Introduction
Pathophysiology of hypercoagulation and thrombosis
Venous thrombosis
Arterial thrombosis
Microvascular thrombosis
Specific causes of hypercoagulation
Background state
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Activating material
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Increased level of procoagulant zymogens
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Decreased level of coagulation inhibitors
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Fibrinolysis abnormalities
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Other hemostasis abnormalities
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Type of thrombosis
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Cancer | ТF, NET, MP | Сancer procoagulant, adhesive molecules | Venous thrombosis | |||
Pregnancy | TF, МР | Fg, VII, VIII, X | Free protein S | PAI-1↑, PAI-2↑ | Thrombocytopenia, platelets activation, VWF↑ | Venous thrombosis, Arterial thrombosis |
Oral contraceptives | Fg, II, VII, VIII, X | ATIII, PS, TFPI | tPA↑, PAI-1↓ | Venous thrombosis | ||
Diabetes mellitus | TF, platelet, monocyte, endothelial МP | Fg, II, V, VII, VIII, and X | ATIII, PC, endothelial ТМ | PAI-1↑, tPA↑ | Enhanced platelet adhesion, aggregation, leukocyte activation, VWF↑ | Arterial thrombosis, Venous thrombosis? |
Detection of hypercoagulability: possible strategies
APTT and INR: are they indeed inappropriate as global assays?
Procoagulant state
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Number of patients in study group
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Data range in control group, mean ± SD unless otherwise indicated
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Data range in group with hypercoagulation, mean ± SD unless otherwise indicated
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Significance
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Predictive value
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Reference
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Comments
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VTE | 605 patients, 1290 - controls | Median(range) 1.00(0.72-1.33) | Median(range) 0.97(0.75-1.41) | <0.001 | APTT ratio < 0.87 OR = 2.4 | [52] | Retrospective study. |
Recurrence after first unprovoked VTE | 918 with a first VTE 101 – with recurrence | 0.97 ± 0.09 | 0.93 ± 0.09 | 0.001 | APTT ratio < 0.95 RR = 1.79 | [53] | Prospective study. Analysis was performed 3 weeks after after completion of anticoagulant therapy. |
Recurrence after first unprovoked VTE | 628 with a first VTE, 71 – with recurrence | APTT ratio < 0.90 RR = 2.38 compared with APTT ratio > 1.05 | [54] | Prospective study. Analysis wasperformed 3-4 weeks after after completion of anticoagulant therapy. | |||
Type 2 diabetes mellitus | 60 patients, 57 controls | Median(range) 0.93 (0.71–1.34) | Median(range) 1.03 (0.79–1.27) | 0.43 | [55] |
Hypercoagulation and thrombin generation
Procoagulant state
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Number of patients in study group
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TG trigger and additional substances
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Data range in control group, mean ± SD unless otherwise indicated
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Data range in group with hypercoagulation, mean ± SD unless otherwise indicated
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Significance
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Predictive value
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Reference
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Comments
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Recurrence after first unprovoked VTE | 254 – with a first VTE, 34 - with recurrence | 1 pM TF 1 uM PL | ETP, nM∙min 1502 ± 446 | ETP, nM∙min 1361 ± 499 | 0.122 | 1 tertile compared to the 3 HR = 2.54 | [68] | Prospective study. Analysis was performed 2-3 months after completion of anticoagulant therapy. |
IIa max, nM 232 ± 82 | IIa max, nM 187 ± 89 | 0.005 | HR = 3.09 | |||||
Tlag, min 12 ± 6 | Tlag, min 13 ± 5 | 0.319 | HR = 2.29 | |||||
1 pM TF 1 uM PL 4 nM TM | ETP, nM∙min 986 ± 422 | ETP, nM∙min 763 ± 468 | 0.009 | HR = 3.35 | [68] | |||
IIa max, nM 201 ± 75 | IIa max, nM 148 ± 88 | <0.001 | HR = 4.49 | |||||
Tlag, min 17 ± 7 | Tlag, min 19 ± 10 | 0.174 | HR = 2.39 | |||||
Unprovoked recurrence after first VTE | 188 with a first VTE, 29 – with recurrence | 5 pM TF 4 uM PL | ETP > 50th percentile HR = 2.9 | [69] | Prospective study. Analysis was performed 2-3 months after completion of anticoagulant therapy. | |||
5 pM TF 4 uM PL 8nM TM | No significant predictive value | [69] | ||||||
Recurrence after first unprovoked VTE | 914 with a first VTE, 100 – with recurrence | 72 pM TF 3.2 uM PL | IIa max, nM 349 ± 108 | IIa max, nM 419 ± 110 | <0.001 | IIa max >400 nM RR = 2.5 | [70] | Prospective study. Analysis was performed after completion of anticoagulant therapy. |
First and recurrent VT | 187 with a first unprovoked VT 404 controls | 1/6 deluted plasma 2.5 pM TF 4 uM PL 1.2 nM TM | Mean ETP(95% CI), nM∙min 1641 (1607 -1676) | Mean ETP(95% CI), nM∙min 1695(1639–1750) | ETP > 90th percentile measured in control subjects DVT HR = 1.7 | [71] | Analysis was performed 3 months after completion of anticoagulant therapy. | |
173 with a first provoked VT 404 controls | Mean ETP(95% CI), nM∙min 1641 (1607 -1676) | Mean ETP(95% CI), nM∙min 1649(1595-1703) | [71] | |||||
59 recurrent VTE | HR of recurrence 1.1 | [71] | ||||||
Recurrence after first unprovoked VTE | 105 with a first VTE, 40 – with recurrence | 5 pM TF 4 uM PL | ETP, nM∙min 1671 ± 514 | ETP, nM∙min 1491 ± 536 | 0.111 | [72] | Prospective study. Analysis was performed upon diagnosis of VTE | |
IIa max, nM 302 ± 91 | IIa max, nM 261 ± 125 | 0.058 | ||||||
Tlag, min 7.2 ± 2.2 | Tlag, min 8.7 ± 5 | <0.001 | ||||||
Acute Ischemic Stroke (men) | 42 patients 408 controls | 5 pM TF 4 uM PL | geometric mean and interquartile range ETP, nM∙min 1755 (1620 - 1940) | geometric mean and interquartile range ETP, nM∙min 1720 (1572 - 1978) | HR = 0.88/sd | [74] | Prospective study. | |
IIa max, nM 327.0 (304.9 - 357.8) | IIa max, nM 330.2 (301.8 - 361.4) | HR = 1.04/sd | ||||||
Acute Ischemic Stroke (women) | 45 patients 666 controls | 5 pM TF 4 uM PL | ETP, nM∙min 1755 (1604 - 1940) | ETP, nM∙min 1863 (1636 -1998) | HR = 1.55/sd | [74] | Prospective study | |
IIa max, nM 333.6 (311.0 - 372.4) | IIa max, nM 357.8 (320.5 - 391.5) | HR = 1.71/sd | ||||||
Coronary Heart Disease events | 186 patients 1000 controls | 5 pM TF 4 uM PL | ETP, nM∙min 1765 (1620 - 1940) | ETP, nM∙min 1772 (1604- 1939 | HR = 1.09/sd | [74] | Prospective study | |
IIa max, nM 333.0 (308.0 - 365.0) | IIa max, nM 330.3 (301.9- 357.8) | HR = 1.02/sd IIa max | ||||||
Prothrombin G20210A mutation | 148 heterozigote, 111 - controls | 6.8 pM TF 30 uM PL | median and interquartile range ETP, nM∙min 1053 (946–1171) | median and interquartile range ETP, nM∙min 1358 (1190–1492) | the carriers as opposed to the non-carriers <0.001 | [75] | ||
IIa max, nM 292 (267–330) | IIa max, nM 349 (307–385) | <0.001 | ||||||
Tlag, min 2.54 (2.46–2.84) | Tlag, min 2.74 (2.46–3.04) | 0.268 | ||||||
3 homozigote | ETP, nM∙min 1661 (1451–1976) | [75] | ||||||
IIa max, nM 466 (446–470) | ||||||||
Tlag, min 3.06 (2.14–5.08) | ||||||||
AT III-inherited deficiency | 9 - controls 18 Type I-IIRS/PE | 5 pM TF 4 uM PL | ETP, nM∙min 2200 ± 320 | ETP, nM∙min 3366 ± 668 | Only Type I-IIRS/PE end controls ETP differs significantlly | [76] | ||
IIa max, nM 377.3 ± 49.1 | IIa max, nM 493.4 ± 75.0 | |||||||
17 -IIHBS heterozygote | ETP, nM∙min 2142 ± 464 | |||||||
IIa max, nM 427.2 ± 98.3 | ||||||||
8 - Cambridge II heterozygote | ETP, nM∙min 2211 ± 268 | |||||||
IIa max, nM 391.4 ± 46.8 | ||||||||
VTE in cancer patients | 1033 cancer patients 77 VTE cases | 71.6 pM TF 3.2 uM PL | median (25th to 75th percentile) ETP, nM∙min 4386 (3804-4890) | median (25th to 75th percentile) ETP, nM∙min 4475 (4087-4915) | 0.197 | IIa max > 611 nM (75th percentile) HR = 2.1 | [80] | Prospective study |
IIa max, nM 499 (360-603) | IIa max, nM 556 (432-677) | 0.014 | ||||||
Type 2 diabetes mellitus | 52 patients, 60 controls | 1 pM TF 1 uM PL | Median (range) ETP, nM∙min 1844 (1,317–2592) | Median (range) ETP, nM∙min 1835 (1213–2656) | 0.96 | [55] | ||
IIa max, nM 264 (97–432) | IIa max, nM 303 (207–434) | <0.001 | ||||||
Tlag, min 7.8 (4.7–18.4) | Tlag, min 5.9 (4.5–11.5) | <0.001 | ||||||
1 pM TF 1 uM PL 4 nM TM | ETP, nM∙min 1301 (535–2381) | ETP, nM∙min 1497 (1061–2418) | 0.003 | [55] | ||||
IIa max, nM 256 (79–433) | IIa max, nM 297 (216–427) | 0.001 | ||||||
Tlag, min 10.4 (6.3–25.8) | Tlag, min 7.8 (5.6–13.6) | <0.001 | ||||||
43 patients, 60 controls | Ca only | ETP, nM∙min 1678 (539–2231) | ETP, nM∙min 1781 (288–2598) | 0.05 | [55] | |||
IIa max, nM 151 (41–289) | IIa max, nM 202 (128–350) | <0.001 | ||||||
Tlag, min 12.6 (7.0–29.5) | Tlag, min 10.8 (7.2–16.1) | <0.001 | ||||||
Diabetes mellitus | 89 patients 49 controls | 5 pM TF 4 uM PL | ETP, nM∙min 1566.4 ± 240.7 | ETP, nM∙min 1876.5 ± 390.0 | <0.001 | [62] | ||
IIa max, nM 252.8 ± 44.6 | IIa max, nM 308.9 ± 39.5 | <0.001 | ||||||
Tlag, min 4.15 ± 0.74 | Tlag, min 3.59 ± 0.62 | <0.001 | ||||||
Normal pregnancy | 19 health pregnant women 10 controls | 5 pM TF 20 uM PL 0.1 mg/ml CTI | ETP, nM∙min 1553 ± 567 | pre-pregnancy ETP, nM∙min 1162 ± 446 | Significant difference between pre-pregnancy and early/late pregnancy P < 0.001 | [82] | ||
IIa max, nM 81 ± 41 | ||||||||
Early ETP, nM∙min 2157 ± 466 | ||||||||
IIa max, nM 159 ± 100 | IIa max, nM 219 ± 117 | |||||||
Late ETP, nM∙min 2410 ± 543 | ||||||||
IIa max, nM 336 ± 178 | ||||||||
Normal pregnancy | 1st Trimester (n = 36) | 5 pM TF 4 uM PL | TG on normal pooled plasma was significantly lower than TG on pregnant women. The exact parameter’s values weren’t shown | ETP, nM∙min 2123 ± 335 | No significant differences between trimesters | [83] | ||
IIa max, nM 366 ± 43 | ||||||||
2nd Trimester (n = 42) | ETP, nM∙min 2067 ± 326 | |||||||
IIa max, nM 374 ± 42 | ||||||||
3rd Trimester (n = 23) | ETP, nM∙min 1915 ± 261 | |||||||
IIa max, nM 336 ± 49 |
Evaluation of thrombosis risk with TEG/ROTEM
Procoagulant state
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Number of patients in study group
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TEG version
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Data range in control group,
mean ± SD unless otherwise indicated
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Data range in group with hypercoagulation, mean ± SD unless otherwise indicated
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Significance
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Predictive value
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Reference
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Comments
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Patients with acute ischemic stroke | 93-Unfavorable outcome evaluatewd by modified Rankin Scale within a year 91-Favorable outcome | Citrate plasma was mixed with kaolin, and loaded in a heparinise-coated cup | means ± SE MA, mm 63.2 ± 0.5 | means ± SE MA, mm 66.1 ± 0.6 | <0.001 | Prediction of unfavorable outcome At higher tertile of MA OR = 1.192 | [92] | Prospective study. |
Postoperative Thrombotic Complications | 240 patients undergoing a wide variety of surgical procedure s, 10 thrombotic complications | celite-activated TEG on native blood samples within 4 min of collection | MA 66 ± 9 | MA 71 ± 9 | [103] | Prospective study. Thromboelastography was performed immediately after surgery. | ||
6 myocardial infarction | MA 66 ± 9 | MA 74 ± 5 | OR = 1.16 | |||||
Postoperative Thrombotic Complications | 152 critically ill patients in the surgical intensive care unit 16 thrombotic complications | native blood, rTEG(activation with kaolin, human recombinant TF, phospholipids) | G > 12.4 dynes/cm OR = 1.25 | [104] | ||||
Normal pregnancy | 65/65 | Recalcified citrate plasma | R, min 7.8 ± 2.5 | R, min 6.1 ± 1.8 | <0.001 | [102] | ||
K, min 2.7 ± 2.3 | K, min 1.4 ± 0.5 | |||||||
Alfa, deg 57.7 ± 11.6 | Alfa, deg 70.6 ± 6.5 | |||||||
MA, mm 61 ± 5.9 | MA, mm 71 ± 3.8 | |||||||
Ly 30, % 0.8 ± 1.7 | Ly 30, % 0.3 ± 0.7 |