Hemostasis: assessment of coagulation in miscarriage

A hemostasis profile is a set of laboratory tests that evaluate the blood coagulation system: the rate and completeness of clot formation, the supply of anticoagulant factors, and fibrinolytic activity. These data are needed to assess the risk of bleeding and thrombotic complications in the mother and to understand the possible role of hemostatic disorders in the pathogenesis of miscarriage. [1]

During pregnancy, the hemostatic system undergoes physiological changes toward hypercoagulability: fibrinogen and some coagulation factor concentrations increase, D-dimer levels change, and anticoagulant activity decreases. This protects against hemorrhage during childbirth, but reduces the safety margin for thrombotic risks. Therefore, interpreting the results requires knowledge of pregnancy norms. [2]

The link between thrombophilia and recurrent early miscarriage has long been debated, but recent meta-analyses and clinical guidelines urge caution: not all markers of hereditary thrombophilia are definitively associated with miscarriage, and mass testing and automatic prescription of anticoagulants do not provide demonstrable benefit. Decisions should be individualized. [3]

An important clinical task is to distinguish between two different situations: 1) obstetric pathology is caused by antiphospholipid syndrome and requires specific therapy to prevent losses; 2) identification of hereditary thrombophilia is often important for assessing the risk of venous thromboembolism in the mother, but does not always change the tactics of pregnancy management to prevent miscarriages themselves. [4]

What tests are included in an extended hemostasiogram when assessing miscarriage and what do they show?

A standard "hemostasis" kit usually includes: a complete blood count with platelet count, prothrombin time and international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen level, D-dimer, and, if indicated, tests for antiphospholipid antibodies and hereditary defects (F5 Leiden and F2 G20210A mutations, protein C deficiency, protein S and antithrombin deficiency). These parameters provide an idea of the overall coagulation, the presence of thrombus formation and fibrinolysis. [5]

Prothrombin and APTT tests are important for identifying significant coagulopathies and for basic hemostasis assessment before surgical interventions. In pregnant women, values may shift, so a single, small deviation without clinical symptoms requires careful interpretation and, if necessary, repeat testing. [6]

Fibrinogen levels typically increase during normal pregnancy; a drop below expected values may indicate a massive, demand-induced coagulopathy. D-dimer levels increase throughout pregnancy, so the threshold values for excluding thrombosis in clinical settings are not the same as for non-pregnant women. Trimester-specific reference values are necessary for accurate interpretation. [7]

Antiphospholipid antibodies are tested separately: this is a test that indicates the possibility of antiphospholipid syndrome, one of the few seropositive conditions with a proven association with recurrent fetal losses and intrauterine death. Positive tests require reconfirmation after 12 weeks and an assessment of clinical manifestations to establish a diagnosis. [8]

Physiological changes in coagulation parameters during pregnancy and how they affect interpretation

Pregnancy is a condition characterized by a natural activation of hemostasis: concentrations of fibrinogen and a number of procoagulant factors increase, while natural anticoagulants exhibit a relative decrease in activity. This leads to an increase in D-dimer levels as pregnancy progresses. Therefore, reference values validated for each trimester should be used for laboratory assessment. [9]

Many studies show a statistically significant increase in D-dimers and fibrinogen from the first trimester to the third. It is a practical error to try to apply cutoff values for non-pregnant patients to exclude thromboembolism or to assess the risk of miscarriage. When assessing the risk of thrombosis, it is better to rely on the clinical presentation and specialized guidelines. [10]

Changes in APTT and prothrombin time remain minor in most cases, but laboratory procedures and reagent kits vary between laboratories. This emphasizes the need for consistency of methods and, if in doubt, repeat testing in the same laboratory. [11]

Finally, certain comorbid conditions—gestational diabetes, smoking, and excess body weight—can enhance prothrombotic dynamics and alter laboratory parameters. It is important to consider these associated risk factors when interpreting the results. [12]

Antiphospholipid syndrome: When testing is necessary and what to do if the results are positive

Antiphospholipid syndrome is an autoimmune condition in which specific antibodies increase the risk of thrombosis and obstetric complications, including recurrent miscarriages and intrauterine death. Diagnostic criteria include a combination of a clinical phenotype and laboratory confirmation of the presence of antibodies on two measurements at least 12 weeks apart. The clinical significance makes testing mandatory for recurrent losses. [13]

Laboratory tests include: 1) lupus anticoagulant; 2) antibodies to cardiolipin; 3) antibodies to β2-glycoprotein I. A positive result from one test requires confirmation after 12 weeks, as transient antibodies may give a false-positive result. [14]

If a diagnosis of antiphospholipid syndrome is confirmed in a pregnant woman with the obstetric phenotype, the evidence base supports the use of combination therapy: low-dose aspirin and low-molecular-weight heparin during the antenatal period, as well as prophylactic therapy after delivery. The strategy should be determined by a physician specializing in high-risk pregnancy in conjunction with a rheumatologist or hematologist. [15]

In cases of positive antibodies without clinical manifestations, the decision on therapy and monitoring is individualized. An assessment of associated risk factors and a discussion of possible options with the patient, including pregnancy management instructions and postpartum prophylaxis strategies, are necessary. [16]

Hereditary Thrombophilias and Recurrent Pregnancy Loss: What the Evidence Says and When Testing Makes Sense

Inherited mutations and deficiencies—factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, protein C, and protein S—are associated with an increased risk of venous thromboembolism during pregnancy and the postpartum period. However, the association between these mutations and recurrent early miscarriage is poorly established and controversial. Recent reviews and guidelines do not recommend routine testing of all women with recurrent losses. [17]

Major guidelines, including ESHRE and ACOG, recommend testing for inherited thrombophilias in targeted cases: a personal history of venous thrombosis, close relatives with a severe thrombotic history, or if the results will impact pregnancy management. Mass screening is ineffective and may lead to unnecessary therapy. [18]

If a woman is diagnosed with an inherited thrombophilia, the primary goal is to prevent maternal venous thrombotic events, not to directly prevent miscarriage. Prophylactic antenatal anticoagulation without other indications lacks convincing evidence of benefit in reducing the incidence of early pregnancy loss. Therefore, prescribing heparins to "prevent miscarriage" in isolated inherited mutations is not standard practice. [19]

The decision to test should be a shared one, with prior counseling about the implications of a positive or negative result, including potential familial genetic implications and the impact on insurance and subsequent care. Discussing the results with a hematologist is recommended. [20]

Practical interpretation of results, action plan and recommendations for the clinician

When initially evaluating a woman with recurrent pregnancy losses, it is important to begin with a general obstetric and genetic diagnosis. Hemostasis testing is indicated in the presence of clinical markers of thrombotic risk, suspected antiphospholipid syndrome, or a personal history of thrombosis. There is no one-size-fits-all algorithm. [21]

If abnormalities are detected in the hemostasiogram, a sequential strategy is required: re-confirmation of clinically significant markers, assessment of associated factors, and consultation with a hematologist. Positive antiphospholipid antibodies require confirmation after ≥12 weeks and discussion of low-dose aspirin with low-molecular-weight heparin therapy in the obstetric phenotype. [22]

If the hemostasis profile is normal and clinical risk factors are absent, further management is aimed at identifying other causes of loss: chromosomal abnormalities, anatomical factors, hormonal imbalances, infectious and immune causes. Hematological examination is considered part of a comprehensive assessment, rather than the primary and definitive cause. [23]

An important practical recommendation is to agree in advance on the methods used when planning testing, the timing of blood collection relative to pregnancy and treatment, and the possibility of repeat testing in the same laboratory to reduce the detection of methodological artifacts. The patient should be informed in advance of possible interpretation options and treatment scenarios. [24]

Tables: Brief Reference and Reference Points

Table 1. Components of the extended hemostasiogram and clinical significance

Test	What does it show?	How does it affect management in case of miscarriage?
Platelets	Platelet count	Thrombocytopenia requires assessment for the risk of bleeding and thrombocytopathy.[25]
Prothrombin time INR	Extrinsic coagulation pathway	Significant abnormalities are rarely associated with miscarriage but are important before invasive procedures.[26]
APTT	Intrinsic coagulation pathway	Prolongation may indicate lupus-type antibodies or coagulopathy.[27]
Fibrinogen	Prothrombotic protein reserve	A decrease may indicate underlying coagulopathy.[28]
D-dimer	Fibrinolysis and thrombopoiesis activity	Trimester-dependent elevation during pregnancy; uninformative without context. [29]

Table 2. Trimester-dependent D-dimer and fibrinogen landmarks (visual, approximate)

Parameter	1st trimester	2nd trimester	3rd trimester
D-dimer, middle landmarks	Elevated compared to non-pregnant women, mean median ≈ 300-500 ng/ml in different studies. [30]	Increasing, often ≈ 350-700 ng/ml. [31]	Further increase, often >400-800 ng/ml. [32]
Fibrinogen, average reference values (g/L)	Increases to ≈ 3-4 g/L. [33]	Above, often 4-5 g/L. [34]	Maximum in the third trimester. [35]

(Note: Specific reference ranges depend on the laboratory methodology. The table provides guidelines based on publications on dynamics.) [36]

Table 3. Antiphospholipid tests and clinical interpretation

Test	What is considered significant?	Clinical significance
Lupus anticoagulant	Positive on two measurements at ≥12 weeks	High significance in obstetric phenotype, requires therapy. [37]
Antibodies to cardiolipin IgG/IgM	High titers reconfirmed	Associated with obstetric complications. [38]
Antibodies to β2-glycoprotein I	High titers reconfirmed	Part of the laboratory criteria for diagnosis. [39]

Table 4. Indications for testing for hereditary thrombophilias according to current recommendations

Indication	Comment
Personal history of venous thrombosis	Testing is justified. [40]
Family history of severe thrombotic episodes	Consider testing for antithrombotic defects.[41]
Presence of other VTE risk markers	Testing is advisable when there is a combination of risk factors. [42]
Isolated recurrent early miscarriages	Routine testing is not recommended; the decision is individualized.[43]

Table 5. Main therapeutic approaches for confirmed conditions

State	Recommended approach for obstetric phenotype
Antiphospholipid syndrome	Low-dose aspirin plus low-molecular-weight heparin during pregnancy; continued postpartum as indicated.[44]
Hereditary thrombophilia without history of VTE	Individual approach. Antithrombotic therapy for the prevention of miscarriage is not routinely recommended. [45]
Hereditary thrombophilia with history of VTE	Prophylactic therapy with low molecular weight heparin in pregnancy and the postpartum period. [46]

A practical summary for the physician treating a patient with recurrent loss

1. During the initial evaluation, the priority is to exclude chromosomal, anatomical, endocrine, and infectious causes. Hematological examination is advisable in the presence of clinical risk markers or in the case of repeated losses with suspected antiphospholipid syndrome. [47]
2. Antiphospholipid antibody testing is mandatory in cases of recurrent pregnancy loss and/or late pregnancy complications. A positive result should be confirmed after ≥12 weeks. If confirmed, treatment with aspirin and low molecular weight heparin is considered. [48]
3. Routine testing for hereditary thrombophilia in all patients with recurrent early miscarriages is not recommended. Testing may be considered if the result will impact patient care or if there is a personal or family history of thrombosis. [49]
4. Interpreting a hemostasiogram during pregnancy requires knowledge of trimester-specific norms. D-dimer and fibrinogen levels increase, so thresholds for non-pregnant women are not applicable. If abnormalities are detected, a consultation with a hematologist is necessary. [50]
5. Decisions regarding the use of anticoagulants to prevent miscarriage should be based on evidence, the presence of antiphospholipid syndrome, a history of thrombosis, and individual maternal risk factors. Self-medication or "one-size-fits-all" regimens are unacceptable. [51]

What else is important for the patient to know and what issues should be discussed during the consultation?

The patient should be informed that a positive thrombophilia test does not always mean that this is the cause of the loss. Potential implications for family members, monitoring and treatment options, including drug side effects, and the management plan for the next pregnancy should be discussed. If the antiphospholipid antibody test is positive, it is important to explain the need for repeat testing. [52]

Also discuss associated modifiable risk factors: smoking, obesity, sedentary lifestyle, and glycemic control in diabetes. Correction of these factors reduces the overall risk of thrombotic complications and improves pregnancy outcomes. [53]

If a decision is made to prescribe therapy, the plan should include the timing of drug initiation and discontinuation, monitoring, delivery plan, and timing of postpartum prophylaxis. This is especially important when prescribing anticoagulants, as it will require coordinated decisions with the obstetrician-gynecologist, anesthesiologist, and hematologist. [54]

Finally, with any positive or controversial result, interdisciplinary discussion is recommended - the “multidisciplinary team” improves decision making and reduces the risk of unnecessary therapy. [55]