0 (0.7–5.9)	1.8 (0.6–5.4)	1.9 (0.6–5.7)
240–299	9	7.2 (3.7–13.8)	2.0 (0.7–6.1)	2.1 (0.7–6.4)	1.6 (0.5–5.2)	1.8 (0.5–6.1)
≥300	13	11.6 (6.8–20.0)	4.0 (1.4–11.4)	4.2 (1.5–12.1)	2.8 (0.9–8.5)	2.9 (0.9–9.5)
p for trend			.01	.01	.08	.09

IR, incidence rate per 100 person-years; HR, hazard ratio; CI, confidence interval; SHR, sub-distribution hazard ratio.

^aAdjusted for age and sex.

^bAdjusted for age, sex, body mass index and planned duration of anticoagulant therapy.

^cAdjusted for age, sex, body mass index, planned duration of anticoagulant therapy, surgery, acute medical conditions (acute myocardial infarction, ischemic stroke, or major infectious disease), estimated glomerular filtration rate, hypertension (systolic blood pressure >160 mmHg), history of bleeding (specifically noted in the medical records of VTE cases), and anemia (hemoglobin level below 11.5 g/dL for women and below 13.0 g/dL for men at VTE diagnosis).

SHR denotes the HR after taking competing risk by death into account.

Figure 2. The risk of major bleeding as a continuous function of platelet count measured at venous thromboembolism diagnosis (a, adjusted for age, sex, body mass index and planned duration of anticoagulation) and at Tromsø study enrollment (b, adjusted for age, sex and body mass index) in a generalized additive regression model. The solid line shows hazards ratios, enclosed by shaded areas indicating 95% confidence intervals. The distribution of platelet count is shown in a density plot at the bottom, and vertical lines indicate quartile cutoffs

Figure 3. One-year cumulative incidence of major bleeding by quartiles of platelet count measured at venous thromboembolism diagnosis estimated by 1-Kaplan-Meier (a) and in the presence of death as competing event (b)

Table III. The 1-year risk of major bleeding according to quartiles of platelet count measured at venous thromboembolism diagnosis in provoked and unprovoked cases

Quartiles of platelet count (10^9/L)	Major bleeding	IR (95% CI)	HR (95% CI)^a	HR (95% CI)^b	HR (95% CI)^c	SHR (95% CI)^c
Provoked
≤192	3	4.0 (1.3–12.5)	1 (reference)	1 (reference)	1 (reference)	1 (reference)
193–239	13	15.8 (9.2–27.2)	4.1 (1.2–14.4)	4.3 (1.2–15.1)	3.5 (1.0–12.5)	3.8 (1.1–13.6)
240–299	10	14.0 (7.5–25.9)	3.5 (1.0–12.7)	3.7 (1.0–13.6)	3.3 (0.9–12.4)	3.6 (1.0–13.2)
≥300	13	15.4 (8.9–26.5)	4.5 (1.3–16.0)	4.7 (1.3–16.6)	3.7 (1.0–13.5)	3.4 (1.0–12.3)
p for trend			.04	.04	.08	.08
Unprovoked
≤192	3	3.7 (1.2–11.4)	1 (reference)	1 (reference)	1 (reference)	1 (reference)
193–239	2	2.5 (0.6–10.0)	0.8 (0.1–4.7)	0.8 (0.1–4.6)	0.7 (0.1–4.5)	0.7 (0.1–4.1)
240–299	6	8.1 (3.6–18.0)	2.4 (0.6–10.1)	2.3 (0.6–9.9)	1.7 (0.4–7.6)	1.8 (0.3–9.9)
≥300	5	8.9 (3.7–21.4)	3.3 (0.8–14.4)	3.3 (0.8–14.6)	2.7 (0.6–12.4)	2.7 (0.5–13.7)
p for trend			.05	.05	0.1	0.2

IR, incidence rate per 100 person-years; HR, hazard ratio; CI, confidence interval; SHR, sub-distribution hazard ratio.

^aAdjusted for age and sex.

^bAdjusted for age, sex, body mass index and planned duration of anticoagulant therapy.

^cAdjusted for age, sex, body mass index, planned duration of anticoagulant therapy, estimated glomerular filtration rate, hypertension (systolic blood pressure >160 mmHg), history of bleeding (specifically noted in the medical records of VTE cases), and anemia (hemoglobin level below 11.5 g/dL for women and below 13.0 g/dL for men at VTE diagnosis)

SHR denotes the HR after taking competing risk by death into account.

Table IV. The 1-year risk of major bleeding in patients with venous thromboembolism according to platelet count measured at Tromsø study enrollment

Categories of platelet count (10^9/L)	Major bleeding	IR (95% CI)	HR (95% CI)^a	HR (95% CI)^b	HR (95% CI)^c	SHR (95% CI)^c
≤192	6	6.0 (2.7–13.3)	1 (reference)	1 (reference)	1 (reference)	1 (reference)
193–239	18	9.3 (5.9–14.8)	1.7 (0.7–4.2)	1.7 (0.7–4.2)	1.6 (0.6–4.0)	1.5 (0.6–3.8)
240–299	19	9.7 (6.2–15.2)	1.9 (0.8–4.9)	1.9 (0.8–4.9)	1.7 (0.6–4.4)	1.6 (0.6–4.1)
≥300	12	10.5 (5.9–18.4)	2.5 (0.9–6.7)	2.5 (0.9–6.8)	2.0 (0.7–5.6)	1.9 (0.6–5.5)
p for trend			.08	.07	.2	.3

IR, incidence rate per 100 person-years; HR, hazard ratio; CI, confidence interval; SHR, sub-distribution hazard ratio.

^aAdjusted for age and sex.

^bAdjusted for age, sex and body mass index.

^cAdjusted for age, sex, body mass index and mean platelet volume.

Categories of platelet count measured at Tromsø study enrollment were established using the same cutoff points of platelet count assessed at VTE diagnosis.

SHR denotes the HR after taking competing risk by death into account.