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. 2026 Sep 23;14(10):e73571. doi: 10.1002/ccr3.73571

Treatment of Deep Vein Thrombosis in Congenital Factor VII Deficiency: A Case Report and Literature Review

Synnøve Gjelsten Mortensen 1,2,✉, Lars Erik Laugsand 2,3, Martin Syvertsen Mykland 4, Erik Magnus Berntsen 3,5, Tobias S Slørdahl 6,7
PMCID: PMC13601654  PMID: 42787507

ABSTRACT

Managing thrombosis in patients with bleeding disorders requires careful assessment of thromboembolic and bleeding risks, tailoring antithrombotic treatment in terms of type, dose, and duration, and considering the need for replacement therapy based on individual factor levels and bleeding history.

Keywords: factor VII deficiency, hematoma, insect bites and stings, thrombosis, venous thrombosis

1. Introduction

Inherited factor FVII deficiency (FVIId) is a rare bleeding disorder with an incidence of symptomatic individuals ranging from 1:300000–1:500000. The prevalence varies significantly between regions, populations, and registries [1, 2, 3, 4, 5, 6, 7]. Norway is an example of a high‐prevalence population regarding severe FVIId [8]. FVIId is an autosomal recessive trait caused by variants in the F7 gene on chromosome 13, leading to either Type 1 or 2 deficiency. Type 1 deficiency refers to a quantitative reduction in both FVII activity and antigen levels, whereas Type 2 deficiency represents a qualitative defect characterized by reduced coagulant activity despite normal or only slightly reduced antigen levels [2, 7, 9, 10, 11]. Despite the prolonged prothrombin time (PT‐INR) characteristic of FVIId, no single test predicts bleeding tendency reliably [8]. The disorder exhibits significant variability in clinical expression, and the correlation between measured FVII:C levels and bleeding severity is weak [2, 3, 7, 12, 13, 14, 15, 16, 17]. It is recognized that FVIId does not inherently prevent thrombosis when triggers are present [12, 18].

Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). The primary pathophysiological mechanisms can be outlined by the Virchow triad: vessel wall damage, turbulence of blood flow and hypercoagulability [19]. More recently it is proposed that thrombus formation is influenced by complex interactions between inflammation, innate immunity and the coagulation system and that inflammation of the vessel wall is the key event initiating thrombus formation, even in intact vessels [20]. According to this model, inflammation acts as a common pathway through which various risk factors can trigger VTE [20]. It is the inflammation‐injured endothelium which starts off the process resulting in a laminar structured thrombus of fibrin, platelets, red and white blood cells [19].

We report an interesting case on a patient with congenital FVIId who developed two very rare conditions: a lower limb DVT temporally associated with and possibly triggered by a horsefly bite, and a potentially severe complication to anticoagulation therapy in the form of an iliacus hematoma leading to femoral nerve palsy. A literature review of reported cases of both venous and arterial thrombosis in patients with inherited FVIId is included.

2. Case Presentation

A 36‐year‐old man with known severe congenital FVIId presented to the Emergency Department (ED) at St. Olav's Hospital, Trondheim, Norway, with a three‐day history of painful swelling in the lower right extremity. The patient suspected the swelling to be a possible soft tissue bleed. His medical history included sporadic minor bleeding episodes requiring FVII replacement therapy, though his bleeding tendency had been relatively mild despite having a FVII activity of < 1.0 IU/dL. The patient had never required regular prophylactic replacement therapy. FVII antigen levels and genetic characterization were not available, and the deficiency could therefore not be reliably classified as Type 1 or Type 2.

The symptoms began following an insect bite on the right calf, suspected to be from a horsefly (family Tabanidae), and progressively worsened. Examination revealed a localized, firm swelling in the proximal dorsolateral right calf extending cranially to the lowermost lateral thigh. The skin was slightly hyperemic, but there was no pitting edema, bruising, varicose veins, eczema, or obvious signs of skin infection. The lesion's central area displayed an insect bite. There was no knee joint effusion or extension deficit pointing in the direction of arthritis or hemarthrosis.

3. Methods

The patient's vitals were stable, except for a sinus tachycardia (105 BPM). Laboratory investigations revealed:

  • Hemoglobin: 14.5 g/dL (13.5–17.0 g/dL)

  • White blood cell count: 10.4 × 109/L (4.1–9.8 × 109)

  • Platelets: 284 × 109/L (145–348 × 109)

  • C‐reactive protein (CRP): 112 mg/L (< 5 mg/L)

  • Prothrombin time‐International Normalized Ratio (PT‐INR): > 10 (0.9–1.2)

As our local laboratory reports prothrombin time as INR rather than PT ratio, the markedly elevated INR reflects the severe prolongation of prothrombin time expected in patients with severe FVII deficiency. D‐dimers, fibrin degradation products, and erythrocyte sedimentation rate were not measured at presentation. The local laboratory did not offer FVII‐activity analysis, which was sent to another laboratory the following day. A bedside ultrasound revealed a non‐compressible segment of the deep vein with a hyperechoic luminal mass extending from the lower adductor canal to the popliteal vein, consistent with a localized DVT (Figure 1). The findings were subsequently confirmed by a radiologist‐performed duplex ultrasound and computed tomography venography, which demonstrated a 5–7 cm thrombus in the lower femoral vein extending into the popliteal vein. Despite the sinus tachycardia, concurrent PE was deemed unlikely.

FIGURE 1.

FIGURE 1

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Point of care ultrasound in the ED. Right: Red marking/artery. Blue marking/vein. Left: Non‐compressible vein, partially compressed artery.

The patient was admitted and the case was discussed with the national referral hospital for patients with hemophilia. The thrombus was in the femoral–popliteal segment, carrying a substantial risk of propagation and pulmonary embolism. Due to the patient's history of only mild bleeding tendency and the poor correlation between factor levels and bleeding tendency in patients with FVII deficiency, a strategy of low molecular weight heparin without factor replacement therapy was chosen. Replacement therapy was deliberately avoided at initiation of anticoagulation, as several reports in the literature describe thrombosis occurring in temporal relation to FVII replacement. His weight was 125 kg and initial treatment with enoxaparin was carefully started at 80 mg (0.64 mg/kg) subcutaneously twice daily. A target anti‐FXa activity within the therapeutic range for twice‐daily LMWH treatment was sought. Anti‐Factor Xa activity 4 h after the second dose measured 0.48 IU/mL, lower than optimal therapeutic range, and the dose was heightened to 100 mg in the morning and 80 mg in the evening. Due to an increase in C‐reactive protein (CRP) level to 180 mg/L, benzylpenicillin (1.2 g IV, QID) was initiated to address a possible localized skin infection. Another measurement of Anti‐Factor Xa activity prior to discharge with the increased dose of enoxaparin was 0.35 IU/mL, but no further dose adjustments were made as symptoms of DVT were improving. After 3 days of hospitalization the patient was discharged with instructions for self‐administration. At first follow‐up 4 days after discharge, he was clinically improving.

Thirty‐seven days after discharge, the patient returned to the ED with weakness, pain, and numbness in the right leg. Symptoms started with mild discomfort in the thigh and groin, before escalating into severe pain radiating to the knee and difficulty walking. Neurological examination revealed reduced muscle strength (MRC Grade 3) in knee extension, hypoesthesia over anteromedial aspect of thigh and medial aspect of knee, and an absent patellar reflex. The clinical findings raised suspicion of a lumbar radiculopathy affecting the L4 root. MRI of the lumbosacral spine revealed a 9 cm hematoma in the right iliacus muscle (Figure 2). Given spontaneous regression of the paresis and stable hemoglobin levels (12.2–11.5 g/dL), a conservative approach was chosen. Enoxaparin was discontinued, and reversal therapy was initiated with 50 mg of protamine sulfate and 1200 IU of nonactivated prothrombin complex concentrate (Prothromplex). At the time anticoagulation was discontinued, the symptoms related to the DVT had resolved and there were no clinical signs of thrombus progression or recurrence. PCC was chosen because it had previously been used successfully in this patient during bleeding episodes and was readily available in the acute setting. In addition, PCC provides replacement of multiple vitamin K‐dependent coagulation factors, which was considered beneficial in the setting of ongoing anticoagulant effect from low molecular weight heparin (LMWH). However, isolated FVII replacement could also have been an appropriate alternative strategy. Pain management with oxycodone and paracetamol was prescribed. Repeat imaging 2 days later showed slight hematoma regression. The patient's neurological symptoms improved, and he transitioned to crutches for mobility. At follow‐up 2.5 months later, the patient was able to walk without aid, but mild residual weakness of knee extension persisted (MRC Grade 4), the diagnosis of iliacus hematoma syndrome (IHS) was made retrospectively.

FIGURE 2.

FIGURE 2

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MRI Coronal T2 STIR showing hematoma and oedema in m. iliacus dextra. Outlined in red: M. iliacus sinistra. Outlined in blue: M. psoas major sinistra. Solid arrow: Hematoma. Dashed arrow: Oedema. Dotted arrow: Dislocated m. psoas major dextra.

A time‐unlimited PubMed search was performed 2024/12/08. Search terms included thrombosis, thrombotic, embolic, embolism, congenital, inherited, factor VII deficiency, FVII deficiency, NOT acquired. The filters “English,” “case report,” “review,” and “systematic review” was applied. A total of 85 case reports and 79 reviews/systematic reviews were identified, of which 56 and 65 were excluded by manual selection. The search is visually outlined in Figures S1 and S2. Additional papers were identified from reference lists of the selected items. A total of 32 papers, 21 on VTE and 11 on arterial thromboses, were available in full text and included in this review. Three original case reports on arterial thrombosis and 14 on VTE could not be retrieved, mostly being papers from before 1990. Key information on thromboses and treatment was systematized in Tables S1 and S2.

4. Conclusion and Results

The case report illustrates that DVT may occur in patients with severe factor VII deficiency and how treatment of this patient resulted in the rare complication of an iliacus hematoma syndrome. At 2 years of follow‐up, he had been 1 year back to full work, with periodically slight numbness in the leg as the only residual symptom and with no recurrent thrombotic events or new major bleeding episodes.

A summary of the patient's clinical course, including diagnostic investigations, treatment decisions, complications, and follow‐up, is provided in the timeline below.

  • Day −3: Onset of painful swelling in the right calf after a suspected horsefly bite.

  • Day 0: Presentation to the Emergency Department. Bedside ultrasound and computed tomography venography confirmed a femoral–popliteal DVT. Treatment with enoxaparin was initiated.

  • Day 1: Anti‐FXa activity measured 0.48 IU/mL 4 h after the second dose. Enoxaparin dose was increased.

  • Day 3: The patient was discharged with instructions for self‐administration of enoxaparin.

  • Day 7: At first outpatient follow‐up, the patient was clinically improving.

  • Day 37: The patient was readmitted with right leg pain, weakness, and sensory symptoms. MRI revealed a right iliacus hematoma. Enoxaparin was discontinued, and protamine sulfate and PCC were administered.

  • Day 39: Repeat imaging showed slight regression of the hematoma.

  • Day 43: The patient was discharged mobilizing with crutches.

  • 2.5 months after readmission: The patient walked without aid, but mild residual weakness of knee extension persisted.

  • 2 years after initial admission: Only slight numbness as a residual symptom, with no recurrent thrombotic events or new major bleeding episodes.

5. Discussion

Thrombosis in patients with congenital FVIId is a very rare event. Our literature review identified a total of 46 incidents of VTE in 33 different persons (PE 11, DVT 17, PE + DVT 6, cerebral venous thrombosis 4, superficial venous thrombosis 2, other 6) and 17 incidents of arterial thromboses in 13 persons (stroke 6, coronary 4, aorto‐iliac axis 3, other 4). DVT was the most common type of VTE and stroke the most common arterial event (Tables S1 and S2).

Our patient presented with a likely triggered thrombosis. Provoking factors were also observed in most cases reported in the literature. Twenty‐nine out of 46 VTEs were attributed to a provoking factor or innate risk factor [12, 18, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32], four were idiopathic [18, 30, 33, 34], and 11 had no information regarding triggers [12, 35, 36, 37, 38]. All but one of the arterial incidents were ascribed to a provoking event or known risk factor. Most common triggers were surgery, replacement therapy, pregnancy, trauma, malignancy, and cardiovascular comorbidities.

Peripheral thromboses triggered by insect bites are uncommon and most existing reports are related to wasp or bee stings [39, 40, 41, 42]. The venom from these insects contains peptides, proteins, and amines with vasoactive, inflammatory, and thrombogenic properties able to induce thrombosis via vascular spasm, endothelial injury, and promotion of a pro‐coagulant state [39, 40]. The saliva from insects in the Tabanidae‐family commonly induce large local reactions and can induce allergic reactions [43], but we did not find any literature linking bites from these flies to thrombosis. To our knowledge, this may represent the first reported case of peripheral venous thrombosis following a horsefly bite. The DVT in this case may have been related to local vein wall inflammation rather than direct toxicity, although causality cannot be established from a single case. Alternatively, the thrombotic process was aided by bacterial inoculation causing a concurrent local infection. A comprehensive thrombophilia workup, including testing for Factor V Leiden, prothrombin G20210A mutation, protein C, protein S, and antithrombin deficiency, was not performed. An underlying inherited thrombophilic predisposition cannot therefore be excluded.

Anticoagulation in FVIId patients should follow the same principles as in non‐deficient individuals, with adjustments as necessary [44]. Several case reports indicate that LMWH, preferably guided by anti‐FXa activity, is a viable option [18, 35]. However, optimal dosing and treatment duration remain uncertain due to limited data and absence of clinical trials in this population. For cases identified through our literature search, treatment and outcomes were reported on 32/46 and 23/46 of the venous incidents. For arterial events, treatment and outcomes were reported on 17/17 and 15/17 of the incidents. Heparin (UFH and/or LMWH) was the most common therapy for VTE. Older reports contained conservative strategies or switched initial heparin treatment into a coumadin derivative. More recent reports did not include conservative strategies and switched initial heparin treatment into a DOAC in selected cases. Reports describe successful use of apixaban, dabigatran, and rivaroxaban in patients without bleeding tendency and FVII:C levels ranging from 2% to 32% [25, 27, 29, 30, 31, 34, 45]. However, their safety profile in this population remains uncertain and warrants further investigation, and extrapolation to patients with severe deficiency should therefore be made with caution. For arterial thrombosis, therapy varied more according to the different presentations. Only three serious adverse events related to antithrombotic therapy were reported: two bleedings after tPA or alteplase in life‐threatening VTE and one non‐traumatic orbital bleeding due to warfarin‐therapy for simple DVT. The surprisingly low number of reported bleeding complications in this high‐risk population could be due to negative selection bias and that a certain number of the reported cases had a relatively high FVII:C combined with low clinical bleeding tendency. In our patient, anticoagulation was initiated to prevent thrombus progression and reduce the risk of PE. LMWH was chosen based on best clinical judgment as evidence‐based guidelines for patients with rare bleeding disorders do not exist and the patient had a mild bleeding tendency with no use of prophylactic factor replacement therapy. As in cases of provoked DVT in non‐bleeding patients, 3 months of anticoagulation were initially planned. Despite a relatively low dose of enoxaparin, he developed a serious bleeding complication—an iliacus hematoma resulting in incomplete femoral nerve palsy. Treatment was discontinued after 5 weeks and focus shifted to mobilization and rehabilitation, which proved effective. Although 3 months of anticoagulation is standard for provoked DVT, therapy was discontinued after 5 weeks due to the major bleeding complication and clear clinical and radiological regression of the thrombosis. This decision reflects the continuous balancing of thrombotic and hemorrhagic risks that characterizes management of thrombosis in FVII deficiency. In retrospect, a strategy combining factor replacement therapy with full‐dose anticoagulation may have reduced the risk of the severe bleeding complication observed in this case. As no evidence‐based recommendations exist for rare bleeding disorders such as FVII deficiency, guidance from hemophilia management strategies may provide a pragmatic framework for balancing bleeding and thrombotic risks. In guidelines for antithrombotic treatment in patients with hemophilia, not including patients with rare bleeding disorders, they recommend a shorter course (e.g., 6 weeks) of anticoagulation while maintaining a trough factor level of > 20 IU/dL in patients with severe hemophilia [46].

Iliacus hematoma syndrome (IHS) is a compression neuropathy of the femoral nerve caused by an iliacus hematoma [47]. Awareness of this unusual entity was not present when the patient was readmitted to the ED, but when reviewing history, every feature of this condition was exposed. Weakness of knee extension, sensory loss in the medial thigh, and absence of the patellar tendon reflex strongly suggest a femoral nerve palsy [48] and an iliacus hematoma was verified by MRI. IHS mostly occurs secondary to trauma, anticoagulation therapy, or hemophilia and can lead to permanent neurological deficit [49]. Depending on the individual, surgical decompression, or conservative management are the possible options [47, 48, 49].

The reported case highlights a clinically challenging situation of thrombosis in patients with congenital FVIId, where the clinician needs to balance the risk of bleeding and thrombosis. It also brings to light the two rare events of a DVT induced by an insect other than a wasp/bee and an iliacus hematoma syndrome. The unusual mechanism behind the DVT highlights the possibility that local inflammation may contribute to DVT development, even in patients with bleeding disorders. The other learning point from this case is that the possible diagnosis of an iliacus hematoma syndrome should be considered in patients with bleeding diathesis and/or anticoagulation therapy presenting symptoms consistent with femoral nerve palsy. A strategy combining factor replacement therapy with appropriate anticoagulation for the shortest effective duration may represent a reasonable approach in patients with congenital FVII deficiency and mild bleeding phenotype. Lastly, we present the first comprehensive table on all cases of thromboses in FVIId reported in English language with a retrievable original manuscript. Hopefully, this table can aid clinicians finding themselves treating thrombosis in a patient with inherited FVIId.

Author Contributions

Synnøve Gjelsten Mortensen: conceptualization, visualization, writing – original draft, writing – review and editing. Lars Erik Laugsand: conceptualization, writing – review and editing. Martin Syvertsen Mykland: writing – review and editing. Erik Magnus Berntsen: visualization, writing – review and editing. Tobias S. Slørdahl: conceptualization, writing – review and editing.

Funding

The authors have nothing to report.

Consent

Written informed consent for publication of the patient's clinical history, examination findings, laboratory results, and radiological images was obtained from the patient. The Wiley standard consent form was signed.

Supporting information

Table S1: Case reports on venous thromboembolism in FVII deficient patients. AF, Atrial fibrillation; aFVII, Activated FVII; APLAs, Antiphospholipid antibodies; ASA, Acetyl salicylic acid; B.I.D, Bis in die/twice daily; CVT, Cerebral vein thrombosis; DVT, Deep vein thrombosis; ECMO, Extracorporeal membrane oxygenation; FFP, Fresh frozen plasma; FVIIc, FVII concentrate; IOP, Intra ocular pressure; OAC, Oral anticoagulation; OCP, Oral contraceptive pill; PCC, Prothrombin complex concentrate; pdFVII, Plasma derived FVII; PE, Pulmonary embolism; PPROM, Preterm premature rupture of membranes (in pregnancy); PS, Protein S; Q.D, Quaque die/once daily; RBC, Red blood cells; rFVIIa, Activated recombinant FVII; SVT, Superficial vein thrombosis; TNM1, Tumor, node, metastasis Stage 1; tPA, Tissue plasminogen activator; TUR‐B, Transurethral resection, bladder; UFH, Unfractionated heparin; US, Ultrasound; WBT, Whole blood transfusion.

Table S2: Case reports on arterial thromboembolism in FVII deficient patients. AF, Atrial fibrillation; B.I.D, Bis in die/twice daily; DES, Drug eluting stent; DIC, Disseminated intravascular coagulation; FVIIc, FVII concentrate; LMWH, Low molecular weight heparin; NSTEMI, Non‐ST‐elevation myocardial infarction; PCC, Prothrombin complex concentrate; PCI, Percutaneous coronary intervention; Q.D, Quaque die/once daily; rFVIIa, Activated recombinant FVII; UFH, Unfractionated heparin.

CCR3-14-e73571-s002.docx (112.1KB, docx)

Figure S1: Literature search for venous thromboembolic events in congenital factor VII deficiency. Flow diagram illustrating the PubMed search and selection process used to identify reports of venous thromboembolism in patients with inherited factor VII deficiency.

Figure S2: Literature search for arterial thrombotic events in congenital factor VII deficiency. Flow diagram illustrating the PubMed search and selection process used to identify reports of arterial thrombosis in patients with inherited factor VII deficiency.

CCR3-14-e73571-s001.docx (37.5KB, docx)

Data Availability Statement

The data that support the findings of this study are openly available in PubMed at https://pubmed.ncbi.nlm.nih.gov/.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1: Case reports on venous thromboembolism in FVII deficient patients. AF, Atrial fibrillation; aFVII, Activated FVII; APLAs, Antiphospholipid antibodies; ASA, Acetyl salicylic acid; B.I.D, Bis in die/twice daily; CVT, Cerebral vein thrombosis; DVT, Deep vein thrombosis; ECMO, Extracorporeal membrane oxygenation; FFP, Fresh frozen plasma; FVIIc, FVII concentrate; IOP, Intra ocular pressure; OAC, Oral anticoagulation; OCP, Oral contraceptive pill; PCC, Prothrombin complex concentrate; pdFVII, Plasma derived FVII; PE, Pulmonary embolism; PPROM, Preterm premature rupture of membranes (in pregnancy); PS, Protein S; Q.D, Quaque die/once daily; RBC, Red blood cells; rFVIIa, Activated recombinant FVII; SVT, Superficial vein thrombosis; TNM1, Tumor, node, metastasis Stage 1; tPA, Tissue plasminogen activator; TUR‐B, Transurethral resection, bladder; UFH, Unfractionated heparin; US, Ultrasound; WBT, Whole blood transfusion.

Table S2: Case reports on arterial thromboembolism in FVII deficient patients. AF, Atrial fibrillation; B.I.D, Bis in die/twice daily; DES, Drug eluting stent; DIC, Disseminated intravascular coagulation; FVIIc, FVII concentrate; LMWH, Low molecular weight heparin; NSTEMI, Non‐ST‐elevation myocardial infarction; PCC, Prothrombin complex concentrate; PCI, Percutaneous coronary intervention; Q.D, Quaque die/once daily; rFVIIa, Activated recombinant FVII; UFH, Unfractionated heparin.

CCR3-14-e73571-s002.docx (112.1KB, docx)

Figure S1: Literature search for venous thromboembolic events in congenital factor VII deficiency. Flow diagram illustrating the PubMed search and selection process used to identify reports of venous thromboembolism in patients with inherited factor VII deficiency.

Figure S2: Literature search for arterial thrombotic events in congenital factor VII deficiency. Flow diagram illustrating the PubMed search and selection process used to identify reports of arterial thrombosis in patients with inherited factor VII deficiency.

CCR3-14-e73571-s001.docx (37.5KB, docx)

Data Availability Statement

The data that support the findings of this study are openly available in PubMed at https://pubmed.ncbi.nlm.nih.gov/.

Articles from Clinical Case Reports are provided here courtesy of Wiley

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