A 64-year-old woman presented with right hip pain of 6 years’ duration, accompanied by limping of 1 years’ duration. Preoperative
pelvis radiograph showed narrowing of joint space, osteophyte formation, and cystis degeneration of the femoral head surrounded
by bony sclerosis, without obvious collapse of the femoral head; the diagnosis was osteoarthrosis. The patient’s blood pressure
on admission was 128/76 mm Hg. The patient had no special previous history. Preoperative blood and coagulation tests were
normal. Total hip arthroplasty was performed via a posterolateral approach, and intraoperative bleeding was 400 mL. In the
first 10 hours postoperatively, the drainage volume decreased slowly, the initial dose of 0.3 mL Fraxiparine was administered,
and the blood pressure was 84~92/45~56 mm Hg. The drainage volume increased gradually, and 10 hours after administration of
Fraxiparine, the drainage volume increased sharply and maintained at a high level. Protamine was applied and the drainage
volume decreased sharply, furthermore, a high concentration of endogenous heparinoids were detected in the blood. Although
no direct evidence were detected, it was clear that the massive hemorrhage was associated with administration of low-molecular-weight
heparin (LMWH). The administration of LMWH combined with continuous low blood pressure caused by surgery and massive bleeding
that resulted in low perfusion and inflammation in microcirculation, induced endogenous heparinoid synthesis in endothelial
cells, and elevated concentration of endogenous heparinoids in blood led to more severe bleeding. Therefore, caution should
be taken with administration of anticoagulant therapy in patients with massive hemorrhage, especially in patients with continuous
low blood pressure.
Drs Shi, Yang, Shen, Kang, Zhou, and Pei are from the Department of Orthopedics, West China Hospital, Sichuan University,
Drs Shi, Yang, Shen, Kang, Zhou, and Pei have no relevant financial relationships to disclose.
Correspondence should be addressed to: Xiao Jun Shi, MD, Department of Orthopedics, West China Hospital, Sichuan University,
Chengdu, China (firstname.lastname@example.org).
The perioperative complications of total hip arthroplasty (THA) and total knee arthroplasty (TKA) are complex, especially
thromboembolism. Due to the severity of deep venous thrombosis, prophylactic anticoagulant therapy is recommended by some
authors. Low-molecular-weight heparin (LMWH) is frequently used in clinical practice for its utility in reducing formation
Low-molecular-weight heparin was not only effective in limiting the formation of clots, but also the rate of clinically relevant
bleeding was low.
Endogenous heparinoids are glycosaminoglycans that are widely distributed in mammal tissues and have similar molecular structure
and anticoagulation activity with heparin. No report exists in the literature about massive hemorrhage in THA or TKA caused
by endogenous heparinoids. This article presents a case of massive hemorrhage following THA in a 64-year-old patient.
A 64-year-old presented with right hip pain of 6 years’ duration. The pain did not radiate, and there was no fever or swelling.
During this period, the pain was intermittent and increased with walking. In the past year, the pain was accompanied by a
Preoperative pelvis anteroposterior radiograph showed narrowing of joint space, osteophyte formation and cystis degeneration
of the femoral head surrounded by bony sclerosis, without obvious collapse of femoral head (Figure ), the diagnosis was osteoarthrosis in the right hip joint. The patient had chronic superficial gastritis, with no history
of nonsteroidal anti-inflammatory drug use, allergic or hemorrhage history, and no chronic liver, kidney, or cardiovascular
Figure 1:. Preoperative Radiograph Shows Narrowing of Joint Space, Osteophyte Formation and Cystis Degeneration of Femoral Head Surrounded
by Bony Sclerosis, Without Obvious Collapse of the Femoral Head.
The patient’s height and weight were 150 cm and 45 kg, respectively. Her blood pressure on admission was 128/76 mm Hg. Preoperative
laboratory tests were normal, including hepatic and renal function and coagulation test. Blood tests revealed hemoglobin was
135 g/L, hematocrit was 0.38, and platelet was 85×109/L, a little lower than normal.
Total hip arthroplasty was performed via a posterolateral approach with a 50-mm uncemented pinnacle acetabular cup, 2 acetabular
screws, size 10 uncemented corail femoral prosthesis, size +1 neck length, and a 32-mm ceramic head (Johnson & Johnson/DePuy,
Warsaw, Indiana). The operation time was 90 minutes, with no obvious vascular damage, and intraoperative bleeding was 400
In the first 10 hours postoperatively, the drainage volume decreased slowly, with the total volume 710 mL (Figure ), and the blood pressure was 84~92/45~56 mm Hg. The initial dose of 0.3 mL Fraxiparine (J20090006; Glaxo Wellcome Rroduction,
France) was administered 10 hours postoperatively according to the protocol for preventing deep venous thrombosis. Platelet
was 63×109/L before administration of Fraxiparine. The drainage volume increased gradually but the coagulation test was normal;
erythrocyte suspension and plasma were supplied consecutively, and tranexamic acid, carbazochrome sodium, and sulfonate reptilase
were applied at this time.
Figure 2:. Plot of Drainage Volume According to Time. At the First 10 Hours, the Drainage Volume Decrease Slowly. The Patient Receives
Low-Molecular-Weight Heparin (LMWH) at the 10th Hour, Then the Drainage Volume Increase Gradually and the Massive Hemorrhage
Occurs 10 Hours Later. After Administration of Protamine (at the 31st Hour), the Drainage Volume Decreases Sharply. Additionally,
No Big Changes Are Detected in Platelet and TT Until 18 Hours After Administration of LMWH.
Ten hours after administration of Fraxiparine, the drainage volume increased sharply and maintained at a high level (Figure
). Cryoprecipitate and fibrinogen were then administered urgently. Prosthesis loosening or concealed fracture surrounding
the prosthesis intraoperatively and disseminated intravascular coagulation or von Willebrand disease were suspected but radiographs
revealed no abnormality (Figure ). The coagulation test found that prothrombin time and activated partial thrombin time were 16.9 seconds (normal range, 9.6~12.8
seconds) and 61.5 seconds (normal range, 20.0~40.0 seconds), respectively. Thrombin time was 19.9 seconds (normal range, 14.0~22.0
seconds). Negative result of plasma protamine paracoagulation test certified that there was no disseminated intravascular
coagulation. Factor VIII:C,Vwf:Ag and Vwf: RCo were negative, indicating von Willebrand disease was not possible.
Figure 3:. Postoperative Radiograph Shows the Prosthesis Has Excellent Position and There Is No Fracture.
Eighteen hours after administration of Fraxiparine, the thrombin time increased, up to 120 seconds, and platelet reduced to
34×109/L, but no big change was detected in activated partial thrombin time and prothrombin time. Platelet transfusion was
With all possible reasons excluded, bleeding was likely induced by exogenous LMWH or endogenous heparinoids. Twenty-one hours
after the administration of LMWH, protamine was applied. The drainage volume decreased sharply to 20 mL per hour in 2 hours.
Two units of platelet was still used 5 hours after bleeding cessation.
The administration of Protamin continued for 2 days. The total bleeding volume was up to 4000 mL and total urine volume was
>30 mL per hour. The result of concentration of blood heparinoids was 3200 ng/mL, far more than the upper limitation of 600
ng/mL, confirming the massive hemorrhage was induced by endogenous heparinoids. The patient recovered quickly and was discharged
14 days later.
Heparin can be classified as exogenous and endogenous, and can inhibit coagulation through anti-coagulator factor Xa. Endogenous
heparinoids are glycosaminoglycans that are widely distributed in mammal tissues and appear to be synthesized by all type
of cells, especially the hepatocyte and endothelial cells, but are main constituents of the vessels and can be linked to the
Being natural anticoagulants, all these glycosaminoglycans have anticoagulation properties and help maintain coagulation
hemostasis at the endothelial surface, and heparin sulfate is the most important glycosaminoglycans.
We excluded potential reasons for hemorrhage including disseminated intravascular coagulation, femoral or acetabular fracture,
low platelet, deficiency of coagulator factors and von Willebrand disease. Figure demonstrates the whole bleeding course, bleeding was almost ceased before the administration of LMWH, and the drainage gradually
increased after the injection of LMWH; the massive hemorrhage observed in our patient can be linked to the administration
of Fraxiparine. The effective reversible action of protamine administration suggested that the bleeding was induced by a heparin-like
As this patient had received LMWH, it is hard to determine whether bleeding was caused by exogenous LMWM or endogenous heparinoids.
However, there was no liver disease, the elimination of exogenous LMWH must be normal, it is known that the peak concentration
occurred 4~6 hours after administration of the Fraxiparine subcutaneously, and the demiperiod of single dose of Fraxiparine
was 10 hours. If the massive hemorrhage was induced by exogenous LMWH, thrombin time would decrease gradually with the excretion
of LMWH. In contrast, the massive bleeding occurred 10 hours after administration of Fraxiparine, and the thrombin time was
normal during this time. Furthermore, the high concentration of heparan sulfate confirmed our speculation.
Both exogenous and endogenous heparinoids are cleared by the liver, and the elevated levels of endogenous heparinoids have
been reported and well discussed in cirrhotic patients.
Senzolo et al
found the presence of endogenous glycosaminoglycans in patients with liver disease may contribute to thrombin coagulopathy.
Comparing patients who had cirrhosis without recent variceal bleeding, Mckee et al
found increased endogenous heparinoids concentration in cirrhotic patients who had recent variceal bleeding, and a high level
of endogenous heparinoids was considered as the possible reason for bleeding.
The presence of endogenous heparinoids in our patient is demonstrated. It has been postulated that endotoxins and inflammation
due to infection could release heparinoids from the endothelium, hepatocyte, and mast cells.
Activation of macrophage or endothelium following ischemic reperfusion injury is another possible source of increased heparinoids.
Additionally, Nader et al
found that the synthesis of heparin sulfate increased when the endothelial cells were exposed to LMWH, ie, LMWH could induce
the production of heparan sulfate in endothelial cells, and the antithrombotic activity of LMWH “in vivo” could be related,
at least in part, to the production of peculiar heparin sulfate by endothelial cells.
Although no direct evidence was detected, a high level of endogenous heparinoids were detected in our patient, and the massive
hemorrhage was associated with administration of LMWH. The administration of LMWH combined with continuous low blood pressure
caused by surgery and massive bleeding, which resulted in low perfusion and inflammation in micro-circulation, induced endogenous
heparinoid synthesis in endothelial cells, and elevated concentration of endogenous heparinoids in blood leaded to more severe
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